GREGORY G. GINSBERG, MD UNIVERSITY OF PENNSYLVANIA PHILADELPHIA, PENNSYLVANIA
NUZHAT A. AHMAD, MD UNIVERSITY OF PENNSYLVANIA PHILADELPHIA, PENNSYLVANIA
An innovative information, education, and management company 6900 Grove Road • Thorofare, NJ 08086
Copyright © 2006 by SLACK Incorporated
ISBN 10: 1-55642-694-1 ISBN 13: 9781556426940
All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without written permission from the publisher, except for brief quotations embodied in critical articles and reviews. The procedures and practices described in this book should be implemented in a manner consistent with the professional standards set for the circumstances that apply in each specific situation. Every effort has been made to confirm the accuracy of the information presented and to correctly relate generally accepted practices. The authors, editor, and publisher cannot accept responsibility for errors or exclusions or for the outcome of the material presented herein. There is no expressed or implied warranty of this book or information imparted by it. Care has been taken to ensure that drug selection and dosages are in accordance with currently accepted/recommended practice. Due to continuing research, changes in government policy and regulations, and various effects of drug reactions and interactions, it is recommended that the reader carefully review all materials and literature provided for each drug, especially those that are new or not frequently used. Any review or mention of specific companies or products is not intended as an endorsement by the author or publisher. Library of Congress Cataloging-in-Publication Data The clinician’s guide to pancreaticobiliary disorders / edited by Gregory Ginsberg, Nuzhat Ahmad. p. ; cm. Includes bibliographical references and index. ISBN 1-55642-694-1 (alk. paper) 1. Pancreas--Diseases. 2. Biliary tract--Diseases. [DNLM: 1. Biliary Tract Diseases. 2. Pancreatic Diseases. WI 700 C64117 2006] I. Ginsberg, Gregory G. II. Ahmad, Nuzhat. RC587.C55 2006 616.3’6--dc22 2005022427 Printed in the United States of America. Published by:
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DEDICATION I dedicate this book to my mother Geraldine McDonnell Ginsberg, always a lady, who schooled me in humor and humility. In her personal struggle with chronic illness she exemplified strong will, perseverance, and grace. G.G.G. Dedicated to Professor Abdus Salam: Pakistani Nobel Laureate in Physics 1979— for leading by example. N.A.A.
CONTENTS Dedication ................................................................................................................v Acknowledgements ....................................................................................................ix About the Editors .....................................................................................................xi Contributing Authors ............................................................................................ xiii Preface .................................................................................................................... xv Chapter 1:
Development and Function of the Pancreas, Bile Duct, and Gallbladder .................................................................................1 Binita M. Kamath, MBBChir; Raman R. Sreedharan, MD; Petar Mamula, MD
Chapter 2:
Gallstones and Gallbladder Disorders .............................................21 Ann Marie Joyce, MD; William B. Long, MD
Chapter 3:
Choledocholithiasis ..........................................................................47 Eric Goldberg, MD; Peter Darwin, MD
Chapter 4:
Bile Duct Injuries ...........................................................................69 Janak N. Shah, MD
Chapter 5:
Ampullary Disorders ......................................................................91 William B. Silverman, MD, FACG
Chapter 6:
Cholangiocarcinoma ......................................................................103 Patrick R. Pfau, MD
Chapter 7:
Infections of the Biliary System ....................................................121 Faten N. Aberra, MD, MSCE
Chapter 8:
Acute Pancreatitis .........................................................................147 John Horwhat, MD; Paul Jowell, MD
Chapter 9:
Chronic Pancreatitis .....................................................................179 Tyler Stevens, MD; Darwin L. Conwell, MD
Chapter 10: Pancreatic Ductal Complications .................................................217 Ali Fazel, MD Chapter 11: Solid Pancreatic Tumor..................................................................239 Shyam Varadarajulu, MD; Mohamad A. Eloubeidi, MD, MHS, FACP, FACG Color Atlas Chapter 12: Pancreatic Cystic Lesions ...............................................................257 David G. Forcione, MD; Brenna C. Bounds, MD
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Chapter 13: Surgical Approaches to Pancreatic Cancer.................................... 287 Giorgos C. Karakousis, MD; Francis R. Spitz, MD Chapter 14: Biliary Tract Surgery .................................................................... 297 Rachel Rapaport Kelz, MD, MSCE; Jon B. Morris, MD Chapter 15: Imaging of the Pancreatobiliary System Using Endoscopic Ultrasound.................................................................. 311 Nuzhat A. Ahmad, MD Chapter 16: Magnetic Resonance Imaging/Magnetic Resonance ....................327 Cholangiopancreatography of the Pancreatobiliary System Wendy C. Hsu, MD; Evan S. Siegelman, MD Chapter 17
Pancreaticobiliary Diseases: The Role of the Interventional Radiologist ...................................................................................353 Richard Shlansky-Goldberg, MD; Aalpen Patel, MD
Index.....................................................................................................................367
ACKNOWLEDGMENTS For their support and inspiration we wish to acknowledge our parents and teachers, our respective spouses and kids, colleagues and students, and most certainly our patients. We are grateful to the contributing authors for their time and dedication devoted to developing a text that will benefit countless clinicians and patients.
ABOUT
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EDITORS
Gregory G. Ginsberg, MD is Professor of Medicine at the University of Pennsylvania School of Medicine, Gastroenterology Division, and Executive Director of Endoscopic Services at the University of Pennsylvania Health Systems. A graduate of Lafayette College, Easton, PA and Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, he completed Internal Medicine and Gastroenterology training at Georgetown University Medical Center, Washington, DC. Dr. Ginsberg’s clinical practice and research have focused on the development of new techniques and the evaluation of new technologies as they apply to endoluminal management disorders of the digestive system. Outside of his professional activity, he finds fulfillment with his wife, Jane, and four daughters, Jenny, Kathleen, Elizabeth, and Meg. Nuzhat A. Ahmad, MD is an Assistant Professor of Medicine at the University of Pennsylvania School of Medicine, Gastroenterology Division, and Associate Director of Endoscopic Services at the University of Pennsylvania Health Systems. She is also the chief of Gastroenterology at the Philadelphia VA Medical Center.
CONTRIBUTING AUTHORS Faten Aberra, MD, MSCE Instructor of Medicine Division of Gastroenterology Hospital of the University of Pennsylvania Philadelphia, PA Brenna Casey Bounds, MD Instructor in Medicine Harvard Medical School Director of Endoscopic Training Massachusetts General Hospital Boston, MA Darwin L. Conwell, MD Department of Gastroenterology and Hepatology The Cleveland Clinic Foundation Cleveland, OH Peter Darwin, MD Associate Professor of Medicine Director of Gastrointestinal Endoscopy University of Maryland Medical School Baltimore, MD Mohamad A. Eloubeidi, MD, MHS, FACP, FACG Associate Professor of Medicine and Pathology Director, Endoscopic Ultrasound Program Co-Director, Pancreatico-biliary Center University of Alabama at Birmingham Birmingham, AL Ali Fazel, MD Assistant Professor of Medicine Co-Director, Center for Endoscopic Ultrasound Division of Gastroenterology, Hepatology and Nutrition Department of Medicine University of Florida Gainesville, FL
David G. Forcione, MD Assistant Physician Gastrointestinal Unit Massachusetts General Hospital Instructor of Medicine Harvard Medical School Boston, MA Eric Goldberg, MD Assistant Professor of Medicine University of Maryland Medical School Baltimore, MD John Horwhat, MD Duke University Durham, NC Wendy C. Hsu, MD Hospital of the University of Pennsylvania Philadelphia, PA Paul Jowell, MD Associate Professor of Medicine Division of Gastroenterology Duke University Medical Center Durham, NC Ann Marie Joyce, MD Instructor of Medicine Hospital of the University of Pennsylvania Philadelphia, PA Binita M. Kamath, MBBChir Division of GI & Nutrition The Children's Hospital of Philadelphia Philadelphia, PA Giorgos C. Karakousis, MD Resident in General Surgery Department of Surgery Hospital of the University of Pennsylvania Philadelphia, PA
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William B. Long, MD Associate Professor of Medicine Hospital of the University of Pennsylvania Philadelphia, PA Petar Mamula, MD Division of GI & Nutrition The Children's Hospital of Philadelphia Philadelphia, PA Jon B. Morris, MD Associate Professor of Surgery Program Director for General Surgery Division of GI Surgery Department of Surgery Hospital of the University of Pennsylvania Philadelphia, PA
Richard Shlansky-Goldberg, MD Department of Radiology Division of Interventional Radiology Hospital of the University of Pennsylvania Philadelphia, PA Evan S. Siegelman, MD Associate Professor of Radiology Department of Diagnostic Radiology Hospital of the University of Pennsylvania Philadelphia, PA William B. Silverman, MD, FACG Professor of Medicine Division of GI/Hepatology Department of Internal Medicine University of Iowa Hospitals & Clinics Iowa City, IA
Aalpen Patel, MD Department of Radiology Division of Interventional Radiology Hospital of the University of Pennsylvania Philadelphia, PA
Tyler Stevens, MD Department of Gastroenterology and Hepatology The Cleveland Clinic Foundation Cleveland, OH
Patrick R. Pfau, MD Assistant Professor of Medicine Director of Gastrointestinal Endoscopy University of Wisconsin Medical School Madison, WI
Francis Spitz, MD Assistant Professor of Surgery Department of Surgery Hospital of the University of Pennsylvania Philadelphia, PA
Rachel Rapaport Kelz, MD, MSCE Assistant Professor of Clinical Surgery Hospital of the University of Pennsylvania Philadelphia, PA
Raman R. Sreedharan, MD Division of GI & Nutrition AI DuPont Hospital for Children Wilmington, DE
Janak N. Shah, MD Director of Therapeutic Endoscopy San Francisco Veterans Medical Center Assistant Clinical Professor of Medicine University of California San Francisco, CA
Shyam Varadarajulu, MD Assistant Professor of Medicine Division of Gastroenterology-Hepatology University of Alabama at Birmingham School of Medicine Birmingham, AL
PREFACE This book was developed as part of the popular Clinician’s Guide series and focuses on the understanding, diagnosis, and management of disorders of the pancreas and biliary systems. Chapters are clear and concise and written in a uniform manner. The multidisciplinary effort provides a broad and complete treatment of the topic. Images, artwork, graphics, and tables provide a visually appealing complement to the robust text. We think clinicians will find this to be a ready and reliable resource when encountering patients with pancreaticobiliary disorders.
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Development and Function of the Pancreas, Bile Duct, and Gallbladder Binita M. Kamath, MBBChir; Raman R. Sreedharan, MD; Petar Mamula, MD
Introduction DEVELOPMENT AND FUNCTION OF THE PANCREAS The pancreas makes its appearance in the fetal embryo as early as the 4th week of gestation. The development of pancreas starts as a dorsal and a ventral outpouching from the endodermal lining of the primitive duodenum (Figure 1-1). The dorsal anlage appears earlier than the ventral anlage and eventually forms the neck, body, tail, and superior part of the head of the pancreas. The ventral anlage appears more caudally and is closely related to the bile duct and hepatic diverticulum and develops into the inferior part of the head and uncinate process of the pancreas. The two parts of the pancreas are brought into apposition by the partial rotation of the duodenum by 7 weeks of gestation, and they eventually fuse together. Each part of the primitive pancreas has an axial duct—the dorsal duct (duct of Santorini) arising directly from the duodenal wall and the ventral duct (duct of Wirsung) arising from the common bile duct. At the time of the fusion of the dorsal and ventral parts of the pancreas, the ducts fuse at the junction of the head and body of the pancreas to form the main pancreatic duct. In the majority of individuals, the ventral duct (duct of Wirsung) becomes the main excretory duct and opens into the major papilla along with the common bile duct. The proximal part of the dorsal duct (duct of Santorini) becomes the accessory duct and is patent in 70% of individuals. A wide variety of anatomic variations exist in relation to the fusion and openings of the dorsal and ventral ducts. Both exocrine and endocrine cells originate from a common pluripotent progenitor under the influence of multiple transcription factors1. Distinct pathways like Hedgehog, Notch, and TGF-ß signaling promote or restrict cell differentiation and morphogenesis. Disruptions in these pathways may lead to development of various congenital anomalies (Table 1-1).
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Figure 1-1. Embryology of the pancreas, liver, and biliary tree. (Reprinted from Moore K, et al. The Developing Human, 1982, with permission from Elsevier.)
Table 1-1
CONGENITAL ANOMALIES OF THE PANCREAS Pancreas divisum Pancreas annulare Heterotopic pancreas Aplasia Hypoplasia Dysplasia Ductal anomalies
The pancreas has an exocrine and an endocrine function. The exocrine function consists of production of various digestive enzymes such as lipase, amylase, proteases, and nuclease by acinar cells. The endocrine function unit are islets of Langerhans composed of four different types of cells: a type secreting glucagon, d type secreting somatostatin, PP cells secreting pancreatic polypeptide, and ß secreting insulin.
DEVELOPMENT OF THE BILIARY TRACT AND THE GALLBLADDER The liver primordium appears as a thickening of the ventral midline endoderm (the hepatic plate) by day 22 of development (see Figure 1-1). The cells in the hepatic plate proliferate to form the hepatic diverticulum that projects into the septum transversum. The proliferating endodermal cells of the hepatic diverticulum invade the septum
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Figure 1-2. Morphogenesis of the intrahepatic ducts in mouse. At embryonic (E) day
15.5 the biliary precursor cells form a single-layered ring called ductal plate, which over the next two days becomes bilayered with focal dilations between the layers. These dilations give rise to the bile ducts, while the rest of the ductal plate regresses. (Adapted from Lemaigre F. Development of the biliary tract. Mechanisms of development. 2003;120:8187, with permission from Elsevier.)
transversum, forming cords of hepatoblasts. These hepatoblasts give rise to the intraand extrahepatic biliary system as well as the parenchymal elements of the liver. The intrahepatic bile ducts develop primarily by a process of differentiation from the hepatocytes at the margins of the portal tracts. This differentiation results in the formation of the so-called ductal plate, a single layer or sleeve of cells surrounding a portal vein 2 (Figure 1-2). The ductal plate becomes a double layer of cells around 7 weeks of gestation. Through a process termed as remodeling, tubular structures form between the two cell layers of the ductal plate. These developing bile ductules express cytokeratins consistent with differentiated biliary epithelium. After completion of remodeling, the nontubular elements of the ductal plate involute, leaving only the centrally located, highly differentiated interlobular duct. Maturation of the intrahepatic biliary tree progresses from the hilum of the liver outwards to the periphery beginning at approximately 11 weeks gestational age and continues for several months after birth. The physiologic and biochemical factors governing the differentiation and remodeling of the ductal plate are essentially unknown at present, though the role of ductal-vascular interactions is increasingly being recognized. The extrahepatic bile ducts and gallbladder develop from the caudal portion or pars cystica of the hepatic diverticulum before the 4th week of gestation. The pars cystica originates from the anterior side of the duodenum but assumes the definitive position of the common bile duct following rotation of the duodenum. The cystic portion of the hepatic diverticulum is initially hollow but the lumen is obliterated by proliferation of epithelial cells. The early gallbladder and extrahepatic biliary tree therefore consist of solid cords of epithelial cells in the 5th week of gestation. Subsequent vacuolization results in the formation of a lumen in the common bile duct by week 6 and this is fol-
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lowed by canalization of the hepatic ducts. Finally, a definitive lumen develops in the cystic duct and the gallbladder by recanalization during the 7th week. The epithelium of the extrahepatic biliary system is continuous with the duodenum at one end and the primitive hepatic cords at the other. The gallbladder is patent by the 3rd month of gestation and its wall contains muscle fibers. Bile secretion starts at the beginning of the 4th month of gestation and thereafter the biliary system constantly contains bile, which is secreted into the gut lumen. The interlobular ducts formed from the differentiation and remodeling of the ductal plate are joined by intrahepatic extensions of the extrahepatic ducts, to complete the bile duct system.
Congenital Abnormalities of the Pancreas PANCREAS DIVISUM Pancreas divisum is the most common congenital anomaly of the pancreas. The incidence has been reported to be between 5% and 11% of the population3. Pancreas divisum arises as a result of the incomplete fusion of the dorsal and ventral ductal structures. This leads to persistence of two drainage systems. The ventral duct (duct of Wirsung) drains only the head of the pancreas through the major papilla. The dorsal duct (duct of Santorini) drains the body and tail of the pancreas through a smaller minor papilla, which is positioned proximal to the major papilla. The minor papilla through which the major portion of the pancreas drains could be too small for proper drainage and can lead to a functional stenosis.
Clinical Manifestations and Evaluation Pancreas divisum may cause recurrent abdominal pain. Additionally, the stenosis of the minor papilla has been implicated as a cause for recurrent pancreatitis. Computed tomography (CT) scan of the abdomen may suggest the diagnosis, but the confirmation of the diagnosis is made by endoscopic retrograde cholangiopancreatography (ERCP) (Figure 1-3). Recently the noninvasive magnetic resonance cholangiopancreatography (MRCP) is being increasingly used.
Management Endoscopic therapies include papillotomy of the minor papilla with or without sphincterotomy of the major ampulla, ductal balloon dilatation, and pancreatic dorsal duct stent placement. Surgical therapy includes minor papilla sphincterotomy and sphincteroplasty.
ANNULAR PANCREAS This is the second most common anomaly of the pancreas, and occurs when a band of pancreatic tissue encircles the second part of the duodenum. There are several theories that have been put forward to explain the anomalous development:
1. Fixation of the tip of the ventral anlage resulting in failure of rotation. 2. Hypertrophy of the dorsal and ventral anlage resulting in a constriction around the duodenum.
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Figure 1-3. Pancreas divisum.
Contrast injection following cannulation of the ampulla of Vater demonstrates a small pancreatic duct of Wirsung. (Reprinted from M. Al Samman. Pancreas Divisum. eMedicine.com, Inc., 2004. Used with permission.)
3. Baldwin’s theory, which describes the persistence of the left ventral bud that normally atrophies during development.
Clinical Manifestations and Evaluation Symptoms depend on the severity of the constriction and most patients are asymptomatic. In severe cases, polyhydramnios is noted during pregnancy followed by feeding difficulty, vomiting, and abdominal distension during the neonatal period. In less severe cases, the manifestations are less dramatic and present at an older age or even adulthood with nausea, post-prandial fullness, vomiting, weight loss, and even gastrointestinal bleeding. In mild cases, there are no symptoms and the diagnosis is made as an incidental finding. In severe cases of constriction presenting in the neonatal period, the abdominal x-ray shows the classic “double bubble sign” (Figure 1-4) suggesting duodenal obstruction. In older children and adults, the upper intestinal contrast study findings of annular filling defect in the duodenum, prestenotic dilatation, and reverse peristalsis in the proximal segment are suggestive of annular pancreas. CT scan of the abdomen, MRCP, and ERCP are other useful investigative modalities. The diagnosis is confirmed at laparotomy.
Management Management is surgical. Surgical division of the pancreatic ring is associated with complications and hence avoided. Bypass surgery is the surgery of choice, whereas duodenostomy is done for isolated stenosis in children. Other extensive bypass surgeries may be performed depending on the anatomy.
HETEROTOPIC PANCREAS This anomaly, also called pancreatic rest, ectopic pancreas, accessory pancreas, or aberrant pancreas, is defined as pancreatic tissue lacking anatomic and vascular
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Figure 1-4. Pancreas
annulare. Abdominal x-ray showing classic “double bubble” sign indicating duodenal obstruction seen in duodenal atresia and annular pancreas. (Used with permission from eMedicine.com, Inc., 2004.)
continuity with the main body of the pancreas. The incidence is up to 15% in autopsy specimens. Approximately 70% of heterotopic pancreas is located in the upper gastrointestinal tract. Other sites include gallbladder, liver, omentum, colon, appendix, Meckel’s diverticulum, intestinal duplication cysts, and extra intestinal sites such as bronchopulmonary sequestration and umbilicus. Histologically, both ductal and acinar tissues are recognized in the tissue.
Clinical Manifestations and Evaluation Symptoms if present include epigastric pain, gastrointestinal bleeding, abdominal distension, nausea, vomiting, and dyspepsia. Complications include mucosal ulcers with gastrointestinal bleeding, intussusceptions, intestinal obstruction, cholecystitis, jejunal atresia, and carcinoma arising from the aberrant tissue. This anomaly is usually found as incidental finding during endoscopy and it appears as discrete submucosal yellow nodules of sizes varying from 2 mm to 4 cm with a central umbilication (Figure 1-5). Biopsy of the nodule can confirm the diagnosis histologically.
Management Incidentally diagnosed heterotopic pancreases ideally do not require any intervention. Endoscopic ultrasound is an effective tool in accurate characterization. If the diagnosis is in doubt, surgical excision is considered, as it is both diagnostic and curative. In the event of complications, surgical excision is the procedure of choice.
PANCREATIC AGENESIS, HYPOPLASIA, AND DYSPLASIA Complete agenesis of the pancreas is incompatible with life and is rare. Partial agenesis is usually due to the abnormal development of the dorsal anlage, and the size and shape of the pancreas vary. In hypoplasia, the size and shape of the gland is
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Figure 1-5. Heterotopic
pancreas. Endoscopic picture of heterotopic pancreas tissue in the antrum of the stomach.
normal but there is fatty tissue replacing the normal epithelial cells and reduced ductal differentiation. In dysplasia, there is abundant fibromuscular tissue with disorganized ductal and parenchymal tissues.
Clinical Manifestations and Evaluation Symptoms are variable and depend on the degree of involvement of the exocrine and endocrine functions. Manifestations include failure to thrive, malabsorption, and insulin-dependent diabetes. Studies including ERCP, MRCP, angiography, and abdominal and endoscopic ultrasound may be helpful. Also, cholycystokinin-secretin stimulation tests may be performed to assess the degree of pancreatic exocrine function. Definitive diagnosis is made during laparotomy or at autopsy.
Management The therapy is mainly supportive with insulin and pancreatic enzyme replacement.
Congenital Abnormalities of the Biliary Tract CONGENITAL ABNORMALITIES OF THE INTRAHEPATIC BILIARY DUCTS Intrahepatic bile duct anomalies encompass a wide range of disorders (Table 1-2). A full discussion of intrahepatic biliary pathology is beyond the scope of this chapter and will be discussed elsewhere. Clinically important conditions have been included briefly.
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Table 1-2
CONGENITAL ANOMALIES OF THE BILIARY TRACT Intrahepatic Bile Duct Anomalies Cystic disorders Solitary cysts Polycistic conditions (ARPKD/CHF, ADPKD, Caroli disease) Bile duct paucity Syndromic-Alagille syndrome Nonsyndromic
Extrahepatic Bile Duct Anomalies Biliary atresia* Agenesis Choledochal cyst Bile duct stenosis Accessory ducts Positional anomalies Duplication Spontaneous perforation Bronchobiliary fistula ADPKD = autosomal dominant polycystic kidney disease, ARPKD/CHF = autosomal recessive polycystic kidney disease/congenital hepatic fibrosis *Biliary atresia is not a true congenital anomaly; see text for further details.
Cystic Disorders Cystic conditions affecting the intrahepatic tree may be solitary or polycystic. The distinction between communicating and noncommunicating cysts is clinically significant, as duct cysts communicating with the biliary tree have a greater likelihood of causing clinical disease. Communicating duct cysts can be associated with cholangitis, stone formation, and (relatively uncommonly) neoplasia. Noncommunicating duct cysts are usually asymptomatic, and may present as an abdominal mass or biliary obstruction. Solitary Cysts
Definition Solitary cysts are noncommunicating developmental cysts, which are lined by simple cuboidal or biliary-type epithelium and are not associated with cysts in other organs. The surrounding hepatic parenchyma displays secondary atrophy, portal fibrosis, and bile duct proliferation.
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Clinical Manifestations and Evaluation Solitary cysts are usually asymptomatic and are identified incidentally on ultrasonography. If symptomatic, most commonly they present as an upper abdominal mass. Rupture, torsion, or hemorrhage of a solitary hepatic cyst may occur. Management Management is surgical excision, if necessary.
Polycystic Conditions Polycystic liver conditions are often associated with cystic disorders of the kidney. Renal tubular development parallels biliary development during gestation. The hallmark hepatic histopathological finding in polycystic liver disease is ductal plate malformation. Autosomal Recessive Polycystic Kidney Disease/Congenital Hepatic Fibrosis
Definition Congenital hepatic fibrosis (CHF) is characterized by ductal plate malformation, communicating cysts, and hepatic fibrosis resulting in portal hypertension and an increased risk of ascending cholangitis. Typically, CHF is associated with autosomal recessive polycystic kidney disease (ARPKD) and these are best considered a single disorder with a wide spectrum of manifestations. Etiopathogenesis Mutations in the polycystic kidney and hepatic disease 1 gene (PKHD1) on chromosome 6p21.1-p12 have recently been identified as the molecular cause of ARPKD/CHF. Clinical Manifestations and Evaluation The clinical manifestations of ARPKD/CHF vary in large part according to the age at first presentation. In newborn patients with ARPKD, the renal lesions are diffuse and prominent clinically, whereas in patients who exhibit the clinical picture of CHF, the renal lesions are often not as evident in early life and are minor. Therefore, renal disease predominates in neonates and infants, whereas the hepatic-related disease predominates in older children and adults. In older patients who present with the hepatic manifestations of CHF, the most significant abnormality is portal hypertension and esophageal varices. Clinically, hematemesis or melena is the presenting sign in 30% to 70% of patients. Palpable kidneys are often noted at initial evaluation and renal dysfunction is present in approximately 20% of patients. A liver biopsy is diagnostic, showing classic ductal plate malformation. Dilatation of the intrahepatic ducts is common in this condition, as is an increased risk for cholangitis. Cholangitis may be occult, acute, or chronic in nature, and contributes significantly to both the morbidity and mortality of congenital hepatic fibrosis. Management There is no therapy for the underlying developmental anomaly in ARPKD/CHF. For portal hypertension, portosystemic shunting has been the treatment of choice, as there is a low incidence of postoperative encephalopathy. Ursodeoxycholic acid therapy and prophylactic antibiotic administration may have a role in selected patients. In
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Figure
1-6. Caroli's disease. Ultrasound of the liver in a neonate with Caroli's disease demonstrating multiple dilated intrahepatic bile ducts.
those patients with chronic cholangitis and/or progressive hepatic dysfunction, liver transplantation may prove to be the optimal therapy. Caroli’s Syndrome and Caroli’s Disease
Definition Caroli’s syndrome describes congenital dilatation of the intrahepatic biliary tree in association with ductal plate malformation. Caroli’s disease, a much rarer condition, involves intrahepatic biliary dilatation only and these cysts are therefore noncommunicating. Both conditions are associated with ARPKD. Etiopathogenesis Caroli’s syndrome results from a derangement of bile duct differentiation including small and large ducts, and could actually be part of the spectrum of ARPKD/CHF. In contrast, Caroli’s disease appears to arise from an arrest in remodeling of the ductal plate at the larger intrahepatic ducts only (and hence there is no associated ductal plate malformation and CHF). Clinical Manifestations and Evaluation Caroli’s syndrome manifests as CHF with portal hypertension and cholangitis. In both Caroli’s syndrome and disease, ductal cyst formation predisposes to bile stasis, lithiasis, and infection. Abdominal CT, ultrasonography (Figure 1-6), and cholangiograms demonstrate irregular cystic dilatation of the large, proximal intrahepatic biliary tree. Cholangiocarcinoma is also a potential complication of these disorders. Management Caroli’s syndrome is managed as CHF. Caroli’s disease requires antibiotics for infection and partial hepatectomy may also be effective if the lesion is discrete. Many patients can be managed with hepatico-jejunostomy. Percutaneous transhepatic cholangiography may be used adjunctively to clear remnant and recurrent stone disease. Autosomal Dominant Polycystic Kidney Disease
Definition Autosomal dominant polycystic kidney disease (ADPKD) is characterized by renal and hepatic cysts (polycystic liver disease), often in association with other visceral anomalies such as intracranial and aortic aneurysms, mitral valve prolapse, pancreatic cysts, and colonic diverticula. ADPKD is rarely associated with CHF.
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Etiopathogenesis ADPKD results from mutations in one of at least three distinct genetic loci, termed PKD1, PKD2, and PKD3. Clinical Manifestations and Evaluation ADPKD is usually symptomatic after age 40, however, it can be anatomically identified even in fetal life. It is important to recognize for its genetic implications, although the functional significance of the finding is not apparent until beyond childhood. The hepatic lesions are primarily duct cysts, which are readily demonstrated ultrasonographically. Cysts increase in size from childhood until 40 to 50 years of age. Commonly, the cysts in this condition are dilated ductal elements, which are not demonstrated to communicate with the distal biliary tree. However, they may manifest clinically with abdominal pain, infection and abscess formation, cyst rupture, bleeding, and biliary obstruction. The renal lesion consists of cysts that appear to arise from multiple areas along the nephron and increase in size with age, resulting in end-stage renal disease in 50% of patients. Cysts may also be found in other organs, including spleen, pancreas, thyroid, ovary, endometrium, seminal vesicles, and epididymis. Arterial aneurysms are present in 15% of cases. Management The renal disease in ADPKD requires careful management. In many cases, the polycystic liver disease does not require treatment. Infection necessitates antibiotics in combination with percutaneous drainage. Surgical fenestration can be helpful for relief of symptoms or biliary compression.
Bile Duct Paucity Decrease in ductal number (paucity) is one of the most significant abnormalities of the intralobular bile ducts in children. Bile duct paucity can occur in association with other features, as in Alagille syndrome (see below) or in isolation—nonsyndromic bile duct paucity. A full discussion of these disorders is beyond the scope of this chapter. Syndromic Bile Duct Paucity—Alagille Syndrome
Definition Alagille syndrome (AGS) is an autosomal dominant multisystem developmental disorder characterized by bile duct paucity, occurring in association with cardiac, musculoskeletal, ocular, facial, renal, pancreatic, and vascular abnormalities. AGS has a frequency of at least 1 in 80,000. Etiopathogenesis The disease gene in AGS has been identified as Jagged1 (JAG1) on chromosome 20p12, which encodes a ligand in the evolutionarily conserved Notch signaling pathway. Clinical Manifestations and Evaluation AGS is characterized by a wide variability in its clinical spectrum, even within individual pedigrees. The diagnosis is made when bile duct paucity on liver histology is accompanied by the major extrahepatic findings of the syndrome: chronic cholestasis, characteristic facies, cardiac murmur (typically due to peripheral pulmonary stenosis), vertebral anomalies (typically butterfly vertebrae), and posterior embryotoxon in the eye.
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Cholestasis is manifest by pruritus and elevations in serum bile acid concentrations. This pruritus is among the most severe in any chronic liver disease. The presence of severe cholestasis results in the formation of xanthomas, characteristically on the extensor surfaces of the fingers, the palmar creases, nape of the neck, and around inguinal trauma sites. Progression to cirrhosis and hepatic failure is recognized in approximately 20% of AGS patients. Management Infants with intrahepatic cholestasis may have significant fat malabsorption and fat-soluble vitamin deficiency. Antihistamines may give some relief for the pruritus, and care should be taken to keep the skin hydrated with emollients. Cholestyramine, ursodeoxycholic acid, and rifampin may improve pruritus, and biliary diversion is emerging as a useful tool for refractory cases. The outcome of syndromic bile duct paucity is highly variable and is most directly related to the severity of the hepatic and cardiac lesions, with mortality predominantly attributable to these two organs. Transplantation does appear to have a higher risk for patients with AGS, due in part to the severity of cardiopulmonary disease.
CONGENITAL ABNORMALITIES OF THE EXTRAHEPATIC BILIARY DUCTS Extrahepatic Biliary Atresia The inclusion of extrahepatic biliary atresia (BA) in this chapter is somewhat controversial as the etiology of this condition is not yet clear and it does not appear to be a true congenital abnormality. However, as it is an early onset disease of the biliary system and the number one cause for pediatric liver transplantation in the United States, it certainly warrants discussion and is therefore included. Definition
BA is a progressive, idiopathic, necroinflammatory process resulting in obliteration of the lumen of the extrahepatic biliary tree within the first 3 months of life. BA occurs with an estimated frequency of 1 in 10 to 15,000 live births, resulting in between 250 and 400 new cases each year in the United States. Etiopathogenesis
BA may represent the final common pathway of several different etiologies but at least two major forms exist: postnatal or nonsyndromic form and the fetal or syndromic form. The pathogenesis of BA remains a mystery and the hypotheses and supporting evidence are beyond the scope of this discussion. Most of the theories and research focus on a viral infection or toxin exposure, developmental defect, genetic predisposition, vascular etiology, and an immune or autoimmune phenomenon4. Clinical Manifestations and Evaluation
Postnatal BA accounts for the majority of cases. These infants appear typically healthy at birth and then present with the characteristic features of jaundice due to conjugated hyperbilirubinemia, pale stools, dark urine, and hepatomegaly within the first 3 months of life. Splenomegaly will be found in most patients. Approximately 15% to 20% of infants have syndromic BA and have associated anomalies including defects of laterality (situs inversus, bilateral bilobed lungs, abdominal situs inversus, intestinal malrotation, anomalies of the portal vein and hepatic artery, polysplenia, and asplenia) and cardiac and renal defects.
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Figure 1-7. Biliary atresia. Intraoperative cholangiogram demonstrating contrast in the gallbladder (arrow) of a 2-monthold girl with biliary atresia with no filling of the intra- or extrahepatic biliary tree.
Rapid diagnosis of BA is necessary to optimize the response to surgery. No single biochemical test is specifically diagnostic of BA, though an elevated GGT suggests a biliary cause. Abdominal ultrasound may identify choledochal cysts or other causes of extrahepatic obstruction. 99mTc-labeled diisopropyl iminodiacetic acid scintigraphy (DISIDA) evaluation of hepatic uptake and biliary excretion into the duodenum may be helpful in indirectly assessing the patency of the biliary system. A liver biopsy (percutaneous or open) will help distinguish obstructive from nonobstructive causes of cholestasis. Histologically, in biliary obstruction there is expansion of the portal spaces with proliferation of bile ductules with bile stasis and plugging. A biopsy suggestive of obstruction mandates surgical exploration and an intraoperative cholangiogram (Figure 1-7), which is the definitive test. Management
If not corrected, BA is uniformly fatal within the first 2 years of life. If a cholangiogram is consistent with BA, a surgical hepatoporto-enterostomy or Kasai procedure is attempted. The two most important indicators in determining the surgical outcome are age at the operation and the surgeon’s experience. Success with biliary drainage is more likely if surgery takes place before 8 weeks of age. However, BA is a progressive condition and despite surgery at an appropriate time, two-thirds of children still require liver transplantation. Biliary atresia is now the most common indication for liver transplantation in infants and children, and although the presence of situs ambiguus may require technical adjustments, associated anomalies do not preclude transplantation.
Choledochal Cyst Definition
Choledochal cysts are segmental dilatations of the biliary tree. They most commonly involve the extrahepatic tree and are therefore considered in this section;
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Figure 1-8. Choledochal cyst classification
(From Todani et al. Congenital bile duct cysts: classification, operative procedures, and review of thirty-seven cases including cancer arising from choledochal cyst. Am J Surg. 1977;134:266, with permission from Excerpta Medica.)
Figure
1-9. Choledochocoele (arrow) endoscopic retrograde cholangiopancreatography image in a 16-year-old girl.
however, they may also involve the intrahepatic system. A classification system is illustrated in Figure 1-8. Five types are recognized: • Type I: Diffuse enlargement of the common bile duct with three subtypes:
a) spherical, b) segmental, and c) cylindrical • Type II: Common bile duct (CBD) diverticulum • Type III: Cystic dilatation of the intraduodenal portion of the CBD choled-
ochocoele (Figure 1-9) • Type IV: Multiple intra- and extrahepatic bile duct cysts • Type V: Multiple intrahepatic bile duct cysts. Cystic dilation of the CBD may become very large. Most commonly there is dilation of the common duct itself (type I) or, rarely, dilation in a diverticulum of the common duct wall (type II). Of cases presenting in childhood, over 90% have been reported as type I and 75% of the remainder as type II. The dilated region is usually sharply demarcated, and the common duct below the cystic area may appear narrowed. Single or multiple intrahepatic cysts are classified as type V cysts and appear to be rare. This category overlaps and blends into Caroli's disease, a condition characterized by intrahepatic dilation of major ducts.
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Figure 1-10. Choledo-
chal cyst. Magnetic resonance cholangiopancreatogram image of a choledochal cyst in a 14-year-old girl.
Choledochal cysts usually are nonsyndromic (ie, usually not associated with primary malformations of other organ systems), but they may occur in association with other anomalies of the hepatopancreatobiliary duct system, including gallbladder agenesis, double gallbladder, and pancreas divisum. Clinical Manifestations and Evaluation
Choledochal cysts may remain asymptomatic throughout childhood, but they may be found in young infants or in adults with histories of symptoms since childhood. Presenting symptoms include biliary colic, jaundice, and a palpable abdominal mass in the right upper quadrant. This classic clinical triad is only seen in approximately 25% of patients. Occasionally patients present with symptoms of acute pancreatitis. Preoperative diagnosis may be difficult, but ultrasound is especially helpful in diagnosing a choledochal cyst in an infant. Hepatobiliary scintigraphy, endoscopic retrograde cholangiography, and MRCP (Figure 1-10) may also be very useful. Management
Once significant symptoms occur, surgery is usually necessary for the choledochal cyst (Figure 1-11). Complications include malignancy, rupture, calculi, and, rarely, portal hypertension and/or hemorrhage. Cholangiocarcinoma develops in 4% to 8% of patients, often after 20 years of age. Despite few abnormalities in liver function, affected patients may have mild to severe degrees of hepatic fibrosis. Because of the occasional association with other anomalies of the biliary tract, as precise an anatomic evaluation as possible must be performed prior to surgery. Response to surgery is usually very good if done early. If excision of the cyst is not possible, a choledochocystojejunostomy may be performed.
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Figure 1-11. Choledo-
chal cyst. Intraoperative image of choledochal cyst in a 14-year-old girl. For full-color version, see page CA I of the Color Atlas.
Other Extrahepatic Biliary Duct Anomalies Definition
Accessory ducts, positional alterations, duplications, and stenosis. It has been stated that the extrahepatic biliary tree has more anomalies than any other area of the body (see Table 1-2). Clinical Manifestations and Evaluation
Many anatomic variations are asymptomatic and found incidentally at surgery, radiography, or autopsy. Anomalies and variants include accessory ducts (extranumerary ducts usually arising from the right lobe of the liver and entering one of the normal extrahepatic ducts); cholecystohepatic ducts or sinuses of Luschka (abnormal duct elements which arise in the liver, pass through the gallbladder wall, and enter one of the normal extrahepatic ducts); duplication or partial division by a septum of the common duct; ectopic orifice of the common duct (in the stomach or proximal duodenum); and numerous variations in the configuration of the hepatic ducts and common duct. Anomalies of potential pathologic significance include the cystic duct draining into the left side of the main duct or directly into the duodenum (short choledochus syndrome); aberrant hepatic duct with dorsocaudal branch draining into the common duct; agenesis of the common duct; intrahepatic junction of the hepatic ducts; and congenital bronchobiliary fistula (usually between the right main stem bronchus and the bile duct system within the left lobe of the liver). An isolated stricture or stenosis of the extrahepatic biliary tree usually occurs secondary to surgery or trauma. However, occasionally these may be congenital and occur most commonly at the bifurcation of the hepatic ducts. Common duct stenosis, localized atresia, and duplication have also all been reported in association with duodenal atresia. Spontaneous perforation of the bile ducts is a rare condition that occurs in the first few months of life. The most common site of perforation is the point at which the cys-
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tic and common hepatic ducts join to form the common duct. The etiology is unclear, but may be caused by an intrinsic weakness at a specific point due to a developmental defect. Spontaneous perforation of the bile ducts may result in a bile leak into the peritoneal cavity with subsequent sterile bile peritonitis and pseudocyst formation. Management
These minor anomalies and variations become significant at surgery. Accidental severing of an anomalous duct may result in postoperative leakage leading to peritonitis. Ligation of an unrecognized duct may be symptomatic if the area of liver that is drained is large enough. In performing cholecystectomy on patients with an anomalous right hepatic duct that empties into the cystic duct, care must be taken to ligate the cystic duct between the gallbladder and the junction with the anomalous duct in order to maintain adequate drainage of the anomalous duct. Unrecognized anomalous ducts may also cause recurrence of symptoms after cholecystectomy.
Congenital Abnormalities of the Gallbladder AGENESIS OF THE GALLBLADDER Definition Congenital absence of the gallbladder.
Clinical Manifestations and Evaluation Agenesis of the gallbladder may be discovered incidentally at autopsy or at surgery for unrelated indications. Absence of the gallbladder may also be found as part of a broader pattern of malformation in children with multiple congenital anomalies (imperforate anus, bicuspid aortic valves, cerebral aneurysms, and in association with extrahepatic biliary atresia). The incidence of gallbladder agenesis has been estimated at 1 in 10,000 among the general population. When symptomatic, the majority has right upper quadrant abdominal pain, whilst others present with symptoms suggestive of acute or chronic cholecystitis. The diagnosis may be difficult to make radiographically as oral cholecystograms or ultrasonography often show false-positive diagnoses of apparently diseased, contracted, and scarred gallbladders, suggesting cholecystitis.
Management After surgical exploration, over 90% of symptomatic patients with gallbladder agenesis are greatly improved or symptom free. This is true both for patients who are found to have associated stones and for those without stones. The reason for improvement in patients without stones is not known. One speculation is that improvement may be the result of lysis of periportal and right upper quadrant adhesions during the exploration. Patients whose symptoms recur postoperatively may be treated with oral smooth muscle relaxants and analgesics, a conservative regimen that has proven successful in most patients with biliary dyskinesia. More extensive evaluation and treatment is only necessary for the few patients who fail to respond.
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Table 1-3
CONGENITAL ANOMALIES OF THE GALLBLADDER Agenesis (syndromic and nonsyndromic) Hypoplasia Diverticulum Duplication and mutiple gallbladders Heterotopic tissue in gallbladder Mobile and interposed gallbladder Positional alterations Septation defects
STRUCTURAL VARIATIONS OF THE GALLBLADDER Definition Numerous variations in gallbladder structure and position have been described.
Clinical Manifestations and Evaluation Anatomic variations (Table 1-3) include: • Multiple gallbladders (see below). • Septation of the gallbladder (see below). • Gallbladder diverticulum. • Ectopic position of the gallbladder (left sided, free floating, retrodisplaced,
retroperitoneal, transverse, intrahepatic, suprahepatic, supradiaphragmatic, in the falciform ligament, in the mesocolon, in the abdominal wall). • Unusually mobile gallbladder and “interposed gallbladder” (anomalous insertion of both hepatic ducts into the gallbladder with the cystic duct draining into the duodenum). • Gallbladder hypoplasia or “microgallbladder” is usually seen in cystic fibrosis. The gallbladder may have a septum dividing the cavity into two parts (septate gallbladder). These parts may be partially or completely separated, leading to a bilobed gallbladder with a single cystic duct (“vesica divisa”). Some authors think of these malformations as duplications, whereas others make a distinction between these and “true” duplications. Cases of multiseptate gallbladder are rare and not considered part of the spectrum of gallbladder duplication but are more clearly due to defects in recanalization. Occasionally, two separate gallbladders, each with its own cystic duct, may develop (“vesica duplex”). Controversy exists over whether these anomalies predispose to stone formation. The cystic ducts may join to form a single, Y-shaped cystic duct; the two
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cystic ducts may remain separate and both empty into the common duct, or one of the cystic ducts may connect elsewhere, such as into an hepatic duct. Occasionally the second or “accessory” gallbladder may be found in another site such as under the left lobe of the liver, imbedded within the liver, or within the gastrohepatic ligament. Multiple gallbladders may be missed by routine radiographic diagnostic studies, especially if one is nonvisualized because of disease. Symptomatic duplication is usually reported in adults and only rarely in childhood. There are probably several different pathogenetic mechanisms involved in the various forms of gallbladder duplication. These include the development of more than one pars cystica primordium at two different sites in the developing common duct, splitting of the pars cystica during the 5th and 6th weeks of development, growth of diverticula from the cystic duct or from intrahepatic ducts, or aberrant canalization after the solid stage of development. There is some suggestion that biliary anomalies may predispose to lithiasis. This seems to be a relatively uncommon complication considering the frequency of biliary tract structural variation. Lithiasis may be related to duct damage from regurgitation of pancreatic secretions (as in anomalous pancreaticobiliary duct union); or mechanical obstruction to gallbladder emptying caused by torsion of the cystic duct in cases of malpositioning (as has been suggested to account for the high incidence of stones in intrahepatic gallbladders). Malposition of the gallbladder may also lead to torsion and gangrene. Gallbladder diverticulum has been associated with malignant transformation.
Management Evaluation and treatment as usual are recommended for symptoms of cholecystitis. Patients with symptomatic multiple gallbladders generally benefit from removal of all of these cystic structures. Most symptomatic gallbladder anomalies require surgery.
HETEROTOPIC TISSUE IN THE GALLBLADDER Definition Ectopic tissue of foregut origin located within the gallbladder mucosa.
Clinical Manifestations and Evaluation Numerous heterotopic tissues have been identified in the gallbladder, though gastric is the most common. Pancreatic, hepatic, thyroid, and adrenal have also been reported. Although extremely rare, these reported cases usually present with clinical symptoms such as abdominal pain and the heterotopic tissue is identified in surgical resections. Lithiasis often coexists. It has also been suggested that heterotopic tissue may promote carcinogenesis of the gallbladder and metaplastic areas surrounding the heterotopic tissue has been reported. Of note, heterotopic gastric tissue has been reported in the biliary tree as well, and as a cause of symptoms such as hemobilia.
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Management Management is surgery, if symptomatic.
References 1. Kim SK, Hebrok M. Intercellular signals regulating pancreas development and function. Genes Dev 2001;15:111-27. 2. Crawford JM. Development of the intrahepatic biliary tree. Semin Liver Dis. 2002;22:213-26. 3. Lerner A, Branski D, Lebenthal E. Pancreatic diseases in children. Pediatr Clin North Am 1996;43:125-56. 4. Sokol RJ, Mack C. Etiopathogenesis of biliary atresia. Semin Liver Dis. 2001;21:51724.
Suggested Reading Adam E, Morgan R. The pancreas. In: Grainger & Allison’s Diagnostic Radiology: A Textbook of Medical Imaging. 4th ed. New York: Churchill Livingstone, Inc.; 2001:1343-1345. Alonzo-Lej F, Revor WB, Pessagno DJ. Congenital choledochal cyst with a report of 2, and an analysis of 94 cases. Surg Gynecol Obstet Internat Abst Surg. 1959;108:130. Benya E. Pancreas and biliary system: Imaging of developmental anomalies and disease unique to children. Radiol Clin North Am. 2002;40(6):1355-1362. Desmet V. Congenital diseases of intrahepatic bile ducts: variations on the theme “ductal plate malformation”. Hepatology. 1992;16(4):1069-1083. Haber BA, Russo P. Biliary atresia. Gastroenterol Clin North Am. 2003;32(3):891913. Emerick KM, Rand EB. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. 1999;29:822-829. Kamath BM, Russo P, Piccoli DA. Heritable disorders of bile ducts. Gastroenterol Clin North Am. 2003;32(3):857-875. Matsumoto Y, Uchida K, Nakase A, Honjo I. Clinicopathologic classification of congenital cystic dilatation of the common bile duct. Am J Surg. 1977;134(5):569574. Schweizer P, Schweizer M. Pancreaticobiliary long common channel syndrome and congenital anomalous dilatation of the choledochal duct—study of 46 patients. Eur J Ped Surg. 1993;3(1):15-21. Whitcomb D. Hereditary and childhood disorders of the pancreas, including cystic fibrosis. In: Feldman. Slesinger & Fordtran’s Gastrointestinal and Liver Disease. 7th ed. Philadelphia, Pa: Elsevier; 2002:881-884. Witzleben CL, Piccoli DA: Disorders of the biliary tract: extrahepatic bile ducts. In: Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins JB, eds. Pediatric Gastrointestinal Disease. Ontario, Canada: B.C. Decker; 2000:915-927.
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Gallstones and Gallbladder Disorders Ann Marie Joyce, MD; William B. Long, MD
Gallbladder Anatomy and Physiology The gallbladder lies under the right lobe of the liver with its superior adventitia fused with the liver capsule and its inferior portion covered by visceral peritoneum. Inferiorly, it is adjacent to the duodenum and the transverse colon, permitting gallstones to infrequently form fistulae into these organs. The cystic duct connects the gallbladder to the extrahepatic bile duct. Anomalies of the extrahepatic ducts including aberrant ducts that drain individual segments of the liver into the gallbladder, cystic duct, or extrahepatic duct can present challenges to surgeons, endoscopists, or radiologists. Duplication and agenesis of the gallbladder are rare anomalies. The cystic artery supplying the gallbladder is an end artery, and the gallbladder is, therefore, susceptible to ischemic injury. About half of bile secreted overnight enters the gallbladder via the cystic duct. In the gallbladder, formation of micelles from bile salt monomers and absorption of electrolytes and water allow great concentration of bile without increase in osmolality. Contraction of the gallbladder and relaxation of the sphincter of Oddi during meals provides bile for the digestive process. Cholecystokinin is the most important hormonal stimulus of gallbladder contraction, but cholinergic nervous stimuli also provoke contraction. Intravenous infusion of cholecystokinin normally leads to greater than 40% emptying of the gallbladder.
Gallstone Pathophysiology Human gallstones are classified into cholesterol, black, brown, and rare other types. Cholesterol stones are the most common stone type in Western countries and are composed primarily of cholesterol, but even “pure” cholesterol gallstones usually have a bilirubin pigment center and many cholesterol stones have concentric layers pigmented by bilirubin, alternating with purer cholesterol layers. Bilirubin is the predominant constituent of black and brown stones that are referred to as “pigment”
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stones. Cholesterol and black stones form nearly exclusively in the gallbladder and brown stones form mainly in the bile ducts. Cholesterol and black stones may pass from the gallbladder into the bile duct. Three factors are believed to be involved in the formation of cholesterol stones:
1. Supersaturation of bile with cholesterol 2. Stasis of bile in the gallbladder 3. Nucleation factors that accelerate cholesterol precipitation from bile. Supersaturation with cholesterol is essential, but may not be sufficient for stone formation. Cholesterol in bile is solubilized by bile salts and phospholipids (mainly lecithin). Supersaturation usually involves excess secretion of cholesterol, but may also reflect decreased bile salt or phospholipid secretion. Cholesterol is secreted with lecithin by the hepatocyte canaliculus in the form of vesicles. Bile salts are secreted by a different canalicular pathway and form pure bile salt micelles. Bile salt micelles interact in the bile ducts and gallbladder with vesicles to form mixed micelles composed of bile salts, cholesterol, and lecithin. The proportion of vesicles and mixed micelles depends on overall bile salt-lecithin ratio, types of bile salts, and total biliary cholesterol. In the gallbladder, crystals of cholesterol may precipitate from cholesterol rich vesicles if adequate bile salt and lecithin are not available. Electron microscopy has demonstrated round vesicles clustered on the surface of growing cholesterol crystals. Individuals without gallstones have bile intermittently supersaturated with cholesterol and such bile may form crystals in the laboratory after incubation for several days. Bile from patients with cholesterol stones (which has similar bile salt, cholesterol and phospholipid concentration as bile of non-stone individuals) forms crystals in only a few days; this accelerated crystalization implies pronucleating or, perhaps, antinucleating factors in bile of stone patients. Retarded gallbladder emptying may provide time needed for supersaturated bile to form crystals and stones, especially if net pronucleating activity is present. Although gallstones may form quite rapidly in certain circumstances (such as patients receiving parenteral feeding or on crash diets), cholesterol stones usually grow slowly and asymptomatically. An imaginative study published in 1986 employed the varying proportion of carbon isotopes in the atmosphere and biosphere since nuclear bomb testing in the 1950s to determine the age of gallstones removed at cholecystectomy in 15 patients.1 Gallstones in these patients grew 1 to 4 mm per year (mean, 2.6 mm per year) and none of the 11 symptomatic patients had symptoms until at least 2 years (mean, 8 years) after stone formation began. Stones in the patients without symptoms had been present for at least 10 years before cholecystectomy. Gracie and Ransohoff 2 also reported delayed onset of symptoms in asymptomatic gallstone patients followed prospectively. Among 123 such patients, only 18 developed severe biliary pain over 24 years. As shown in Table 2-1, multiple conditions are associated with increased risk of cholesterol gallstone formation. From a pathophysiologic standpoint, it is probably inaccurate to regard cholesterol or pigment stone disease as a single disease. Increased cholesterol secretion, decreased bile salt secretion or both have been reported in patients with cholesterol gallstones. Conditions of increased risk may also reflect alterations of gallbladder motility or nucleation factors.
Gallstones and Gallbladder Disorders Table 2-1
INCREASED RISK OF GALLSTONE FORMATION Cholesterol Stones Female gender Increasing age Obesity Rapid weight loss Prolonged fasting TPN Western diet Lack of exercise Pregnancy and multiparity Race (eg, certain Native American groups) Family history Apo E genotype Disease of terminal ileum (eg, Crohn's disease) Diabetes Cerebrotendinous xanthomatosis Vagotomy Medications Estrogen and progesterone Octreotide Clofibrate Gilbert’s syndrome?
Pigment Stones Increasing age Hemolytic anemia Prosthetic cardiac valve Cirrhosis Gilbert’s syndrome? Juxta-papillary diverticulum Biliary parasites Foreign matter in bile ducts Choledochocysts, Caroli’s disease
Other Types of Stones or Sludge Ceftriaxone
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Cholesterol Stone Formation CHOLESTEROL SUPERSATURATION The ratio of cholesterol to phospholipid and bile salt in hepatic bile increases at low bile salt flow rates, which occur overnight or with more prolonged fasting. During fasting, most of the bile salt pool is sequestered in the gallbladder and even individuals without stones may have hepatic bile supersaturated with cholesterol, whereas bile in the gallbladder is rich in bile salts and may remain unsaturated with cholesterol. Cholesterol stone formation requires supersaturation of bile in the gallbladder. Such supersaturation with cholesterol may occur because of increased cholesterol secretion or decreased bile salt secretion. Supersaturation caused by increased cholesterol secretion appears to be the major cause of cholesterol lithiasis associated with obesity, rapid weight loss, and estrogen therapy. Native Americans with cholesterol gallstones have bile salt pools that are reduced by up to 50% and reduced bile salt secretion.3 Reduction in bile salt pool has been noted before onset of stones and may be an intrinsic defect. Cholesterol synthesis is also increased in these groups, perhaps driven by reduced bile salt pool and need for precursor cholesterol in bile salt synthesis. Increased fecal bile salt loss has been identified. The combination of high synthetic rate of bile salts, reduced bile salt pool, and increased fecal loss suggests that increased intestinal loss of bile salts may be an underlying defect in cholesterol gallstone disease. Supersaturation produced by reduced bile salt secretion has also been found in patients with ileal resection or disease in whom enterohepatic circulation of bile salts is reduced and in cerebrotendinous xanthomatosis in which bile salt synthesis is reduced. Normal gallbladder mucosa absorbs some cholesterol, reducing cholesterol saturation in the gallbladder. Gallbladder mucosa of patients with cholesterol stones, however, loses this capacity to absorb cholesterol.4 Abnormal function of the gallbladder mucosa may be a pathogenic cofactor for gallstone formation.
GALLBLADDER HYPOMOTILITY Gallbladder hypomotility provides opportunity for crystallization, aggregation of crystals, and growth to macroscopic stones from supersaturated bile. Gallbladder hypomotility may be determined in patients and controls by ultrasound or nuclear medicine studies of fasting volume, ejection volume, and contracted volume. Although there is great overlap of values, asymptomatic cholesterol gallstone patients, in general, have greater fasting and postprandial gallbladder volume and decreased percent gallbladder emptying compared to gallstone-free individuals.5 Greater fasting volume and decreased percent emptying of the gallbladder persist 1 year after dissolution of stones by oral ursodeoxycholic acid therapy, suggesting that altered gallbladder function is not necessarily caused by the stones, but may be an underlying disorder. On the other hand, studies in animal gallstone models reveal that supersaturated bile induces defects in contractility of gallbladder muscle, implying that motility defects may be a result of an abnormality in bile. Gallbladder muscle from patients with cholesterol stones has increased membrane cholesterol/phospholipid ratio and decreased membrane fluidity resulting in impaired muscle contractility.6 These abnormalities are corrected by removing the excess cholesterol from the plasma membranes.
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Impaired gallbladder emptying and increased incidence of gallstones occur in the latter part of pregnancy, in individuals treated with oral contraceptives or somatostatin, following spinal cord injury, with diabetes mellitus, after vagotomy, and in patients receiving long-term parenteral nutrition. These associations suggest that alteration of gallbladder motility contributes to gallstone formation. In none of these situations, however, is gallbladder hypomotility likely to be the only factor leading to stone formation. For instance, patients with severe spinal cord injury have a threefold increase in risk of gallstones, but these patients may have disorders of gastric, duodenal, and colonic motility; dietary changes; muscle atrophy; and weight loss, in addition to decreased gallbladder motility.
NUCLEATING FACTORS Several studies indicate that a nucleating factor, or less likely absence of an antinucleating factor, is important in initiating crystal and stone formation. Individuals free of gallstones may intermittently have supersaturated with cholesterol without crystal formation and, in vitro, such bile usually takes 2 to 3 weeks to form crystals. In contrast, gallbladder bile of cholesterol stone patients forms crystals in vitro in a few days.7 Patients with pigment stones have nucleation time (time required to form crystals) similar to that of individuals with no stones. Seeding with crystals of supersaturated bile from nonstone individuals initiates rapid crystal formation, suggesting that antinucleating factors are not present. Many investigations suggest that gallbladder mucin is a major nucleating factor. Mucin is found in human gallstones, and in animal models increased secretion of gallbladder mucin occurs as early as 18 hours after beginning a lithogenic diet and precedes crystal formation. Cholesterol crystals also first appear in the mucus layer. In vitro studies demonstrate that nucleation time is inversely proportional to the concentration of added mucin. In part, the action of mucin to accelerate crystal formation may result from its ability to bind cholesterol and concentrate it.8 Cholesterol concentration is 3 to 4 times higher in the mucous gel covering the gallbladder mucosa than in luminal bile. The complexity of understanding the pathogenesis of gallstone disease is emphasized by a study of 20 patients with cholesterol gallstones showing a 50% prolongation of colonic transit time compared with stone-free controls. Colon transit time correlated with serum chenodeoxycholic acid (a secondary bile acid produced in the colon) that has been previously found to stimulate secretion of biliary cholesterol and increase mucus glycoprotein content of bile. Other than mucin, some biliary proteins, including IgM and IgG, have been reported to accelerate cholesterol nucleation. One study found that biliary IgA was a potent inhibitor of cholesterol crystallization in model bile. Another study 9 questioned the importance of mucin, immunoglobulin, and other proteins for cholesterol precipitation from gallbladder bile. Analysis of bile from 52 patients with cholesterol stones and 40 patients without stones found that only cholesterol saturation, and not protein or mucin concentration, correlated with in vitro cholesterol crystal formation.
AGE, SEX, AND R ACE Age, sex, and genetic factors (including race) appear to play major roles in gallstone formation. Prospective ultrasound studies of more than 14,000 random US civilians
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performed between 1988 and 1994 estimated that 6.3 million men and 14.2 million women aged 20 to 74 years have gallstones10. The difference in gallstone prevalence between men and women was much greater in the younger individuals. At age 20 to 29 years, 1% of men and 4% of women had stones, but in 60- to 74-year-old individuals, prevalence of gallstones was 17% for men and 16% for women. The increased risk of gallstone formation in women compared to men occurs before age 60, suggesting that estrogen secretion may be involved. Multiparity also increases risk of gallstones. During pregnancy cholesterol secretion in bile and gallbladder volume and stasis increase; these events may underlie the increased development of gallstones. Race plays an important role in incidence of gallstones. The ultrasound study mentioned above confirmed earlier studies that black men and women have a lower prevalence of gallstones than whites. The highest overall prevalence in this study was in Mexican American women, of whom 27% had stones, compared to 17% in nonHispanic white and 14% in black women. Other studies have identified an unusually high prevalence in women of the Pima tribe of Arizona, among whom more than 70% of adult women have gallstone disease. A high rate in other indigenous American groups in Alaska, New Mexico, Chile, and Bolivia with very different diets, environments, and cultures argues for a genetically determined predisposition to stone formation among indigenous Americans.11 Although no gene that predisposes to stone formation has been identified in Native Americans, it has been speculated that nutritional deprivation among the first persons to cross the Bering land bridge from Asia 10,000 to 20,000 years ago may have selected a gene that promoted storage of nutrients. Under conditions of plenty, such a “thrifty” gene might now result in stone formation. Even though obesity is common in some Native American populations, the high prevalence of gallstones among young nonobese Pimas and Chileans supports a genetic, in addition to nutritional or environmental, factor. In Native Americans, as in other populations, female sex, increasing age, high percent body fat, multiparity, and low serum HDL cholesterol have been identified as independent risk factors for gallstone formation. Biliary cholesterol hypersecretion has been reported in Pima Indians and in normal weight Chileans and may be under genetic control. The hypothesis that cholesterol gallstone formation has genetic influences is also supported by findings that some families have an increased frequency of gallstones, that gallstones are more frequent in first-degree relatives of gallstone patients, and that cholesterol supersaturation and gallstone formation is increased in monozygotic compared with dizygotic twins. Comparing 171 first-degree relatives of patients with gallstones with 200 matched controls in Israel, gallstones were found in 21% of the first-degree relatives and only 9% of the control group. As multiple factors appear to increase the risk of cholesterol gallstone formation, there are likely to be multiple genetic factors involved. A peculiar form of cholesterol gallstone disease associated with mutation in the MDR3 gene that regulates the phosphotidylcholine translocator across the canalicular membrane of the hepatocyte has been described in six patients12 . These patients had cholesterol crystals in bile, high bile cholesterol/phospholipid ratio, cholestasis, recurrence of symptoms after cholecystectomy, and prevention of recurrence by ursodeoxycholic acid therapy. Genetic factors have been identified in inbred mice that form cholesterol gallstones. One gene is associated with gallbladder hypomotility and prolonged intestinal transit. Another gene is associated with low plasma HDL and increased biliary cholesterol. A murine genetic gallstone “map” has been described and may provide clues in the quest for genes that predispose to human gallstone formation13.
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OBESITY AND WEIGHT LOSS Obesity is a major risk factor for cholesterol gallstones14. This association is most evident in women. Overweight women with a BMI of 30 kg/m 2 or more have at least double the risk for cholesterol stones as women of lesser weight. With more severe obesity, the risk is as high as seven times that of women with BMI less than 24 kg/m 2 . Studies of obesity in men suggest a similar but less severe association with cholesterol stones. Dieting with rapid weight loss over several weeks leads to development of stones in 12% of individuals. Greater weight loss increases the risk. Thirty-eight percent of 111 obese patients treated with gastric bypass formed stones after surgery and a third of these became symptomatic. Cholesterol saturation has been found to increase in most, but not all, patients with rapid weight loss. Obese subjects risk gallstone development both by being obese and by experiencing periods of rapid weight loss. Truncal obesity in men was correlated with increased stone formation in one study. With weight stabilization after weight loss, biliary cholesterol secretion and saturation decreases. Obesity is associated with excessive hepatic secretion of cholesterol and this is the suspected reason for increased incidence of cholesterol stones. Most, but not all, studies report normal gallbladder contractility in obese compared to lean individuals. In vitro, accelerated cholesterol crystal formation has not been found in bile of obese patients without stones.
LACK OF EXERCISE Lack of exercise increases the risk of gallstone formation in both men and women. About 60,000 women in the Nurses Health Study prospectively reported their physical activity and whether they had undergone cholecystectomy during 10 years.15 Cholecystectomy was used as an indicator of symptomatic cholelithiasis (other smaller studies have indicated that exercise is associated with a reduced prevalence of gallstones). Relative risk of cholecystectomy among women with the highest quintile of physical activity was 0.69 compared to the risk in the lowest quintile. The beneficial effect of exercise was seen even when the data were controlled for obesity and recent weight loss. A similar protective effect of physical activity has been found among men in prospective studies. The protective effect of exercise may involve several metabolic pathways other than its effect on controlling weight. Exercise increases high-density lipoprotein, improves glucose tolerance, and reduces colonic transit time; each of these effects has been associated with reduced risk of gallstones.
MEDICATION Certain medications dispose to gallstone formation. Men and women taking estrogen have increased incidence of gallstones and cholecystectomy, perhaps caused by the observed increased secretion of biliary cholesterol. Clofibrate is also associated with increased biliary cholesterol and gallstones. Octreotide decreases gallbladder contractility and use for months is associated with gallstone formation. The cephalosporin ceftriaxone is excreted in bile, and biliary sludge or stones formed by precipitated drug have been reported in 43% of children receiving high doses; sludge may dissolve when the medication is discontinued.
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GILBERT’S SYNDROME Bile in most individuals contains only trace amounts of unconjugated bilirubin. Limited studies, however, reveal that individuals with Gilbert’s syndrome may have increased, although small, amounts of unconjugated bilirubin in bile. Patients with hemolytic anemia, thalessemia, spherocytosis, and sickle cell disease have a significant increase in gallbladder stones if they also have Gilbert’s syndrome; the type of stones in patients with both hemolysis and Gilbert’s syndrome has not been reported. We recently studied 52 patients with common duct stones removed after endoscopic sphincterotomy and found that 23% were homozygous for the Gilbert’s gene; this frequency of Gilbert’s syndrome is increased (p<0.05) compared to that reported in Europeans (average of three large studies, 12%)16. Surprisingly, the prevalence of Gilbert’s homozygosity was at least as great in cholesterol (27%) as in pigment stone patients (20%). Cholesterol stones often have a central nidus of unconjugated bilirubin. We speculate that Gilbert’s syndrome may increase the risk of stone formation in susceptible individuals, even without increased hemolysis, because of the slight increase in insoluble unconjugated bilirubin in bile that may serve as a nidus for stone formation.
Biliary Sludge Biliary sludge was recognized with the advent of transabdominal ultrasound studies of the gallbladder in the latter 1970s. Sludge in the gallbladder produces low amplitude acoustic echoes without shadowing on ultrasound. When present, it is in the dependent portion of the gallbladder and shifts with postural changes. Direct microscopic examination of gallbladder or duodenal bile after gallbladder contraction is more sensitive than transabdominal ultrasound for detection of sludge. Endoscopic ultrasound is also very sensitive. Sludge is composed of precipitates of cholesterol monohydrate crystals, calcium bilirubin granules, and other calcium salts embedded in a mucus gel17. The bilirubin is usually unconjugated. The source of unconjugated bilirubin is unclear. Bilirubin is secreted by the liver mainly as a diglucuronide, with small amounts of monoglyceride and minimal unconjugated bilirubin. Deconjugation of bilirubin is thought to occur through action of beta-glucuronidase that may originate from chronic low-grade biliary infection or from biliary epithelium. The chemical composition of sludge may vary. It consists primarily of calcium bilirubinate in patients receiving total parenteral nutrition, cholesterol crystals in pregnant women, and calcium-ceftriaxone complexes in patients receiving high-dose ceftriaxone therapy. The mucus content of gallbladder bile is higher in individuals with sludge than in either normal controls or patients with gallstones; mucus content in hepatic bile, however, does not differ among these groups, indicating that the mucus is of gallbladder origin. Microscopic study shows early glandular metaplasia of gallbladder mucosa; patients with stones usually have more pronounced changes, including mucosal thickening and fibrosis. Most investigators believe that the pathogenesis of sludge is similar to that of gallstones. Although sludge may resolve without residual pathology, the development of sludge may precede gallstone formation. Sludge has been reported in 26% and 31% of pregnant women, but the sludge disappeared spontaneously in most 1 year after delivery; stones developed in 2% to 5%. High incidence of sludge also occurs with prolonged fasting, total parenteral nutrition, rapid weight loss, octreotide therapy, and
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bone marrow transplantation; in these situations, the sludge usually resolves if the precipitating cause is removed.
Pigment Gallstones There are two major types of pigment stones: “black” stones that form in the gallbladder, and “brown” stones, which form principally in bile ducts18. Black stones are relatively hard and amorphous, composed of a mixture of bilirubinate polymer, calcium bilirubinate, and calcium carbonate and phosphate. Inorganic calcium salts often make black stones radiodense. Brown stones are softer, often laminated, and consist mainly of calcium bilirubinate with lesser amounts of calcium soaps of fatty acids derived from lecithin and a significant amount of cholesterol. Brown stones do not contain enough calcium to be radiodense. Both types of stones contain an unmeasured residue believed to be mainly glycoprotein. Black stones and surrounding bile is sterile unless there is associated cholecystitis, but brown stones have evidence of bacteria, especially Escherichia coli. Although less is known of the pathophysiology of pigment than of cholesterol stones, similar factors of metastable bile, nucleating factors, and bile stasis probably are important in stone formation.
BLACK STONES Black stones are found more commonly in hemolytic conditions, cirrhosis, and with increasing age. Ileal resection or ileal Crohn’s disease also increases the risk of gallstones two- to threefold; the increased risk appears to be for both cholesterol and black stones19. Increased total and unconjugated bilirubin is found in the bile of these patients and may reflect enterohepatic circulation of bilirubin. No consistent change in the concentration of cholesterol, bile acid, or phospholipids has been noted in bile of patients with black stones. Minute areas of herniation of gallbladder epithelium through the muscle layer of the gallbladder produces a condition known as adenomyomatosis or RokitanskyAschoff sinuses. These sinuses are more frequent with increased age and sometimes contain black pigment microstones. Sixty-four of 179 cholecystectomized patients had adenomyomatosis and 38 of the 64 (59%) had black stones20. Rokitansky-Aschoff sinuses may contribute to the formation of black stones.
BROWN STONES Bile associated with brown stones has a reduction in total bile acid concentration, perhaps explained by biliary absorption of unconjugated bile acids deconjugated by bacterial enzymes21. Chronic low-grade bacterial infection of bile may be the key event in formation of brown pigment stones. Occasionally brown stones contain a central foreign body such as suture material or parasite ovum that appears to have served as a nidus for stone formation. Brown stones form more frequently after cholecystectomy, in ectatic bile ducts, and in association with parasitic biliary infections (especially in Asia).
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Acute Calculous Cholecystitis Acute cholecystitis is an inflammatory condition of the gallbladder produced by a combination of cystic duct obstruction and irritation of gallbladder mucosa. The irritating factor may be a gallstone or, perhaps, a component of pathologic bile. In experimental animals, cystic duct ligation without a luminal irritant such as lysolecithin may not produce cholecystitis. Lysolecithin is not present in normal bile, but is found in bile of patients with acute cholecystitis and produces acute cholecystitis when introduced into the gallbladder of experimental animals. Lysolecithin may be generated from biliary lecithin by phospholipase A, an enzyme in gallbladder mucosa. Prostaglandins play an important role in the early stages of acute cholecystitis. Induction of cholecystitis by lysolecithin is associated with increased production of prostaglandins and white blood cell invasion of mucosa. Inhibition of prostaglandin generation by diclofenac, an inhibitor of prostaglandin synthetase, may prevent development of cholecystitis in patients with biliary colic. Hydrophobic bile acids may also be involved in the pathogenesis of acute cholecystitis. In acute cholecystitis, gallbladder muscle in patients and animals has impaired contractile response to acetylcholine and cholecystokinin. In vitro, the relatively hydrophobic chenodeoxycholic acid reproduces the muscle dysfunction observed in experimental acute cholecystitis. Pretreating animals with the relatively hydrophilic ursodeoxycholic acid can prevent gallbladder muscle dysfunction 22 . Ursodeoxycholic acid treatment also was associated with reduced prostaglandin formation. Gallbladder infection, usually with gram-negative enteric bacteria, develops in about half of patients in the first few days, but infection is not believed to be an initiating factor. If obstruction of the cystic duct persists, bile pigments may be absorbed and the gallbladder becomes distended with mucoid material; this condition is known as hydrops of the gallbladder.
Acute Acalculous Cholecystitis Occasionally, patients with acute cholecystitis do not have gallstones. This form of cholecystitis tends to occur in elderly patients otherwise ill from trauma, burns, recent surgery, immune deficiency, systemic vasculitis, or hemodynamic instability 23. Prolonged fasting exposes the gallbladder to the potential noxious effects of concentrated stagnant bile. Reduced blood flow to the gallbladder in the conditions mentioned is believed to add ischemic to chemical injury and gangrene may develop. Inhibition of prostaglandins in animal models reduces tissue damage, indicating that prostaglandins play an early pathogenic role in acalculous, as well as in calculous, cholecystitis. Infection with gram negative or anaerobic bacteria may complicate the initial injury.
Acalculous Biliary Pain Biliary colic typically is a steady pain in the epigastrium or right upper quadrant, and lasts 15 minutes to 1 or 2 hours. It is not associated with significant acute inflammation, but usually is caused by a gallstone transiently obstructing the cystic duct. Less commonly, similar pain occurs in patients without gallstones. Most patients with acalculous biliary pain are younger adult women. Etiology of pain in those without stones is unclear. Some have cholesterol or bilirubinate crystals in bile or minute gall-
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bladder stones missed on ultrasound. Others have gallbladders that empty less than 35% after stimulation with intravenous cholecystokinin. In vitro, gallbladder muscle of these patients exhibits decreased contractile response to cholecystokinin and the defect appears to reflect a distinct muscle abnormality rather than decreased membrane fluidity as described in cholesterol gallstone disease24. Most carefully evaluated patients respond to cholecystectomy and many have histologic evidence of chronic cholecystitis.
Gallbladder Cancer Most gallbladder cancers are adenocarcinomas; squamous carcinoma is infrequent. Seventy to 90% of patients with gallbladder cancer have gallstones and the worldwide distribution of gallbladder cancer correlates with that of gallstones. Very high prevalence of gallbladder cancer is seen in certain Native American groups, particularly in Bolivia and Chile. Increased risk is also seen in association with calcification of the gallbladder, choledochocysts, congenital drainage of the pancreatic duct into the bile duct, sclerosing cholangitis, and chronic biliary infection with Salmonella typhi. Chronic inflammation of gallbladder epithelium resulting from these conditions may dispose to development of cancer. Gallbladder polyps greater than 1 cm have increased risk of cancer. Microsatellite instability does not seem to play a role, but p53 expression is common in these tumors25.
Medical Management of Gallstones The majority of patients who have gallstones will never develop symptoms. About one in ten patients with gallstones will develop symptoms or complications of gallstones when followed over a 5-year period. Elective cholecystectomy was the standard treatment for asymptomatic gallstones, but it is now accepted that this should be reserved for those patients with symptoms. Some patients who have gallstones present with nausea, vomiting, mild abdominal discomfort, and belching. It can be difficult to determine if these symptoms are related to the gallstones. Some of these patients with dyspepsia actually have improvement in their symptoms after a cholecystectomy. The physician’s clinical judgment plays a major role in deciding whether these patients should undergo a cholecystectomy. Nonsurgical treatment for asymptomatic or minimally symptomatic gallstones can be effective in a select group of patients. The main modality is bile acid dissolution therapy. Extracorporeal shock wave lithotripsy has been replaced in general by laparoscopic cholecystectomy. Medical management can be effective in patients who have small stones, mild biliary colic without evidence of cholecystitis or cholangitis, radiolucent stones, and a patent cystic duct. Ursodeoxycholic acid is the main bile acid used for the treatment of cholesterol gallstones. Chenodeoxycholic acid is no longer used because of mild side effects. Ursodeoxycholic acid desaturates bile by decreasing biliary cholesterol formation. Its effectiveness depends on the size of the stones and the cholesterol content 26. Ursodeoxycholic acid is given at night because the bile acid secretion is the lowest and cholesterol saturation is the highest. The usual dose is 10 to 15 mg/kg of body weight per day 27. A meta-analysis of studies using ursodeoxycholic acid showed promising results28. Approximately 37% of highly selected patients had complete dissolution of stones; the highest rates in the group are with stones less than 5 mm. If there has
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Chapter 2
been no reduction in size after 6 months, dissolution is unlikely. In patients without a history of cholecystitis or severe gallstone symptoms, chronic ursodeoxycholic acid therapy (600 mg daily) can reduce the likelihood of biliary colic and cholecystitis, even without dissolution of stones. Need for cholecystectomy in 527 patients followed for up to 18 years was reduced from 88% to 26% in patients with nonsevere symptoms before therapy 29. Chronic therapy with ursodeoxycholic acid may be appropriate in patients with mild or no symptoms if they are poor operative risks. Extracorporeal shock wave lithotripsy (ESWL) has been used in the medical management of gallstones but rapidly went out of favor following introduction of laparoscopic cholecystectomy. ESWL increases the surface-to-volume ratio, which helps the effectiveness of ursodeoxycholic acid, and ESWL creates fragments of stones that are cleared through the common bile duct into the duodenum. Ursodeoxycholic acid works with lithotripsy to help dissolve the stones30. In a study of 711 patients 6, 68% and 84% of patients were stone-free at 6 and 12 months after high-energy shockwave lithotripsy with adjuvant bile acid therapy. Petechiae of the skin at the site of shock-wave entry occurred in 8%, transient gross hematuria occurred in 4%, and liver hematoma occurred in 0.1% of the patients31. Biliary colic can be exacerbated in a small proportion of patients due to the passage of the small fragments. Stones often recur.
Acute Calculous Cholecystitis DIAGNOSIS Acute cholecystitis usually presents with right upper quadrant pain of at least several hours and fever. Laboratory investigations reveal a leukocytosis with immature blast forms. In some cases, there is a mild increase in transaminases. An elevated total bilirubin may indicate biliary obstruction secondary to choledocholithiasis or Mirizzi’s syndrome. Transabdominal ultrasound is commonly used to evaluate gallbladder disease. Ultrasound is easy, readily available, and accurate in evaluating the gallbladder. On ultrasound, there may be pericholecystic fluid, a thickened gallbladder wall (>4 mm), a distended gallbladder, and Murphy’s sign. Murphy’s sign is defined as tenderness in the right upper quadrant with palpation. This sign has a positive predictive value of 90%32 . Cholescintigraphy, also known as hepatobiliary iminodiacetic acid (HIDA) scan, is another imaging test of the gallbladder. The tracer is taken up by the liver, secreted in the bile, and then flows through the common bile duct into duodenum. In patients with patent cystic duct, the tracer should be taken up by the gallbladder as well as enter the small bowel. If there is nonvisualization of the gallbladder but high clinical suspicion, morphine sulfate can be administered. The morphine contracts the sphincter of Oddi, increasing the pressure in the common bile duct facilitating filling the gallbladder. This test is not accurate in patients that are fasting, on TPN, or critically ill. Some studies have shown that HIDA has a greater sensitivity and specificity when compared with ultrasound. The two tests together are additive33. In our institution, the HIDA scan is reserved for those patients with high clinical suspicion for acute cholecystitis and a normal ultrasound.
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CT scan and MRI may also be used to evaluate cholecystitis. An advantage of these tests is that the remainder of the abdomen can be evaluated.
TREATMENT Once the diagnosis of acute cholecystitis is made, the patient is admitted to the hospital. Conservative management should include basic measures such as fasting, fluid and electrolyte resuscitation, and pain medications. If the patient is vomiting, a nasogastric tube is placed. Antibiotics covering gram-negative rods and anaerobes should be started if there are signs of sepsis or failure to improve after 12 to 24 hours. Organisms are rarely aspirated from the gallbladder. The organisms that have been involved with acute cholecystitis include Escherichia coli, Klebsiella, Streptococcus faecalis, Clostridium welchi, Proteus, and Enterobacter. Laparoscopic cholecystectomy is currently the standard treatment for acute cholecystitis. The first cholecystectomy was done in 1882 by Langenbuch. Laparoscopic cholecystectomy has become more common since its introduction in the late 1980s. General anesthesia is administered to an appropriate surgical candidate undergoing a laparoscopic cholecystectomy. A trocar is placed into the umbilicus and pneumoperitoneum induced with a nonflammable gas. A telescope is then placed through the umbilicus. Three additional trocars are placed (subxiphoid, right midclavicular line, and anterior axillary line). The gallbladder is retracted away from the liver. The cystic artery and duct are identified and dissected. Clips are placed on each. The gallbladder is dissected from the liver and delivered intact through the umbilical incision. An intraoperative cholangiogram can be performed during a laparoscopic cholecystectomy to evaluate the anatomy of the biliary tree and to detect choledocholithiasis. A prospective study of 514 patients undergoing laparoscopic cholecystectomy showed that routine cholangiography was not needed 34. Preoperative endoscopic retrograde cholangiopancreatography (ERCP) is performed in patients with a high suspicion for choledocholithiasis. These patients usually have jaundice, dilated common bile duct, visualized common bile duct stones on imaging study, or cholangitis. An urgent ERCP is recommended in gallstone pancreatitis in a patient presenting with cholangitis and pancreatitis. A preoperative ERCP is sometimes advocated for patients who have had a Billroth II gastrectomy; if the ERCP is not successful and a stone is identified at surgery then a common duct exploration will be performed. ERCP is not recommended in patients who do not have evidence of choledocholithiasis or to define the biliary anatomy for the surgeon. The mortality related to laparoscopic cholecystectomy is 0 to 0.07% 35,36 .The conversion rate to open, which has decreased with more experience, is 2.2% to 5.2%35,37. There are intraoperative complications and postoperative complications. At the time of surgery, there can be bleeding from transection of the superior epigastric artery or its branches, or from the trocar site. Intraperitoneal bile spillage occurs in 30% of cases38-40. There can also be a thermal injury. Postoperatively, patients can develop abdominal pain related to a bile leak from a misplaced clip or bile duct injury. Bile leakage may be treated with ERCP and stent placement allowing bile to preferentially flow into the duodenum. In cases of bile duct transection, surgery may be required. The timing of cholecystectomy for the treatment of acute cholecystitis is controversial. In a recent meta-analysis by Papi et al36, a total of 12 studies were reviewed to determine the appropriate timing of surgery. In this review, early operation, defined
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Figure 2-1. Mirizzi’s
syndrome: Stone in the cystic duct causes extrinsic compression of the main bile duct. (Thanks to Dr. Francis J. Scholz, Lahey Clinic, Burlington, Mass.)
as surgery within 72 hours of admission, did not carry a higher risk of mortality and morbidity compared to delayed operation. About 20% of patients required emergent surgery because of perforation or recurrent symptoms in the delayed group. In critically ill patients at high risk for surgery, percutaneous cholecystostomy and drainage may be performed. This is commonly done using local anesthetic and ultrasound guidance, is technically successful in 98% to 100%, and is effective in 75% to 90%41,42 . Mortality, which may be due to underlying disease, is 20% 42 . Most of these patients will undergo a cholecystectomy when they become medically stable.
Mirizzi’s Syndrome Mirizzi’s syndrome was first described in 1948 as an extrinsic compression of extrahepatic bile duct by an impacted stone in the cystic duct or gallbladder neck causing jaundice. It is rather uncommon—seen in 1% of patients undergoing cholecystectomy. Patients usually present with biliary colic, jaundice, and fever. Abdominal ultrasound can reveal evidence of biliary obstruction. In 1982, McSherry et al43 classified Mirizzi’s syndrome into two types, which is important in terms of surgical management. In type I, there is extrinsic compression of the common hepatic duct. In type II, the calculus erodes through the septum between the cystic and common bile duct leading to a cholecystocholedochal fistula. ERCP can demonstrate the extrinsic compression (Figure 2-1) and a stent can be placed for decompression prior to cholecystectomy.
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In patients with type I, a partial cholecystectomy is effective because of the significant degree of inflammation involving the common bile duct44. A complete cholecystectomy in these patients may lead to a major common bile duct injury. The approach to a patient with type II depends on the size of the fistula. Small fistulas can be treated with partial cholecystectomy and cholecystocholedochoduodenostomy, whereas a larger fistula is better served with a Roux-en-Y hepaticojejunostomy45. Patients with suspected Mirizzi’s syndrome may have associated malignancy as frequently as 27% of cases46.
Biliary-Enteric Fistula Fistulas can occur between the biliary tree and the bowel, skin, blood vessels, or lungs. Fistulas most commonly occur in acute or chronic cholecystitis. Cholecystoenteric fistula occurs when a stone erodes through the gallbladder to the duodenum, stomach, colon, or jejunum. About 75% are cholecystoduodenal fistula47. This occurs in cholecystitis and cholelithiasis. Patients may be asymptomatic and noted to have pneumobilia on a plain abdominal film. In asymptomatic patients, surgery is not needed. If the fistula is symptomatic or discovered intraoperatively, a cholecystectomy with closure of the duodenal defect should be performed. The next most common fistula is a cholecystocolic fistula. Patients usually have a history of biliary colic and present with acute onset of worsening abdominal pain, fever, chills, and possibly steatorrhea. The acute change in abdominal pain is related to the colonic flora being introduced into the biliary tract. The bile is released directly into the colon, which bypasses the usual absorption in ileum, resulting in steatorrhea. A fistula can be demonstrated on a barium enema. A cholecystectomy should be performed. A choledochoduodenal fistula may be caused by perforation of common duct stone or rarely by duodenal peptic ulcer disease and hepatobiliary neoplasms. Patients may complain of several years of peptic ulcer disease. The fistula can be demonstrated with UGI, EGD, or ERCP. Treatment is based on the causative disease. A parapapillary fistula is a subgroup of choledochoduodenal fistula. This occurs in the setting of choledocholithiasis, papillary carcinoma, or postpapillotomy. Treatment is through ERCP. Thoracobiliary and bronchobiliary fistulas are extremely rare but associated with significant morbidity. They are caused by thoracoabdominal trauma, malignancies, liver abscess, parasitic liver disease (eg, echinococcosis, amoebic disease), choledocholithiasis, postoperative biliary stenosis, or rare congenital disorder. These fistulas typically develop from cholangitis that eventually forms an abscess. This abscess ruptures toward the pleural space with progression into the bronchial tree. Patients present with bilitysis (bile pigments in sputum) and have evidence of bronchiolitis. They usually have right upper quadrant pain, pleuritic chest pain, fever, chills, and leukocytosis. Surgery is recommended in congenital cases and acquired cases may respond to stenting. Cholecutaneous fistula rarely occurs because of the early recognition of cholangitis. It occurs more commonly in females in the 5th to 7th decade of life. The opening is in the right upper quadrant or via the falciform ligament at the umbilicus. This fistula is demonstrated through a sonogram or ERCP. Treatment is a cholecystectomy with repair of the fistulous tract.
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Figure 2-2. Gallstone ileus caused by a huge stone having perforated into the colon, obstructing the narrower sigmoid colon. (Thanks to Dr. Jorge Obando, Lahey Clinic, Burlington, Mass.)
Gallstone Ileus Gallstone ileus is a mechanical gallstone obstruction of the bowel that usually occurs in the elderly. A 2- to 2.5-cm gallstone erodes through the gallbladder into the duodenum and becomes lodged within the small bowel usually at the level of the ileocecal valve. Less commonly, a large stone may perforate into the colon and obstruct distally (Figure 2-2). The stone(s) may also become lodged in the duodenum (known as Bouveret’s syndrome48) or at a colonic stricture. The patient presents with typical symptoms of bowel obstruction, ie, abdominal distension, abdominal pain, and vomiting. Occasionally “tumbling obstruction” occurs as the stone intermittently obstructs in progressively narrower small bowel. The diagnosis can be difficult to make and therefore may be delayed. Rigler et al49 described some plain film findings: pneumobilia, bowel obstruction, and visualized stones. These findings can also be seen on a CT scan of the abdomen (see Figure 2-2). On a plain film, air within the gallbladder and duodenum can be noted and is known as Balthazar’s sign50,51. An abdominal ultrasound can sometimes localize the stone within the intestine and document a diseased gallbladder. The treatment depends on the presentation and the comorbidity of the patient. The procedure can be done in a one-step or two-step approach. The one-step is enterotomy with removal of stone including cholecystectomy. The two-step is to remove the stone and then remove the gallbladder at a later date. The mortality is up to 20%52 .
Emphysematous Cholecystitis Emphysematous cholecystitis, reported by May and Strong in 1971, is a form of cholecystitis that results from thrombosis or occlusion of cystic artery with ischemic necrosis of the gallbladder wall53. Gas forming organisms, such as Clostridia, infect
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Figure 2-3. Emphysematous cholecystitis: Gas seen within wall of gallbladder. (Thanks to Dr. Francis J. Scholz, Lahey Clinic, Burlington, Mass.).
the gallbladder wall. Emphysematous cholecystitis more commonly occurs in diabetic, elderly men and may occur in severe acalculous cholecystitis. Clinical presentation is similar to that of severe acute cholecystitis. Air is seen in the right upper quadrant on ultrasound, plain abdominal film, and CT scan (Figure 2-3). Patients should be started on broad-spectrum antibiotics. Early cholecystectomy is required because of the high risk of perforation. Conversion to open cholecystectomy ranges from 40% to 50% in earlier studies54,55. The complication rate is 21% to 27%55,56.
Acute Acalculous Cholecystitis DIAGNOSIS The diagnosis of acute acalculous cholecystitis can be difficult to make because of the lack of specific findings and complexity of affected patients. It is an important diagnosis to make because of its high mortality. Acute acalculous cholecystitis should be suspected in critically ill patients with unexplained fever and hyperamylasemia. A patient with acute acalculous cholecystitis may also have a similar presentation to a patient with calculous cholecystitis. An abdominal ultrasound is a valuable test that can be done at the bedside. Gallbladder wall thickening (>4 mm), presence of pericholecystic fluid, and Murphy’s sign can be seen. The sensitivity ranges from 67% to 92% and specificity is greater than 90%57. A CT scan of abdomen can identify some of the changes in the gallbladder described above and it can also detect other intra-abdominal pathology. CT scan has a very sensitivity and specificity of 100%57. A HIDA scan may not be particularly useful in these patients because of their fasting state. The concentrated, viscous bile within the gallbladder in fasting patients may impede filling of the gallbladder. The administration of morphine sulfate can help reduce the false positive rate58. In acalculous cholecystitis, there can be no cystic duct obstruction so a HIDA scan can have a high false negative rate.
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TREATMENT Early recognition is the most important aspect of treatment given the rapid progression of disease. There is a much higher complication rate and mortality rate associated with acalculous cholecystitis compared with calculous cholecystitis. Broadspectrum antibiotics are used to cover both gram negative and anaerobic organisms. It is also important to correct the hemodynamic instability of the patient. If the patient’s condition allows, the best treatment is laparoscopic cholecystectomy. A less invasive approach would be a percutaneous cholecystostomy tube that can usually be placed at the bedside. A nasobiliary tube placed directly into the gallbladder at the time of ERCP can help decompress the inflamed gallbladder. This method was shown to be effective in a small study of 20 patients59.
Acalculous Biliary Pain Acalculous biliary pain can be difficult to diagnose. Patients usually present with biliary colic but no gallstones are detected. If there is a high clinical suspicion, a HIDA scan is performed. Delayed gallbladder emptying, as defined as an ejection fraction of less than 35%, can represent acalculous biliary pain. Caulfield et al reviewed multiple studies that demonstrate that symptomatic patients with an ejection fraction of less than 50% have a 97% improvement or complete resolution of symptoms after a cholecystectomy60. The resected gallbladder usually shows evidence of chronic cholecystitis 61.
Gallbladder Polyps DIAGNOSIS The majority of polyps are found incidentally on abdominal ultrasound as nonmobile filling defects (Figure 2-4). These polyps range from a few millimeters to 2 cm in size and can be single or multiple. Adenomas and adenomyomas of the gallbladder have malignant potential. The majority of gallbladder polyps are cholesterol based and have no malignant potential but can become quite large. With imaging modalities it can be difficult to determine the type of polyp, and therefore its malignant potential. Symptomatic polyps or polyps greater than 1.5 cm usually require surgery because of high malignant potential. Endoscopic ultrasound (EUS) can be used to further define polyps. In a study comparing polyps less than 20 mm using transabdominal ultrasound and endoscopic ultrasound, EUS faired better in determining cancer. Sensitivity of EUS is 91.7% compared with 54.2% for abdominal ultrasound62 . Size, number, shape, and echogenecity of the polyp have been studied and can be used to determine the risk of developing cancer. Polyps less than 10 mm have a 0 to 5% chance, polyps ranging from 10 to 15 mm a 11% to 13% chance, and polyps greater than 15 mm have about 46% to 70% chance of being malignant. Solitary polyps and sessile polyps have a higher risk of being malignant. With ultrasound evaluation, polyps that are isoechoic with the liver parenchyma have a tendency to be a cancer63.
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Figure 2-4. Large gallbladder polyp
seen on ultrasound. (Thanks to Dr. Francis J. Scholz, Lahey Clinic, Burlington, Mass.)
TREATMENT The introduction of laparoscopic cholecystectomy has made the decision to operate easier. It is generally recommended that patients that have gallbladder polyps and are symptomatic or patients with polyps that are greater than 15 mm should have surgery.
Gallbladder Cancer DIAGNOSIS Abdominal pain is a common presentation of gallbladder carcinoma. The pain is usually similar to that of biliary colic or acute cholecystitis. Some patients have nausea, weight loss, or anorexia. Jaundice occurs in less than 50% of patients. Patients may also present with ascites, palpable mass in right upper quadrant, and hepatomegaly. Laboratory investigations are usually not helpful because they are nonspecific. The liver profile can reflect biliary obstruction with elevated alkaline phosphatase and bilirubin. Some tumor markers, CEA, AFP, and human choriogonadotropic hormone may be elevated. The tumor markers are more helpful to follow progress of the disease. There is no ideal imaging modality to diagnose gallbladder cancer. A transabdominal ultrasound is a common modality to investigate biliary colic, right upper quadrant pain, and gallbladder pathology. Most patients will have gallstones 64. CT is useful to evaluate local spread of disease and to detect liver metastases. The introduction of endoscopic ultrasound has improved the staging of gallbladder cancer. Endoscopic ultrasound can further investigate the wall of the gallbladder. A study by Azuma et al62 showed that EUS correctly diagnosed gallbladder cancer (86.5%) compared with abdominal ultrasound (51.7%). Larger studies are needed to determine the usefulness of EUS in gallbladder cancer. A small study of six patients underwent fine needle aspiration of a gallbladder mass and lymphadenopathy65. The technique proved to be possible and safe. Aspiration of the gallbladder and lymphadenopathy may be able to improve the accuracy of EUS.
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CT scan and MRI can also help diagnose gallbladder cancer and determine the presence of gallbladder disease. CT scan of the abdomen can also identify a mass within or replacing the gallbladder. It is particularly useful for staging of the disease because it can detect liver involvement or significant lymphadenopathy. Angiography can detect tumor vessels in gallbladder wall and encasement of other vessels, such as portal vein. It is the most specific and reliable tool to stage gallbladder cancer66. Cholangiogram during the time of an ERCP can be helpful to relieve the obstruction but can also be diagnostic. The cholangiogram can reveal a stricture at the common hepatic duct. There may be failure to fill the gallbladder.
TREATMENT Gallbladder cancer is detected in about 1% of gallbladder surgeries 67. The extent of surgery depends on the general health of the patient along with the extent of the tumor. About 70% of patients are unresectable at the time of diagnosis. In carcinoma in situ or a T1 tumor, cholecystectomy is appropriate. This is the typical presentation with incidental carcinoma and reoperation does not have to occur. If cancer is detected perioperatively, then an open extended cholecystectomy is usually performed. This includes a hepatic resection as well as lymph node dissection. This aggressive surgery can improve survival68. If the pancreas or duodenum are involved, a hepatopancreatoduodenectomy may be performed. In many cases, palliative therapy is the only option because of the delayed presentation and overall poor prognosis. Biliary stenting with metal stents can relieve biliary obstruction. Radiation or celiac ganglion nerve block may be considered for pain relief. Roux-en-Y choledochojejunostomy can help to relieve obstruction. Chemotherapy has a poor response. About 10% to 20% response rate is seen with mitomycin and 5-FU69. There is no improvement in survival with radiation.
SURVIVAL The 5-year survival rate is less than 5% in most cases because of late presentation. If the cancer is found incidentally, survival significantly improves. For stage I tumors, the 5-year survival is 60%. For patients with stage II, the 5-year survival rate is 24% but this can improve close to 60% if these patients undergo an extended cholecystectomy. For stage III and stage IV, the 5-year survival rate is 9% and 1%, respectively 70,71.
Porcelain Gallbladder Porcelain gallbladder is a gallbladder with calcification of the wall. It may present with right upper pain or be asymptomatic. The diagnosis can be made with a plain film of the abdomen, a right upper quadrant ultrasound, or a CT scan of the abdomen (Figure 2-5). The significance of porcelain gallbladder is its association with gallbladder adenocarcinoma. About 20% of gallbladders with calcification will contain a malignancy 72,73. The resection of a calcified gallbladder is usually done through an open approach, but in cases with a patent cystic duct and uncalcified gallbladder neck, laparoscopic cholecystectomy has been successful74.
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Figure 2-5. Porcelain gallbladder: Plain film demonstrating the calcified gallbladder. (Thanks to Dr. Francis J. Scholz, Lahey Clinic, Burlington, Mass.)
Summary Gallstones are very common in the population, but the majority are asymptomatic. If a stone becomes dislodged, then problems can occur, which include cholecystitis, cholangitis, fistula formation, or Mirizzi's syndrome. In certain situations, the gallbladder can become inflamed in the absence of stones. The main modality of treatment for gallbladder disease is a cholecystectomy. In the future, emphasis should be placed on the prevention of gallstone disease and improvement of the medical management of gallstones.
References 1. Mok HYI, Druffel ERM, Rampone WM. Dating gallstones from atmospheric radiocarbon produced by nuclear bomb explosions. N Engl J Med. 1986;314:1075-1077. 2. Gracie WA, Ransohoff DF. The natural history of silent gallstones: The innocent gallstone is not a myth. N Engl J Med. 1982;307:798-800. 3. Grundy SM, Metzger AL, Adler RD. Mechanisms of lithogenic bile formation in American Indian women with cholesterol gallstones. J Clin Invest. 1972;51:30263043.
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4. Corradini AG, Elisei W, Giovannelli L, et al. Impaired human gallbladder lipid absorption in cholesterol gallstone disease and its effect on cholesterol solubility in bile. Gastroenterology. 2000;118:912-920. 5. Jazrawi RP, Pazzi P, Petroni ML, et al. Postprandial gallbladder motor function: Refilling and turnover of bile in health and in cholelithiasis. Gastroenterology. 1995;109:582-591. 6. Chen Q, Amaral J, Biancani P, Behar J. Excess membrane cholesterol alters human gallbladder muscle contractility and membrane fluidity. Gastroenterology. 1999;116:678-685. 7. LaMont JT, Carey MC. Cholesterol gallstone formation, 2: pathobiology and pathomechanics. Prog Liver Disease. 1992;10:165-191. 8. Nunes DP, Afdhal NH, Offner GD. A recombinant bovine gallbladder mucin polypeptide binds biliary lipids and accelerates cholesterol crystal appearance time. Gastroenterology. 1999;116:936-942. 9. Miquel JF, Nunez L, Amigo L, et al. Cholesterol saturation, not proteins or cholecystitis, is critical for crystal formation in human gallbladder bile. Gastroenterology. 1998;114:1016-1023. 10. Everhart JE, Khare M, Hill M, Maurer KR. Prevalence and ethnic differences in gallbladder disease in the United States. Gastroenterology. 1999;117:632-639. 11. Miquel JF, Covarrubias C, Villaroel L, et al. Genetic epidemiology of cholesterol cholelithiasis among Chilean Hispanics, Amerindians, and Maoris. Gastroenterology. 1998;115:937-946. 12. Rosmorduc O, Hermelin B, Poupon R. MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis. Gastroenterology. 2001;120:1459-1467. 13. Lammert F, Carey MC, Paigen B. Chromosomal organization of candidate genes involved in cholesterol gallstone formation: A murine gallstone map. Gastroenterology. 2001;120:221-238. 14. Everhart J. Contributions of obesity and weight loss to gallstone disease. Ann Intern Med. 1993;119:1029-1035. 15. Leitzman MF, Rimm EB, Willett WC, et al. Recreational physical activity and risk of cholecystectomy in women. N Engl J Med. 1999;341:777-84. 16. Beilstein MC, Ahmad NA, Ginsberg GG, et al. Gilbert’s syndrome and choledocholithiasis. Gastroenterology. 2004;126:A232. 17. Lee SP, Nichols JF. Nature and composition of biliary sludge. Gastroenterology. 1986; 90:677-686. 18. Ostrow JD. The etiology of pigment gallstones. Hepatology. 1984;4:215S-222S. 19. Brink MA, Slors JFS, Keulemans YCA, et al. Enterohepatic cycling of bilirubin: A putative mechanism for pigment gallstone formation in ileal Crohn’s disease. Gastroenterology. 1999;116:1420-1427. 20. Cariati A, Cetta F. Rokitansky-Aschoff sinuses of the gallbladder are associated with black pigment gallstone formation: a scanning electron microscopy study. Ultrastructural Pathology. 2003;27:265-270. 21. Akiyoshi T, Nakayama F. Bile acid composition in brown pigment stones. Dig Dis Sci. 1990;35:27-32. 22. Xiao ZL, Biancani BP, Carey MC, Behar J. Hydrophilic but not hydrophobic bile acids prevent gallbladder muscle dysfunction in acute cholecystitis. Hepatology. 2003; 37:1442-1450.
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23. Ryu JK, Ryu KH, Kim KH. Clinical features of acute acalculous cholecystitis. J Clin Gastroenterol. 2003;36:166-169. 24. Amaral J, Xiao Z, Chen Q, Yu P, Biancani P, Behar J. Gallbladder muscle dysfunction in patients with chronic acalculous disease. Gastroenterology. 2001;120:506-511. 25. Sessa F, Furlan D, Genasetti A, Billo P, Feltri M, Capella C. Microsatellite instability and p53 expression in gallbladder carcinomas. Diagn Mol Pathol. 2003; 12:96-102. 26. Senior JR, Johnson MF, DeTurck DM, et al. In vivo kinetics of radiolucent gallstone dissolution by oral dihydroxy bile acids. Gastroenterology. 1990;99:243. 27. Roda E, Festi D, Lezoche E, et al. Strategies in the treatment of biliary stones. Gastroenterol Int. 2000;13:7. 28. May GR, Sutherland LR, Shaffer EA. Efficacy of bile acid therapy for gallstone dissolution: A meta-analysis of randomized trials. Aliment Pharmacol Ther. 1993;7:139. 29. Tomida S, Abei M, Yamaguchi T, et al. Long-term ursodeoxycholic acid therapy is associated with reduced risk of biliary pain and acute cholecystitis in patients with gallbladder stones: A cohort analysis. Hepatology. 1999;30:6. 30. Schoenfield LJ, Berci G, Carnovale RL, et al. The effect of ursodiol on the efficacy and safety of extracorporeal shock-wave lithotripsy of gallbladder stones. The Dornier National Biliary Lithotripsy Study. N Engl J Med. 1990;323:1239. 31. Sackmann M, Pauletzki J, Sauerbruch T, et al. The Munich Gallbladder Lithotripsy Study: Results of the first 5 years with 711 patients. Ann Intern Med. 1991;114:290. 32. Ralls PW, Colletti PM, Lapin SA, et al. Real-time sonography in suspected acute cholecystitis. Radiology. 1985;155:767. 33. Kalimi R, Gecelter G, Caplin D, et al. Diagnosis of acute cholecystitis: Sensitivity of sonography, cholescintigraphy, and combined sonography-cholescintigraphy. J Am Coll Surg. 2001;193:609-613. 34. Clair DG, Carr-Locke DL, Becker JM, et al. Routine cholangiography is not warranted during laparoscopic cholecystectomy. Arch Surg. 1993;128:551-554. 35. MacFadyen BV Jr , Vecchio R, Ricardo AE, Mathis CR. Bile duct injury after laparoscopic cholecystectomy. The United States experience. Surg Endosc. 1998;12:315-321. 36. Papi C, Catarci M, D’Ambrosio L, et al. Timing of cholecystectomy for acute calculous cholecystitis: A meta-analysis. Am J Gastroenterol. 2004;99:147-155. 37. Bingener-Casey J, Richards ML, Strodel WE, et al. Reasons for conversion from laparoscopic to open cholecystectomy: a 10-year review. J Gastrointest Surg. 2002;6:800-805. 38. Assaff Y, Matter I, Sabo E, et al. Laparoscopic cholecystectomy for acute cholecystitis and the consequences of gallbladder perforation, bile spillage, and “loss” of stones. Eur J Surg. 1998;164:425-431. 39. Kimura T, Goto H, Takeuchi Y, et al. Intraabdominal contamination after gallbladder perforation during laparoscopic cholecystectomy and its complications. Surg Endosc. 1996;10:888-891. 40. Soper NJ, Dunnegan DL. Does intraoperative gallbladder perforation influence the early outcome of laparoscopic cholecystectomy? Surg Laparosc Endosc. 1991;1:156161. 41. Spira RM, Nissan A, Zamir O, et al. Percutaneous transhepatic cholecystostomy and delayed laparoscopic cholecystectomy in critically ill patients with acute calculous cholecystitis. Am J Surg. 2002;183:62-66.
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42. Byrne M, Suhocki P, Mitchell R, et al. Percutaneous cholecystostomy in patients with acute cholecystitis: experience of 45 patients at a US referral center. J Am Coll Surg. 2003;197:206-211. 43. McSherry CK, Ferstenberg H, Virshup M. The Mirizzi’s syndrome: Suggested classification and surgical therapy. Surg Gastroenterol. 1982;1:219-225. 44. Cottier DJ, McKay C, Anderson JR. Subtotal cholecystectomy. Br J Surg. 1991;78:13261328. 45. Karademir S, Astarcioglu H, Sokmen S, et al. Mirizzi’s syndrome: Diagnostic and surgical considerations in 25 patients. J Hepatobiliary Pancreat Surg. 2000;7:72-77. 46. Redaelli CA, Buchler MW, Schilling MK, et al. High coincidence of Mirizzi’s syndrome and gallbladder carcinoma. Surgery. 1997;121:58-63. 47. Morrissey K, McSherry C. Internal biliary fistula and gallstone ileus. In: Surgery of the Liver and Biliary Tree. Philadelphia: Churchill-Livingstone; 1994:909-922. 48. Bouveret L. Sténose du pylore adhérent à la vésicule. Rev Méd (Paris). 1896;16:1-16. 49. Rigler L, Borman C, Noble J. Gallstone obstruction: pathogenesis and roentgen manifestations. JAMA. 1941;117:1753-1759. 50. Balthazar EJ, Schechter LS. Gallstone ileus. The importance of contrast examinations in the roentgenographic diagnosis. AJR Am J Roentgenol. 1975;125:374-379. 51. Balthazar EJ, Schechter LS. Air in gallbladder: a frequent finding in gallstone ileus. AJR Am J Roentgenol. 1978;131:219-222. 52. Svartholm E, Andren-Sandberg A, Evander A, et al. Diagnosis and treatment of the gallstone ileus. Report of 83 cases. Acta Chir Scand. 1982;148:435-438. 53. May RE, Strong R. Acute emphysematous cholecystitis. Br J Surg. 1975;58:453458. 54. Eldar S, Sabo E, Nash E, et al. Laparoscopic cholecystectomy for the various types of gallbladder inflammation: a prospective trial. Surg Laparosc Endosc. 1998;8:200207. 55. Eldar S, Sabo E, Nash E, et al. Laparoscopic vs open cholecystectomy for acute cholecystitis. Surg Laparosc Endosc. 1997;7:407-414. 56. Eldar S, Sabo E, Nash E, et al. Laparoscopic cholecystectomy for acute cholecystitis: prospective trial. World J Surg. 1997;21:540-554. 57. Mirvis SE, Vainright JR, Nelson AW, et al. The diagnosis of acute acalculous cholecystitis: A comparison of sonography, scintigraphy, and CT. AJR Am J Roentgenol. 1986;147:1171. 58. Flancbaum L, Choban PS, Sinha R, Jonasson O. Morphine cholescintigraphy in the evaluation of hospitalized patients with suspected acute cholecystitis. Ann Surg. 1994;220:25. 59. Brugge WR, Friedman LS: A new endoscopic procedure provides insight into an old disease: Acute acalculous cholecystitis. Gastroenterology. 1994;106:1718. 60. Canfield AJ, Hetz SP, Schriver JP, et al. Biliary duskiness: A study of more than 200 patients and review of the literature. J Gastrointestinal Surg. 1998;2:443-448. 61. Poynter MT, Saba AK, Evans RA, et al. Chronic acalculous biliary disease: cholecystokinin cholescintigraphy is useful in formulating treatment strategy and predicting success after cholecystectomy. Am Surg. 2002;68(4):382-4. 62. Azuma T, Yoshikawa T, Araida T, et al. Differential diagnosis of polypoid lesions of the gallbladder by endoscopic ultrasonography. Am J Surg. 2001;181:65-70. 63. Sugiyama M, Atomi Y, Kuroda A, et al. Large cholesterol polyps of the gallbladder: Diagnosis by means of US and endoscopic US. Radiology. 1995;196:493-7.
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64. Khan ZR, Neugut AI, Ahsan H, Chabot JA. Risk factors for biliary tract cancers. Am J Gastroenterol. 1999;94:149-152. 65. Jacobson BC, Pitman MB, Brugge WR. EUS-guided FNA for the diagnosis of gallbladder masses. Gastrointest Endosc. 2003;57(2):251-254. 66. Rosch J, Grollman JH, Jr, Steckel RJ. Arteriography in the diagnosis of gallbladder disease. Radiology. 1969;92(7):1485-1491. 67. Wanebo HJ, Vezeridis MP. Carcinoma of the gallbladder. J Surg Oncol. 1993;3(Suppl):134-139. 68. Taner CB, Nagorney DM, Donohue JH. Surgical treatment of gallbladder cancer. J Gastrointest Surg. 2004;8:83-89. 69. Falkson G, MacIntyre JM, Moertel CG. Eastern Cooperative Oncology Group experience with chemotherapy for inoperable gallbladder and bile duct cancer. Cancer. 1984;54:965-969. 70. American Joint Committee on Cancer. Manual of Staging of Cancer. 4th ed. Philadelphia: Lippincott-Raven; 1992. 71. Chijiiwa K, Tanaka M. Carcinoma of the gallbladder: An appraisal of surgical resection. Surgery. 1994;115:751-756. 72. Ashur H, Siegal B, Oland Y, et al. Calcified gallbladder (porcelain gallbladder). Arch Surg. 1978;113:594-596. 73. Shimizu M, Miura J, Tanaka T, et al. Porcelain gallbladder. Relation between its type by ultrasound and incidence of cancer. J Clin Gastroenterol. 1989;11:471-6. 74. Kuroki T, Tajima Y, Matsuzaki S. Pre- and intraoperative evaluation of biliary system for successful laparoscopic cholecystectomy in porcelain gallbladder patients. Hepatogastroenterology. 2002;49:621-624.
chapter
3
Choledocholithiasis Eric Goldberg, MD; Peter Darwin, MD
Epidemiology of Choledocholithiasis Gallstone disease is extremely prevalent in the United States. More than 6 million men and 14 million women aged 20 to 74 have gallbladder disease, and 8.7 million Americans have undergone cholecystectomy1. The annual cost of this common digestive ailment exceeds 6 billion dollars per year 2. Choledocholithiasis, defined as the presence of gallstones in the common bile duct, is seen in up to 15% of patients with gallbladder stones2 . The majority of patients with choledocholithiasis have secondary stones, which are stones that have originated within the gallbladder. Primary common bile duct stones are rare in the United States but are seen commonly in patients of Asian descent. Because the majority of stones originate within the gallbladder, the pathogenesis of choledocholithiasis is similar to the pathogenesis of cholelithiasis (Chapter 2) and is covered only to a limited extent here.
Pathogenesis of Cholesterol Stones The major constituents of bile are cholesterol, bile acids, phospholipids, and bilirubin. Cholesterol is hydrophobic and is therefore insoluble in water. However, bile acids are able to solubulize cholesterol through the formation of mixed micelles3. Phospholipids are also able to solubulize cholesterol through the formation of vesicles4. The initial step in cholesterol gallstone formation is the production of lithogenic bile (Figure 3-1). Lithogenic bile occurs when bile becomes supersaturated with cholesterol. Although production of lithogenic bile via cholesterol supersaturation is the precipitating event in cholesterol gallstone formation, additional pathogenic mechanisms must be present for stones to develop. Nucleation is the process by which cholesterol in supersaturated bile aggregates to form solid crystals. Cholesterol crystals form from aggregation of vesicular cholesterol5. The higher the proportion of cholesterol to phospholipid within vesicles, the more readily nucleation occurs 6. The gallbladder
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Estrogen Replacement Therapy
Obesity
Cholesterol Supersaturation
Pregnancy
Gallstones
Progesterone
Oral Contraception
Nucleation
Gallbladder Hypomotility
Ceftriaxone
TPN
Octreotide
Figure 3-1. Pathogenesis mechanisms involved in cholesterol gallstone formation. milieu is also important in the pathogenesis of cholesterol gallstones. Concentration of bile within the gallbladder increases cholesterol to phospholipid ratios within cholesterol vesicles. This enhances the nucleation process within the gallbladder when compared to the biliary and hepatic ducts7. This may help explain why secondary bile duct stones are much more common than primary bile duct stones. Gallbladder stasis plays a crucial role in the formation of gallstones by allowing crystals to aggregate into larger stones.
Pathogenesis of Pigmented Stones Black pigmented stones result from increased excretion of bilirubin and may be seen in patients with chronic hemolytic diseases, vascular prostheses, and cirrhosis. The major component of black pigmented stones is bilirubin, but they also contain varying amounts of calcium salts, glycoproteins, and mucin8. Bilirubin is also the major constituent of brown pigmented stones. Brown pigmented stones are strongly associated with bile chronically infected by bacteria. Bacteria, such as Eschericha coli, use the enzyme B-glucuronidase to hydrolyze conjugated bilirubin into insoluble bilirubin salts. Similar to cholesterol stones, gallbladder function contributes to pigmented stone formation. Gallbladder hypomotility, precipitation of insoluble calcium salts, and secretion of mucin and glycoproteins all contribute to lithogenesis.
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Secondary Bile Duct Stones Choledocholithiasis is found in 8% to 18% of all patients with symptomatic gallstones2 . In the Western hemisphere, most common bile duct stones are secondary stones and composed primarily of cholesterol9. Two facts strongly support the theory that most stones in the common bile duct originate in the gallbladder. First, stones that are recovered from the gallbladder are similar in composition to stones recovered from the common bile duct in patients undergoing cholecystectomy and common bile duct exploration. Second, more than 80% of patients who have common bile duct stones also have concomitant gallbladder stones10.
Primary Bile Duct Stones Although most stones that form in the gallbladder are composed predominantly of cholesterol, primary bile duct stones are typically pigmented. Factors that lead to their formation include biliary stasis, biliary infection, and the presence of periampullary diverticula. The role of infection in the pathogenesis of primary common bile duct stones has been investigated through cultures of stones recovered from the common bile duct. In one investigation, 100% of brown pigmented stones and 74% of cholesterol stones recovered from the common bile duct were culture positive11. Gram-negative enteric organisms were among the most frequently cultured organisms. Periampullary diverticula may predispose patients to the formation of primary duct stones. In one study, 88% of patients with periampullary diverticula had recurrent common bile duct stones following cholecystectomy compared with 32% of patients without periampullary diverticula12 . One potential explanation is that colonization of the periampullary diverticulum by bacteria leads to chronic biliary infection. Some reports suggest that a low cystic duct insertion may also predispose patients to developing primary bile duct stones13.
Hepatolithiasis (Intrahepatic Duct Stones) Hepatolithiasis refers to stones that occur proximal to the common hepatic duct. The prevalence of hepatolithiasis is much higher in Southeast Asia than the Western hemisphere. In the Swedish population, a necropsy study showed a prevalence of .6%14. In Southeast Asia, the overall prevalence is 10%15. Parasitic infection of the biliary tree by Clonorchis sinensis and Ascaris species may play a role in the pathogenesis of hepatolithiasis16. However, not all patients with hepatolithiasis have evidence of biliary parasitic infestation, and not all patients with infection develop intrahepatic stones. Therefore, other pathogenic mechanisms such as diet, biliary stasis, and genetics are likely involved.
Microlithiasis and Biliary Sludge Biliary sludge, also known as microlithiasis, is a viscous suspension of biliary fluid containing crystals and small stones. The pathogenesis, etiology, clinical presentation, complications, and management of sludge in the common bile duct is nearly identical to that of true choledocholithiasis. Therefore, biliary sludge in the common bile duct should be considered as a form of choledocholithiasis.
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Risk Factors for Choledocholithiasis In the United States, most common bile duct stones are cholesterol stones that originate from the gallbladder. Therefore, the risk factors for choledocholithiasis mirror the risk factors for cholelithiasis (see Chapter 2). Specific risk factors for increased likelihood of choledocolithiasis include concurrence of juxta-ampullary diverticulum, dilated common bile duct, and history of choledocolithiasis.
Clinical Manifestations Choledocholithiasis may come to clinical attention in a variety of ways. First, it may present with symptoms such as biliary colic and jaundice. Second, it may present with complications including acute pancreatitis, ascending cholangitis, and secondary biliary cirrhosis. Third, patients with choledocholithiasis may have incidentally discovered abnormalities on laboratory or imaging studies. Finally, some patients with choledocholithiasis remain asymptomatic and never present to their clinician. Although the natural history of cholelithiasis has been well established, the natural history of choledocholithiasis is less clear. Older studies suggest that more than 50% of patients with asymptomatic choledocholithiasis will develop symptoms or complications over a 13-year period 23. In a recent review of patients with choledocholithiasis discovered at the time of laparoscopic cholecystectomy, 35% of patients spontaneously passed their common bile duct stones without significant complications by 6 weeks24.
BILIARY PAIN The pain caused by choledocholithiasis is nearly indistinguishable from classic biliary pain caused by stones intermittently obstructing the cystic duct. Biliary pain is often erroneously named “biliary colic” but it is not colicky. It is a constant pain that may last for hours. Biliary pain is typically felt in the right upper quadrant or epigastrium, and may radiate to the right shoulder or interscapular area. It is often associated with nausea and vomiting. Biliary pain in the setting of choledocholithiasis is secondary to the sudden obstruction of the common bile duct, resulting in increased luminal pressure and distention of the common bile duct. Although malignant biliary obstruction results in similar ductal distention, the gradual onset of the obstruction renders it less likely to produce pain.
JAUNDICE When common bile duct stones partially or completely obstruct the flow of bile, jaundice ensues. Cystic duct obstruction typically does not cause jaundice (exception in Mirizzi syndrome—see below). Therefore, when a patient with cholelithiasis presents with biliary colic and jaundice, there should be strong clinical suspicion of a concomitant bile duct stone.
ASCENDING CHOLANGITIS Bile in healthy subjects is sterile. However, in patients with choledocholithiasis, bacterial colonization of common duct calculi occurs. In one review, bacteria were
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found in the bile of 58% of patients with common bile duct stones25. Translocation of enteric organisms across the sphincter of Oddi into stagnant bile is the major mechanism of bacterial entry into the biliary system. Ascending cholangitis is a potentially life-threatening bacterial infection of the biliary tree. Charcot’s triad of fever, biliary pain, and jaundice signifies the presence of ascending cholangitis. However, this triad is present in only one half of patients with ascending cholangitis. When sepsis ensues, patients may develop hypotension and altered mental status. These findings together with Charcot’s triad are referred to as Reynold’s pentad. Most commonly, the bacteria causing cholangitis are enteric in origin including Escherichia coli, Klebsiella species, and Enterococcus species. Anaerobic bacteria such as Bacteroides species have also been implicated.
SECONDARY BILIARY CIRRHOSIS Prolonged extrahepatic biliary obstruction from choledocholithiasis can result in the development of cirrhosis. The duration and extent of the obstruction are the major factors determining the likelihood of developing secondary biliary cirrhosis. On average, secondary biliary cirrhosis develops after the common bile duct has been obstructed for more than 5 years26.
GALLSTONE PANCREATITIS Gallstones are the most common cause of acute pancreatitis in the United States. Acute pancreatitis results when gallstones temporarily obstruct the Ampulla of Vater either by impaction or passage through the ampulla. The exact mechanism by which gallstones cause pancreatitis remains unclear. Reflux of bile into the pancreatic duct may contribute, in addition to mechanical ampullary obstruction from stones or edema 27. Analysis of medical records of 2,583 patients with gallstones from Rochester, Minnesota demonstrates that 3% of patients with cholelithiasis develop acute gallstone pancreatitis. For patients with cholelithiasis, the relative risk of acute pancreatitis was 12 to 25 times in women and 14 to 35 times in men. After cholecystectomy, the relative risk of pancreatitis decreased in both genders to less than two times28. Although the incidence of gallstone pancreatitis in patients with choledocholithiasis has not been thoroughly analyzed, it is likely much higher than seen with simple cholelithiasis alone. Smaller stones (<0.5 cm) may be more prone to causing acute pancreatitis than larger stones. Larger stones are less likely to pass from the gallbladder into the common bile duct and therefore, less likely to cause pancreatitis. Biliary sludge may also trigger acute pancreatitis. In one review, 74% of patients labeled as having idiopathic pancreatitis were found to have evidence of either biliary sludge or biliary crystals (microlithiasis) 29. Furthermore, cholecystectomy in patients with biliary sludge or microlithiasis has been shown to decrease the recurrence of pancreatitis30.
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Diagnosis LABORATORY TESTING The typical laboratory abnormalities that are encountered in patients with choledocholithiasis include cholestatic elevation of bilirubin and alkaline phosphate. Rarely will the bilirubin rise greater than 10 mg/dL for a simple common duct stone. Significant elevation of transaminases may be seen, often noted in conjunction with an elevated amylase and lipase from the passage of a small stone. However, AST and ALT rarely are higher than 1000. Choledocholithiasis may also present with normal liver function tests (LFTs). The cholestatic pattern of LFT abnormalities is not specific for common bile duct (CBD) stones, and therefore confirmatory tests are required.
ULTRASONOGRAPHY Extracorporal ultrasonography is widely used for the diagnosis of hepatobiliary disease. As it is safe, well-tolerated and relatively inexpensive, it is often the initial test performed when symptomatic gallstone disease is suspected. Sonography is the method of choice for imaging the gallbladder and is highly reliable for detecting small gallstones and ductal dilation31. However, the sensitivity in detecting common bile duct stones is low. Although a few studies have reported sensitivities as high as 80%, most reports note detection rates of less than 50% for common bile duct stones32 . As choledocholithiasis may occur in normal size bile ducts and without stones in the gallbladder, biliary ultrasound is not reliable for the definitive exclusion of common bile duct stones.
COMPUTED TOMOGRAPHY Standard computed tomography (CT) scanning has been shown to have better sensitivity than ultrasound for the diagnosis of choledocholithiasis33. However, most gallstones are not radio-opaque, and can be difficult to detect with conventional CT. Helical CT without contrast has been reported to have better sensitivity than conventional CT, and may be a reasonable screening technique in patients with suspected common bile duct stones. Oral contrast-enhanced CT cholangiography is a promising technique for the diagnosis of CBD stones, with a sensitivity significantly higher than helical CT34. Despite the increased ability of helical CT to detect CBD stones compared to US, helical CT lacks sufficient sensitivity to definitively exclude the diagnosis in patients who have a high pretest probability of having CBD stones.
RISK STRATIFICATION Following clinical evaluation, initial imaging, and laboratory studies, patients should be stratified into risk groups to determine the need for further diagnostic or therapeutic interventions. Three different risk groups have been suggested 35.
• Low risk patients: Normal LFTs and normal bile duct size on imaging. • Intermediate risk patients: History of cholangitis or biliary pancreatitis, and/or unexplained LFT abnormalities (alkaline phosphates <2x normal or elevated transaminases), and/or moderate bile duct dilation (8 to 10 mm in diameter).
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Figure 3-2. Magnetic reso-
nance cholangiopancreatogram demonstrating a large stone in the distal common bile duct.
• High risk patients: Recent episode of cholangitis or biliary pancreatitis, jaundice, alkaline phosphates >2x normal, and a dilated bile duct (>10 mm in diameter).
MAGNETIC RESONANCE CHOLANGIOPANCREATOGRAPHY Magnetic resonance cholangiopancreatography (MRCP) is a noninvasive modality designed specifically to image the biliary and pancreatic ducts (Figure 3-2). MRCP uses a T2 weighted sequence allowing visualization of static fluid in the ducts. The risks and complications are negligible when compared with invasive imaging modalities such as endoscopic retrograde cholangiopancreatography (ERCP). There is extensive literature with MRCP for the diagnosis of common bile duct stones. The sensitivity and specificity for choledocholithiasis are reported to be well over 90%36. Small stones, impacted distal stones, and sludge may be missed. As this test has a significantly higher sensitivity than both ultrasound and CT, it should be considered when there is a low to intermediate clinical suspicion for a common duct stone. Patients with a high clinical suspicion for a common bile duct stone should proceed directly to ERCP, as a therapeutic intervention will likely be required.
HEPATOBILIARY IMINODIACETIC ACID (HIDA) CHOLESCINTIGRAPHY Technetium-HIDA is primarily used to exclude cystic duct obstruction in patients with suspected acute cholecystitis. However, findings on HIDA scanning may also suggest the presence of choledocholithiasis. These include absent or delayed bowel visualization and prominent bile ducts. Occasionally, HIDA scanning may show abnormalities suggestive of choledocholithiasis in patients with normal ultrasound studies37. Because other noninvasive imaging studies, such as MRCP, have superior sensitivity to HIDA scanning, HIDA scanning has a limited role in the routine diagnosis of choledocholithiasis.
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Figure 3-3. Endoscopic
retrograde cholangiogram showing multiple filling defects within a moderately dilated common bile duct.
PERCUTANEOUS TRANSHEPATIC CHOLANGIOGRAPHY Percutaneous transhepatic cholangiography (PTC) is an invasive imaging technique in which contrast is injected into a catheter that has been percutaneously inserted into a dilated intrahepatic duct. A percutaneous cholangiogram has both diagnostic and therapeutic applications. However, management of choledocholithiasis by means of PTC requires time to have the percutaneous tract dilated and matured. Therefore, multiple sessions are required. The ability for single-step intervention by ERCP has limited PTC in most centers to those patients with altered surgical anatomy or a failed endoscopic approach. Local expertise dictates the role for interventional radiology in the diagnosis and management of common bile duct stones.
ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY ERCP is the gold standard test for the diagnosis of choledocholithiasis to which all other imaging modalities are compared (Figure 3-3). The sensitivity and specificity of ERCP for choledocholithiasis exceed 90%. Although the diagnostic and therapeutic applications of ERCP are well documented, the indications for this test as a diagnostic modality are evolving. The sensitivity and specificity of MRCP and endoscopic ultrasonography (EUS) for the diagnosis of CBD stones are comparable to that of ERCP, without the risk for major complications, notably acute pancreatitis. With the widespread availability of MRCP and EUS, the need for diagnostic ERCP to exclude a common bile duct stone has decreased. For patients with a high clinical suspicion of choledocholithiasis, ERCP should clearly be the first line test because therapeutic interventions are likely to be required in this group of patients.
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ENDOSCOPIC ULTRASONOGRAPHY EUS allows the ultrasound transducer to be positioned in the duodenum for optimum visualization of the bile duct. The specificity of EUS has been shown to be superior to both ultrasound and CT for the diagnosis of choledocholithiasis38. Preliminary studies have also shown the diagnostic accuracy of EUS to be superior to MRCP and even ERCP in the evaluation of common bile duct stones35,39. EUS is currently being evaluated for the diagnosis of common bile duct stones in patients with a low to intermediate clinical suspicion of a stone. These situations include exclusion of common duct stones prior to laproscopic cholecystectomy or in patients who have recovered from gallstone pancreatitis. Because EUS offers a highly accurate test with few complications and avoids the need for fluoroscopy, its role is also being evaluated in pregnant patients. However, EUS does require sedation and has no therapeutic capability. The limited availability outside academic centers makes general recommendations difficult. The ideal setting for this modality is EUS coupled with same-setting therapeutic ERCP if common duct stones are seen.
INTRAOPERATIVE CHOLANGIOGRAPHY Intraoperative cholangiography (IOC) may be performed during cholecystectomy to exclude CBD stones40. If CBD stones are discovered, surgical removal should be considered. Alternatively, the patient can be referred for ERCP post cholecystectomy. For patients with a low to intermediate clinical suspicion of common duct stones, IOC is a cost-effective diagnostic technique with little added risk.
Endoscopic Management of Choledocholithiasis SPHINCTEROTOMY Since the advent of endoscopic sphincterotomy in the 1970s, the management of common bile duct stones has transitioned from surgical to predominantly endoscopic treatments. Endoscopic sphincterotomy is performed by cutting both the superficial and deep muscles of the sphincter of Oddi. The primary purpose of endoscopic sphincterotomy is to remove the barrier impeding the passage of stones from the common bile duct into the duodenum. In addition, sphincterotomy expands the orifice to the bile duct large enough to accommodate a variety of devices used by the endoscopist for the extraction of stones. Endoscopic sphincterotomy is performed with a sphincterotome. Sphincterotomes can be categorized into three types: pull-type sphincterotomes, push-type sphincterotomes, and needle-knife sphincterotomes. Pull-type sphincterotomes are by far the most commonly used. In cases where cannulation is difficult, a needle-knife sphincterotome is sometimes used. Push-type sphincterotomes are rarely used today. Pull-type sphincterotomes have a cutting wire attached to the distal tip of the instrument. This wire can be tightened to “bow” the distal tip of the sphincterotome. During sphincterotomy, current is applied through the cutting wire from an electrosurgical cautery generator.
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Figure
3-4. Endoscopic sphincterotomy performed via the standard pull technique. For full-color version, see page CA II of the Color Atlas.
The first step when performing standard pull-type sphincterotomy is cannulation of the bile duct. Next, a guidewire is passed through the lumen of the sphincterotome into the biliary tree. Then, the sphincterotome is withdrawn from the bile duct until the distal one-third of the cutting wire is in the papillary orifice. The sphincterotome is then bowed so that the cutting wire is in contact with the roof of the papilla. Finally, electrocautery current is applied though the wire, until the papilla and sphincter of Oddi have been adequately incised (Figure 3-4). The orientation of the incision should be longitudinal to the direction of the intraduodenal portion of the bile duct. The length of sphincterotomy should be determined based on numerous factors including size of the stone(s) to be removed, size of the papilla, and diameter of the bile duct. In general, larger stones require a larger sphincterotomy. Although a larger sphincterotomy facilitates stone extraction, this must be balanced against the risk of duodenal perforation and post-sphincterotomy bleeding which increases with increasing size of sphincterotomy. When performed by physicians experienced with ERCP, the success of endoscopic sphincterotomy exceeds 95%. Needle-knife sphincterotomes are used primarily to access sphincterotomy in cases in which cannulation of the bile duct is not possible with standard sphincterotomes or catheters. The needle-knife sphincterotome is a catheter that has a short cutting wire extending from its tip. Similar to the pull-type sphincterotome, electrocautery current can be applied through the wire for cutting purposes. However, unlike the pull-type sphincterotomy, which is usually performed over a guidewire, the needle knife is used freehand similar to a scalpel. The papilla is unroofed using the needle knife until access to the bile duct can be achieved. Once the bile duct is successfully cannulated, completion of the sphincterotomy is usually performed using standard pull type sphincterotomes. Needle-knife sphincterotomy used in difficult CBD cannulation is commonly referred to as “precut” sphincterotomy or preferably “access” sphincterotomy.
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Table 3-1
COMPLICATIONS OF ENDOSCOPIC SPHINCTEROTOMY Early • • • •
Pancreatitis Hemorrhage Perforation Cholangitis
Late • • • •
Recurrent stone formation Sphincter stenosis Cholecystitis Cholangitis
Complications of endoscopic sphincterotomy are classified as either early (within 30 days) or late (Tables 3-1 and 3-2). Early complications occur in less than 10% of sphincterotomies and include pancreatitis, perforation, and hemorrhage41. Late complications occur in nearly 25% of patients and include recurrent common bile duct stones, papillary stenosis, cholangitis, and cholecystitis.
BILIARY SPHINCTER DILATION Although endoscopic sphincterotomy is the primary technique used to open the biliary sphincter to facilitate stone extraction, there are certain situations where endoscopic sphincterotomy is either unsafe or may not be feasible. Examples of this situation include: patients with coagulopathy; markedly distorted ampullary anatomy from periampullary diverticula; patients with Billroth II anatomy; and patients who may not be able to receive blood transfusions should post-sphincterotomy bleeding occur, such as Jehovah’s witnesses. In these situations, endoscopic balloon dilation of the papillary orifice is a reasonable alternative to endoscopic sphincterotomy. Endoscopic balloon dilation of the papilla is performed by placing a dilating balloon across the biliary sphincter and into the bile duct. The balloon is then inflated to a maximum diameter of 8 to 10 mm. Most studies addressing endoscopic balloon dilation of the papilla have used 8 mm balloons. The dilation creates a papillary orifice that allows the extraction of most stones less than 10 mm in size. Stones larger than 10 mm can also be removed through the dilated papillary orifice, but may require additional techniques such as lithotripsy. There are a few advantages to performing endoscopic balloon dilation of the papilla compared to endoscopic sphincterotomy. First, the risk of significant bleeding is much lower with balloon dilation. Second, sphincter of Oddi function is preserved following the procedure. However, the clinical significance of sphincter preservation remains unclear as long-term follow-up studies in patients who have undergone
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Table 3-2
MANAGEMENT OF THE EARLY COMPLICATIONS OF ENDOSCOPIC SPHINCTEROTOMY Complication
Incidence
Pancreatitis Hemorrhage
5% to 30% 1% to 2%
Perforation
0.1% to 0.5%
Cholangitis
1% to 5%
Treatment NPO, IV Fluids, Pain Control Endoscopic (epinephrine, hemoclip, balloon tamponade) or Angiographic Embolization or Surgery Conservative (NPO, Antibiotics, Nasobiliary tubes, biliary endoprosthesis) or Surgery Antibiotics
sphincterotomy have not shown a high incidence of adverse consequences. The major disadvantage to endoscopic balloon dilation of the papilla is a high rate of post-ERCP pancreatitis42 . Most therapeutic endoscopists perform endoscopic balloon dilation only when endoscopic sphincterotomy is unsafe or not possible.
STONE EXTRACTION Following sphincterotomy or balloon dilation of the papilla, most stones smaller than 1 cm can be extracted with either extraction balloons or baskets (Figure 3-5). In cases where multiple common bile duct stones are present, the most distal stones should be removed first.
Extraction Balloons Extraction balloons have an inflatable balloon on their distal tip. The technique for stone extraction involves inserting the distal tip of the balloon catheter into the bile duct and above the level of the stone. Then, the balloon is inflated and pulled down the bile duct and through the papillary orifice. Multiple different balloon sizes are available and should be tailored to the size of the bile duct and stone to be removed.
Extraction Baskets Multiple different types of extraction baskets are available. Choice of a particular type of basket depends on the size and shape of the stone to be removed. The technique of basket extraction involves insertion of the basket into the bile duct to the level of the stone. The stone is then captured within the basket and extracted through the papilla. One potential risk of basket extraction is that the basket can itself become impacted at the level of the ampulla. This situation occurs when the basket captures
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59
Figure 3-5. Four choles-
terol gallstones removed from the common bile duct using an extraction balloon. For full-color version, see page CA II of the Color Atlas.
a stone that is too large to be removed through the papilla. Although this situation is rare in expert hands, it potentially requires surgical removal. Therefore, baskets should not be used to extract stones that are larger than the sphincterotomy.
LITHOTRIPSY Mechanical Lithotripsy Mechanical lithotripsy was initially used by urologists for the management of ureteral stones, and later employed by biliary endoscopists for the crushing and removal of large or difficult CBD stones. The basic technique involves insertion of a lithotripsy compatible basket into the bile duct. Once the stone is captured within the basket, the basket is compressed, which crushes the stone. When standard retrieval methods fail, mechanical lithotripsy should be the next maneuver attempted, as it is technically easy to perform and safe. It should be considered as first line therapy if the stone to be extracted is too large relative to the duct or sphincterotomy size, or in the presence of a distal biliary stricture. The initial lithotriptors were extremely cumbersome to use and stiff, making cannulation challenging. There are several flexible basket lithotriptors now available that make cannulation easier compared to the initial models. They can be used for simple basket extraction or converted to mechanical lithotriptors when needed. Once a stone is secured in the basket, extraction should be attempted with gentle pressure. If extraction is difficult, a metal lithotripsy sheath is fed over the basket and a screw type handle tightened to crush the stone within the sheath. The Trapezoid basket (Boston Scientific, Natick, Mass) allows both cannulation over a wire and lithotripsy with a single step device (Figure 3-6). It is essential when removing large or difficult stones to be certain the basket is lithotriptor compatible should the basket get impacted in the ampulla.
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Figure 3-6. Endo-
scopic retrograde cholangiography. A trapezoid basket is being used to crush a stone.
There are several series looking at success using mechanical lithotripsy. Complete stone clearance has been reported from 88% to 98% 43. Often, multiple sessions with short-term stenting are required to achieve complete clearance.
EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY ESWL uses shock waves generated external to the body to fragment calculi. There is extensive urologic experience with ESWL, and the equipment has evolved from fixed units requiring water submersion to the smaller, mobile devices currently available. ESWL has been used successfully for both pancreatic and biliary tract stones. Localization of biliary stones is performed under either ultrasound or fluoroscopic guidance. Stone localization is aided by the presence of a biliary endoprosthesis. Indwelling nasobiliary or percutaneous catheters allow for “on the spot” cholangiography and flushing of the crushed stone fragments. Alternatively, ERCP may be performed immediately after ESWL to perform extraction of large residual fragments. Technically, ESWL is a straight forward and safe method for the fragmentation of large stones. In our institution, ESWL is performed if mechanical lithotripsy fails and surgical extraction is not planned. Several series have demonstrated stone clearance rates of up to 90%.44 Several sessions of ESWL may be required to achieve adequate fragmentation. Side effects and complications are generally not severe and include hematuria, hemobilia, and hyperamylasemia.
ELECTROHYDRAULIC LITHOTRIPSY Electrohydraulic shock waves were first used to fragment bladder stones in the 1950s. A “spark-gap” device conducts a high voltage electric discharge that creates a mechanical shock wave. Some of the initial work in the biliary tree was performed
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using a dog model45. Because the shock wave can also injure normal tissue, electrohydraulic lithotripsy (EHL) should be applied either with a balloon-guided catheter or under direct visualization. Direct vision of the stone to be fragmented is accomplished using a “Mother-Baby” system where a small choledochoscope is introduced through the therapeutic channel of a duodenoscope. The choledocoscope is then passed into the biliary tree to localize the stone. Once the stone is localized, an EHL fiber is passed through the working channel of the choledochoscope, and the tip of the EHL fiber is applied as close as possible to the surface of the stone. Because EHL requires a liquid medium to generate sufficient shock waves to fragment the stone, saline is continuously irrigated into the bile duct. Intraductal saline irrigation also facilitates the clearance of stone debris generated from lithotripsy. Direct comparison of ESWL and intracorporeal electrohydraulic lithotripsy has yielded similar results, with clearance of difficult stones in greater than 70% of cases46. As with other forms of nonmechanical lithotripsy, the technique is often limited to specialized centers.
Laser Lithotripsy Laser lithotripsy uses athermic shock waves to fragment stones. Laser lithotripsy systems currently used in clinical practice include cumarin and rhodamine 6G dye lasers, frequency doubled double pulse-pulse neodymium:YAG, and holmium:YAG lasers. Initial laser lithotripsy required cholangioscopy and direct stone visualization to prevent injury to normal tissue. Newer “smart laser” systems with stone recognition ability limit the potential for tissue trauma and allow treatment with less than ideal visualization. The systems fire only if catheter tip and stone are in direct contact. “Blind” fragmentation of CBD stones using an optical stone tissue detection system has proven to be of benefit in large or difficult stones. In a series of stones not amenable to standard therapy, 87% ultimately achieved complete stone clearance47. A randomized comparison favored intracorporeal laser lithotripsy over ESWL for difficult bile duct stones48. Because it is technically challenging, laser lithotripsy is generally limited to specialized tertiary care centers.
BILIARY STENTING FOR CHOLEDOCHOLITHIASIS Endoscopic removal of common bile duct stones is successful in greater than 90% of cases. In situations where endoscopic removal of common bile duct stones is unsuccessful, long-term management is dependent on the age and general health status of the patient. For young and otherwise healthy patients, surgical common bile duct exploration and stone removal should strongly be considered to help avoid long-term complications of choledocholithiasis such as secondary biliary cirrhosis. In elderly patients with multiple comorbidities, biliary stenting with 10 French plastic stents is a viable temporary and long-term option for managing choledocholithiasis. Biliary endoprostheses provide adequate decompression of the biliary tree and prevent stone impaction at the level of the ampulla. Bile is able to flow both through the stent and around the stent to maintain biliary drainage. Plastic biliary endoprostheses generally remain patent for approximately 3 months duration. After 3 months, occlusion of endoprostheses is common because of stone debris and bacterial biofilm, which obstruct the lumen of the stent. Even in the circumstance of stent occlusion, bile drainage around the stent may be sufficient to prevent symptoms of biliary obstruction in patients with
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choledocholithiasis. Another benefit of biliary stenting is that the stent itself may help break up large stones, making future endoscopic attempts at stone removal more successful. Stone fragmentation occurs as a result of friction generated against the stone by the stent, which rubs against the stone during intestinal peristalsis. In one review of 23 elderly patients with large common bile duct stones who were treated with biliary endoprostheses, 87% remained completely asymptomatic after a mean follow-up of 23 months49. The major long-term complications of biliary endoprostheses for management of choledocholithiasis is recurrent biliary obstruction and cholangitis. This can usually be treated medically with antibiotics and stent exchange. When performing plastic biliary stent insertion for choledocholithiasis, a few management techniques are important to consider. First, a sphincterotomy should be performed prior to stent placement. This will facilitate bile drainage around the stent should stent occlusion occur. Second, 10 French stents have longer patency rates than 7 French stents and are preferred. Third, for patients with markedly dilated bile ducts, there is a concern for stent migration with straight plastic stents. Double pigtail stents may have an advantage in this circumstance, as their position in the bile duct is more secure. Finally, repeat ERCP with an attempt at stone extraction should be considered within a few months of initial stent placement. If multiple attempts at stone removal are unsuccessful, long-term biliary stenting is usually sufficient to prevent biliary complications. Patients managed with long-term biliary endoprosthesis should be followed closely by their physician. If the patient develops symptoms of biliary obstruction or laboratory abnormalities consistent with biliary obstruction, replacement of the stent should be performed.
PERCUTANEOUS TRANSHEPATIC CHOLANGIOGRAPHIC MANAGEMENT CHOLEDOCHOLITHIASIS
OF
Once a percutaneous tract to the biliary system has been obtained, dilated, and matured, therapeutic interventions can be performed. Mechanical lithotripsy using basket devices have been used as has laser or electrohydraulic lithotripsy through a percutaneously inserted choledochoscope. Percutaneous expulsion of bile duct calculi into the duodenum by dilating the papilla with a balloon catheter has been used both from a T-tube tract and transhepatically. Technical success has been reported in over 90% of cases50.
MANAGEMENT OF CHOLEDOCHOLITHIASIS DISCOVERED DURING INTRAOPERATIVE CHOLANGIOGRAPHY The optimum strategy for the treatment of stones found by intraoperative cholangiogram has not been determined. Numerous options are available. First, the stone can be removed via open or laparoscopic common bile duct exploration51. Second, attempts can be made to extract the stone through the cystic duct. Third, post cholecystectomy ERCP with stone extraction is a viable option in centers with an experienced therapeutic endoscopist. Finally, as previously noted, a significant percentage of small stones may pass spontaneously and it may be reasonable to simply observe the patient.
Choledocholithiasis
NONINVASIVE MANAGEMENT DISSOLUTION THERAPY
OF
63
CHOLEDOCHOLITHIASIS: STONE
Methyl-tert-butyl ether (MTBE) and mono-octanoin are both effective agents for the dissolution of cholesterol stones. Several series have evaluated their use in refractory CBD stones. The solvents are infused by either nasobiliary catheters or a T-tube for a mean of 7 days52 . In one trial, complete stone clearance could be achieved in 49%53. Multiple complications have been reported including death from cholangitis during the infusion. With the advent of other methods for the treatment of refractory stones, chemical dissolution has fallen from favor. Experience with oral dissolution for CBD stones is limited. Several reports suggest that chenodeoxycholic acid (CDCA) or ursodeoxycholic acid (UDCA) may be effective. A controlled study showed improvement compared to placebo in patients with retained CBD stones54. Treatment of nonextractable CBD stones has been attempted with combination of UDCA and endoprosthesis. In a study of 22 patients with “defiant” stones, 10 were treated with a combination of UDCA and stent placement, and 12 were treated with stent placement alone55. It appeared that UDCA facilitated the later extraction of these difficult stones. Although it is difficult to make firm recommendations based on this nonrandomized study, UDCA may be beneficial in patients with difficult to treat stones, especially if future extraction attempts are intended.
THE ROLE OF CHOLECYSTECTOMY CHOLEDOCHOLITHIASIS
IN
THE
MANAGEMENT
OF
Cholecystectomy is an integral part of the management of patients with choledocholithiasis, as patients with choledocholithiasis are susceptible to other complications of gallstone disease such as cholecystitis. The value of cholecystectomy was demonstrated in a trial of 120 patients who underwent endoscopic sphincterotomy for choledocholithiasis who were then randomized to either a “wait and see” group or cholecystectomy group. Of the patients in the “wait and see group”, 47% had recurrent biliary symptoms within 2 years compared to 2% of patients in the cholecystectomy group. Furthermore, patients who developed recurrent biliary symptoms in the “wait and see” group more often required conversion from laparoscopic cholecystectomy to open cholecystectomy compared to patients who initially underwent cholecystectomy56. For patients who are poor operative candidates, it is acceptable to perform endoscopic sphincterotomy and stone extraction, and then follow the patient’s clinical course to determine whether the benefits of future cholecystectomy outweigh the operative risks.
Rare Presentations of Gallstone Disease MIRIZZI'S SYNDROME Stones in the gallbladder or cystic duct typically do not cause jaundice, because the flow of bile from the hepatic ducts, through the common bile duct, and into the duodenum is unimpeded. Jaundice associated with gallstone disease is usually caused by migration of stones into the common bile duct. However, Mirizzi's syndrome is an
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exception to this rule. Mirizzi's syndrome is caused by obstruction of the common hepatic duct from external compression by either a stone impacted in the cystic duct or by severe inflammation around the cystic duct. Mirizzi's syndrome is covered in more detail in Chapter 2.
HEPATOLITHIASIS Hepatolithiasis is a condition characterized by the formation of primary pigmented stones within the intrahepatic bile ducts. It is rare in the United States, but common in patients from Southeast Asia. An increasing incidence is now being encountered in the United States because of immigration of patients from Southeast Asia. Other names for this disorder include Oriental cholangiohepatitis and recurrent pyogenic cholangitis. Although the cause of this disorder is poorly understood, bacterial infection and possibly parasitic infection of the biliary tree is believed to be important in the pathogenesis. Patients with hepatolithiasis develop numerous intrahepatic bile duct stones, intrahepatic biliary strictures, and areas of biliary dilation. Although the entire biliary tree can be affected, the left hepatic duct and its branches are more commonly involved. Affected patients often present with recurrent episodes of cholangitis characterized by fever, jaundice, and right upper quadrant pain. Diagnosis may be suggested by CT scan or ultrasound which shows intrahepatic stones and biliary dilation. Cholangiography can also be used to make the diagnosis. An important consideration is that ERCP may underestimate disease extent because of its inability to visualize segments proximal to a biliary stricture. MRCP is an extremely helpful complementary imaging technique to better define involvement of the entire biliary tree. Management of patients with hepatolithiasis usually requires collaboration between gastroenterologists, surgeons, and interventional radiologists. In patients who present acutely with signs and symptoms of biliary obstruction and infection, ERCP may be performed. However, clearance of stone burden and achievement of biliary decompression can be difficult even in the hands of experienced therapeutic endoscopists, because of the presence of multiple biliary strictures. For patients who cannot have their biliary tree entirely cleared by ERCP, strong consideration should be given to percutaneous transhepatic cholangiography or surgery. Surgical options include stone removal, biliary bypass via a hepaticoenterostomy, and hepatic resection. Although not commonly performed in the United States, percutaneous transhepatic choledochoscopy with stone extraction is a frequently used procedure in Asian countries to manage patients with hepatolithiasis. Even in patients who have complete clearance of stones from their biliary system, recurrence is common. Therefore, patients with hepatolithiasis should undergo periodic surveillance for recurrent stone disease with either ultrasonography or MRCP. In patients in whom recurrent stone disease occurs, strong consideration should be made to clear the stones before symptoms ensue. In addition to cholangitis, complications of hepatolithiasis include secondary biliary cirrhosis and cholangiocarcinoma.
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Conclusions Because of the high prevalence of gallbladder disease in the United States, secondary choledocholithiasis with cholesterol stones is frequently encountered. Over the past few decades, great strides have been made in the diagnosis and management of choledocholithiasis. Diagnosis of choledocholithiasis has markedly improved with newer noninvasive imaging techniques such as MRCP and EUS. The therapy of choledocholithiasis has evolved from invasive open common bile duct explorations to endoscopic methods of stone extraction. Large, difficult to remove stones can now be managed with lithotripsy techniques, such as mechanical lithotripsy, electrohydraulic lithotripsy, and ESWL. As endoscopic equipment continues to evolve, further improvements in the diagnosis and management of choledocholithiasis can be expected. In the future, smaller endoscopes that can be inserted directly into the bile duct will allow direct visualization of stones and may preclude the need for fluoroscopy. Newer, easier to use extraction devices will allow even the most difficult stones to be managed in nontertiary care settings. For the rare patient who has stones that can not be endoscopically extracted, stents with improved long-term patency rates may prevent the need for surgery and further endoscopic procedures. Ongoing research will likely result in improvements in the rate of post-ERCP complications, such as pancreatitis. In addition, pharmacological prevention of stone recurrence can be expected in the future.
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33. Mitchell S, Clark RA. A comparison of CT and sonography in choledocholithiasis. AJR Am J Roentgenol. 1984;142:79. 34. Soto JO, Alvarez O, Munera F, et al. Diagnosing bile duct stones: Comparison on unenhanced helical CT, CT cholangiography and MR cholangiography. AJR Am J Roentgenol. 2000;175:1127-1134. 35. Palazzo L, O’Toole. EUS in common bile duct stones. Gastrointest Endo. 2002;56: S49-57. 36. MacEneaney P, Mitchell M, McDermott R. Update on magnetic resonance cholangiopancreatography. Gastronterol Clin North Am. 2002;31:731-746. 37. Colletti PM, Ralls PW, Lapin SA, et al. Hepatobiliary imaging in choledocholithiasis. Clin Nucl Med. 1986;11:482-486. 38. Sugiyama M, Atomi Y. EUS for the diagnosis of choledocholithiasis. Gastrointest Endosc. 1997;45:143-6. 39. De Ledinghen V, Lecesne R, Raymond J, et al. Diagnosis of choledocholithiasis: EUS or MRCP. Gastro Endo. 1999;49:26-31. 40. Flowers JL, Zucker K, Graham S. Laproscopic cholangiography. Ann Surg. 1992;211:230. 41. Cotton PB, Geenen JE, Sherman S, et al. Endoscopic sphincterotomy for stones by experts is safe, even in younger patients with normal ducts. Ann Surg. 1998; 227:201204. 42. DiSario JA, Freeman ML, Bjorkrnan DJ, et al. Endoscopic balloon dilation compared to sphincterotomy (EDES) for extraction of bile duct stones: Preliminary results [abstract]. Gastrointest Endosc. 1997;45:AB129. 43. Hintz R, Adler A, Veltzke. Outcome of mechanical lithotripsy of bile duct stones in an unselected series of 704 patients. Hepatogastroenterology. 1996;43:473-476. 44. Lomanto D, Fiocca F, Nardovino M, et al. ESWL experience in the therapy of difficult bile duct stones. Dig Dis Sci. 1996;41:2397-2403. 45. Sievert C, Silvas E. Evaluation of electrohydraulic lithotripsy as a means of gallstone fragementaion in the canine model. Gastrointest Endosc. 1987;32:233-235. 46. Adamek H, Maier M, Jokobs R, et al. Management of retained bile duct stones: A prospective open trial comparing extracorporeal and intracorporeal lithotripsy. Gastrointest Endosc. 1996;44:40-47. 47. Hochberger J, Bayer J, May A, et al. Laser lithotripsy of difficult bile duct stones: Results in 60 patients using a rhodamine 6G dye laser with optical stone tissue detection system. Gut. 1998;43:823-890. 48. Neuhaus H, Zillinger C, Born P, et al. Randomized study of intracorporeal laser lithotripsy verses extracorporial shock-wave lithotripsy for difficult bile duct stones. Gastrointest Endosc. 1998;47:27-34. 49. Van Steenbergen W, Pelemans W, Fevery J. Endoscopic biliary endoprosthesis in elderly patients with large bile duct stones: Long-term follow-up. J Am Geriatr Soc. 1992;40:57-60. 50. Garcia-Garcia L, Lanciego C. Percutaneous treatment of bile duct stones: Sphincteroplasty and occlusion balloon for the clearance of bile duct calculi. AJR Am J Roentgenol. 2004;182:663-670. 51. Ebner S, Rechner J, Beller S, et al. Laproscopic management of common bile duct stones. Surg Endosc. 2004;18:762-765. 52. Diaz D, Bories P, Ampeles M, et al. Methyl-tert-butyl ether in the endoscopic treatment of common bile duct radiolucent stones in elderly patients with nasobiliary tube. Dig Dis Sci. 1992;37:79-100.
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53. Stock S, Carson G, Lavelle M, et al. Treatment of common bile duct stones using mono-octanoin. Br J Surg. 1992;79:653-654. 54. Salvioli G, Salati R, Lugli R, et al. Medical treatment of biliary duct stones: Effect of ursodeoxycholic acid administration. Gut. 1983;24:609-14. 55. Johnson G, Geenen J, Venu R, et al. Treatment of nonextractable common bile duct stones with combination of ursodeoxycholic acid and endoprosthesis. Gastro Endo. 1993;39:528-531. 56. Boerma D, Rauws EA, Keulemans YC, et al. Wait and see policy or laparoscopic cholecystectomy after endoscopic sphincterotomy for bile duct stones: A randomized trial. Lancet. 2002;360:761-5.
chapter
4
Bile Duct Injuries Janak N. Shah, MD
Introduction Bile duct injuries may be attributed to a variety of mechanisms, but most are caused iatrogenically, as complications of surgical procedures. Injuries to the bile ducts are a considerable cause of morbidity in afflicted patients. In earlier years, therapy frequently was operative. However, since the early 1990s, minimally invasive procedures have emerged as a replacement to surgery, and are now used as the first-line treatment for many bile duct injuries. This chapter will review bile duct injuries and their treatment, with specific emphasis on the endoscopic therapy of bile duct injuries. Special issues of biliary injuries as related to laparoscopic cholecystectomy and liver transplantation will be emphasized.
Etiology Most biliary injuries are iatrogenic in nature, occurring as complications of surgery, such as laparoscopic cholecystectomy, liver transplantation, and other hepatobiliary operations1,2 . Nonoperative hepatobiliary procedures, such as those used in the ablation of hepatic tumors, are increasingly used in the modern era, and may also lead to iatrogenic damage to the bile ducts. Common causes of biliary injuries are listed in Table 4-1.
LAPAROSCOPIC CHOLECYSTECTOMY AND BILE DUCT INJURIES Laparoscopic cholecystectomy was introduced in the late 1980s, and has since essentially replaced open cholecystectomy for the treatment of symptomatic gallbladder stones3. Given the lack of tactile feedback and three-dimensional visualization during laparoscopic cholecystectomy, there has been increased concern for iatrogenic injury using the laparoscopic approach. Although overall morbidity and mortality rates for open versus laparoscopic cholecystectomies appear similar, injuries to the bile ducts occur more frequently following the laparoscopic approach4.
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Table 4-1
ETIOLOGIES OF BILE DUCT INJURIES Postsurgical Cholecystectomy (laparoscopic or open) Liver transplantation Hepatobiliary surgery (eg, hepatic resection)
Other Iatrogenic Tumor ablation therapies: radiofrequency ablation, cryoablation, chemoembolization Liver biopsy Transjugular intrahepatic portosystemic shunt (TIPS procedure) External beam radiotherapy
Noniatrogenic Penetrating trauma (eg, stab wound, gun shot wound) Blunt trauma (eg, motor vehicle accident)
Potential factors that predispose to the risk of injury during laparoscopic cholecystectomy include anatomical variations of the biliary system (eg, accessory duct of Luschka, absent or short cystic ducts), acute or chronic inflammation of the gallbladder, maneuvers used to control hemorrhage intraoperatively (eg, electrocautery, laser), and improper surgical technique4. Aberrant right hepatic ducts are found in 8% of patients undergoing cholecystectomy and in 17% of patients with complications following cholecystectomy, and seem to be important predisposing factors for bile duct injuries5,6. Numerous large series from the United States and worldwide reveal that biliary tract injuries complicate laparoscopic cholecystectomy in 0.5% to 0.8% of cases7-11. Types of injuries following surgery include bile leaks and fistulas, biliary strictures, and complete or partial bile duct transection4. Leaks are the most common biliary complication, and mostly arise from the cystic duct stump or accessory ducts of Luschka4,7,8. Complete transection of the bile duct comprises less than 2% of overall bile duct injuries following laparoscopic cholecystectomy, but may represent a much higher proportion at tertiary referral centers 4. As might be expected, increased surgical experience appears to decrease the rates of biliary complications3,9,10. The routine use of intraoperative cholangiography may lower complication rates11,12 .
LIVER TRANSPLANTATION AND BILE DUCT INJURIES Cadaveric orthotopic liver transplantation (OLT) is now routinely used in the management of patients with end stage liver disease who are appropriate candidates for such therapy. Since the late 1990s, over 4,000 liver transplants have been performed
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in the United States annually13. Although overall graft survival and patient outcomes have improved since the advent of OLT, biliary injuries following transplantation remain a common problem, and occur in 6% to 34% of OLT recipients14-17. The most common types of biliary complications following OLT include bile leaks and strictures. Bile leaks complicate liver transplantation in 8% to 26% of cases15-18. The use of surgically placed biliary drainage tubes (T-tubes) during bile duct reconstruction may be associated with an increase rate of this complication. Several studies reveal an over two- to threefold higher rate of bile leaks in patients receiving duct-to-duct anastomoses with T-tubes compared to those without T-tubes15,19,20. Bile leaks usually occur either at the T-tube insertion site (majority), or at the biliary anastomosis. Whereas T-tube associated leaks are due to the physical defect at the biliary insertion site, anastomotic leaks are often the result of local ischemia and necrosis21. Most bile leaks are diagnosed within 3 months of surgery, and those located at the T-tube site are usually temporally related to the manipulation or removal of the catheter16. Although it may be difficult to predict which patients will develop bile leaks after T-tube removal, duct mural irregularities on final T-tube cholangiograms (prior to removal) have been associated with the development of bile leaks22 . Biliary strictures occur in 3% to 16% of OLT recipients, and represent the second most common type of biliary injury following transplantation14,15,17-19,23. In contrast to bile leaks, they are often encountered later in the post-transplant period16. Biliary strictures may be classified by their location, either as anastomotic or nonanastomotic. Nonanastomotic strictures involve the biliary tree of the donor graft, are attributed to ischemia from graft preservation injury or hepatic artery thrombosis, and are also referred to as ischemic type biliary strictures24,25. Anastomotic strictures are attributed to a combination of surgical technique, fibrotic healing, and local tissue ischemia 26. Although bile leaks are more common in the setting of T-tubes, the opposite effect is seen for biliary strictures, and therefore T-tube use is favored at some centers. Numerous studies, including two randomized trials, demonstrate higher rates of biliary strictures in OLT patients receiving duct-to-duct anastomoses without T-tubes as compared to those with T-tubes (10% to 20% versus 2% to 8%)19,20,27,28. A direct anastomosis between the bile duct and intestine (choledochojejunostomy) also seems to be associated with an increased risk of anastomotic strictures16,25. A less common biliary complication after OLT is the development of primary bile duct stones, sludge, and casts. Stones and/or sludge occur in 2% to 13% of OLT recipients, and are usually diagnosed later in the post-transplant period (4 to 18 months post-OLT) 29-31. An underlying biliary stricture is encountered in over two-thirds of patients with bile duct stones31. Biliary casts are more diffuse lithogenic formations (“cast-like” appearance) that arise in the donor biliary tree. Biliary cast syndrome appears to be independently associated with both hepatic ischemia and biliary strictures, and is seen in up to 6% of OLT recipients, usually within 1 year of transplantation32 . Living donor liver transplantation (LDLT) is being increasingly performed in the Unites States,33 and raises specific issues related to biliary injuries after transplantation. The two main types of biliary complications of LDLT are the same as those of cadaveric OLT, but the incidence of bile leaks and strictures may be greater. Leaks are found in 10% to 40%, and strictures are encountered in about 20% of LDLT recipients34-36. There are limited data directly comparing biliary injuries following
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cadaveric OLT and LDLT. The available data are conflicting, as one study from Asia demonstrated similar biliary complication rates (6%) for LDLT and OLT, whereas a US study revealed a three- to fourfold higher rate of both bile leaks and strictures in LDLT recipients36,37. However, an increased rate of biliary complications in LDLT patients seems highly plausible, as biliary reconstructions may involve multiple and smaller diameter duct-to-duct anastomoses36,38. An additional type of injury unique to LDLT is the formation of leaks at the cut surface of the split liver graft38. With the rise in LDLT being performed worldwide, bile duct injuries involving donors are also being increasingly recognized. Bile leaks occur in 2.5% to 6% of donors, and biliary strictures occur in about 1% 33,39,40. As might be expected, the risk of biliary injuries in donors is higher at transplant centers performing fewer LDLT procedures33. Also, the risk appears greater when utilizing right hepatectomy grafts, likely due to the creation of a sharper angle at the porta hepatis between the native common bile duct and left hepatic duct 39,40.
OTHER CAUSES OF BILE DUCT INJURIES Nonoperative medical procedures may also lead to bile duct injuries. Large studies demonstrate that bile leaks and biliary strictures complicate 0.2% to 2% of cases following the minimally invasive treatment of hepatic tumors using techniques such as radiofrequency ablation, laser thermotherapy, and transarterial chemoembolization41-43. Although it may be difficult to predict which patients will develop injury after tumor ablation treatment, results from one recent investigation suggest that the incidence of bile duct injury following transarterial chemoembolization may be increased in noncirrhotic livers, during therapy of tumors of nonhepatocellular origin, and with highly selective embolization of distal arterial branches44. Other tumor ablation techniques, such as hepatic cryoablation and external beam radiation therapy, may also give rise to bile leaks and biliary strictures, respectively45-48. Iatrogenic bile duct injury may occur during other minimally invasive procedures such as transjugular intrahepatic portosystemic shunts (TIPS) and liver biopsy. During placement of TIPS, inadvertent fistulous connections between hepatic veins and the biliary system may be created49,50. Liver biopsies are associated with bile leaks and biliovascular fistulas in fewer than 1% of cases51,52 . Noniatrogenic causes of biliary injuries are usually due to trauma, and include complications of gun shot wounds as well as blunt wounds53. Specific types of injury consist of bile leaks (most common), biliovascular fistulas, and strictures. As most published information on biliary complications secondary to trauma is based on case reports and case series, the true incidence is difficult to determine54,55.
Clinical Presentation and Diagnosis BILIOVASCULAR FISTULAE Biliary injuries that result in fistulous connections between bile ducts and vascular structures are rare, two-thirds of which are caused iatrogenically 56. Patients with bilioarterial fistulas usually present with signs and symptoms of upper GI hemorrhage due to hemobilia. Persistent clots in the biliary tree may also lead to signs and symptoms of biliary obstruction. Endoscopy may reveal blood exiting the papilla, but the diag-
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nosis is usually confirmed at angiography 56. Patients with fistulas between the biliary and hepatic venous systems may present with hemobilia, jaundice (due to bilemia or obstruction from intraductal clot), or biliary sepsis 49,50,56. Contrast opacification of the biliary system during endoscopic retrograde cholangiopancreatography (ERCP) will demonstrate the presence of a fistulous tract between the biliary and hepatic venous system50. The common clinical features and diagnostic methods for various types of biliary injuries are summarized in Table 4-2.
BILE LEAKS Bile leaks result from defects in the bile duct wall, and should be suspected in patients with history of hepatobiliary surgery or abdominal trauma who present with abdominal pain, fever, peritoneal signs, or new onset ascites1,13. Iatrogenic bile leaks tend to present early in the postoperative period, and may be recognized in association with T-tube manipulations13,18. Mild elevations of serum liver tests and white blood cell counts may be present57,58. Leaks that freely communicate with the peritoneal cavity may result in diffuse abdominal pain from bile peritonitis. Those that connect to more localized collections (bilomas) may produce focal areas of tenderness. Although abdominal pain and tenderness are common presenting features, these may be absent in corticosteroid use13. Direct cholangiography is considered the reference standard to establish the diagnosis of a bile leak59. The presence and anatomic location of leaks are easily visualized at percutaneous transhepatic cholangiography (PTC) or endoscopic retrograde cholangiopancreatography (ERCP). Moreover, therapeutic measures can be undertaken immediately (see section on Management). When leaks are suspected in postcholecystectomy and post-OLT patients, specific attention should be paid to the cystic duct stump (Figure 4-1), and biliary anastomosis and/or T-tube site, respectively4,18. Hepatobiliary scintigraphy is also highly accurate in detecting bile leaks (>85%), and is a useful noninvasive modality to establish the diagnosis58-60. Due to the excellent performance characteristics of nuclear scintigraphy for detection of biliary complications, some advocate that ERCP is unnecessary if the hepatobiliary scan is normal61. However, cholangiography remains the benchmark for establishing the diagnosis, and should be performed when there is high suspicion despite negative hepatobiliary scinitigraphy. Other noninvasive imaging techniques such as CT and MRI may demonstrate intraperitoneal fluid collections and thereby suggest bile leaks in patients with the appropriate clinical history. However, the presence of a bile leak cannot be definitively diagnosed using standard CT or MRI. In small case series, MR cholangiopancreatography (MRCP) has suggested the presence of leaks that were later confirmed at ERCP62 , but MRCP is not a conventional method for detecting leaks. CT cholangiography, which involves thin section spiral CT scanning after the administration of an intravenous cholangiographic agent, may become an effective means of identifying bile leaks, but has not been studied in large series 63,64.
BILIARY STRICTURES Biliary strictures should be suspected in patients with history of biliary tract surgery who present with jaundice, signs and/or symptoms of cholangitis, or abnormal serum liver tests of a cholestatic pattern18,65. In comparison to leaks, strictures are
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Table 4-2
BILE DUCT INJURIES: CLINICAL PRESENTATION AND DIAGNOSTIC METHODS Biliary Injury
Clinical Presentation
Primary Diagnostic Test
Bile leak
Abdominal pain/tenderness Fever New onset ascites (on exam or imaging) Bilious output from surgical drains Recent manipulation of T-tube Mild elevation serum liver tests Elevated WBC count
ERCP / PTC or Hepatobiliary scintigraphy
Biliary Stricture
Jaundice Cholangitis Elevated liver tests (cholestatic pattern) Dilated biliary ducts (Ultrasound/CT/MRI) Abnormal liver biopsy
ERCP / PTC or MRCP
Bilioarterial fistula
Upper GI hemorrhage Angiography (hemobilia): hypotension, tachycardia, shock hemetemesis, melena, hematochezia decrease hemoglobin/hematocrit Biliary obstruction (intraductal clot)
Biliovenous fistula
Jaundice/biliary obstruction ERCP (intraductal clot) Hyperbilirubinemia (bilemia) Upper GI hemorrhage (hemobilia)
`
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Figure 4-1. Balloon occlusion cholangiogram at ERCP demonstrates contrast extravasation at cystic duct stump (arrow) near surgical drain in a patient following laparoscopic cholecystectomy.
usually identified later after the inciting event, even months to years after surgery1. Occasionally, patients will present with clinical or histologic evidence of end stage liver disease years after the initial insult that caused the stricture. Abdominal ultrasound, CT, or MRI often demonstrate dilation of the intrahepatic or extrahepatic biliary tree, but these findings may be absent, especially in the post-OLT setting13. At times, a liver biopsy performed for evaluation of cholestasis may reveal histologic findings (eg, pericholangitis, bile ductular proliferation) that initiate the concern of biliary stricture or obstruction13. As for bile leaks, direct cholangiography at PTC or ERCP remains the reference standard for establishing the diagnosis of biliary strictures1,2 . Even subtle strictures can be detected, and their location precisely characterized. During cholangiography, likely sites of possible strictures (eg, biliary anastomosis in post-OLT patients) should be specifically investigated. Therapeutic measures can also be undertaken during PTC or ERCP (see Management section). Other noninvasive imaging techniques have proven useful in the diagnosis of biliary strictures. Hepatobiliary scintigraphy can detect the presence of biliary obstruction, but is less useful in this regard than for bile leaks59,60. Although the lack of radiotracer activity in the duodenum may suggest complete bile duct obstruction, hepatobiliary scans cannot discriminate the underlying cause (stricture versus biliary stone). MRCP has emerged as a valuable, noninvasive method of characterizing biliary strictures, and appears comparable to PTC and ERCP in this regard66,67. The unprocessed MR images that are reconstructed to produce the MRCP may provide additional, useful information on extraductal abnormalities 67. In complete bile duct transection or high grade strictures in which ERCP may only demonstrate the distal biliary tree, MRCP can depict the entire biliary system, both proximal and distal to the stricture 68. Although the focus of this chapter is on bile duct injuries and benign disease, one must always entertain the possibility of biliary strictures due to malignant disease. There should be a low threshold to thoroughly investigate strictures that present in patients with a clinical presentation worrisome for malignancy, or without a definite history of hepatobiliary surgery or other potential biliary injury.
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Management Although bile duct injuries are attributed to a variety of iatrogenic and noniatrogenic causes, the techniques that should be used in their treatment remain similar. A variety of endoscopic, percutaneous, and surgical methods are available. The optimal approach is highly dependent on local expertise, and is best determined under multidisciplinary discussions involving surgeons, interventional radiologists, and therapeutic endoscopists. The therapy of bile leaks, strictures, and other ductal injuries is described in this section. Specific treatment considerations related to biliary injuries following laparoscopic cholecystectomy and liver transplantation will also be addressed.
MANAGEMENT OF BILE LEAKS The treatment of bile leaks has evolved with advances in minimally invasive techniques. Although small leaks may spontaneously heal with conservative management within a day, those with persistent symptoms should undergo therapy17,22 . In earlier years, the only treatment options were surgical. In the modern era, management may consist of endoscopic, percutaneous, and surgical approaches. Available therapeutic techniques and other management aspects for bile leaks are listed in Table 4-3. Many centers that have experienced biliary endoscopists favor the endoscopic approach, as this avoids surgical morbidity and the uncomfortable presence of percutaneous catheters. Endoscopic options include endoscopic sphincterotomy, biliary stent placement, nasobiliary drain, or a combination thereof18,31,69-71. The physiologic goal of endoscopic therapy is to decrease the pressure gradient between the biliary system and duodenum70. This promotes bile flow preferentially into the small intestine bypassing the leak site, and allows the bile duct defect to heal. Endoscopic sphincterotomy alone has been used for bile leaks with high success rates (88%) in one study69. However, it is not favored as sole therapy at many centers13,18, and a direct comparison of sphincterotomy to biliary endoprosthesis in a canine model revealed significantly longer time to healing in the group treated with sphincterotomy 72 . Nasobiliary drains and plastic biliary stents effectively treat bile leaks in 80% to 100% of patients18,31,70,71,73,74. One advantage of nasobiliary drains over indwelling stents is the ability to maintain access for repeat cholangiography and assessment of leak closure. Healing is confirmed for most leaks within 1 week, and the nasobiliary tube can then be removed75. However, the presence of a nasobiliary catheter can be irritating to some patients, alterations of patient position may lead to inadvertent dislodgement from the biliary tree, and therefore many centers prefer treatment using biliary stents13,18. Additionally, one group has suggested improved success rates with biliary endoprostheses as compared to nasobiliary drains based on a small series of patients with bile leaks following laparoscopic cholecystectomy 74. Some centers advocate the use of long biliary stents that traverse the site of leak (“leak-bridging”)13,71. Theoretically, these may form an additional physical barrier at the leak site, and divert bile away from the defect. However, short biliary stents that just traverse the papilla and decrease the transpapillary pressure gradient appear to be equally effective for uncomplicated bile duct leaks (Figure 4-2) 70. Biliary stent placement does not require sphincterotomy18,31,74, and positioning attempts should be made through the intact papilla. Regardless of whether a leak-bridging or
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Table 4-3
BILE LEAKS: TREATMENT TECHNIQUES AND MANAGEMENT ASPECTS Endoscopic Biliary stent (transpapillary or leak-bridging) Nasobiliary drain Endoscopic sphincterotomy
Percutaneous Transhepatic biliary drain Biloma / abscess drainage (* adjunct therapy to other techniques)
Surgical Primary repair of defect Biliary reconstruction
Other Treatment of biliary obstruction, if present (calculi, strictures) Antibiotics for bile peritonitis
Figure 4-2A. ERCP demonstrates
contrast leak (arrow) along T-tube tract in OLT recipient. Reprinted with permission from Pfau P, et al., Endoscopic management of postoperative biliary complications in orthotopic liver transplantation. Gastrointestinal Endoscopy. 2000;52:55-63. Copyright 2000, American Society for Gastrointestinal Endoscopy.
78 Figure
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4-2B. Placement transpapillary stent (10F, 5cm).
of
Figure 4-2C. Interval ERCP at 4
weeks demonstrates no evidence of bile leak (stent removed immediately prior to cholangiogram).
transpapillary stent is used, a large diameter stent (10 French or higher) is optimal, as the increased diameter should improve internal bile flow. The placement of a biliary stent requires a repeat endoscopy for removal. Repeat ERCP should be performed within 4 to 8 weeks, and leak closure is seen in 84% to 100% of patients18,31,70,71. Any associated fluid collections should be percutaneously drained when infection is suspected, as adjunct therapy to the endoscopic management of leaks76,77. Broad spectrum antibiotics are usually prescribed for patients with bile peritonitis. When leaks are identified during T-tube removal, the placement of a drainage catheter adjacent to the biliary insertion site via the T-tube tract should be considered, as this technique reduced the incidence of bile peritonitis from 20% to 9% in one study 78. Areas of distal bile duct obstruction (eg, calculi, strictures) should also be addressed, as these may elevate intraductal pressures and contribute to delayed or unsuccessful healing of the leak site18,31,77. New endoscopic techniques hold promise for the treatment of bile leaks. One group has compared botulinum toxin injection into the sphincter of Oddi to endobiliary stents for the treatment of cystic duct leaks in a canine model, and found both techniques equally effective79. If results are confirmed in larger human trials, an advantage of this method over biliary stenting would be the avoidance of repeat
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endoscopy for stent removal. Another group has described a novel method using nbutyl-2-cyanoacrylate glue for the occlusion of biliary fistulas. Leaks were closed in 7 of 9 patients using cyanoacrylate glue at one ERCP procedure, and obviated the need for surgical intervention after prior failed endoscopic therapy 80. Both of these innovative techniques may expand the role of endoscopic treatment of bile leaks, but further studies will be required. For patients who have failed or are not candidates for endoscopic therapy due to inaccessibility of the bile duct (failed cannulation or surgically altered anatomy), transhepatic biliary drainage may be used for treatment of leaks with similar success rates to endoscopic therapy 81. However, percutaneous biliary access and therapy in a non-dilated biliary system may be technically challenging and requires interventional radiology expertise. Although minimally invasive therapies are highly successful in the management of bile leaks, their failure warrants surgical treatment. Patients with more complex ductal injuries or larger size leaks are more likely to require surgical management 71,77,82 . Initial palliation with endoscopic stenting, however, enables operative repair to be performed electively and perhaps at a center with more experience in such management. Common surgical options for the management of bile leaks include primary repair and biliary reconstruction (eg, choledochojejunostomy, hepaticojejunostomy)18,31,71,82-84, and are discussed elsewhere in this textbook.
MANAGEMENT OF BILIARY STRICTURES Advances in minimally invasive therapy have substantially impacted the treatment approach to biliary strictures. Progress in endoscopic and percutaneous methods has minimized the need for surgery for most strictures. Initial treatment attempts for strictures that are accessible and traversable with guidewires should be at ERCP or PTC, prior to considering operative treatment. Biliary strictures can be successfully treated endoscopically in 60% to 90% of cases14,31,65,85-87. Therapy may require several interval ERCP procedures (2 to 8 ERCPs) performed over one year or more, using repeat stricture dilations and multiple biliary stents (1 to 6 stents) 65. An algorithm for the endoscopic treatment of benign bile duct strictures is suggested in Figure 4-3. The first step is stricture dilation, performed using rigid or pneumatic dilation catheters. Subsequently, one or more polyethylene stents that traverse the stricture should be placed. The largest diameter and maximum number of stents that are possible should be deployed. The stricture dimensions and bile duct size will dictate the caliber and number of stents, as well as the initial dilation diameter. Placement of more than one stent usually requires endoscopic sphincterotomy. Repeat ERCP is suggested at 3 months, with removal of the indwelling stents and reassessment of the stricture. If the stricture is not adequately resolved, repeat dilation and stenting should be performed, with an increased number of stricture-traversing stents, if possible. This cycle should be continued at 3-month intervals until stricture resolution. Adequate treatment may be judged on cholangiographic findings, the ability to pull inflated balloon catheters through the stricture, and persistence of normal serum liver tests after removal of biliary stents (Figure 4-4). In rare instances, standard ERCP may be unsuccessful despite an accessible papilla due to failed biliary cannulation or inability to traverse the stricture. In this setting, the percutaneous transhepatic placement of a guidewire or catheter into the duode-
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Step 1: Stricture Dilation at ERCP
· ·
Balloon or rigid dilators Dilation size depends on stricture and bile duct diameters
Step 2: Biliary Stent Placement ·
Maximum number/diameter of polyethylene stents as possible across stricture
Step 3: Repeat ERCP at 3 Months ·
Remove previously placed stents Reassess stricture
·
Stricture Present · · ·
Repeat Steps 1-3 Increase dilation diameter Increase stent caliber/number Consider surgical therapy after endoscopic treatment duration greater than 18-24 months
Stricture Resolved · · ·
Clinical follow-up Follow-up serum liver tests Reevaluate for signs/symptoms suggestive of recurrent stricture
Figure 4-3. Algorithm for endoscopic management of benign bile duct strictures.
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Figure 4-4A. ERCP demonstrates anastomotic stricture in a patient 3 months after OLT. Reprinted from Rerknimitr R, et al., Biliary tract complications after orthotopic liver transplantation with choledochocholedochostomy anastomosis. Gastrointestinal Endoscopy, 55:224-31. Copyright 2002, American Society for Gastrointestinal Endoscopy.
Figure 4-4B. Balloon dilation of anastomotic stricture at ERCP.
num may allow successful subsequent ERCP for stricture therapy. This combined endoscopic and PTC technique (“rendezvous” procedure) permits endoscopic biliary access after prior failed ERCP in over 90% of patients88. The rendezvous method is favored over PTC procedures alone, as biliary stricture therapy with PTC may require long-term percutaneous access (1 year or more) and large caliber dilations of the percutaneous, transhepatic tract88. In patients with surgically altered anatomy in which the papilla is inaccessible endoscopically, percutaneous therapy should be considered. Specific instruments are similar to those used endoscopically, and include balloon dilators and biliary drains/ stents. Success rates for transhepatic stricture management are comparable to those achieved endoscopically (approximately 80%) 89,90. There may be an additional role of PTC therapy for proximal and hilar strictures, as endoscopic maneuvers are less successful for treating strictures at those locations87.
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Figure 4-4C. Radiograph after balloon
dilation and placement of 2 plastic stents that traverse the stricture (10F).
Figure 4-4D. Interval cholangiogram
demonstrates complete resolution of anastomotic stricture after successful endoscopic therapy.
Failure of nonoperative management of bile duct strictures justifies surgical therapy. ERCP or PTC failures may occur at the initial procedure when encountering a complete or nearly obstructed stricture. Inability to traverse the stenosis at initial ERCP with either guidewires or stents is reported in approximately 20% of cases 85. Minimally invasive techniques may also be ultimately unsuccessful due to stricture persistence despite treatment, or stricture recurrence. Restenosis develops in 20% of patients within 2 years of stent removal, and at least 40% of these fail repeat endoscopic therapy 85. Operative measures usually involve biliary reconstruction, and may include choledochoduodenostomy, choledochojejunostomy, and hepaticojejunostomy. For select, poor operative candidates who have failed minimally invasive therapy but have ERCP or PTC-accessible strictures, large-diameter self-expandable metallic stents may be considered91. However, metallic stent placement is permanent, and repeat biliary interventions may be required over the long-term in over 50% of
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patients92 . Selection for such therapy is probably best on a case-by-case basis after thorough discussions involving the patient and a multidisciplinary team. Recent technological innovations hold promise for future treatments. Bioabsorbable self-expanding biliary stents have been developed, and may provide large caliber stent therapy for benign strictures without the potential detriment of permanent metallic stents93. However, these are not yet commercially available. Advances in EUS techniques now allow for EUS-guided access to the biliary tree for therapeutic purposes, and may expand the opportunity for endoscopic therapy of previously inaccessible strictures94.
MANAGEMENT OF BILIOVASCULAR FISTULAS Fistulous tracts between the biliary and hepatic arterial system often present as hemobilia. Therapy for this type of injury is twofold, and includes angiographic embolization of the fistula and the ERCP/PTC treatment of clot related biliary obstruction, if present13,56. Surgery is indicated when embolization fails. Overall mortality for this type of fistula is 5%56. Fistulas between the biliary tree and hepatic veins may be treated with biliary stents for decompression in a similar fashion as for bile leak therapy50. Stent placement should promote bile flow in a normal direction instead of into the venous system. However, there is a theoretical risk of flow reversal that may lead to hemobilia if the biliary tree is decompressed to the point of a substantial pressure difference between the two systems50. Fistulas that arise in relation to TIPS may require shunt revision49.
SPECIAL MANAGEMENT CONSIDERATIONS WITH LAPAROSCOPIC CHOLECYSTECTOMY Major bile duct injuries following laparoscopic cholecystectomy usually affect the extrahepatic biliary system, and are often due to accidental ligation, laceration, resection, and/or misapplied clipping of the right, left, or common duct (Figure 45)4,84. Although they usually require operative repair84, dislodgement of partially impinging clips on the extrahepatic duct using balloon dilation at ERCP has been described95. Timely recognition and repair of bile duct injuries following laparoscopic cholecystectomy are extremely important as a long interval between injury and evaluation is associated with the development of liver cirrhosis96.
SPECIAL MANAGEMENT CONSIDERATIONS WITH LIVER TRANSPLANTATION The general approach to the repair of bile leaks and strictures for OLT recipients is similar to that for other patients, and is described in previous sections. However, one specific transplant issue regarding bile leaks worth recognizing is that the endoscopic treatment success is significantly poorer for anastomotic leaks compared to T-tube site leaks (43% versus 95%)18. Anastomotic breakdown is likely a reflection of local ischemia, and may be more difficult to address nonoperatively than leaks at other sites. A particular post-OLT concern with strictures is that those located in the proximal donor biliary system (nonanastomotic) may be the result of ischemia. Concurrent hepatic artery thrombosis or stenosis is found in about 50% of patients with nonanastomotic strictures, and should be investigated and treated, if present13.
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Figure 4-5A. Radiograph demonstrates
numerous surgical clips (arrow) in the region of the common hepatic duct in a patient with prior laparoscopic cholecystectomy.
Figure 4-5B. Cholangiogram reveals major bile duct injury with large volume of contrast extravasation near hilum and no opacification of intrahepatic ducts. This patient required operative repair with hepaticojejunostomy.
One unique type of biliary complication of liver transplantation is the formation of bile duct casts, and occurs in at least 6% of OLT recipients with an associated mortality of 10% 32 . Biliary casts are successfully treated in 60% using endoscopic and percutaneous methods, but operative reconstruction is required for failure of minimally invasive therapy 32 . Most liver transplant recipients are on immunosuppressive regimens. Antibiotic prophylaxis should be considered prior to ERCP or PTC treatment of biliary complications, especially in the setting of possible bile duct obstruction or stricture 97.
Future Considerations The diagnosis and treatment of bile duct injuries is evolving. Advances in noninvasive imaging will likely replace the current standard of direct cholangiography at ERCP or PTC for the diagnosis of most biliary injuries. More importantly, innova-
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tions in technology and endoscopic techniques (eg, bioabsorbable stents, EUS-guided biliary access and bilioenteric anastomoses) 93,94, should expand the role of minimally invasive therapy and allow an even greater proportion of patients with bile duct injuries to be treated nonoperatively. Physicians caring for such patients will need to keep current with new developments in a variety of fields, including noninvasive imaging, therapeutic endoscopy, interventional radiology, and surgery.
Conclusion Injuries to the bile ducts are usually caused iatrogenically, and remain an important source of morbidity for afflicted patients. The most common types of injury include biliary leaks and strictures. An increasing incidence of bile duct injuries may be anticipated given the ongoing popularity of laparoscopic cholecystectomy and the expected rise in liver transplantation. Minimally invasive techniques, such as ERCP, play a vital role in the evaluation of such injuries, and should be used as first-line treatment for the majority.
References 1. Costamagna G, Shah SK, Tringali A. Current management of post-operative complications and benign biliary strictures. Gastrointest Endosc Clinics N Am. 2003;13:635648. 2. Frattaroli FM, Reggio D, Guadalaxara A, et al. Benign biliary strictures: a review of 21 years experience. J Am Coll Surg. 1996;183:506-513. 3. The Southern Surgeons Club. A prospective analysis of 1518 laparoscopic cholecystectomies. N Engl J Med. 1991;324:1073-1078. 4. MacFadyen BV, Vecchio R, Ricardo AE, et al. Bile duct injury after laparoscopic cholecystectomy. Surg Endosc. 1998;12:315-321. 5. Kullman E, Borch K, Lindstrom E, et al. Value of routine intraoperative cholangiography in detecting aberrant bile ducts and bile duct injuries during laparoscopic cholecystectomy. Br J Surg. 1996;83:171-175. 6. Suhocki PV, Meyers WC. Injury to aberrant bile ducts during cholecystectomy: a common cause of diagnostic error and treatment delay. AJR Am J Roentgenol. 1999;172:955-959. 7. Fathy O, Zeid MA, Abdallah T, et al. Laparoscopic cholecystectomy: a report on 2000 cases. Hepatogastroenterology. 2003;50:967-971. 8. Scott TR, Zucker KA, Bailey RW. Laparoscopic cholecystectomy: a review of 12,397 patients. Surg Laparoscopy Endosc. 1992;2:191-198. 9. Regoly-Merei J, Ihasz M, Szeberin Z, et al. Biliary tract complications in laparoscopic cholecystectomy. A multicenter study of 148 biliary tract injuries in 26,440 operations. Surg Endosc. 1998;12:294-300. 10. Deziel DJ, Millikan KW, Economou SG, et al. Complications of laparoscopic cholecystectomy: a national survey of 4,292 hospitals and an analysis of 77,604 cases. Am J Surg. 1993;165:9-14. 11. Flum DR, Dellinger EP, Cheadle A, et al. Intraoperative cholangiography and the risk of common bile duct injury during cholecystectomy. JAMA. 2003;289:16391644.
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12. Flum DR, Koepsell T, Heagerty P, et al. Common bile duct injury during laparoscopic cholecystectomy and the use of intraoperative cholangiography: adverse outcome or preventable error? Arch Surg. 2001;136:1287-1292. 13. Tung BY, Kimmey MB. Biliary complications of orthotopic liver transplantation. Dig Dis. 1999;17:133-144. 14. Klein AS, Savader S, Burdick JF, et al. Reduction of morbidity and mortality from biliary complications of liver transplantation. Hepatology. 1991;14:818-823. 15. Rolles K, Dawson K, Novell R, et al. Biliary anastomosis after liver transplantation does not benefit from T tube splintage. Transplantation. 1994;57:402-404. 16. Greif F, Bronsther OL, Van Thiel DH, et al. The incidence, timing, and management of biliary tract complications after orthotopic liver transplantation. Ann Surg. 1994;219:40-45. 17. O’Connor TP, Lewis D, Jenkins RL. Biliary tract complications after liver transplantation. Arch Surg. 1995;130:312-317. 18. Pfau P, Kochman ML, Lewis JD, et al. Endoscopic management of postoperative biliary complications in orthotopic liver transplantation. Gastrointest Endosc. 2000;52:55-63. 19. Rouch DA, Emond JC, Thistlethwaite JR, et al. Choledochocholedochostomy without a T-tube or internal stent in transplantation of the liver. Surg Gynecol Obstet. 1990;170:239-244. 20. Koivusalo A, Isoniemi H, Salmela K, et al. Biliary complications in one hundred adult liver transplantations. Scand J Gastroenterol. 1996;31:506-511. 21. Sheng R, Sammon JK, Zajko AB, et al. Bile leak after hepatic transplantation: cholangiographic features, prevalence, and clinical outcome. Radiology. 1994;192:413416. 22. Shuhart MC, Kowdley KV, McVicar JP, et al. Predictors of bile leaks after T-tube removal in orthotopic liver transplant recipients. Liver Transpl Surg. 1998;4:62-70. 23. Randall HB, Wachs ME, Somberg KA, et al. The use of T-tube after orthotopic liver transplantation. Transplantation. 1996;61:258-261. 24. Sanchez-Urdazpal L, Gores GJ, Ward EM, et al. Diagnostic features and clinical outcome of ischemic-type biliary complications after liver transplantation. Hepatology. 1993;17:605-609. 25. Colonna JO, Shaked A, Gomes AS, et al. Biliary strictures complicating liver transplantation. Incidence, pathogenesis, management, and outcome. Ann Surg. 1992;216:344-350. 26. Porayko MK, Kondo M, Steers JL. Liver transplantation: late complications of the biliary tract and their management. Semin Liver Dis. 1995;15:139-155. 27. Vougas V, Rela M, Gane E, et al. A prospective randomized trial of bile duct reconstruction at liver transplantation: T-tube or no T-tube? Transpl Int. 1996;9:492495. 28. Nuno J, Vicente E, Turrion VS, et al. Biliary tract reconstruction after liver transplantation: with or without T-tube? Tranplant Proc. 1997;29:564-565. 29. Barton P, Maier A, Steininger R, et al. Biliary sludge after liver transplantation: 1. Imaging findings and efficacy of various imaging procedures. AJR Am J Roentgenol. 1995;164:859-864. 30. Somberg KA, Osorio RW, Lake JR, et al. Choledocholithiasis following orthotopic liver transplantation (OLT): clinical features, risk factors, and endoscopic management (abstract). Gastrointest Endosc. 1993;39:328.
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31. Rerknimitr R, Sherman S, Fogel EL, et al. Biliary tract complications after orthotopic liver transplantation with choledochocholedochostomy anastomosis: Endoscopic findings and results of therapy. Gastrointest Endosc. 2002;55:224-31. 32. Shah JN, Haigh WG, Lee SP, et al. Biliary casts after orthotopic liver transplantation: clinical factors, treatment, and biochemical analysis. Am J Gastroenterol. 2003;98:1861-1867. 33. Brown RS, Russo MW, Lai M, et al. A survey of liver transplantation from living adult donors in the United States. N Engl J Med. 2003;348:818-825. 34. Testa G, Malago M, Valentin-Gamazo C, et al. Biliary anastomosis in living related liver transplantation using right liver lobe: techniques and complications. Liver Transpl. 2000;6:710-714. 35. Ishiko T, Egawa H, Kasahara M, et al. Duct-to-duct biliary reconstruction in living donor liver transplantation utilizing right lobe graft. Ann Surg. 2002;236:235-240. 36. Shah JN, Ahmad NA, Shetty K, et al. Biliary tract complications following living donor liver transplantation: types and endoscopic management (abstract). Gastrointest Endosc. 2003;57:AB203. 37. Park JS, Kim MH, Lee SK, et al. Efficacy of endoscopic and percutaneous treatments for biliary complications after cadaveric and living donor liver transplantation. Gastrointest Endosc. 2003;57:78-85. 38. Icoz G, Kilic M, Zeytunlu M, et al. Biliary reconstructions and complications encountered in 50 consecutive right-lobe living donor liver transplantations. Liver Transpl. 2003;9:575-80. 39. Hasegawa K, Yazumi S, Egawa H, et al. Endoscopic management of postoperative biliary complications in donors for living donor liver transplantation. Clin Gastroenterol Hepatol. 2003;1:183-188. 40. Lo CM. Complications and long-term outcome of living liver donors: a survey of 1,508 cases in five Asian centers. Transplantation. 2003;75:S12-5. 41. Rhim H, Yoon KH, Lee JM, et al. Major complications after radio-frequency thermal ablation of hepatic tumors: spectrum of imaging findings. Radiographics. 2003; 23:123-134. 42. Vogl TJ, Straub R, Eichler K, et al. Malignant liver tumors treated with MR imaging-guided laser-induced thermotherapy: experience with complications in 899 patients (2,520 lesions). Radiology. 2002;225:367-377. 43. Kim HK, Chung YH, Song BC, et al. Ischemic bile duct injury as a serious complication after transarterial chemoembolization in patients with hepatocellular carcinoma. J Clin Gastroenterol. 2001;32:423-427. 44. Yu JS, Kim KW, Jeong MG, et al. Predisposing factors of bile duct injury after transcatheter arterial chemoembolization (TACE) for hepatic malignancy. Cardiovasc Intervent Radiol. 2002;25:270-274. 45. Sarantou T, Bilchik A, Ramming KP. Complications of hepatic cryosurgery. Sem Surg Oncol. 1998;14:156-162. 46. Iannitti DA, Heniford T, Hale J, et al. Laparoscopic cryoablation of hepatic metastases. Arch Surg. 1998;133:1011-1015. 47. Nakakubo Y, Kondo S, Katoh H, et al. Biliary stricture as a possible late complication of radiation therapy. Hepatogastroenterology. 2000; 47: 1531-1532. 48. Schmets L, Delhaye M, Azar C, et al. Postradiotherapy benign biliary stricture: successful treatment by self-expandable metallic stent. Gastrointest Endosc. 1996; 43:149-152.
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49. Boyer TD. Transjugular intrahepatic portosystemic shunt: current status. Gastroenterology. 2003;124:1700-1710. 50. Mallery S, Freeman ML, Peine CJ, et al. Biliary-shunt fistula following transjugular intrahepatic portosystemic shunt placement. Gastroenterology. 1996;111:1353-1357. 51. Cohen MB, A-Kader HH, Lambers D, et al. Complications of percutaneous liver biopsy in children. Gastroenterology. 1992;102: 629-632. 52. Grant A, Neuberger J. Guidelines in the use of liver biopsy in clinical practice. Gut. 1999;45:IV1-IV11. 53. Parks RW, Chrysos E, Diamond T. Management of liver trauma. Br J Surgery. 2000;87:519-520. 54. Degiannis E, Khelif K, Leandros E, et al. Gunshot injuries of the extrahepatic biliary ducts. Eur J Surg. 2001;167:618-621. 55. Harrell DJ, Vitale GC, Larson GM. Selective role for endoscopic retrograde cholangiopancreatography in abdominal trauma. Surg Endosc. 1998;12:400-404. 56. Green MH, Duell RM, Johnson CD, et al. Haemobilia. Br J Surg. 2001;88:77386. 57. Mutignani M, Shah SK, Tringali A, et al. Endoscopic therapy for bile leaks from aberrant right hepatic ducts severed during cholecystectomy. Gastrointest Endosc. 2002;55:932-936. 58. Brooks DC, Becker JM, Connors PJ, et al. Management of bile leaks following laparoscopic cholecystectomy. Surg Endosc. 1993;7:292-295. 59. Brugge WR, Rosenberg DJ, Alavi A. Diagnosis of postoperative bile leaks. Am J Gastroenterol. 1994;89:2178-2183. 60. Brugge WR, Alavi A. Cholescintigraphy in the diagnosis of the complications of laparoscopic cholecystectomy. Semin Ultrasound CT MR. 1993;14:368-374. 61. Kurzawinski TR, Sleves L, Farouk M, et al. Prospective study of hepatobiliary scintigraphy and endoscopic cholangiography for the detection of early biliary complications after orthotopic liver transplantation. Br J Surg. 1997;84:620-623. 62. Khalid TR, Casillas VJ, Montalvo BM, et al. Using MR cholangiopancreatography to evaluate iatrogenic bile duct injury. AJR Am J Roentgenol. 2001;177:1347-1352. 63. Wicky S, Gudinchet F, Barghouth G, et al. Three-dimensional cholangio-spiral CT demonstration of a post-traumatic bile leak in a child. Eur Radiol. 1999;9:99-102. 64. Stockberger SM, Johnson MS. Spiral CT cholangiography in complex bile duct injuries after laparoscopic cholecystectomy. J Vasc Interv Radiol. 1997;8:249-252. 65. Costamagna G, Pandolfi M, Mutignani M, et al. Long-term results of endoscopic management of postoperative bile duct strictures with increasing numbers of stents. Gastrointest Endosc. 2001;54:162-168. 66. Taylor AC, Little AF, Hennessy OF, et al. Prospective assessment of magnetic resonance cholangiopancreatography for noninvasive imaging of the biliary tree. Gastrointest Endosc. 2002;55:17-22. 67. Chaudhary A, Negi SS, Puri SK, et al. Comparison of magnetic resonance cholangiography and percutaneous transhepatic cholangiography in the evaluation of bile duct strictures after cholecystectomy. Br J Surg. 2002;89:433-436. 68. Yeh TS, Jan YY, Tseng JH, et al. Value of magnetic resonance cholangiopancreatography in demonstrating major bile duct injuries following laparoscopic cholecystectomy. Br J Surg. 1999;86:181-184. 69. Llach J, Bordas JM, Elizalde JI, et al. Sphincterotomy in the treatment of biliary leakage. Hepatogastroenterology. 2002;49:1496-1498.
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70. Bjorkman DJ, Carr-Locke DL, Lichtenstein DR, et al. Postsurgical bile leaks: endoscopic obliteration of the transpapillary pressure gradient is enough. Am J Gastroenterol. 1995;90:2128-2133. 71. Morelli J, Mulcahy HE, Willner IR, et al. Endoscopic treatment of post-liver transplantation biliary leaks with stent placement across the leak site. Gastrointest Endosc. 2001;54:471-475. 72. Marks JM, Ponsky JL, Shillingstad RB, et al. Biliary stenting is more effective than sphincterotomy in the resolution of biliary leaks. Surg Endosc. 1998;12:327-330. 73. Al-Karawi MA, Sanai FM. Endoscopic management of bile duct injuries in 107 patients: experience of a Saudi referral center. Hepatogastroenterology. 2002;49:12011207. 74. Neidich R, Soper N, Edmundowicz S, et al. Endoscopic management of bile leaks after attempted laparoscopic cholecystectomy. Surg Laparosc Endosc. 1996:6:348354. 75. Sherman S, Jamidar P, Shaked A, et al. Biliary tract complications after orthotopic liver transplantation. Endoscopic approach to diagnosis and therapy. Transplantation. 1995;60:467-470. 76. Kozarek RA, Ball TJ, Patterson DJ, et al. Endoscopic treatment of biliary injury in the era of laparoscopic cholecystectomy. Gastrointest Endosc. 1994;40:10-16. 77. Ponchon T, Gallez JF, Valette PJ, et al. Endoscopic treatment of biliary tract fistulas. Gastrointest Endosc. 1989;35:490-498. 78. Goodwin SC, Bittner CA, Patel MC, et al. Technique for reduction of bile peritonitis after T-tube removal in liver transplant patients. J Vasc Interv Radiol. 1998;9:986990. 79. Brodsky JA, Marks JM, Malm JA, et al. Sphincter of Oddi injection with botulinum toxin is as effective as endobiliary stent in resolving cystic duct leaks in a canine model. Gastrointest Endosc. 2002;56:849-851. 80. Seewald S, Groth S, Sriram PVJ, et al. Endoscopic treatment of biliary leakage with n-butyl-2-cyanoacrylate. Gastrointest Endosc. 2002;56:916-919. 81. Ernst O, Sergent G, Mizrahi D, et al. Biliary leaks: treatment by means of percutaneous transhepatic biliary drainage. Radiology. 1999;211:345-348. 82. Bergman JJ, van den Brink GR, Rauws EA, et al. Treatment of bile duct lesions after laparoscopic cholecystectomy. Gut. 1996;38:141-147. 83. Thuluvath PJ, Atassi T, Lee J. An endoscopic approach to biliary complications following orthotopic liver transplantation. Liver International. 2003;23:156-162. 84. Bauer TW, Morris JB, Lowenstein A, et al. The consequences of major bile duct injury during laparoscopic cholecystectomy. J Gastrointest Surg. 1998;2:61-66. 85. Bergman JJ, Burgemeister L, Bruno MJ, et al. Long-term follow-up after biliary stent placement for postoperative bile duct stenosis. Gastrointest Endosc. 2001;54:154-161. 86. Morelli J, Mulcahy HE, Willner IR, et al. Long-term outcomes for patients with post-liver transplant anastomotic biliary strictures treated by endoscopic stent placement. Gastrointest Endosc. 2003;58:374-379. 87. Draganov P, Hoffman B, Marsh W, et al. Long-term outcome in patients with benign biliary strictures treated endoscopically with multiple stents. Gastrointest Endosc. 2002;55:680-686. 88. Verstandig AG, Goldin E, Sasson T, et al. Combined transhepatic and endoscopic procedures in the biliary system. Postgrad Med J. 1993;69:384-388.
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89. Kim JH, Lee SK, Kim MH, et al. Percutaneous transhepatic cholangioscopic treatment of patients with benign bilio-enteric anastomotic strictures. Gastrointest Endosc. 2003;58:733-738. 90. Roumilhac D, Poyet G, Sergent G, et al. Long-term results of percutaneous management for anastomotic biliary stricture after orthotopic liver transplantation. Liver Transpl. 2003;9:394-400. 91. Schmets L, Delhaye M, Azar C, et al. Postradiotherapy benign biliary stricture: successful treatment by self-expandable metallic stent. Gastrointest Endosc. 1996;43:149152. 92. Tesdal IK, Adamus R, Poeckler C, et al. Therapy for biliary stenoses and occlusions with use of three different metallic stents: single-center experience. J Vasc Interv Radiol. 1997;8:869-879. 93. Ginsberg G, Cope C, Shah JN, et al. In vivo evaluation of a new bioabsorbable selfexpanding biliary stent. Gastrointest Endosc. 2003;58:777-784. 94. Mallery S, Matlock J, Freeman ML. EUS-guided rendezvous drainage of obstructed biliary and pancreatic ducts: report of 6 cases. Gastrointest Endosc. 2004;59:100107. 95. Bauer TW, Morris JB, Lowenstein A, et al. The consequences of a major bile duct injury during laparoscopic cholecystectomy. J Gastrointest Surg. 1998;2:61-66. 96. Leggett P, Atwa H, Hamat H. Use of endoscopic retrograde cholangiopancreatography to dislodge clip impingement on the common hepatic duct. Surg Endosc. 2001;15:1490. 97. Nordin A, Halme L, Makisalo H, et al. Management and outcome of major bile duct injuries after laparoscopic cholecystectomy: from therapeutic endoscopy to liver transplantation. Liver Transpl. 2002;8:1036-1043. 98. Hirota WK, Petersen K, Baron TH, et al. Guidelines for antibiotic prophylaxis for GI endoscopy. Gastrointest Endosc. 2003;58:475-482.
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5
Ampullary Disorders William B. Silverman, MD, FACG
Introduction Ampullary disorders of the major papilla of Vater are twofold: the first being problems of the sphincter itself (sphincter of Oddi dysfunction) and the second concerning disorders of the mucosa around the major papilla (ampullary dysplasia). These will be discussed in this chapter.
Sphincter of Oddi Dysfunction Sphincter of Oddi dysfunction has been described by Geenen and colleagues1. It is thought to cause outflow obstruction of either the biliary and/or pancreatic ductal system, leading to symptoms of abdominal pain, nausea, and vomiting as well as signs (elevated hepatic enzymes, elevated amylase or lipase, dilated bile duct and/or pancreas ductal systems). It has been most often described in the post-cholecystectomy situation, hence the name “post-cholecystectomy syndrome”. The underlying pathophysiology is thought to be related to sphincter muscle dysfunction, resulting in increased sphincter muscle tone, failure of the sphincter to relax, or fibrosis either in the muscle or in the region of the muscle resulting in a fixed outlet obstruction. Causes for this problem are not known with certainty. The passage of occult biliary lithiasis may also be involved.
DIAGNOSIS Sphincter of Oddi dysfunction may be categorized as either biliary or pancreatic, depending on the patient’s symptoms and serum and radiographic imaging study abnormalities. Most investigative work has involved the biliary system. More recently, studies investigating the pancreatic portion of this disorder have been described.
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Table 5-1
CLASSIC CRITERIA FOR BILIARY SPHINCTER OF ODDI DYSFUNCTION SOD TYPE Pain
Abnormal Hepatic Enzymes on 2 Occasions
Dilated CBD
Delayed Drainage >45 min
I II III
+ + -
+ or + -
+ or + -
+ + +
SOD = sphincter of Oddi dysfunction; CBD = common bile duct
MILWAUKEE CLASSIFICATION—BILIARY Criteria used in the classic Milwaukee classification (Table 5-1) include suggestive abdominal pain that is episodic, lasting 45 minutes to several hours, and is located in the epigastrium and right upper quadrant. There may be elevated hepatic enzymes >2 times the upper limit of normal on more than one occasion, a dilated biliary ductal system, and delay in drainage of contrast from the biliary ductal system immediately after a retrograde cholangiogram. Presence of all of these factors constitutes Type I biliary sphincter of Oddi dysfunction. This is believed to be due to fibrosis at the level of the sphincter muscle, resulting in a fixed obstruction. Presence of suggestive pain plus elevated serum liver test or dilated biliary ducts or delay in contrast after retrograde cholangiogram constitutes sphincter of Oddi dysfunction Type II, believed to be a functional obstruction at the level of the muscle resulting from sphincter spasm. Presence of suggestive abdominal pain in the absence of either radiographic or serum blood test abnormalities would be consistent with Type III biliary sphincter of Oddi dysfunction. The criteria for biliary sphincter of Oddi dysfunction have been relaxed somewhat in recent years by clinical investigators. The reasons for this are mostly pragmatic. Rather than having elevated serum liver numbers on two occasions, one occasion is frequently considered satisfactory. Likewise, hepatic enzyme elevation greater than two times the upper limit of normal has been relaxed to 1½ times the upper limit of normal or simply any elevation at all would be considered adequate for the distinction between sphincter of Oddi dysfunction Type II versus Type III. Finally, the criteria of “delay in contrast after retrograde cholangiogram” has been largely abandoned. The distinction between classic and contemporary criteria for sphincter of Oddi dysfunction has been well summarized in a recent review by Petersen 2 .
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Table 5-2
CLASSIC CRITERIA FOR PANCREATIC SPHINCTER OF ODDI SOD
Pain
Abnormal Pancreas Dilated Delayed Drainage Enzymes on 2 PD >8 min Occasions
I II III
+ + +
+ + -
+ or + -
+ or + -
SOD = sphincter of Oddi dysfunction; PD = pancreas duct
PANCREATIC SPHINCTER OF ODDI DYSFUNCTION The classification is similar to that used in biliary disorders (Table 5-2). There have been fewer investigations in this area relative to biliary dyskinesia. Patients typically present with clinical pancreatitis. It is important to exclude other causes of pancreatitis, including gallstones, tumors, medications, viruses, pancreas divisum, and inherited disorders (familial pancreatitis, cystic fibrosis, celiac disease, hypertriglyceridemia, etc).
DIAGNOSTIC TESTING FOR SPHINCTER OF ODDI DYSFUNCTION Patients with pain suggestive of a pancreaticobiliary origin plus putative serum laboratory or radiographic abnormalities (dilated biliary or pancreatic ductal system in the absence of obstructing mass lesion) are often evaluated for sphincter of Oddi dysfunction. The Milwaukee criteria mentioned above are used for initial screening. Older, noninvasive provocation tests (morphine-prostigmine test) were described by Nardi and Acosta 3. Elevated serum liver numbers accompanied by typical symptoms after this test were considered diagnostic of biliary sphincter of Oddi dysfunction. Unfortunately, the test was poorly tolerated by patients and was later abandoned in favor of other tests, notably sphincter of Oddi manometry. Sphincter of Oddi manometry with ERCP is considered the current gold standard for the diagnosis of sphincter of Oddi dysfunction. Sphincter of Oddi manometry, as currently practiced, employs a triple lumen perfusion catheter placed into the lumen of the sphincter of Oddi. It is performed during the same session as ERCP, although it was customarily performed during a separate session years ago. Basal sphincter pressure, phasic sphincter pressure, frequency of contractions, duration of contractions, and the determination of antegrade/simultaneous/retrograde contractions within the perfused catheters are the classic diagnostic criteria measured. Most contemporary investigators use only basal sphincter pressure to diagnose sphincter of Oddi dysfunction. Depending on the technique used, either three or two perfusion catheter channels can be used to measure pressure. If two leads are used, the third catheter channel is used to aspirate perfused fluid, to prevent overfilling of the pancreatic ductal
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system. The aspiration technique, described by investigators in Indiana, has resulted in a statistically significant reduction in ERCP/Sphincter of Oddi manometry related pancreatitis rates compared to nonaspiration methods. Validation of sphincter of Oddi manometry in predicting clinical improvement after endoscopic sphincterotomy has been published by Geenen and colleagues in a well-designed prospective randomized control trial. Elevated basal sphincter pressure greater than 40 mm Hg, relative to duodenal pressure, was shown to be the most useful predictor of relief of symptoms after biliary sphincterotomy in patients with biliary sphincter of Oddi dysfunction Type II. Because the majority of patients with sphincter of Oddi dysfunction Type I will have elevated basal sphincter pressure on manometry, the clinical utility of performing this extra test during ERCP test for Type I patients has been questioned. Most investigators do empiric endoscopic sphincterotomy without the manometry. As noted in a recent review article, supportive data for this traditional practice are lacking. Contemporary interpretation of biliary and pancreatic sphincter of Oddi manometry involves determination of basal sphincter pressure alone. The other criteria (phasic or peaks sphincter pressures, frequency of contractions, duration of contractions, or the determination of retrograde contractions) have been largely abandoned both in clinical and research arenas. Abnormalities of these latter criteria due to physiologic phenomena such as migrating motor complex have been suggested by others. Delay in ductal drainage at the time of ERCP has been found to occur in patients without manometric criteria for sphincter of Oddi dysfunction. Given the risks inherent in ERCP/manometry, as well as the equivocal benefits to many patients, the development of a noninvasive screening test for patients with potential sphincter of Oddi would be desirable. Two tests done include provocative pancreatic or biliary ultrasound testing or provocative biliary cholescintigraphy. Correlation with the current gold standard (sphincter of Oddi manometry), however, has been disappointing. Hence, while these noninvasive provocative tests may be well tolerated, their clinical utility may be suboptimal.
DIFFERENTIAL DIAGNOSIS OF SPHINCTER OF ODDI DYSFUNCTION The symptoms and signs seen with sphincter of Oddi dysfunction are seen in other diseases as well. It is important to exclude these other entities. In the setting of sphincter of Oddi Type I, fixed obstruction due to tumor involving the ampulla of Vater, pancreatic head, or biliary ductal system needs to be excluded. Occult biliary lithiasis or microlithiasis would cause biliary or pancreatic ductal system dilation with fluctuating elevations in either biliary or pancreatic serum liver tests and would present in a similar manner as sphincter of Oddi Type II. Idiopathic pancreatitis may be due to pancreatic sphincter of Oddi dysfunction or may be a separate entity unrelated to the sphincter of Oddi dysfunction. Chronic pancreatitis, unrelated to the sphincter of Oddi, may present with abdominal pain and fluctuations in serum amylase or lipase. Whether sphincter of Oddi dysfunction occurs in the setting of chronic pancreatitis remains controversial. More controversial still is whether elevated pancreatic basal sphincter pressures in chronic pancreatitis are a cause of that entity or an epi-phenomenon resulting from it. Most frustrating is the evaluation and management of biliary and pancreatic sphincter of Oddi dysfunction Type III. In this entity, patients present with “sugges-
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tive” biliary or pancreatic symptoms. Even the most seasoned senior clinician would admit difficulty implicating a pancreaticobiliary etiology of abdominal pain, to the exclusion of all other potential etiologies, in this situation. The coexistence of gut motility disorders in this entity has been shown. Equally so, coexistence of luminal gut barostatic abnormalities has been demonstrated. Additional disease processes to exclude in the setting of abdominal pain with normal serum testing and radiographic testing include peptic ulcer disease, coronary artery disease, musculoskeletal related pain, gut ischemia, and somatization disorders. The list is long. A careful, methodical approach is key here.
TREATMENT OF SPHINCTER OF ODDI DYSFUNCTION In patients with Type I sphincter of Oddi dysfunction, after excluding ductal obstruction due to mass lesions, ERCP with biliary or pancreatic endoscopic sphincterotomy would be the treatment of choice. Addition of sphincter of Oddi manometry in this setting is not commonly done. Biliary or pancreatic sphincter of Oddi dysfunction Type II and III normally requires the addition of sphincter of Oddi manometry to ERCP to measure ductal basal sphincter pressure. Empiric sphincterotomy in the absence of confirmatory sphincter of Oddi manometry abnormality for SOD II has been suggested by some, but is to be discouraged based on a recent consensus conference conclusion. Traditionally, biliary sphincterotomy alone, which also ablates the common sphincter segment, has been the treatment of choice in treating both biliary and pancreatic SOD II and III. Pancreatic sphincterotomy was believed to be hazardous. Dual (biliary and pancreatic) sphincterotomy has been advocated when there is manometric confirmation of pancreatic sphincter hypertension. This is based on the observation that many patients with pancreatic sphincter hypertension who are treated with “biliary only” sphincterotomy will require repeat ERCP with pancreatic sphincterotomy for persistent symptoms 4. As manometry and sphincterotomy of the pancreatic duct are associated with an increased rate of ERCP related complications, these should be reserved for centers that offer expertise in these procedures. Sphincter of Oddi dysfunction Type III, with its “suggestive” pain but absence of serum or radiographic testing abnormalities, continues to remain both the most frustrating to treat and the most controversial category of sphincter of Oddi dysfunction. Whether the symptoms described by the patient are, in fact, due to abnormalities at the level of the sphincter of Oddi, or whether they are functional and related to other portions of the gut (irritable bowel syndrome variant) has been suggested. Empiric trials of medications such as anticolon tricyclic antidepressants and sphincter relaxing medicines such as nitrates and calcium channel blockers prior to consideration of ERCP with sphincter of Oddi manometry have been advocated, as the rate of complications from ERCP may exceed the benefit in this setting. Improvement in symptoms after endoscopic sphincterotomy varies widely from 30% to 80%, depending upon whether the patient has type I, II, or III SOD and whether there is biliary and/or pancreatic sphincter involvement. Interpretation of positive results is hampered by both small study sample size and a lack of standardization regarding outcomes. In general, patients with Type I SOD respond better to sphincter ablation than do Type II patients. Type III SOD patients tend to respond the least well.
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COMPLICATIONS OF TREATMENT Complications of sphincter of Oddi manometry and endoscopic treatment of patients with sphincter of Oddi dysfunction are largely related to those inherent to the ERCP procedure, rather than being unique to the manometry, and include pancreatitis (5% to 30%), perforation (<1%), bleeding (1% to 2%), and cardiopulmonary complications (<1%). The risk of pancreatitis in this group of patients is higher than those with other disorders for which ERCP is performed5. Either edema at the level of the major papilla or spasm of the pancreatic portion of the sphincter of Oddi is believed to be the cause of the increased rate of pancreatitis following the ERCP procedure. Placement of a temporary narrow caliber pancreatic stent after ERCP in this setting has been shown to substantially reduce the incidence of post-ERCP pancreatitis 6. Either trimming of the upstream barb to allow spontaneous passage of that stent or subsequent endoscopic removal of the stent several weeks post index ERCP is commonly done. Leaving the stent in place for a long duration is discouraged as pancreatic ductal damage may occur.
Ampullary Dysplasia Dysplastic lesions of the ampulla of Vater include adenomas, lipomas, neuroendocrine tumors, gastrointestinal stromal tumors, adenocarcinoma originating at the major papilla, as well as metastatic lesions. Adenoma of the major papilla are seen both sporadically and in the setting of familial polyposis syndromes such as familial adenomatous polyposis (FAP). Adenomas in FAP present at a younger age than those in whom the lesions present sporadically. Sporadic lesions tend to present in patients who are middle aged or older. Adenocarcinoma of the ampulla of Vater occurs in 2.9 cases per million of the general population. Twenty-five percent of these may be resectable surgically.
SIGNS AND SYMPTOMS Presenting signs and symptoms in patients with ampullary adenomas or adenocarcinomas of the major papilla are related to obstruction of the pancreaticobiliary tree at that level. These include elevated hepatic enzymes and jaundice, which is most commonly painless. Elevated amylase and/or lipase or symptoms related to acute pancreatitis are less commonly seen. Rarely, these patients present with GI bleeding.
DIAGNOSTIC MODALITIES In patients who present with painless jaundice, radiographic studies such as ultrasound and CT scan are commonly performed. Dilation of the biliary or pancreatic ductal systems directs the clinician toward a lesion at the level of the ampulla of Vater. Subsequent ERCP and/or endoscopic ultrasound (EUS) is frequently the next step. Side-viewing endoscopy allows a better view of the major papilla than end-viewing endoscopy, which may either overestimate or underestimate the degree of involvement of the ampulla. ERCP-related therapy might permit relief of the obstructive jaundice, as well as tissue sampling from the major papilla. EUS allows evaluation of lesion depth into the mucosa and local/regional staging. These two tests are complimentary. Magnetic resonance cholangiopancreatography (MRCP) is a newer modality and not
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Figure 5-1. Endoscopic snare resection
of a villous adenoma of the ampulla of Vater. Here, the ampulla of Vater is visualized with a side viewing duodenoscope. Note the fungating appearance of the ampullary orifice. For full-color version, see page CA III of the Color Atlas.
universally available. It is not clear yet whether this test offers significant advantages over CT scan in evaluating ductal dilation, lesion location, and depth of parenchymal involvement. Tissue sampling may be done either via endoscopic pinch biopsy, snare ampullectomy, or EUS-directed fine needle aspiration. Between 35% and 60% of ampullary adenomas may harbor small foci of adenocarcinoma. Diagnostic accuracy rates of biopsies range from 45% to 80% according to a recent review by Martin and Haber 7. False negative endoscopic biopsies have been described in 25% to 60% of patients with carcinoma and are mostly attributed to sampling error. EUS is accurate for T-staging of ampullary adenomas and adenocarcinomas but less accurate for N and M staging. EUS imaging cannot distinguish malignant from nonmalignant tissues. However, EUS-directed fine needle aspiration can do this, and may compliment tissue acquisition done by a brushing and pinch biopsy. The role of EUS in the staging of ampullary carcinoma is further discussed in Chapter 15.
TREATMENT MODALITIES FOR AMPULLARY ADENOMAS AND ADENOCARCINOMAS Endoscopic snare ampullectomy has been reported by numerous groups for treatment of ampullary adenomas or early T1 adenocarcinomas. Current techniques for performing an endoscopic snare resection of an ampullary adenoma vary from institution to institution. In general, however, pancreatic and biliary sphincterotomies are performed with stenting of the pancreas duct and selective stenting of the bile duct. En bloc snare resection or piecemeal snare resection of the lesion are then used (Figures 5-1 and 5-2). Prophylactic injection of saline and epinephrine to elevate the lesion from the submucosal tissue prior to snare resection is done in many centers. EUS offers advantages of determining depth of lesion involvement but is not universally performed. As reported by Desilets and colleagues 8, 13 of 41 patients referred for endoscopic snare resection of ampullary adenomas underwent the procedure. A mean of 2.7 ERCPs were performed per patient and 92% were deemed lesion-free. Endoscopic snare resection was unsuccessful in one patient. Pancreatitis developed in one patient. Complication rates have been higher in other series with rates as high
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Figure 5-2. Dual sphincterotomies of
the pancreatic and biliary orifices have been performed. The pancreatic duct has been stented with a short, narrow caliber stent in preparation for snare ampullectomy. For full-color version, see page CA III of the Color Atlas.
as 20% noted. Bleeding and perforation are the most common immediate complications. Ampullary scarring with subsequent ductal obstruction has also been reported. Recurrence of dysplastic tissue at the resection site may be seen in 20% to 33% of cases. Because the precise depth of adenoma penetration as well as depth of tissue resection may be hard to gauge, endoscopic snare resection risks failing to remove all dysplastic tissue. Endoscopic surveillance with or without EUS is prudent, although there is a lack of standardization as to how frequently this should be done. Ideal candidates for endoscopic snare resection would be those in whom surgical resection would be poorly tolerated or where local surgical expertise is not available.
SURGICAL RESECTION The first surgical resection of the ampulla of Vater was performed by Halsted in 1899. Local excision for patients with T1 carcinomas has been advocated by some, however, the question of incomplete tissue resection remains. It has also been suggested that up to 10% of patients with T1 lesions will have local lymph node involvement. For this reason, many groups prefer to perform pancreaticoduodenectomy, either the classic Whipple resection or the pyloric sparing procedure. Whipple resection is a specialized procedure best performed by those individual surgeons or groups with sufficient experience and volume to assure satisfactory outcomes. Procedure-related mortality should be less than 5%. Morbidity associated with the procedure remains substantial, ranging from 25% to 50% 9.
Conclusion Sphincter of Oddi Type I may be treated with empiric endoscopic sphincterotomy after exclusion of other lesions, most notably malignancy (ampullary, pancreatic, cholangiocarcinoma). Sphincter of Oddi dysfunction Types II and III are best managed conservatively. The decision to intervene with ERCP and sphincter of Oddi manometry should be based on failure of conservative management to resolve or control symptoms and signs adequately. The differential diagnosis for sphincter of Oddi dysfunction Type II would include occult biliary lithiasis and idiopathic pancreatitis. For
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sphincter of Oddi dysfunction Type III, it would include functional bowel disorders. Exclusion of other entities, such as coronary artery disease, dissecting aortic aneurysm, and musculoskeletal symptoms, is also important. Ampullary adenomas may be associated with inherited syndromes, such as familial adenomatous polyposis, or may occur sporadically. Obstructive signs and symptoms of bile duct or pancreas duct obstruction usually prompt the diagnosis. Endoscopic snare resection for small lesions may be performed by experienced operators. Issues of incomplete tissue resection or lesion recurrence are important when considering endoscopic resection. Larger lesions or those lesions with submucosal involvement may require surgical resection via pancreaticoduodenectomy. This may be best accomplished in a referral center.
Areas for Future Development As shown at the recent NIH State of the Science Conference, most investigations of sphincter of Oddi dysfunction have either been in prospective randomized control trials involving small numbers of patients, or larger retrospective analyses and case series10. Because this is a frequently encountered clinical entity, large, well-designed, multicenter, prospective randomized controlled trials are needed. Whether the current data accumulated to date would withstand the rigors of such a trial is unknown. A similar multicenter trial of endoscopic ampullary resection would also be desirable.
References 1. Geenen JE, Hogan WJ, Dodds WJ, Toouli J, Venu RP. The efficacy of endoscopic sphincterotomy after cholecystectomy in patients with sphincter of Oddi dysfunction. N Engl J Med. 1989;320:82-87. 2. Petersen BT. An evidence-based review of sphincter of Oddi dysfunction: part 1, presentations with “objective” biliary findings (types I and II). Gastrointest Endosc. 2004;59(4):525-534. 3. Nardi GL, Acosta JM. Papillitis and stenosis of the sphincter of Oddi. Surg Clin North Am. 1973;53(5):1149-1160. 4. Eversman D, Fogel EL, Rusche M, Sherman S, Lehman G. Frequency of abnormal pancreatic and biliary sphincter of Oddi manometry compared with clinical suspicion of sphincter of Oddi dysfunction. Gastrointest Endosc. 1999;50:637-641. 5. Freeman ML, Nelson DB, Sherman S, et al. Complications of endoscopic biliary sphincterotomy. N Engl J Med. 1996;335:909-18. 6. Tarnasky P, Palesch YY, Cunningham JT, Mauldin PD, Cotton PB, Hawes RH. Pancreatic stent prevents pancreatitis after biliary sphincterotomy in patients with sphincter of Oddi dysfunction. Gastroenterology. 1998;115:1518-1524. 7. Martin JA, Haber GB. Ampullary adenoma: clinical manifestations diagnosis and treatment. Gastrointest Endosc Clinics N Am. 2003;13:649-669. 8. Desilets DJ, Dy RM, Qu PM, Hanson DL, Elton E, Mattia A, Howell DA. Endoscopic management of tumors of the major papilla: refined techniques to improve outcome and avoid complications. Gastrointest Endosc. 2001;54:2002-2008. 9. Yeo CJ, Cameron JL, Sohn TA, et al. 650 consecutive pancreatico-duodenectomies in the 1990s: Pathology, complications and outcomes. Ann Surg. 1997;226:248-260.
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10. Cohen S, Bacon BR, Berlin JA, et al. National Institutes of Health State-of-theScience Conference statement: ERCP for diagnosis and therapy, January 14-16, 2002. Gastrointest Endosc. 2002;56:803-809.
Bibliography Abraham HD, Anderson C, Lee D. Somatization disorder in sphincter of Oddi dysfunction. Psychosom Med. 1997;59:459-466. Anderson JB, Cooper MJ, Williamson RCN. Adenocarcinoma of the extrahepatic biliary tree. Ann Royal Coll Surg Engl. 1985;67:139-143. Ashkark A, Deeb LS, Bikhazik, Arnaout MS. Unusual manifestation of an ampullary tumor presenting with severe upper GI bleeding. Digestion. 1999;60:583. Binmoeller KF, Boaventura S, Ramsperger K, Soehendra N. Endoscopic snare resection of benign adenomas of the papilla of Vater. Gastrointest Endosc. 1993;39:127131. Bleau BL, Gostout CJ. Endoscopic treatment of ampullary adenomas and familial adenomatous polyposis. J Clin Gastroenterol. 1996;22:237. Chun A, Mitrani C, Startz T, DiLorenzo C. Visceral algesia in irritable bowel syndrome, fibromyalgia and sphincter of Oddi dysfunction, type III. Dig Dis Sci. 1999;44:631-636. Coyle WJ, Pineau BC, Tarnasky PR, et al. Evaluation of unexplained acute and acute recurrent pancreatitis using endoscopic retrograde cholangiopancreatography, sphincter of Oddi manometry and endoscopic ultrasound pancreatitis. Endoscopy. 2002;34:617-623. Faisel A, Quadri A Catalano, M Meyerson S, Geenen J. Does a pancreatic stent prevent post-ERCP pancreatitis? A prospective randomized study. Gastrointest Endosc. 2002;34:617-623. Halsted WS. Contributions to the surgery of the bile passages, especially of the common bile duct. Boston Medical Journal. 1899;141:645-654. Ledine JG, Kurlz RC. Ampullary neoplasia and endoscopic approach. Gastroenterology. 1990;98:539-541. Lillemoe KD. Tumors of the gallbladder bile ducts and ampulla. Seminars in Gastrointestinal Diseases. 2003;14:208-221. Petersen BT, An evidence-based review of sphincter of Oddi dysfunction: part 2, presentations with “objective” pancreatic findings (types1 and II) and presumptive type III. Gastrointest Endosc. 2004;59:670-687. Sherman S, Lehman GA, Jamidar P, Hawes RH, Silverman W, Madura J. Efficacy of endoscopic sphincterotomy and surgical sphincteroplasty for patients with sphincter of Oddi Dysfunction: randomized controlled study [abstract]. Gastrointest Endosc. 1994;40:P125. Sherman S, Troiano FP, Hawes RH, Lehman GA. Sphincter of Oddi manometry. Decreased risk of clinical pancreatitis with use of a modified aspirating catheter. Gastrointest Endosc. 1990;36:462-466. Silverman WB, Slivka A, Rabinovitz M, Wilson J. Hybrid classification of sphincter of Oddi dysfunction based on simplified Milwaukee criteria: effect of marginal liver and pancreas test elevations. Dig Dis Sci. 2001;46:278-281.
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Soffer EE, Johlin FJ. Intestinal dysmotility in patients with sphincter of Oddi dysfunction: a reason for failed response to sphincterotomy. Dig Dis Sci. 1994;39:19421944. Tarnasky PR, Hoffman BJ, Aabakken L, et al. Sphincter of Oddi dysfunction is associated with chronic pancreatitis. Am J Gastroenterol. 1997;92:1125-1129. Trazi RY, Hermann RF, Voyt DP. Results of surgical management of peri-ampullary tumors. A 35-year experience. Surgery. 1986;100:716-723. Yamaguchi K, Enjoji M. Adenoma of the Ampulla of Vater: putative precancerous lesion. Gut. 1991;32:1558.
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Cholangiocarcinoma Patrick R. Pfau, MD
Introduction Cholangiocarcinoma is a rare but deadly cancer that arises from the epithelium of the intrahepatic and extrahepatic biliary ductal system. Incidence in the United States has been estimated at 1:100,000 people per year1. Cholangiocarcinoma continues to have a poor 5-year survival of 10% or less, and for reasons that are not completely understood, the mortality of some types of cholangiocarcinoma has been rising in the last 20 years2 . This article briefly reviews the pathology and classification of cholangiocarcinoma with greater emphasis on the risk factors, clinical presentation, and the latest methods of tumor diagnosis and treatment.
Pathology and Classification The vast majority of cholangiocarcinomas (greater than 90%) are adenocarcinomas. Adenocarcinomas of the biliary tree can be further subdivided into schirrous or sclerosing tumors, nodular tumors, or papillary cancers. Sclerosing cancers are the most common, approximately 95%, and are associated with a severe fibrotic, desmoplastic reaction, making a preoperative diagnosis and determination of the true extent of disease difficult. Nodular cholangiocarcinomas tend to invade early and have a poor prognosis. Papillary tumors protrude and grow within the duct and may have a more favorable outcome with higher resection and survival rates3 (Figure 6-1). Anatomic classification of bile duct cancers is important because outcome is different based upon tumor location. Anatomic location greatly influences the choice of diagnostic modalities, and more importantly the type of therapy and chance for curative resection. Cholangiocarcinomas can be first classified as intrahepatic, perihilar, or distal extrahepatic tumors4. Approximately 20% to 25% of cholangiocarcinomas are intrahepatic cancers and classically present as liver mass lesions. These tumors present in similar ways to and must be differentiated from metastatic cancer or primary
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Figure 6-1. Cholangiogram demonstrating a filling defect in the common hepatic duct. Tissue retrieved at the time of ERCP was consistent with a papillary tumor of the bile duct.
hepatocellular cancer. Fifty to sixty percent of cholangiocarcinomas are perihilar and have been classically defined by Bismuth and Castaing5 (Figure 6-2). The remaining 20% to 25% of cholangiocarcinomas are classified as distal extrahepatic tumors, which are defined as common duct cancers below the anatomic point at which the common duct traverses posterior to the duodenum.
Risk Factors Increasing age is associated with cholangiocarcinomas, with the majority of cases diagnosed in patients between the age of 50 to 70. A slight male predominance exists. Cholangiocarcinoma is often diagnosed one to two decades earlier if a patient has an associated risk factor, though most patients do not have a prior identified risk factor before diagnosis. The pathogenesis by which all risk factors for cholangiocarcinoma are thought to lead to cancer is chronic inflammation. Ongoing chronic irritation and inflammation of the biliary tree can predispose to dysplastic changes and carcinogenesis of the biliary ductal epithelial cells 6. The most important and frequent risk factor in the United States for cholangiocarcinoma is the chronic inflammatory disorder of the biliary tree called primary sclerosing cholangitis (PSC). Thirty percent of patients in the United States with cholangiocarcinoma also have the diagnosis of PSC. The lifetime risk of cholangiocarcinoma is 5% to 15% in patients with PSC. A recent study has shown PSC to carry a greater than 1500 fold relative risk for cholangiocarcinoma compared to the general population4,7. Annual risk or incidence of cholangiocarcinoma in patients with PSC is estimated at 1.5%, but greater than one-third of cancers are diagnosed within 2 years of the diagnosis of PSC. Both alcohol ingestion and smoking tobacco have been suggested to increase the chance of cholangiocarcinoma in patients with concomitant PSC. Though somewhat controversial, patients with ulcerative colitis in the absence of symptomatic PSC may also have a slight increased risk for cholangiocarcinoma. Hereditary biliary ductal cystic disease such as choledochal cysts or Caroli’s disease with multiple cysts are associated with cancers of the bile ducts. This risk increases over time and has led to the general recommendation that choledochal cysts be
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Figure 6-2A. Bismuth classification of hilar cholangiocarcinoma. Type I tumors involve the common hepatic duct below the confluence of the right and left hepatic ducts.
Figure 6-2B. Type II tumors involve the bifurication/hilum but do not extend into the intrahepatic ducts.
Figure 6-2C. Type IIIA tumors involve
the common hepatic duct and extend into the right hepatic ducts.
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Figure 6-2D. Type III B involve the
common hepatic duct and extend into the left hepatic ducts.
Figure 6-2E. Type IV tumors involve the bifurication and extend into both the right and left hepatic ducts.
resected at the time of the diagnosis, usually in childhood. Due to the increased use of cross-sectional imaging, choledochal cysts are becoming more frequently recognized in adulthood, with resection also recommended in adults due to the association with cholangiocarcinoma. Chronic intraductal choledocholithiasis can lead to chronic ductal inflammation. The parasite flatworms Opisthorchiasis viverrini and Clonorchis sinensis may lead to intraductal stone formation and are associated with a 25 to 50 factor increased risk of cholangiocarcinoma8. The liver flukes are one factor associated with an inflammatory and pathologic entity termed Oriental cholangiohepatitis that is similar to PSC. Oriental cholangiohepatitis causes chronic inflammation of the biliary tree, subsequently leading to intrahepatic stones and structuring, and increases the risk for cholangiocarcinoma. Thorostat radiopaque medium that is no longer used in practice has also been linked to cholangiocarcinoma and is mentioned primarily for historical purposes. Other industrial chemicals such as nitrosamines, dioxin, asbestos, and polychlorinated biphenyls may be associated with cholangiocarcinoma 2 .
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Cirrhosis may result in as high as a 10-fold elevated risk for intrahepatic cholangiocarcinoma9. The link of cirrhosis and intrahepatic cholangiocarcinoma may particularly apply to chronic hepatitis C infection, which can lead to chronic inflammatory bile duct damage.
Clinical Presentation Cholangiocarcinoma of the hilum or distal bile duct come to clinical attention most commonly when the tumor obstructs the bile duct, resulting in jaundice, clay colored stools, and darkened urine. Pruritus is associated with the onset of jaundice in as many as two-thirds of patients. Though cholangiocarcinoma often causes biliary obstruction, it rarely presents with cholangitis. However, an increased risk of cholangitis occurs in patients with cholangiocarcinoma when the bile duct is instrumented with endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC), particularly when adequate biliary drainage is not achieved at the time of the procedure. Due to the fact that cholangiocarcinoma is often detected at an advanced stage, the other major group of symptoms are more nonspecific and similar to symptoms found with advanced malignancy of any kind, including weight loss, anorexia, and fatigue. Abdominal pain in the right upper quadrant in the region of the tumor can also be found. Intrahepatic cholangiocarcinomas present far less frequently with symptoms of biliary obstruction. The more common presentation of intrahepatic cholangiocarcinoma is that of a large liver mass, including abdominal pain, weight loss, anorexia, malaise, and night sweats 6. The main physical finding in patients with cholangiocarcinoma of the hilum or distal bile duct is obviously jaundice. Hepatomegaly may be found and less frequently a palpable right upper quadrant mass or palpable gallbladder (Courvoiseir’s sign) can be found in tumors of the distal common bile duct. Common laboratory abnormalities are consistent with obstructive disease in the biliary system. This includes predominantly elevated bilirubin, alkaline phosphatase, and gamma glutamyl transpeptidase. Aminotransferases are usually only mildly elevated8. Anemia may be present due to the anemia of chronic disease.
Diagnosis TUMOR MARKERS Tumor markers, particularly cancer antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA), have been extensively evaluated and are frequently used in supporting the diagnosis of cholangiocarcinoma because of the difficulty in imaging and obtaining tissue from cancers of the biliary tree. The majority of studies examining tumor markers have been performed in patients with preexisting primary sclerosing cholangitis to aid in differentiating benign from malignant strictures. The most frequently quoted study reported a sensitivity and specificity for the detection of cholangiocarcinoma in PSC patients of greater than 85% for CA 19-9 levels greater than 100 U/ml10. Further studies have found CA 19-9 levels to be less accurate. CA 19-9 level is affected by the presence of cholangitis and cholestasis with bilirubin levels as low as
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3 mg/dl, resulting in false positive elevation of CA 19-9 secondary to benign causes of biliary obstruction. CEA alone has not proven to be an accurate test in detecting cholangiocarcinoma. However, the combined use of CEA and CA 19-9 in what has been termed the Ramage index (CA 19-9 + CEA x 40 > 400) was shown to have an accuracy of 86% in diagnosing cholangiocarcinoma11. As a result of the question of the accuracy of tumor markers and high rate of false positive tests with benign biliary obstruction, tumor markers have not been proven nor are recommended as effective screening tests. Tumor markers do have a role in supporting the diagnosis of cholangiocarcinoma in patients with the clinical and imaging characteristics consistent with cholangiocarcinoma and in patients with PSC to help differentiate benign from malignant strictures.
IMAGING Noninvasive Ultrasound can be obtained in a patient with new onset jaundice and can detect the level of dilation and suspected obstruction. Ultrasound with Doppler imaging may also be useful in suggesting tumor invasion or compression of the portal vein or hepatic artery. Ultrasound suffers from poor sensitivity, rarely visualizing the exact tumor and providing little information on the extent of the disease and thus resectability of the tumor. Spiral or helical computed tomography (CT) scanning can provide more diagnostic information, including the presence of lymphadenopathy, presence of hepatic metastases, and help determine if there is involvement of the hepatic artery and portal vein. CT scan is the test of choice for intrahepatic cholangiocarcinoma, which presents as a hepatic mass lesion. However, for hilar and distal duct cholangiocarcinoma, CT scan does not usually identify the primary tumor and does not provide enough definition of the ductal anatomy and detail of the exact extent the tumor extends through the bile ducts. The noninvasive imaging modality of choice for cholangiocarcinoma detection and evaluation of extent of disease is magnetic resonance imaging (MRI) in association with magnetic resonance cholangiography (MRC). MRI/MRC provides cross-sectional imaging that examines the liver and can identify the primary mass lesion along with evaluating the local extent of the tumor. Magnetic resonance angiography can also be used to investigate the large regional vessels for involvement with the tumor. Most importantly, particularly with the use of 3-D reconstruction imaging obtained with MRC, the exact extent of the tumor can be delineated, including potential involvement into the intrahepatic ducts, which can be of great aid to the surgeon in assessing resectability. MRCP has been shown in hilar cholangiocarcinomas to be superior to ERCP in detecting extent of disease, giving more detail on intrahepatic extent of tumor12 . Further MRCP does not have the associated risks of bleeding, perforation, cholangitis, and pancreatitis that may occur with the invasive tests of ERCP or PTC.
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Figure 6-3. Cholangiogram obtained at
time of ERCP showing a tight sclerotic stricture of the common hepatic duct classified as a Bismuth Type I cholangiocarcinoma.
Invasive Direct cholangiography either through PTC or endoscopic retrograde cholangiography (ERC) has been the traditional method to image the biliary system prior to the advent of MRCP. Both tests are invasive and have associated risks of bleeding, perforation, cholangitis, and pancreatitis (unique to ERC). No definitive study has shown either modality (PTC versus ERC) to be clearly superior in regard to imaging the duct, determining the extent of tumor, or in complication rate. In practice, however, ERC is favored for distal common duct tumors and simpler hilar cancers such as Bismuth Type II or III class tumors (Figure 6-3). Though not proven, PTC may provide better visualization for more proximal cholangiocarcinomas and lessen the chance for cholangitis that can occur with ERC in Bismuth Type IV tumors when segments of the liver may not be completely drained at the time of the intervention. Two distinct advantages of direct cholangiography as compared to the non-invasive imaging studies are the ability to provide preoperative drainage of the biliary system if desired and to obtain tissue sampling. For distal common duct tumors, controversy has existed over whether preoperative drainage with biliary stents improves or worsens outcome and risk of postoperative infection in patients who go on to have operative resection of the tumor. Recently a synthesis of all current studies has come to the conclusion that preoperative stenting of distal malignant strictures prior to surgery does not affect outcome adversely or positively13. Therefore, it is recommended that preoperative drainage is not performed unless acute cholangitis is present or there is to be a delay of several weeks prior to surgery in the jaundiced patient. In practice because of the length of time needed for a complete preoperative evaluation, a delay often exists and placing stents preoperatively remains a common occurrence. In hilar cholangiocarcinoma, elevated bilirubin has been shown to be a predictor of poor outcome14. Stenting via ERC or PTC is thus generally recommended prior to surgery, particularly if hepatic resection is potentially going to be performed. The goal is to stent and decompress the unaffected side or lobe that is not planned to be resected. This can lead to atrophy of the segment of the liver that is to be resected, hypertrophy of the liver that is to be left in situ, and leads to a better overall outcome.
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A major weakness of noninvasive imaging is that no method, particularly in patients with PSC, is able to accurately differentiate benign from malignant strictures. Direct cholangiography either by PTC or ERC has the distinct advantage of being able to obtain tissue and cytology samples at the time of the test. Techniques used to obtain cytology or biopsy specimens include bile aspiration for cytology, brush cytology, needle aspiration cytology, or forceps biopsy15. The main drawback of tissue sampling via cholangiography for the diagnosis of cholangiocarcinoma is the low sensitivity with a high number of false negatives. Sensitivity for malignant bile duct strictures with brush cytology alone is usually less than 50%, with sensitivity slightly greater than 60% when multiple sampling methods such as cytology and forceps biopsy are combined16,17. Specificity for brush cytology is typically greater than 90%. An exception to this is found in patients with PSC in whom specificity is lower because of the difficulty in differentiating dysplastic cells from atypical cells associated with chronic inflammation.
Newer and Alternative Imaging Methods Newer and complementary diagnostic modalities for cholangiocarcinoma include Positron Emission Tomography (PET) scanning and the endoscopic methods of EUS, intraductal ultrasound, and choledochoscopy. PET scanning with fluoro-2deoxy-D-glucose (FDG) is based on the high glucose uptake and metabolic rate of cholangiocarcinoma. Cholangiocarcinoma as well as areas of inflammation take up more and accumulate more FDG and thus light up as a hot spot on PET scan. Early reports with small numbers of patients suggest PET may have a role in differentiating benign from malignant strictures in PSC18. The main difficulty PET has with diagnosing cholangiocarcinoma in general and particularly in PSC patients is with false positive tests because of the trouble in differentiating uptake found in cancer versus chronic inflammation. PET appears to have little ability or role in the detection of local lymph nodes, with difficulty separating primary tumor from local nodes. PET may have its largest impact in detecting distant metastases not seen with conventional cross-sectional imaging19,20. Standard EUS appears to have a role in providing another technique for tissue acquisition through EUS-guided fine needle aspiration (EUS-FNA). In patients with suspected cholangiocarcinoma and negative tissue sampling by direct cholangiography, EUS-FNA was able to obtain a cytologic diagnosis with a sensitivity of 86% to 89% and accuracy rates of 88% to 91%21,22 . EUS-FNA is able to obtain cytology from the primary tumor, but may even be more useful in visualizing local nodes not seen on other imaging methods. Cytologic samples can then be obtained from locoregional nodes through EUS, making a cytologic diagnosis and affecting staging of the cancer. Cholangioscopy is a method whereby a choledochoscope is passed into the duct through another endoscope using the mother-daughter endoscopic approach at the time of ERC. Cholangioscopy allows direct visualization of a suspected malignant stricture or ductal mass lesion. Intraductal ultrasound is performed by passing a high frequency (12 to 30 mHz) ultrasound probe via an ERC wire so that the ultrasound probe is directly within the stricture, permitting better identification of the tumor, depth of invasion, and possibly staging of the cancer. Difficulties with these two methods are lack of availability, lack of standardization of what a tumor appears to be on cholangioscopy and intraductal ultrasound, and finally a paucity of studies demonstrating an effect on management or outcome with either cholangioscopy or intraductal ultrasound.
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Staging The American Joint Committee on Cancer (AJCC) staging for intra- and extracholangiocarcinoma is seen in Tables 6-1 and 6-2, respectively. However, the AJCC staging of cholangiocarcinoma does not always have a tremendous clinical impact, as the prime purpose of staging cholangiocarcinoma is to determine resectability. Clinical staging of cholangiocarcinoma is based on the knowledge that the only chance for cure is surgical resection and patients have been found to consistently have better outcomes when surgical resection can be performed with negative margins. Thus, the goal of clinical staging is to correctly identify patients who will be resectable at surgery and to guide the surgeon in performing the appropriate surgery to obtain tumor-free margins. Staging for cholangiocarcinoma should determine resectability by: • The presence or absence of distant metastases • The presence of either distant and/or local lymph nodes • Assessment of the invasion of major vascular structures • Delineating the proximal and distal extent of the tumor. At the minimum, evaluation of metastatic disease should include chest x-ray, cross sectional imaging with CT scan or MRI, and in most centers laparoscopy to examine for liver studding or peritoneal metastases. PET scan may aid in detecting distal metastases and EUS can detect locoregional lymph nodes not seen on CT scan in 15% to 20% of patients23. Traditionally, absence of invasion of the hepatic artery or portal vein has been considered necessary for successful surgical resection but this is rapidly evolving 24. Preoperative definition of portovascular involvement, particularly in regard to hilar tumors usually includes encasement/occlusion of the main portal vein proximal to the bifurication or atrophy of one liver lobe with encasement of the contralateral portal vein branch 24. More aggressive surgical resection criteria are now being used with resection precluded only by bilateral hepatic arterial or bilateral portal venous encasement 24. Vascular assessment is performed using a combination of transabdominal or endoscopic ultrasound with Doppler and a CT or MR angiographic study. All of these imaging studies separate or together have significant rates of false positive and false negative rates in the examination of vascular invasion necessitating staging laparotomy in many cases to determine if the patient has major vascular involvement and is resectable. Extent of tumor is needed to further determine surgical resectability and the correct surgical approach to be used, which is usually defined by the anatomic classification described by Bismuth5,6 (see Figure 6-2). Extent of tumor is determined by cholangiography, either MRC or direct cholangiography with ERC or PTC. Extent of tumor in determining resectability is of most importance in cases of hilar cholangiocarcinomas. A tumor can be considered unresectable if there is bilateral hepatic duct involvement up to secondary radicals or less stringently atrophy of one lobe of the liver with secondary biliary radical involvement on the contralateral lobe25. Despite the multiple imaging technologies available, resectability frequently needs to and should be determined at the time of laparotomy. Vascular invasion and extent of tumor in the biliary tree can often only definitively be determined at the time of surgery. This is reflected by the findings that in physically fit surgical candidates
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Table 6-1
AMERICAN JOINT COMMITTEE ON CANCER TNM STAGING OF INTRAHEPATIC CHOLANGIOCARCINOMA TNM Stage T Stage T1 T2
T3
T4 N stage N0 N1 M stage M1
Degree of Tumor Spread Solitary tumor 2 cm or less without vascular invasion Solitary tumor 2 cm or less with vascular invasion; or multiple tumors less than 2 cm limited to one lobe; or a solitary tumor greater than 2 cm without vascular invasion Solitary tumor greater than 2 cm with vascular invasion; or multiple tumors less than 2 cm limited to one lobe with vascular invasion; multiple tumors greater than 2 cm limited to one lobe with or without vascular invasion Multiple tumors on more than one lobe or tumor involving major branch of the portal or hepatic vein No regional lymph nodes Regional lymph node metastasis Distant metastasis
approximately 75% will be found unresectable at surgery but only 15% to 25% of these same patients will be deemed inoperable on preoperative imaging studies24,25. For this reason, cholangiocarcinoma remains a surgical disease, not just in management but also in directing management.
Management SURGERY Intrahepatic cholangiocarcinoma presents as a liver mass lesion and surgical management is thus hepatic resection of the involved lobe. Intrahepatic cholangiocarcinomas are often not resectable due to a high incidence of lymph node or remote organ metastases in as many as 70% or more of patients26, with only 15% to 20% of patients with intrahepatic cholangiocarcinomas having resectable cancer 27. However, intrahepatic cholangiocarcinomas that undergo resection with negative margins have better survival rates than resected hilar or distal extrahepatic cholangiocarcinomas. After suc-
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Table 6-2
AMERICAN JOINT COMMITTEE ON CANCER TNM STAGING OF EXTRAHEPATIC CHOLANGIOCARCINOMA TNM Stage
Degree of Tumor Spread
T Stage T1a
Bile duct mucosa
T1b
Muscular layer of bile ducts
T2
Periductal connective tissue
T3
Vessel or organ invasion
N Stage N1a
Positive hepatic, cystic, or common duct nodes; hepatoduodenal ligament nodes
N1b
Positive distant nodes including peripancreatic, periduodenal, periportal, celiac, superior mesenteric, posterior pancreaticoduodenal lymph nodes
M Stage M1
Distant metastases (liver, peritoneum)
cessful resection of intrahepatic cholangiocarcinoma, 5-year survival rates have been found to be as high as >40%, with median survival ranging from 9 to 30 months26. Distal extrahepatic cholangiocarcinomas are treated with pancreatoduodenectomy. Negative resection margins in distal cholangiocarcinomas are achieved in up to 40% of patients. Five-year survival rates are 20 to 30% after successful surgical resection, slightly better than that found with resected hilar tumors 4,27. The surgery performed for hilar cholangiocarcinoma is based on the extent of disease or Bismuth classification. Tumors that are below the confluence of the right and left hepatic ducts or only reach the confluence (Bismuth Types I and II, respectively) are treated with resection of the extrahepatic bile ducts with at least 5 mm diseasefree margins, a regional lymphadenectomy, and then reconnected with a Roux-en-Y hepaticojejunostomy. Treatment of Bismuth Type III cholangiocarcinomas where the tumor involves the common hepatic duct and either the right or left hepatic ductal systems are now routinely treated in tertiary care centers with hepatic lobe resection in addition to the removal of the extrahepatic bile ducts and a lymphadenectomy. More aggressive surgery with hepatic lobectomy has led to an increased percentage of patients who have negative resection margins, which in turn results in a significantly improved median survival rate, with 3-year survival as high as 70% 24,28. Resection of the caudate lobe
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in any tumor that involves the confluence is also becoming more routine and improves the rate of margin-negative resections25. Surgeons in Asia and now increasingly in the West are becoming more aggressive with Type IV hilar cholangiocarcinomas and with local vascular invasion by performing lobectomy in association with resection of the portal vein and hepatic artery. These latter methods remain controversial because of the potential increased immediate surgical morbidity and mortality but most studies demonstrate an increased number of patients who have successful complete resections and a resultant improved patient survival rate when these surgical techniques are used. Orthotopic liver transplantation has traditionally been thought to be contraindicated in the treatment of cholangiocarcinoma due to the high rate of recurrence and very poor survival rate. However, small studies have shown that selected patients with early stage locally nonresectable cholangiocarcinomas can achieve acceptable 5-year survival rates29,30. These patients are generally treated with pretransplant neoadjuvant chemotherapy and radiation. With a limited number of organs available for transplantation, patient selection is crucial prior to transplanting patients for cholangiocarcinomas. Patients who are young, have early stage disease, and possibly patients with PSC are the groups of patients with the most potential benefit found with liver transplantation.
CHEMOTHERAPY AND R ADIATION No randomized controlled studies have demonstrated a definitive survival benefit with the addition of adjuvant treatment to surgery for cholangiocarcinoma—either radiation, chemotherapy, or their combined use. However, half of all cholangiocarcinomas have lymph node metastases at the time of diagnosis and locoregional recurrence is common postsurgical resection, suggesting a potential benefit of adjuvant therapy4,31. Though results are mixed, a number of retrospective uncontrolled studies have shown a benefit with adjuvant radiation or chemoradiotherapy in incompletely resected tumors or patients with microscopic positive margins at surgery. Radiation therapy in particular is usually offered for macro- or microscopic disease after surgery in fit patients. Data and benefit of adjuvant treatment in patients with completely resected cholangiocarcinoma is even less clear. In patients with completely resected tumors, studies examining radiation and chemotherapy have failed to show a clear survival advantage32,33. Due to insufficient proof of its efficacy, adjuvant therapy in the setting of completely resected cholangiocarcinoma should be given on an individual case-to-case basis and preferably in the setting of a clinical trial. Standard external beam radiation for locally advanced cholangiocarcinoma not amenable to surgical treatment and recurrent cholangiocarcinoma has not been shown to prolong survival or improve quality of life. External radiation has been shown to play an important palliative role in localized painful metastases, bleeding from the primary tumor, and biliary decompression4,8. Benefits, including survival benefits, have been reported in a few smaller studies with conformal radiation, intraductal brachytherapy, and transcatheter irradiation in conjunction with chemotherapy and external beam radiation34,35. Further studies are needed to verify these findings. The literature in addition has not shown consistent improved survival and outcome with systemic chemotherapy for nonresectable cholangiocarcinoma. Partial responses
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have been shown with multiple different medications, with the most experience being with 5-Fluorouracil (5-FU) based treatments. Difficulty with chemotherapy is that recurrence is usually locoregional rather than distant. Also, there are no adequate radiographic markers of disease progression and recurrence in cholangiocarcinoma to document response to or failure of therapy. Five-FU based treatment strategies usually have partial responses in approximately 20% of patients. Newer agents, particularly gemcitabine alone or in combination with cisplatin have increased partial response rates to 30% to 50%, with small increases in the median time to tumor progression4,35. Consistently the most important predictor of response to chemotherapy is performance status at the time of initiation of treatment. High performance status translates into an increased chance of responding to chemotherapy and more importantly a significant improvement in quality of life with chemotherapy, which is the major goal in the treatment of nonresectable cholangiocarcinoma. Again, the need to enroll patients with advanced cholangiocarcinoma in clinical trials involving newer chemotherapeutic agents or combinations is crucial.
PALLIATION Palliation of cholangiocarcinoma primarily means decompressing the bile duct to relieve jaundice and sometimes pruritis. Modalities available are surgical bypass of the biliary tree or through placement of biliary stents via an endoscopic or percutaneous method. Comparison of surgical versus stent therapy has found no significant differences in overall survival or clinical success rates but a significantly increased procedure-related morbidity and mortality has been demonstrated with surgery 36. Thus biliary stenting is the recommended treatment for relief of jaundice in cholangiocarcinoma over surgery except in cases when stenting fails or occasionally when expected survival is thought to be for greater than 1 year. The percutaneous route for stenting is more invasive with the need for at least initial external drainage as compared to endoscopic stenting. Endoscopic placement of stents should be the primary mode of palliating cholangiocarcinoma with percutaneous stenting reserved for endoscopic failures and in cases in which on prestenting imaging it is evident that the tumor extends proximally into the liver and will not be able to be stented retrogradely via the endoscope. For distal cholangiocarcinoma, the stent type and delivery method of choice is a covered or uncovered self-expandable metal stent (SEMS) placed via the ERCP scope. Metal stents have been shown to have a high rate of relief of jaundice and have a median duration of patency at least twice that of plastic stents37. Metal stents in addition require fewer needs for reintervention and result in fewer episodes of cholangitis. More controversy exists with proximal complicated hilar tumors because of the increased difficulty in stenting these types of strictures. For hilar tumors, MRCP is recommended prior to ERCP placement of stents to guide the endoscopist in the placement of the stent (Figure 6-4). MRCP can indicate the exact location of the strictures and proximal areas of dilation to target stent placement. This allows safe stent placement into the proper lobe/segment of the liver while minimizing the chance of cholangitis38. As with distal cholangiocarcinoma, placement of SEMS (uncovered) are preferred in hilar tumors, particularly in patients who will survive 6 months or longer. SEMS decrease costs overall to the patient, and lead to fewer recurrent hospitalizations10.
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Chapter 6 Figure 6-4A. Series of cholangiograms demonstrating the placement of a self-expanding metal stent (SEMS) in a patient with an unresectable hilar cholangiocarcinoma. Preprocedure imaging showed a hilar tumor with more pronounced dilation of the right hepatic system. Using the pre-ERC imaging as a guide, a wire was placed into the right hepatic ducts.
Figure 6-4B. A catheter was then
advanced over the wire and a cholangiogram was obtained of the selected right ductal system.
Figure 6-4C. Finally, a self-expanding
metal stent was placed across the strictured hilar tumor with drainage of the right system and subsequent resolution of the patient’s jaundice.
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The necessity to drain both sides of the liver in patients with Type IV hilar tumors by stenting bilaterally is unclear. Recent data shows that unilateral stenting into the easiest segment to access will relieve jaundice in greater than 85% of patients with minimal complications39. However, a small but not insignificant number of patients will need bilateral stent placement, which can usually be accomplished with ERC and SEMS. Thus for hilar cholangiocarcinoma, palliation of jaundice is adequately achieved and maintained in most but not all cases with unilateral stenting and preferably with metallic stents to prolong patency. Photodynamic therapy (PDT) for palliation in cholangiocarcinoma is a more recent option available to aid in biliary decompression. PDT works by providing the patient with a photosensitizer, usually hematoporphyrin, that becomes concentrated in the tumor. Light is then applied via a laser probe passed through the endoscope directly within the tumor. This has been shown to aid in relief of jaundice, and in early studies, to provide a survival benefit over just biliary stenting alone40.
Conclusion Overall survival for cholangiocarcinoma remains poor, with 5-year survival occurring in just 10% of patients22 . However, tremendous strides have been made in the surgical techniques and approach to cholangiocarcinoma with more aggressive techniques, including hepatic resection. This in recent reports has increased 5-year survival to as high as 20% to 50%14,25,41,42 . Thus, future efforts in the treatment of cholangiocarcinoma should be directed at increasing the number of patients who can undergo resection and even more importantly curative resection. This begins with improving and developing better screening methods for cholangiocarcinoma, particularly for patients with primary sclerosing cholangitis. Continued and improved advancement in imaging is needed to better determine who is a potential candidate for resection prior to surgery. With regard to surgery itself, the surgical techniques more recently being employed need to be further tested, tried, and applied to better determine if more aggressive surgical techniques do lead to better outcomes. More studies need to be performed with the use of adjuvant and neoadjuvant therapy to determine if outcomes in patients with both curative and noncurative surgery can be improved. Finally, a huge percentage of patients cannot undergo surgery and life expectancy is usually less than 1 year. Improvement and studies in the palliative care of cholangiocarcinoma is crucial, with better radiochemotherapy programs and more novel treatments such as biliary PDT being investigated and put into clinical use. When progress is made in all of these areas, we can hope to finally improve outcomes in the overall treatment of cholangiocarcinoma.
References 1. Callery MR, Meyers WC. Bile duct cancer. In: Cameron JL, ed. Current Surgical Therapy. 6th ed. Baltimore, Md: Mosby; 1998: 455-461. 2. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology. 2001;33:1353-1357. 3. Tajima Y, Kuroki T, Fukuda K, et al. An intraductal papillary component is associated with prolonged survival after hepatic resection for intrahepatic cholangiocarcinoma. Br J Surg. 2004;91: 99-104.
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4. Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut. 2002;51(Suppl 6):VI1-VI9. 5. Bismuth H, Castaing D. Hepatobiliary Malignancy. London: Edward Arnold; 1994. 6. Gores GJ. Cholangiocarcinoma: current concepts and insights. Hepatology. 2003;37: 961-969. 7. Burak K, Angulo P, Pasha TM, et al. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis patients. Am J Gastroenterol. 2004;99:523526. 8. De Groen PC, Gores GJ, LaRusso NF, et al. Biliary tract cancers. N Engl J Med. 1999;341:1368-1378. 9. Sorensen HT, Friis S, Olsen JH, et al. Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark. Hepatology. 1998;28:921-925. 10. Nichols JC, Gores GJ, LaRusso NF, et al. Diagnostic role of serum CA 19-9 in patients with primary sclerosing cholangitis. Mayo Clin Proc. 1993;68:874-879. 11. Ramage JK, Donaghy A, Farrant JM, et al. Serum tumor markers for the diagnosis of cholangiocarcinoma in primary sclerosing cholangitis. Gastroenterology. 1995;108:865-869. 12. Yeh TS, Jan YY, Tseng JH, et al. Malignant perihilar biliary obstruction: magnetic resonance cholangiopancreatographic findings. Am J Gastroenterol. 2000;95:432440. 13. Strasberg SM. ERCP and surgical intervention in pancreatic and biliary malignancies. Gastrointest Endosc. 2002;56(Suppl):S213-S217. 14. Su CH, Tsay SH, Wu CC, et al. Factors influencing postoperative morbidity, mortality, and survival after resection for hilar cholangiocarcinoma. Ann Surg. 1996;223:384-394. 15. Hawes RH. Diagnostic and therapeutic uses of ERCP in pancreatic and biliary tract malignancies. Gastrointest Endosc. 2002;56(Suppl):S201-S205. 16. Jailwala J, Fogel EL, Sherman S, et al. Triple-tissue sampling at ERCP in malignant biliary obstruction. Gastrointest Endosc. 2000;51:383-390. 17. Ponchon T, Gagnon P, Berger F, et al. Value of endobiliary brush cytology and biopsies for the diagnosis of malignant bile duct stenosis: results of a prospective study. Gastrointest Endosc. 1995;42:565-572. 18. Keiding S, Hansen SB, Rasmussen HH, et al. Detection of cholangiocarcinoma in primary sclerosing cholangitis by positron emission tomography. Hepatology. 1998;28:700-706. 19. Fritscher-Ravens A, Bohuslavizki KH, Broering DC, et al. FDG-PET in the diagnosis of hilar cholangiocarcinoma. Nucl Med Commun. 2001;22:1277-1285. 20. Kluge R, Schmidt F, Caca K, et al. Positron emission tomography with [(18)F]fluoro2-deoxy-D-glucosefor diagnosis and staging of bile duct cancer. Hepatology. 2001;33:1029-1035. 21. Fritscher-Ravens A, Broering DC, Knoefel WT, et al. EUS-guided fine-needle aspiration of suspected hilar cholangiocarcinoma in potentially operative patients with negative brush cytology. Am J Gastroenterol. 2004;99:45-51. 22. Eloubeidi MA, Chen VK, Jhala NC, et al. Endoscopic ultrasound-guided fine needle aspiration biopsy of suspected cholangiocarcinoma. Clin Gastroenterol Hepatol. 2004; 2:209-213.
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23. Gores GJ. Early detection and treatment of cholangiocarcinoma. Liver Transpl. 2000; 6(Suppl2):S30-S34. 24. Tsao JI, Nimura Y, Kamiya J, et al. Management of hilar cholangiocarcinoma: comparison of an American and a Japanese experience. Ann Surg. 2000;232:166-174. 25. Burke EC, Jarnagin WR, Hochwald SN, et al. Hilar cholangiocarcinoma: patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system. Ann Surg. 1998;228:385-394. 26. Shirabe K, Shimada M, Harimoto N, et al. Intrahepatic cholangiocarcinoma: its mode of spreading and therapeutic modalities. Surgery. 2002;131(1 Suppl):S159S164. 27. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma: a spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg. 1996;224:463-475. 28. Nakeeb A, Tran KQ, Black MJ, et al. Improved survival in biliary malignancies. Surgery. 2002;132:555-563. 29. Sudan D, DeRoover A, Chinnakotla S, et al. Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma. Am J Transplant. 2002;2:774-779. 30. De Vreede I, Steers JL, Burch PA, et al. Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma. Liver Transpl. 2001;7:1023-1033. 31. Jarnagin WR, Ruo L, Little SA, et al. Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. Cancer. 2003;98:1689-1700. 32. Pitt HA, Nakeeb A, Abrams RA, et al. Peri-hilar cholangiocarcinoma: postoperative radiation therapy does not improve survival. Ann Surg. 1995;221:788-798. 33. Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreatobiliary carcinoma. Cancer. 2002;95:16851695. 34. Foo ML, Gunderson LL, Bender CE, et al. External radiation therapy and transcatheter iridium in the treatment of extrahepatic bile duct carcinoma. Int J Radiat Oncol Biol Phys. 1997;39:929-935. 35. Hejna M, Pruckmayer M, Raderer M. The role of chemotherapy and radiation in the management of biliary cancer: a review of the literature. Eur J Cancer. 1998;34:977986. 36. Smith AC, Dowsett JF, Russell RC, et al. Randomized trial of endoscopic stenting versus surgical bypass in malignant low bile duct obstruction. Lancet. 1994;344:16551660. 37. Flamm CR, Mark DH, Aronson N. Evidence based assessment of ERCP approaches to managing pancreatobiliary malignancies. Gastrointest Endosc. 2002;56(Suppl): S218-S225. 38. Freeman ML, Overby C. Selective MRCP and CT-targeted drainage of malignant hilar biliary obstruction with self-expanding metal stents. Gastrointest Endosc. 2003;58:41-49. 39. DePalma GD, Galloro G, Siciliano S, et al. Unilateral versus bilateral endoscopic hepatic duct drainage in patients with malignant hilar biliary obstruction: results of a prospective, randomized, and controlled study. Gastrointest Endosc. 2001;53:547553.
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40. Ortner MA, Liebetruth J, Schreiber S, et al. Photodynamic therapy of nonresectable cholangiocarcinoma. Gastroenterology. 1998;114:536-542. 41. Miyazaki M, Ito H, Nakagawa K, et al. Aggressive surgical approaches to hilar cholangiocarcinoma: hepatic or local resection? Surgery. 1998;123:131-136. 42. Kosuge T, Yamamoto J, Shimada K, et al. Improved surgical results for hilar cholangiocarcinoma with procedures including major hepatic resection. Ann Surg. 1991;230:663-671.
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7
Infections of the Biliary System Faten N. Aberra, MD, MSCE
Introduction Infections affecting the biliary tree are as vast and include bacteria, viral, and parasitic infections. This chapter will provide information on the etiology, pathogenesis, clinical presentation, diagnostic testing, and treatment of the various infectious syndromes and organisms that affect the biliary system (Table 7-1).
Acute Cholecystitis Acute cholecystitis is inflammation of the gallbladder. There are two major types of acute cholecystitis—calculous and acalculous.
ACUTE CALCULOUS CHOLECYSTITIS Etiology and Pathophysiology In calculous cholecystitis, which makes up over 90% of cholecystitis cases, gallstones obstruct the gallbladder outlet leading to poor drainage of bile1, 2 . The blockage of bile drainage leads to increased intraluminal gallbladder pressure, gallbladder distention, and supersaturated cholesterol bile acids, triggering an inflammatory reaction leading to gallbladder wall edema1. Prostaglandin E2 and I2 have been shown to mediate the inflammatory response3. Venous and lymphatic obstruction may develop, as well as ischemia and necrosis of the gallbladder. In the early stages of cholecystitis, bile is sterile, but later in the process infection occurs. The most common organisms cultured from bile are Escherichia coli, Klebsiella, and Enterococcus 2 . Complications of acute calculous cholecystitis occur in 2% to 30% of patients and include gallbladder perforation, gallbladder gangrene, emphysematous cholecystitis, empyema, and cholecystoenteric fistulas1,2 . Factors associated with a worse prognosis include diabetes, male gender, advanced age, high temperature, and significant leukocytosis4.
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Table 7-1
ORGANISMS INVOLVED IN BILIARY DISEASE Microbial Class
Organism
Clinical Associated Syndrome
Bacteria
Escherichia coli Klebsiella pneumonia and oxytoca Enterococcus faecalis Enterobacter cloacae Proteus Streptococcus Bacteroides fragilis Clostridium perfringins Pseudomonas Staphylococcus epidermis Salmonella Coxiella burnetti Non-01 vibrio cholerae Mycobacterium avium intracellulare
Cholecystitis/cholangitis Cholecystitis/cholangitis
Virus
Cytomegalovirus
Hepatotropic viruses: A, B, C, E Reovirus 3 Rotavirus (groups A and C)
Cholecystitis/cholangitis Cholangitis# Cholangitis Cholangitis Cholangitis Cholangitis Cholangitis# Cholangitis# Acalculous cholecystitis Acalculous cholecystitis Acalculous cholecystitis AIDS related cholangiopathy
Acalculous cholecystitis/AIDS related cholangiopathy/vanishing bile duct syndrome post OLT* Cholestasis Biliary atresia^ Biliary atresia^
Fungi
Candida albicans
Acalculous cholecystitis
Parasites
Ascaris Clonorchis sinensis
Biliary obstruction, cholangitis Cholangitis/recurrent pyogenic cholangitis/cholangiocarcinoma Cholangitis/cholecystitis/ cholangiocarcinoma
Opisthorchis viverrini and felineus
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Table 7-1, continued
Microbial Class
Organism
Clinical Associated Syndrome
Parasites
Fasciola hepatica Echinococcosis granulosus and multilocularis Microsporidia Cryptosporidia Isospora belli
Biliary colic, cholangitis Obstructive jaundice, biliary colic, cholangitis; Budd-Chiari; cirrhosis AIDS-related cholangiopathy AIDS-related cholangiopathy AIDS-related cholangiopathy
# = cholangitis associated with history of biliary procedures *OLT = orthotopic liver transplantation ^ = controversial
Clinical Presentation Patients may have symptoms of upper abdominal pain or right upper quadrant pain associated with fever, nausea, or vomiting 2,5. Studies have shown that mid-epigastric pain occurs as frequently as right upper quadrant pain5. Patients may also complain of pain in the back, right scapula, or right clavicular region 2 . On physical exam, right upper quadrant pain elicited by palpation under the right costal margin when the patient inspires is called Murphy’s sign. In a systematic review of clinical predictors for acute cholecystitis, Murphy’s sign had a sensitivity of 0.65 (95% CI, 0.59-0.71), specificity 0.87 (95% CI, 0.85-0.89), and likelihood ratio positive of 2.8 (95% CI, 0.8-8.6)5. Patients may also have hyperalgesia to light palpation of the infrascapular area or right upper quadrant6. Another sign associated with acute cholecystitis is Boas’ sign, point tenderness in the region to the right of the 10th to 12th thoracic vertebrae 5,7-9. There is yet to be a study assessing the test characteristics for a combination of symptoms and signs.
Diagnostic Tests Leukocytosis (white blood cell count >10,000/mL) may be present, sensitivity 0.63 (95% CI, 0.60-0.67) and specificity 0.57 (95% CI, 0.54-0.59)5. The presence of both leukocytosis and fever based on two studies with a total of 351 patients had a surprisingly low sensitivity of 0.24 (95% CI, 0.21-0.26) and specificity of 0.85 (95% CI, 0.76-0.91)5. Leukocytosis with a left shift may also be present. Ultrasound is an excellent diagnostic test, but it is not perfect for making a diagnosis of cholecystitis with a sensitivity of 88% (95% CI, 74-100%) and specificity of 80% (95% CI, 62-98%)5. Sonographic features of acute cholecystitis are gallblad-
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der wall thickening, pericholecystic fluid, gallbladder distention, and a sonographic Murphy’s sign 2 . Radionuclide scanning has better test characteristics, with sensitivity and specificity greater than 90%, but cannot assess for other biliary or abdominal pathology10-16. A false positive radionuclide scan may occur if the patient has been in a prolonged fasting state, on total parenteral nutrition, or has hepatic impairment. Although somewhat controversial, ultrasound is usually the first diagnostic test completed due to the ease of performing the test by the operator, portability, lower cost, and additional information on abdominal pathology that may be obtained. In patients with a high clinical suspicion of acute cholecystitis and negative ultrasound findings, radionuclide scan is usually the next test completed. Other modalities for radiological diagnosis of acute cholecystitis include computed tomography (CT) and magnetic resonance imagine/magnetic resonance cholangiopancreatography (MRI/MRCP). CT has been found to be inferior to both ultrasound and radionuclide scan for diagnosing acute cholecystitis17, whereas MRI/MRCP with recent improvements and modification of technology has been shown to have excellent test characteristics that equal and even in some studies surpass ultrasound17-20. Due to cost and availability at hospitals, ultrasound is still preferred over MRI/MRCP.
Treatment Initial management of a patient diagnosed with acute calculous cholecystitis is cessation of parenteral nutrition, intravenous fluids, and analgesia. The choice of analgesia is usually a narcotic, meperidine or morphine. Meperidine was recommended in the past due to the belief that there was less spasm and lower pressures of the sphincter of Oddi compared to use with morphine. This belief was recently challenged and it was determined that the substantiation was based on case reports rather than controlled studies21. Antibiotics should be started if a patient has a high fever, tachycardia, hypotension, or there is no clinical improvement after 12 hours. Broad spectrum antibiotics are preferred and anaerobic coverage is usually added to severe cases. Curative treatment for acute calculous cholecystitis is cholecystectomy. Aside from emergent surgery, early or late (usually defined as 6 to 12 weeks) surgery has not been shown to differ in morbidity or mortality and thus early surgery is generally preferred due to decreased hospitalization costs2 . Laparascopic cholecystectomy has become the surgical approach of choice over open cholecystectomy unless there is complicated disease such as gallbladder perforation. For some patients, the risk of surgery outweighs the benefit and percutaneous cholecystostomy is a reasonable option, with a success rate of 75% to 90% reported1,2 . Percutaneous cholecystostomy can be performed at bedside in patients who cannot be moved from the intensive care unit. Once the patient has recovered, elective cholecystectomy should be performed.
ACUTE ACALCULOUS CHOLECYSTITIS Etiology and Pathophysiology In 2% to 12% of cholecystitis cases, gallstones are not found and this is termed acalculous cholecystitis2 . Acute acalculous cholecystitis usually occurs in patients who are severely ill such as septic, trauma, or burn patients2,22,23. Other risk factors for
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acute acalculous cholecystitis include immunosuppression, HIV, lymphoproliferative disorders, prolonged fasting, total parenteral nutrition, acute renal failure, vascular disease, systemic vasculitides, male gender, and extremes of age22,24,25. Perhaps the underlying mechanisms leading to acalculous cholecystitis are ischemia and gallbladder stasis.26 One study revealed that 70% of patients with acalculous cholecystitis had atherosclerotic disease27. Many nonenteric organisms can cause acalculous cholecystitis. Salmonella, Cytomegalovirus, Coxiella burnetii, non-O1 Vibrio cholerae, Ascaris, and Candida albicans are but a few of the nonenteric organisms that may cause cholecystitis along with other systemic disease25,28-38.
Clinical Presentation Patient symptoms are similar to that for acute calculous cholecystitis with the exception that abdominal pain localizing in the right upper quadrant occurs less frequently.
Diagnostic Tests The initial test is usually an ultrasound as in acute calculous cholecystitis. If the results are not conclusive, then radionuclide scan should be considered. Because many patients with acalculous cholecystitis are usually critically ill and have been fasting, radionuclide scanning is completed with a morphine injection to decrease false positive scans39,40.
Treatment Percutaneous cholecystostomy is usually preferred in critically ill patients over cholecystectomy during initial presentation, and later in their hospital course they usually do not need cholecystectomy 2 . Endoscopic biliary drainage in this setting has been assessed but has not been in favor as it offers few advantages over percutaneous drainage41,42 . Treatment is otherwise similar to acute calculous cholecystitis with the exception that acalculous cholecystitis is usually secondary to another disease and the primary disease must be treated. The morbidity and mortality from acute acalculous cholecystitis is higher than in calculous cholecystitis, with mortality usually a result of their underlying disease22 .
Bacterial Cholangitis ETIOLOGY AND PATHOPHYSIOLOGY The term cholangitis is used to describe inflammation of the bile ducts that may be due to noninfectious and infectious causes. Infections affecting the biliary tree are bacterial, viral, and parasitic infections. Patients with bacterial cholangitis often have a history of biliary disease (including prior biliary duct infection), have a median age between 50 and 60 years, and equal gender distribution43-45. Due to the protective barriers of continuous bile flow and sphincter of Oddi protection from intestinal debris, bile is usually sterile46. Biliary obstruction independently does not always lead to cholangitis. The components required for bacterial biliary infections to occur are obstruction of biliary flow and colonization of bacteria.
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Bacterial concentrations in the small bowel increase with lack of bile salts. Bile is believed to have bactericidal properties and with biliary obstruction there is less bile salt, decreased biliary IgA, and increased hypochlorhydria in the small intestine43. Bile salt has been shown in vitro to reduce bacterial migration into enterocytes and perhaps prevent endotoxin translocation43,47. Bacteria may ascend into the common bile duct, or attain access into the biliary tree through the portal vein and lymphatics43. Cholangitis usually ensues when biliary pressures are greater than 15 cm of water48. Complete obstructions are associated with bactibilia in 10% of cases, compared to 64% of partial obstructions49,50. There are numerous causes of biliary obstruction, some of which are iatrogenic. The most common cause of biliary obstruction is choledocholithiasis51. Other causes of biliary obstruction leading to bacterial infection include benign strictures (such as primary sclerosing cholangitis), malignant strictures, ampullary stenosis (benign or malignant), choledochal cysts, sump syndrome, juxtapapillary diverticulum, biliary casts in orthotopic transplant liver recipients, pancreatic tumors, pancreatitis, and parasites 43,46,52 . Juxtapapillary diverticulum may obstruct the sphincter of Oddi by debris trapped in the diverticulum blocking bile exiting the sphincter and also by leading to dysfunction of the sphincter, allowing bacteria to ascend the biliary tree53. Biliary sludge also may contribute to obstruction54. The risk is higher for cholangitis with obstruction from choledocholithiasis than from neoplastic strictures43.
MICROBIOLOGY Bacteria primarily involved in cholangitis originate from the gastrointestinal tract. The bacteria most commonly involved in acute cholangitis are Escherichia coli, Klebsiella, and Enterococcus 53. Other bacteria also isolated are Enterobacter, Proteus, and Streptococcus 55. Bacteroides fragilis is the most common anaerobic organism isolated, followed by Clostridium perfringens, found in up to 15% of appropriately cultured cases43. Aerobes are more commonly isolated but this may be due to poor techniques available in isolating anerobes43. There have also been case reports of Haemophilus influenza causing cholangitis, with many of the cases in association with alcoholism and cancer56. More than one organism is cultured from bile 30% to 87% of the time43. Twenty-one to 83% of patients are bacteremic with 33% to 84% of blood and bile isolates matching43. Iatrogenic causes include endoscopic retrograde cholangiopancreatography (ERCP), surgery, and interventional radiological procedures involving the bile ducts. When biliary stents or drains are placed, bacteria may enter the biliary system due to contamination of the device, ascent of intestinal bacteria into the biliary tree, access through the portal venous system, and migration of skin flora57. Bacteria associated with biliary prosthetics include Pseudomonas, K oxytoca, K pneumoniae, Enterobacter cloacae, S. epidermis, and Enterococcus faecalis 2,57,58.
CLINICAL PRESENTATION Unfortunately, symptoms generally occur once the infection has become systemic and can sometimes be vague. The classic symptoms of bacterial cholangitis are fever, right upper quadrant abdominal pain, and jaundice, also called Charcot’s triad. All three symptoms occur in 50% to 100% of cases2,43,59. Fever is the most common
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symptom, occurring in 95% of cases, with right upper quadrant pain in 90% and jaundice in 80%51,60. If symptoms are not identified early, then sepsis may ensue with symptoms and signs of confusion, lethargy, and hypotension. On rare occasions, symptoms of Charcot’s triad are present in the setting of altered mental status and hypotension; this is termed Reynold’s pentad 2 . Nausea and vomiting occurs in up to 50% of patients45,58. Abdominal pain may not always be located in the right upper quadrant, may not always be present, and on physical exam there may be very few abdominal findings.
DIAGNOSIS Most often the diagnosis of cholangitis can be diagnosed clinically, and laboratory and radiographic studies are supportive. Laboratory results may reveal leukocytosis, hyperbilirubinemia (88% to 100%), elevated alkaline phosphatase (78%), and mild elevations of transaminases, although transaminases of >1000 may occur if biliary pressures acutely rise2,43. Serum amylase may be elevated in up to 30% to 40% of patients without pancreatitis58,61. Several radiographic imaging modalities are useful for diagnosing biliary obstruction that may be causing cholangitis, including ultrasound, CT, radionuclide scanning, MRCP, and ERCP. A brief overview of these studies will be discussed here, but more detail will be provided in other chapters on the work-up for various causes of obstruction. Ultrasound and CT are usually the first imaging tests completed. Ultrasound is useful for diagnosing biliary obstruction by detecting biliary dilation and aiding in differentiating between cholecystitis and cholangitis. However, in early or low level obstruction, biliary dilation may not be present and may be undetected by ultrasound. Sensitivities range from 80% to 99% for detection of obstruction and the sensitivity is significantly lower for detection of stones, approximately 15% 62 . The literature is conflicting as to whether ultrasound is accurate in determining the location or level of biliary obstruction and whether CT scan is superior63-65. Spiral or helical CT scan may provide increased sensitivity over a normal CT, as will CT cholangiography. MRCP, with sensitivities of 89% to 93% and specificities of 90% to 99% for diagnosing obstruction, is superior to both ultrasound and CT and rivals ERCP in diagnosing and locating biliary obstruction62, 66-69. MRCP may be obtained when therapeutic ERCP is believed to be too high risk or unnecessary and a diagnosis has not yet been determined. ERCP and PTC are excellent tools for the diagnosis and treatment of an obstruction in patients with cholangitis who are not improving clinically on antibiotics or whom initially present as very ill. The sensitivity and specificity of ERCP for diagnosing obstruction has been reported as 89% to 98% and 89% to 100%, respectively43. Neither ERCP and PTC should be used solely for diagnostic purposes due to the risks associated with these procedures and the availability of MRCP. Cholescintigraphy may be useful in detecting mild partial biliary obstructions in patients with a subtle clinical presentation of obstruction, and mildly abnormal liver function tests with an obstructive pattern without jaundice and a normal ultrasound. Cholescintigraphy also has the advantage of differentiating between cholecystitis and biliary obstruction and possibly detecting both simultaneously62 .
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TREATMENT In patients suspected of having cholangitis, blood cultures should be obtained, and antibiotics and supportive care (volume repletion, coagulation and electrolyte parameters corrected) initiated. Antibiotics with broad spectrum coverage should be considered. The decision on the specific antibiotics chosen may be based on factors such as prior biliary procedures, age, and local microbial sensitivities. Several antibiotics have been considered good choices due to the effectiveness against the organisms commonly involved in cholangitis and include fluoroquinolones, third generation cephalosporins (cefoperazone and ceftazidime), ampicillin and gentamicin combination, pipericillin, and mezlocillin. Ciprofloxacin, as compared to netilmicin, imipenem, ceftazidime, cefoperazone, and ampicillin, has been shown to have the highest concentrations in bile during an obstruction55. Whether high antimicrobial biliary concentrations improve outcomes is still unclear 70. Another factor to take into consideration when selecting an antibiotic is that cefoperazone, ceftazidime, and netilmicin tend to not cover Enterococcus. Ampicillin has been associated with higher resistance of organisms71. Cephalosporins, ampicillin with gentamicin, and fluoroquinolones do not have anaerobic coverage, so the addition of metronidazole should be considered if treating with these antibiotics. Antimicrobial therapy should be initiated quickly, but the cornerstone of treatment is decompression of biliary obstruction. ERCP success rates for drainage have been reported as high as 90% to 100%72-78. ERCP therapeutic techniques involved in decompression include sphincterotomy, stone extraction, and stent or drain placement. In patients with gallbladder stones without common bile duct stones or other forms of obstruction, sphincterotomy has been shown to decrease the duration of cholangitis and hospital stay, but does not reduce the incidence of recurrent cholangitis. In critically ill patients, nasobiliary drains or stents may be preferred over sphincterotomy and stone extraction due to less risk of procedure-related complications such as bleeding, perforation, and pancreatitis72 . Endoscopic stents and drains are usually temporary and removed after a patient has recovered. Long-term stenting is indicated in conditions with chronic mechanical obstruction, including benign and malignant strictures. In cases of hepatolithiasis, intrasegmental cholangitis, inability to access the papilla due to prior surgery, or ERCP failure, PTC is an option43. PTC’s success rate of 90% for relief of obstruction is slightly less than that of ERCP79. As in ERCP, biliary drains can be placed by PTC. ERCP is preferred over PTC and surgery due to lower mortality rates, fewer complications, shorter hospitalization, and high success rates76,77,79,80. Surgery was the main form of treatment for cholangitis prior to the advent of endoscopic and interventional radiological procedures. Due to the high risk of mortality (as high as 50%), surgical intervention is limited to those that have failed medical therapy and nonsurgical techniques of drainage2,58. Surgical options include choledochotomy, surgical sphincteroplasty, decompression, T-tube insertion, and removal of the gallbladder if also involved58. The risk of postoperative mortality and morbidity declines if surgery is completed on an elective basis44, 58. Patients who had cholangitis due to stones will also eventually require elective cholecystectomy. A management algorithm for patients with possible acute cholecystitis or bacterial cholangitis is provided in Figure 7-1.
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Upper Abdominal Pain, Fever, Jaundice
Physical exam: assess for Murphy's sign
RUQ ultrasound
gallstones
+ ductal stones (+/gallstones)
Antibiotics and t/c elective cholecystectomy
Antibiotics, ERCP or PTC
send cbc, lfts, if febrile start antibiotics and IVF after sending blood cultures
+ sonographic signs of cholecystitis
Antibiotics, PTC for drainage
-RUQ ultrasound
t/c HIDA or MRCP
Figure 7-1. Algorithm for acute cholecystitis/cholangitis work-up.
PROGNOSIS Acute obstructive suppurative cholangitis is a quickly progressive form of cholangitis that requires emergent drainage and has a high rate of greater than 60% mortality58. Poor prognostic indicators for mortality in acute cholangitis include acute renal failure, cholangitis associated with liver abscesses or liver cirrhosis, cholangitis secondary to high malignant biliary strictures or after percutaneous transhepatic cholangiography, abnormal platelet counts, hypoalbuminemia, female gender, and age43, 81.
Parasites Several parasites invade the biliary tract and may induce inflammation, stricture formation, and/or obstruction leading to secondary bacterial cholangitis. The most common parasites infecting the biliary system are Ascaris lumbricoides, Clonorchis sinensis, Opisthorchis viverrini and felineus, Fasciola hepatica, and Echinococcus granulosus and multilocularis 46.
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Figure 7-2.
Ascaris life cycle. Obtained with permission from CDC DPD library.
ASCARIS LUMBRICOIDES Background Ascaris is the most common parasite associated with cholangitis. Ascaris is a nematode (roundworm) primarily located in the tropics and subtropics and over 1 billion people are estimated to be infected with this parasite82,83. Eggs of the worm reside in the soil and mature into larvae within 10 to 12 days (Figure 7-2). The larvae may be accidentally ingested due to contamination of food. The shell of the larvae is usually broken in the duodenum, and when larvae are in the third stage they are highly infectious. At this larval stage, they may penetrate the wall of the intestine at the level of the cecum and enter the portovenous system and lymphatics. After entering the portovenous system, they travel to numerous organs (liver, heart, and lung) by way of the pulmonary artery. Larvae that have penetrated the lungs tend to enter bronchial cavities and work themselves up the bronchial tree to the level where they may be swallowed into the gastrointestinal tract. By the time they re-enter the gastrointestinal tract, they have matured and may be at a late larval stage or young adults. The parasite further matures in the gastrointestinal tract into adulthood. At this stage, Ascaris tends to invade the biliary tree by way of the ampulla, leading commonly to obstruction (see Figure 7-2). The worms may ascend the biliary tree, making their way into the liver and may even penetrate through liver tissue, through Gibson’s capsule, and into the peritoneum. If trapped in the biliary tree, dead worms can cause a more reactive inflammatory response than live worms 84. Biliary colic, acute cholecystitis, acute cholangitis, acute pancreatitis, and hepatic abscess may develop83.
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Clinical Manifestation Symptoms of biliary infection are similar to that of bacterial cholangitis: abdominal pain, fever, and jaundice. Patients may also have hepatomegaly.
Diagnosis Supporting information for biliary Ascariasis is peripheral eosinophilia. Ultrasound usually reveals dilated ducts and may show movement of a linear structure85,86, but the diagnosis is usually made by ERCP. Pigmented stones and/or adult worms may be visualized or retrieved from the biliary tree. Dead worms and larval shells are a nidus for calcification and stone formation84. Stool studies may be negative for the parasite.
Treatment If obstruction is present, then endoscopic extraction should be done. In addition, patients should be treated with levamisole or tetramisole hydrochloride and mebendazole. Pyrantel pamoate should be added if there is a heavy parasite burden83,84. Antibiotics and supportive treatment should also be started if obstruction is present and secondary bacterial cholangitis is likely.
LIVER FLUKE CHOLANGITIS This class of trematodes (flukes) includes Opisthorchis viverrini and felineus, Clonorchis sinensis, and Fasciola hepatica. Opisthorchis and Clonorchis are primarily located in Asia (China, Hong Kong, Vietnam, and Korea) and Russia.
Clonorchis Sinensis Background
Intermediate hosts of Clonorchis are snails and fish. The fluke enters humans after they eat raw fish that are infected. The Clonorchis adult worms are approximately 15×3 mm (Figure 7-3) 87. Clonorchis can penetrate through the ampulla and ascend the biliary tree where eggs are deposited. The adult flukes reside in the medium-sized and small intrahepatic bile ducts and, occasionally, in the extrahepatic bile ducts, gallbladder, and pancreatic duct88. The flukes can cause mechanical obstruction, inflammatory reaction, adenomatous hyperplasia, and periductal fibrosis. Embryonated eggs are passed into feces and reintroduced to the intermediate hosts (Figure 7-4). Clinical Manifestation
Most patients infected with Clonorchis are asymptomatic and symptoms are usually seen with heavy worm infestation. If symptoms are present, jaundice is most common. Diagnosis
It is very unusual to have significant ductal dilation by ultrasound or CT scan89. Mild diffuse ductal dilation may be detected, especially in intrahepatic ducts, and hepatic abscesses may also be present89,90. Clonorchis can usually be diagnosed definitively by detecting eggs in the feces.
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Figure 7-3. A. Ascaris in ampulla. B. Worm
removed by dormia basket. Reprinted with permission from Al-Karawi M, Sanai FM, Yasawy MI, et al. Biliary strictures and cholangitis secondary to ascariasis: endoscopic management. Gastrointest Endosc. 1999;50:695-697. For full-color version, see page CA IV of the Color Atlas.
Figure 7-4. Clonorchis life cycle. Obtained with permission from CDC DPD image library.
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Figure 7-5. Picture of adult Clonorchis.
Reprinted with permission from Chu DW, Li JC, Lee DW, Rong ZX, Chen XW, Chan AC. Unusual presentations of hepatic clonorchiasis. Gastrointest Endosc. 2003;58:637-639.
Treatment
By the time cholangitis occurs, which is usually secondary bacterial, ductal fibrosis, strictures, and stones may have formed. Treatment is similar to that for bacterial cholangitis, primarily antibiotics and possibly ERCP, PTC, or surgery may be required based on findings. Treatment for Clonorchis is praziquantel (75 mg/kg/day in three doses for 1 day) or albendazole in a dose of 10 mg/kg for 7 days87. Prognosis
There is a close relationship of Clonorchis with recurrent pyogenic cholangitis and an increased incidence of cholangiocarcinoma.
Opisthorchis viverrini and felineus O viverrini and felineus are commonly found in Asia and Eastern Europe. It has been a major public health problem in many parts of Southeast Asia, including Thailand, Lao PDR, Vietnam, and Cambodia91. Opisthorchis usually infects dogs and cats. As in Clonorchis, snails and fish are the intermediate hosts. Humans may be infected by ingesting raw fish that contains the parasite. The life cycle is similar to Clonorchis, with Opisthorchis residing in the biliary tree (Figure 7-6). In early infection or low infectious burden, few changes in the biliary structures are found. On the other hand, patients with a large infectious burden or chronic infection have been shown to have proliferation of ductal epithelial cells, bile duct hyperplasia, and periductal fibrosis91. In heavy infections with Opisthorchis, adult flukes may be seen in the gallbladder, common bile duct, and pancreatic duct 92 . Cholelithiasis is not particularly frequent in Opisthorchiasis 93. However, biliary sludge is often seen in the gallbladder in heavy O viverrini infections94, 95. Eggs and worm fragments have been observed in gallstones and in sludge supporting the role of the parasite in initiating cholelithiasis96. Infection in humans may lead to cholangitis, obstructive jaundice, hepatomegaly, cholecystitis, and cholelithiasis. Diagnosis is usually confirmed by the presence of eggs in feces. Treatment is with praziquantel. There is an increased risk for cholangiocarcinoma in those infected with O viverrini.
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Figure 7-6.
Opisthorcis life cycle. Obtained with permission from CDC DPD image library.
Fasciola hepatica Fasciola hepatica is found in most parts of the world except for North America and usually infects sheep and cattle. The adult fluke is large, flat, brownish, and leaf-shaped and measures approximately 2.5×1 cm87. The intermediate host is aquatic plants such as watercress (Figure 7-7). Humans may become infected by accidental ingestion of contaminated watercress. The infective larvae penetrate the intestinal wall, pass into the peritoneum, migrate into the liver, and take several weeks to eventually migrate into the biliary ducts where they reside. In the acute phase of the infection, patients may have symptoms such as fever, right upper quadrant pain, and arthralgias even with light infectious burden97,98. A few weeks after the worms enter the bile canaliculi, symptoms may decline or disappear completely. In the chronic phase, patients may develop biliary colic or cholangitis97. Extrahepatobiliary disease may also develop, such as pulmonary infiltrates, pleuropericarditis, meningitis, or lymphadenopathy 97. On examination hepatomegaly may be present. Blood tests may reveal eosinophilia, and serologic tests may help in establishing the diagnosis. Ova may be recovered from bile or stool and a concentration method such as formol ether is necessary to enhance the chance of finding eggs87 (Figure 7-8). CT examination of the liver may show small nodules or tortuous linear tracks87. MRI may also be useful. Individual cases with obstruction of bile ducts and biliary cirrhosis have been reported, but they are extremely rare. Medical treatment is useful for the hepatic stage of the disease. Bithionol (30 to 50 mg/kg on alternate days for 10 to 15 doses) is the drug of choice for treating fascioliasis87. Triclabendazole may also be used. During the biliary stage, ERCP may be required to relieve obstruction99.
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Figure 77. Fasciola
hepatica life cycle. Obtained with permission from CDC DPD image library.
Figure 7-8. Fasciola hepatic egg. Obtained with permission from CDC DPD image library.
Echinococcosis E granulosus and E multilocularis belong to the family of cestodes (tapeworms) and are associated with biliary disease. E Granulosus
E granulosus is found where there are poor sanitary conditions and cattle, dogs, and humans live in close proximity. Cases have occurred in Europe, particularly near the Mediterranean and Russia, New Zealand, Australia, and parts of South America. Both E granulosus and E multilocularis have been spreading to new regions throughout the world. Canines, such as dogs, wolves, and foxes, serve as the intermediate hosts and are vectors for human infection87 (Figure 7-9). E granulosus develops in the intestine of dogs and eggs are passed into the feces. Sheep, cattle, swine, goats, camels, horses, and
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Figure 7-9.
Echinococcosis life cycle. Obtained with permission from CDC DPD image library.
humans may accidentally be infected by ingesting contaminated food. When humans ingest the eggs, the embryo passes into the gastrointestinal tract and develops. The eggs hatch into infective larva called oncospheres. The oncospheres pass through the duodenal wall and find their way to the portal and lymphatic system, going to sites such as the liver, lung, spleen, muscle, bone, kidney, and brain. The embryo grows into large two-layered cysts and may cause symptoms once larger than 10 cm. The liver is the most common site for E granulosus to inhabit, and more than 90% of the time it inhabits the liver and/or lung100. Symptoms are usually absent and primarily based on the size and location of cysts. Patients may present with jaundice, cholangitis, vague upper abdominal pain, or abdominal mass when the cysts are large. Cysts have also been shown to compress or erode into the bile ducts, portal vein, hepatic veins, and lymphatics. Patients may present with other systemic symptoms as they may infect almost any organ in the body. The diagnosis may be made by a combination of cross-sectional imaging (such as ultrasound, CT, or MRI) and serology 84,87. Serology is 80 to 100% sensitive and 88% to 96% specific for liver cyst infection but less sensitive for lung (50% to 56%) or other organ involvement (25 to 56%) 87. Antigen based assays are less sensitive than antibody based assays100. Imaging remains more sensitive than serodiagnosis, and a characteristic scan in the presence of negative serologic results should still suggest the diagnosis of Echinococcosis 87. Fine needle aspiration is not preferred for diagnosis due to the risk for cyst rupture, but it can be done safely. Cyst leak or rupture may lead to anaphylaxis and secondary seeding of larvae. The primary treatment is surgical removal of the cysts and medical treatment with benzimidole agents such as albendazole (10 mg/kg/day in divided doses or 400mg BID for 1 to 3 months) or mebendazole (40 mg/kg/day divided into three doses) pre- and postoperatively. Agents such as chlorhexidine, hydrogen peroxide, 80% alcohol, hypertonic saline, and 0.5% cetrimide may also be injected into the cyst once some fluid is removed to reduce the risk of rupture. Surgical resection of cysts
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Figure 7-10.
ERCP image of Echinococcosis involving the hepatobiliary system. Reprinted with permission from Rodriguez AN, Sanchez del Rio AL, Alguacil LV, De Dios Vega JF, Fugarolas GM. Effectiveness of endoscopic sphincterotomy in complicated hepatic hydatid disease. Gastrointest Endosc. 1998;48:593-597.
has a 2% mortality, morbidity of 23%, and recurrence rate of 10.4%101. Albendazole is preferred because it has better absorption, but is associated with side effects such as leukopenia and jaundice. If cysts are inoperable, benzimidole medication may be used but the cure rate is low (29%). A new formulation of albendazole shows promise due to higher bioavailability with cure rates as high as 80% to 90%102 . Studies show praziquantel (25 mg/kg/day) may increase the efficacy of albendazole by increasing the absorption100. Another option for inoperable cysts is the PAIR procedure (puncture, aspiration, injection, and reaspiration) and the success rate is not yet known. PAIR is contraindicated in cysts that are superficial, inaccessible, calcified, solid, or in communication with bile ducts100. If cholangitis is present, antibiotics should also be added to the treatment regimen103. E multilocularis
E multilocularis is found in western and central Europe, Russia, Turkey, Japan, Kurile Islands, China, Alaska, and northern Canada and causes alveolar cyst disease. The definitive hosts are fox that pass parasitic eggs in the feces, which may contaminate grass and wild fruits. Usually the eggs are ingested and grow within rodents, but humans may also accidentally ingest contaminated fruits and vegetables. E multilocularis is more aggressive than E granulosum. Humans may also acquire the parasite by contact with an infected fox. E multilocularis passes through the human body in a similar pattern as that of E granulosum, but E multilocularis cysts reproduce asexually by lateral budding. Invasion into tissue by this parasite has been described as a highly aggressive tumor and may be mistaken for a tumor on imaging studies. The liver is the most common organ involved (Figure 7-10). Clinical manifestations occur gradually and may include upper abdominal pain, jaundice, and hepatomegaly. Patients may also manifest symptoms related to cholangitis, portal hypertension (from secondary biliary cirrhosis or parasitic portal thrombosis), and Budd-Chiari syndrome.
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The diagnosis is usually made by serologic and imaging studies. Imaging studies may be suspicious for carcinoma or sarcoma. Surgery is the primary form of treatment. Since wide resection margins are necessary for cure, partial hepatectomy or even liver transplantation may be needed. Adjuvant albendazole therapy (up to 20 mg/kg/day) should be given preoperatively to increase the likelihood of cure by surgery and continued for 2 years postoperatively. Patients who are inoperable may be treated with benzimidazoles.
Recurrent Pyogenic Cholangitis ETIOLOGY AND PATHOPHYSIOLOGY Recurrent pyogenic cholangitis, also known as Oriental cholangiohepatitis, is a syndrome of strictures of the bile duct, hepatolithiasis, intermittent obstruction, and recurrent biliary infections. It is more commonly encountered in people in China, Southeast Asia, and the Philippines, although it is more commonly seen now in Western countries due to Asian immigration. It appears to be declining in the Eastern hemisphere due to improved economic development104. Clonorchis sinensis, Ascaris, and other endemic parasites are commonly detected in patients with this syndrome, although the exact etiology and pathogenesis are not yet fully known.
CLINICAL MANIFESTATION Symptoms are similar to acute bacterial cholangitis: fever, abdominal pain, and jaundice.
DIAGNOSIS Ultrasound, CT scan, MRCP, ERCP, and PTC are all useful in providing information to aid in the diagnosis. ERCP and PTC are not recommended for only diagnostic purposes due to higher risk of complications. Ultrasound typically reveals ductal dilation, periportal echogenicity, and common bile duct thickening manifested by a hypoechoic stripe lying internal to the echogenic line of the normal bile duct. CT is useful in visualizing proximal to the obscure ductal obstruction and providing more detailed information of hepatic lesions. MRCP was shown to be superior to cholangiography in detecting all strictures 86% versus 44%, verified surgically. Cholangiography provides detail on ductal anatomy.
TREATMENT In addition to supportive management, initiation of antibiotics and drainage of all obstructive lesions are required. Percutaneous and surgical means for drainage are required more frequently than in acute bacterial cholangitis and the technique used is determined by location of the strictures. Hepatic-jejunostomy may be required for treatment and for easier access to hepatobiliary ducts that are involved105,106. Other surgical options include surgical sphincteroplasty, choledochojejunostomy, and choledochoduodenostomy107. Choledochoduodenostomy is a more attractive surgical option because it can be done laparascopically and keeps the bile duct accessible for endoscopy107.
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AIDS-Related Cholangiopathy ETIOLOGY AND PATHOPHYSIOLOGY Abnormalities of the bile ducts in AIDS patients were first noted by Margulis et al in 1986. In 1989, Cello et al described the syndrome in more detail. The estimated prevalence may be as high as 45% in AIDS patients, although the true incidence is not known, as patients may not have cholangiography available to make the diagnosis and many are asymptomatic with the syndrome108. Male homosexuals are more likely to have the syndrome109. The etiology is not yet known but opportunistic infections such as cryptosporidium, cytomegalovirus, and microsporidium are suspected with cryptosporidiosis reported most frequently, in 20% to 62% of patients109,110. Cytomegalovirus is detected in 23% to 42% of patients and Microsporidia is detected in 10% of patients111. E bieneusi accounts for most of the Microsporidia cholangitis cases, but E intestinalis has also been reported112 . Mycobacterium avium intracellulare and Isospora belli have also been reported in AIDS-related cholangitis in <5% of cases112 . In approximately 40% to 50% of cases, no microorganism is detected113,114.
CLINICAL MANIFESTATION The most common clinical feature of this syndrome is abdominal pain, usually localizing in the right upper quadrant, in approximately 90% of patients112 . Other common clinical features of this syndrome are nausea, vomiting, fever, and elevation of alkaline phosphatase. Hyperbilirubinemia is rare (<10%) and transaminases are usually mildly elevated108-110. Many patients may also have diarrhea and weight loss111. The clinical picture does not appear to vary based on the underlying organism detected115.
DIAGNOSIS Diagnosis of AIDS-related cholangiopathy can usually be made by presence of clinical features and ultrasound revealing ductal dilation or thickening. If ultrasound does not provide any additional information, ERCP may be considered. The most common cholangiogram finding is papillary stenosis associated with intrahepatic sclerosing cholangitis in 50% to 60% of patients110. Cello initially described four cholangiographic patterns seen in AIDS-related cholangiopathy. Papillary stenosis in 1% to 20% of patients, sclerosing cholangitis in 20% of patients, combination of papillary stenosis and sclerosing cholangitis in 50% of patients, and long 1 to 2 cm extrahepatic bile duct strictures in 15% of cases can resemble primary sclerosing cholangitis116. Acalculous cholecystitis and pancreatic ductal abnormalities have also been reported109. Biopsies or bile sampling should be obtained for microbial assessment. Biopsies and bile aspiration from multiple sites increases the diagnostic yield111,113. The histopathology of biopsies obtained of the ampulla and bile ducts typically show periductal inflammation and apoptotic cholangiocytes usually next to opportunistic organisms such as cryptosporidium109. ERCP is useful in excluding other diagnoses, such as primary bile duct lymphoma, intrahepatic Kaposi’s sarcoma with common bile duct compression, and pancreatic adenocarcinoma with papillary involvement109.
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TREATMENT The primary treatment for AIDS cholangiopathy is endoscopic sphincterotomy and biliary stents for strictures. Medical therapy alone for the underlying organism detected does not appear to be effective111,117,118. Gancyclovir and foscornet are used for CMV cholangitis. Albendazole is used to treat Microsporidia. Ursodeoxycholic acid has also been shown to reduce pain and decrease cholestasis in patients who do not improve with sphincterotomy119.
PROGNOSIS The median survival for patients with AIDS cholangiopathy is from 4 to 9 months111,117,120,121. In a study by Ko et al, poor prognostic factors were a history of opportunistic infection involving the digestive tract, lung, eye, nervous system, skin, or systemic involvement at the time when AIDS cholangiopathy was diagnosed; cryptosporidium infection; and alkaline phosphatase greater than 1000 IU/L or 8 times the normal value. CD4 lymphocyte counts, type of cholangiopathy, and the performance of sphincterotomy were not correlated with the survival of patients with AIDS cholangiopathy121.
Viruses The hepatropic viruses—hepatitis A, hepatitis B, hepatitis C, hepatitis E—can cause cholangitis, albeit rare. Biopsies of bile ducts in patients with these viruses may reveal lymphoid aggregates84. Hepatitis A and E can cause canalicular cholestasis and the bile ducts are normal84. In children, CMV, reovirus 3, and rotavirus (groups A and C) have been associated with biliary atresia84. CMV is a common opportunistic infection in orthotopic liver transplantation patients. In these patients, CMV has been linked to vanishing bile duct syndrome but this has not yet been proven84.
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75. Leese T, Neoptolemos JP, Baker AR, Carr-Locke DL. Management of acute cholangitis and the impact of endoscopic sphincterotomy. Br J Surg. 1986;73:988-92. 76. Lai EC, Mok FP, Tan ES, et al. Endoscopic biliary drainage for severe acute cholangitis. N Engl J Med. 1992;326:1582-6. 77. Sugiyama M, Atomi Y. Treatment of acute cholangitis due to choledocholithiasis in elderly and younger patients. Arch Surg. 1997;132:1129-33. 78. Sugiyama M, Atomi Y. Endoscopic sphincterotomy for bile duct stones in patients 90 years of age and older. Gastrointest Endosc. 2000;52:187-91. 79. Joseph PK, Bizer LS, Sprayregen SS, Gliedman ML. Percutaneous transhepatic biliary drainage. Results and complications in 81 patients. JAMA. 1986;255:2763-7. 80. Pessa ME, Hawkins IF, Vogel SB. The treatment of acute cholangitis. Percutaneous transhepatic biliary drainage before definitive therapy. Ann Surg. 1987;205:389-92. 81. Gigot JF, Leese T, Dereme T, Coutinho J, Castaing D, Bismuth H. Acute cholangitis. Multivariate analysis of risk factors. Ann Surg. 1989;209:435-8. 82. Misra SP, Dwivedi M. Clinical features and management of biliary ascariasis in a non-endemic area. Postgrad Med J. 2000;76:29-32. 83. Khuroo MS. Ascariasis. Gastroenterol Clin North Am. 1996;25:553-77. 84. Carpenter HA. Bacterial and parasitic cholangitis. Mayo Clin Proc. 1998;73:473-8. 85. Khuroo MS, Zargar SA, Yattoo GN, et al. Sonographic findings in gallbladder ascariasis. J Clin Ultrasound. 1992;20:587-91. 86. Khuroo MS, Zargar SA, Mahajan R, Bhat RL, Javid G. Sonographic appearances in biliary ascariasis. Gastroenterology. 1987;93:267-72. 87. Mandell G. Principles and Practice of Infectious Diseases. New York: Churchill Livingstone, Inc.; 2000. 88. Lim JH. Radiologic findings of clonorchiasis. AJR Am J Roentgenol. 1990;155:10018. 89. Choi BI, Kim HJ, Han MC, Do YS, Han MH, Lee SH. CT findings of clonorchiasis. AJR Am J Roentgenol. 1989;152:281-4. 90. Choi BI, Park JH, Kim YI, et al. Peripheral cholangiocarcinoma and clonorchiasis: CT findings. Radiology. 1988;169:149-53. 91. Sripa B. Pathobiology of opisthorchiasis: an update. Acta Trop. 2003;88:209-20. 92. Pungpak S, Riganti M, Bunnag D, Harinasuta T. Clinical features in severe opisthorchiasis viverrini. Southeast Asian J Trop Med Public Health. 1985;16:405-9. 93. Schistosomes, liver flukes and Helicobacter pylori. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 7-14 June 1994. IARC Monogr Eval Carcinog Risks Hum. 1994;61:1-241. 94. Elkins DB, Haswell-Elkins MR, Mairiang E, et al. A high frequency of hepatobiliary disease and suspected cholangiocarcinoma associated with heavy Opisthorchis viverrini infection in a small community in north-east Thailand. Trans R Soc Trop Med Hyg. 1990;84:715-9. 95. Mairiang E, Elkins DB, Mairiang P, et al. Relationship between intensity of Opisthorchis viverrini infection and hepatobiliary disease detected by ultrasonography. J Gastroenterol Hepatol. 1992;7:17-21. 96. Riganti M, Pungpak S, Sachakul V, Bunnag D, Harinasuta T. Opisthorchis viverrini eggs and adult flukes as nidus and composition of gallstones. Southeast Asian J Trop Med Public Health. 1988;19:633-6.
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97. Arjona R, Riancho JA, Aguado JM, Salesa R, Gonzalez-Macias J. Fascioliasis in developed countries: a review of classic and aberrant forms of the disease. Medicine. (Baltimore) 1995;74:13-23. 98. Saba R, Korkmaz M, Inan D, et al. Human fascioliasis. Clin Microbiol Infect. 2004;10:385-7. 99. Sezgin O, Altintas E, Disibeyaz S, Saritas U, Sahin B. Hepatobiliary fascioliasis: clinical and radiologic features and endoscopic management. J Clin Gastroenterol. 2004;38:285-91. 100. McManus DP, Zhang W, Li J, Bartley PB. Echinococcosis. Lancet. 2003;362:1295304. 101. Buttenschoen K, Carli Buttenschoen D. Echinococcus granulosus infection: the challenge of surgical treatment. Langenbecks Arch Surg. 2003;388:218-30. 102. Chai J, Menghebat, Wei J, et al. Observations on clinical efficacy of albendazole emulsion in 264 cases of hepatic cystic echinococcosis. Parasitol Int. 2004;53:3-10. 103. Crippa FG, Bruno R, Brunetti E, Filice C. Echinococcal liver cysts: treatment with echo-guided percutaneous puncture PAIR for echinococcal liver cysts. Ital J Gastroenterol Hepatol. 1999;31:884-92. 104. Lo CM, Fan ST, Wong J. The changing epidemiology of recurrent pyogenic cholangitis. Hong Kong Med J. 1997;3:302-304. 105. Cosenza CA, Durazo F, Stain SC, Jabbour N, Selby RR. Current management of recurrent pyogenic cholangitis. Am Surg. 1999;65:939-43. 106. Stain SC, Incarbone R, Guthrie CR, et al. Surgical treatment of recurrent pyogenic cholangitis. Arch Surg. 1995;130:527-32; discussion 532-3. 107. Tang CN, Siu WT, Ha JP, Li MK. Laparoscopic choledochoduodenostomy: an effective drainage procedure for recurrent pyogenic cholangitis. Surg Endosc. 2003;17:1590-4. 108. Cello JP. AIDS-Related biliary tract disease. Gastrointest Endosc Clin N Am. 1998;8:963. 109. Chen XM, LaRusso NF. Cryptosporidiosis and the pathogenesis of AIDScholangiopathy. Semin Liver Dis. 2002;22:277-89. 110. Wilcox CM, Monkemuller KE. Hepatobiliary diseases in patients with AIDS: focus on AIDS cholangiopathy and gallbladder disease. Dig Dis. 1998;16:205-13. 111. Bouche H, Housset C, Dumont JL, et al. AIDS-related cholangitis: diagnostic features and course in 15 patients. J Hepatol. 1993;17:34-9. 112. Sheikh RA, Prindiville TP, Yenamandra S, Munn RJ, Ruebner BH. Microsporidial AIDS cholangiopathy due to Encephalitozoon intestinalis: case report and review. Am J Gastroenterol. 2000;95:2364-71. 113. Pol S, Romana CA, Richard S, et al. Microsporidia infection in patients with the human immunodeficiency virus and unexplained cholangitis. N Engl J Med. 1993;328:95-9. 114. Cello JP, Chan MF. Long-term follow-up of endoscopic retrograde cholangiopancreatography sphincterotomy for patients with acquired immune deficiency syndrome papillary stenosis. Am J Med. 1995;99:600-3. 115. Nash JA, Cohen SA. Gallbladder and biliary tract disease in AIDS. Gastroenterol Clin North Am. 1997;26:323-35. 116. Cello JP. Acquired immunodeficiency syndrome cholangiopathy: spectrum of disease. Am J Med. 1989;86:539-46. 117. Forbes A, Blanshard C, Gazzard B. Natural history of AIDS related sclerosing cholangitis: a study of 20 cases. Gut. 1993;34:116-21.
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118. Molina JM, Oksenhendler E, Beauvais B, et al. Disseminated microsporidiosis due to Septata intestinalis in patients with AIDS: clinical features and response to albendazole therapy. J Infect Dis. 1995;171:245-9. 119. Chan M, Koch J, Cello J. Ursodeoxycholic acid for symptomatic AIDS-associated cholangiopathy. Gastrointest Endosc. 1994;40:A108. 120. Ducreux M, Buffet C, Lamy P, et al. Diagnosis and prognosis of AIDS-related cholangitis. AIDS. 1995;9:875-80. 121. Ko WF, Cello JP, Rogers SJ, Lecours A. Prognostic factors for the survival of patients with AIDS cholangiopathy. Am J Gastroenterol. 2003;98:2176-81. 122. al-Karawi M, Sanai FM, Yasawy MI, Mohammed AE. Biliary strictures and cholangitis secondary to ascariasis: endoscopic management. Gastrointest Endosc. 1999;50:695-7. 123. Chu DW, Li JC, Lee DW, Rong ZX, Chen XW, Chan AC. Unusual presentations of hepatic clonorchiasis. Gastrointest Endosc. 2003;58:637-9. 124. Rodriguez AN, Sanchez del Rio AL, Alguacil LV, De Dios Vega JF, Fugarolas GM. Effectiveness of endoscopic sphincterotomy in complicated hepatic hydatid disease. Gastrointest Endosc. 1998;48:593-7.
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8
Acute Pancreatitis John Horwhat, MD; Paul Jowell, MD
Introduction Despite advancements in medicine, acute pancreatitis (AP) remains a significant problem for the clinician who is called upon to treat those afflicted with this illness. The improvements in antibiotics, nutrition, imaging, and intensive care over the past two decades, while encouraging, have done little to impact the mortality associated with this disorder. The goals for this chapter on AP are to construct a comprehensive overview of the evaluation, management, and treatment of a common, prevalent, and morbid disorder. Rather than focusing on subtleties and nuances of this disorder, we believe it will be more instructive to the clinician caring for patients with AP to describe the “big picture” of AP by outlining the manner in which we approach patients with AP in our institution.
Background Acute pancreatitis is a disorder that can range in severity from a mild, self-limited illness in 75% to 80%, to a severe illness with complications requiring intensive care or surgical intervention in 15% to 25%, and death in approximately 5%. In terms of importance, it may even be said that pancreatitis has changed the face of history, as historians postulate that both Ludwig von Beethoven (alcohol-induced pancreatitis) and Alexander the Great (death from alcohol-induced pancreatitis) may have succumbed to this disorder or its complications1,2 . An Internet search revealed further notable people that have suffered or died secondary to pancreatitis or its complications. US Attorney General John Ashcroft (gallstone pancreatitis), musicians Dizzie Gillespie (death from AP) and Johnny Cash (death from pneumonia after AP), Apollo 14 astronaut Stuart Allen Roosa (death from AP), and actors Matthew Perry (hospitalized for AP) and Maximilian Schell (collapsed in public due to attack of AP) have all been afflicted by this disorder. In addition to these celebrities, data compiled by The National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK)
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report the incidence of AP as 17 new cases per 100,000 people (1976-1988) and that AP is responsible for 125,000 hospitalizations and 911,000 office visits per year (1987 data). The same NIDDK report stated that pancreatitis (both acute and chronic) was responsible for 2,700 deaths per year (1985 data), while annual reports more recently tabulated by the Centers for Disease Control and Prevention on causes of death in the United States reported 3,289 deaths in 1999 and 3,377 deaths in 2000 secondary to pancreatitis (both acute and chronic). It is concerning that the number of deaths attributed to pancreatitis has failed to decrease over time. If the care we are able to provide patients hospitalized with AP has improved over the past two decades, why do these government publications suggest a progressive climb in the number of deaths attributable to pancreatitis each year? Clearly, there has been an increase in the use of medications associated with a risk for causing AP over the last two decades, especially highly active antiretroviral therapy (HAART) in the HIV population3. Without knowing the denominator of the population with pancreatitis, the apparent increase in death numbers may not actually correspond to an increase in death rate. Regardless, even in the year 2004, it is plain to see that AP remains a disease that continues to cause substantial morbidity and mortality. We hope that this chapter will help provide clinicians with a better understanding of AP, which might translate to an eventual decline in the morbidity and mortality attributed to this illness.
Diagnosis As with most disease states in medicine, the most important and readily available diagnostic tools available to the clinician evaluating a patient suspected of having AP are the clinical history and physical examination. The consulting gastroenterologist seeing a patient suspected of having AP may already have access to medical records, laboratory tests, and radiographic images and if so, the diagnosis of AP may already be quite evident. Even if the exact etiology of AP cannot be determined during the first encounter with the patient, the physician who makes initial contact with the patient in the office or emergency department must first rely on the basic history and physical to ensure the patient with AP is correctly diagnosed and management initiated in the proper direction. In order to narrow one’s clinical suspicion sufficiently toward the diagnosis of AP, it is important to have a basic understanding of the anatomy of the pancreas to understand AP and its potential complications. First, the character of the pain should be consistent with the diagnosis. As a solid retroperitoneal organ, the pain is different from that felt by the hollow viscera. Typically a deep, boring, severe epigastric pain is described, though the pain may also be felt along the left flank or through to the back as well. Abdominal distention with nausea and vomiting are frequently experienced. Signs of tachycardia, tachypnea, and fever are also not uncommon. The patient may describe restlessness and agitation with initial pacing being later replaced by lying on the side, leaning forward, or curling into the fetal position to seek comfort. The retroperitoneal location of the pancreas places it in close proximity to the stomach, colon, small bowel, and diaphragm and helps explain the wide variety of signs and symptoms with which AP patients present. As a result of the intimate contact of the inflamed pancreas with the stomach and duodenum, the inflammatory reaction with these adjacent viscera can result in a motility disturbance that is responsible for the loss of appetite, nausea, and vomiting common
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to this disorder. Local contact with other loops of small bowel or colon results in ileus and constipation, respectively. Contact with the diaphragm and lung bases can lead to atelectasis or local pneumonitis with tachypnea, shortness of breath, pleural effusion, and, in the worst cases, adult respiratory distress syndrome. Effects on the circulation from the release of inflammatory cytokines and vasoactive mediators may cause fluid shifts, and when combined with hypovolemia from nausea and vomiting, can lead to renal insufficiency, shock, vascular collapse, and coma. These signs and symptoms can be ascertained within the first few minutes of contact with the patient and ensuing care can be initiated early if AP is, in fact, the correct diagnosis. Unfortunately, however, clinical experience has taught us that a perforated gastric or duodenal ulcer, cholecystitis, and even severe pneumonia can present with the signs and symptoms discussed above. Fortunately, unless practicing in a remote location or under austere conditions without laboratory support, a few simple laboratory tests enable the clinician to be more confident in diagnosing AP—namely, the serum amylase and serum lipase. Elevation of the serum amylase as a marker for pancreatic disease was first described in 19294. Although AP may be seen with normal amylase levels, when coupled with an elevated serum lipase in the right clinical context, the combination of an elevated amylase and lipase is almost universally accepted as the standard means of diagnosing AP. Both amylase and lipase are elaborated from acinar cells in the pancreas and their levels will rise following injury to or inflammation affecting the pancreas. Serum amylase levels will rise within 2 to 12 hours of pancreatitis symptoms, peak within the first 48 hours, and remain elevated for 3 to 5 days before returning to baseline5. A relatively short serum half-life of 2 hours results in more rapid clearance from the circulation than lipase. Delay in presentation can result in missing the amylase peak and is one scenario in which AP may be diagnosed with a normal amylase. In comparison, serum lipase will rise within 4 to 8 hours of symptom onset, peak at 24 hours, and may remain elevated for 8 to 14 days before normalizing5. The ability for renal tubules to reabsorb lipase, but not amylase, results in a more prolonged serum half-life of 6.9 to 13.7 hours 6. As clinicians, we place a lot of trust in these levels to aid in making the diagnosis of AP. The astute clinician should be aware, however, of situations that may lead to either false-positive or falsenegative amylase and lipase values (Tables 8-1, 8-2, and 8-3). We have found that patients with elevations of amylase and lipase below a cutoff of three times the upper limit of normal rarely have pancreatic pathology and therefore use this threshold for making a diagnosis of AP7. Frequently, in urgent care centers or emergency departments, when the clinical scenario concerning the patient with acute abdominal pain remains unclear, an abdominal CT scan will be performed to aid in the diagnostic evaluation. When available, CT scan or MRI can be very useful in securing the diagnosis, especially when other causes of pain with elevated amylase and/or lipase are being considered. The CT scan, when showing clear evidence of pancreatic inflammation, is very specific for pancreatitis. A negative CT scan, however, does not rule out pancreatitis. The role of imaging in AP is discussed in more detail later in this chapter.
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Table 8-1
MEDICATIONS ASSOCIATED WITH A RISK OF HYPERAMYLASEMIA, HYPERLIPASEMIA AND/OR ACUTE PANCREATITIS (Asterisk indicates medications associated only with elevated serum lipase, italicized medications are associated with both increased amylase and lipase.)
Anti-CNS (include anticonvulsants, antidepressants and antipsychotics) Carbamazepine Olanzapine Clozapine Riluzole Gabapentin Risperidone Lamotrigine Sertraline Maprotiline Valproic acid Mirtazapine Anti-infectives (includes antibiotics, antifungals, antiretrovirals and antivirals) Abacavir/lamivudine/zidovudine Minocycline Amphotericin B liposome Nelfinavir Ampicillin Nitrofurantoin Atovoquone Paromomycin Ceftriaxone Pentamidine Ciprofloxacin Pyrimthamine/sulfadoxine Cotrimoxazole Ribavirin/Interferon alfa Dapsone Rifampin Didanosine Ritonavir Enfuvirtide Roxithromycin Erythromycin Saquinavir Foscarnet Sodium Stibogluconate Ganciclovir Stavudine Indinavair Sulfamethizole Isoniazid Sulfamethoxazole Lamivudine Sulfisoxazole Lopinavir/ritonavir Tacrolimus Meglumine antimoniate Tenofovir Methacycline Tetracycline Metronidazole Zalcitabine
Acute Pancreatitis Table 8-1, continued
Antihypertensives Alacepril Amlodipine/benazepril Bemetizide Benazepril Bendroflumethiazide Benzthiazide Bumetanide Butizide Captopril Chlorothiazide Chlorthalidone Cilazapril Cyclothiazide Delapril Diazoxide Enalapril Ethacrynic acid Fosinopril Furosemide Hydrochlorothiazide Hydroflumethiazide Imidapril
Indapamide Irbesartan Irbesartan/hydrochlorothiazide Lisinopril Lisinopril/ hydrochlorothiazide Losartan Methyclothiazide Methyldopa Metolazone Moexipril Nadolol Perinopril Polythiazide Quinapril Quinethazone Ramipril Spirapril Trandolapril Triamterene/hydrochlorothiazide Trichlormethiazide Zofenopril *Thiazide diuretics
Anti-inflammatories (includes antirheumatics, dermatologics and steroids) Acitretin Ketorolac *Adrenocorticotropic hormone Mefenamic acid Auranofin Methylprednisolone Betamethasone Naproxen Celecoxib Paramethasone Corticotropin/cosyntropin Piroxicam Cortisone Prednisone Deflazacort Prednisolone Dexamethasone Rofecoxib Diclofenac Sulindac Fluocortolone Triamcinolone Hydrocortisone Indomethacin
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Table 8-1, continued
Antineoplastics (includes anti-immunologics) Asparaginase Infliximab Azathioprine Interferon gamma Bexarotene Mercaptopurine Cyclophosphamide Paclitaxel Cytarabine Pegaspargase Doxorubicin Vincristine Hydroxyurea Vinorelbine Cardiac medications (includes antihyperlipidemics) Amiodarone Dexrazoxane *Ardeparin Fenofibrate Atorvastatin Fluvastatin Bezafibrate Procainamide Clofibrate Simvastatin Gastrointestinal medications *Bethanechol Cimetidine Diphenoxylate Mesalamine Monoctanoin Octreotide Miscellaneous Calcifediol Calcitriol Codeine Combination contraceptives Danazol Dicumarol Diethylstilbestrol Ergocalciferol Ethanol Intravenous fat emulsion Iodine -125 *Triprolidine/pseudoephedrine
Olsalazine Phenolphthalein Polyethylene glycol Ranitidine Sulfasalazine
Iothalamate Isotretinoin *Methacholine Methimazole *Pentazocine Propofol *Secretin Sodium phenylbutyrate Somatrem Somatropin Tretinoin
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Table 8-2
CONDITIONS AND MEDICATIONS THAT DECREASE SERUM AMYLASE AND LIPASE VALUES Amylase Citrates Hypertriglycidemia OxalateSaquinavir
Lipase Calcium ions Hydroxyurea Protamine Somatostatin 5-ASA
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Table 8-3
CONDITIONS ASSOCIATED WITH AN ELEVATED AMYLASE OR LIPASE Nonpancreatic Intestinal Disorders Abdominal radiation Abdominal surgery Abdominal trauma Acute cholecystitis Appendicitis Bowel infarction Bowel obstruction Bowel perforation Ectopic production of amylase by malignancy Breast Cervix Endometroid carcinoma of ovary Leukemia (plasmacytoma) Lung/bronchogenic/pseudomesotheliomatous carcinoma Multiple myeloma Liver disease Cirrhosis Massive liver necrosis Pelvic inflammatory disease Peptic ulcer disease Ruptured ectopic pregnancy Severe gastroenteritis
Macroamylasemia and Conditions Associated With Macroamylasemia Celiac disease HIV Lymphoma Monoclonal gammopathy Myeloma Pregnancy Rheumatoid arthritis SLE Ulcerative colitis
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Table 8-3, continued
Salivary Disease Infection (parotiditis, mumps) Postradiation Sialolithiasis with ductal obstruction Trauma
Other Alcoholism Anorexia nervosa/bulimia Burns Cerebral trauma Diabetic ketoacidosis Idiopathic Renal failure
Etiology of Pancreatitis There are many causes of pancreatitis. Most of these are listed in Tables 8-4, 8-5, and 8-6. We use the history, laboratory tests, and radiological studies to evaluate patients for the etiology of their pancreatitis. The history is very important, especially when identifying alcohol, medications, and hereditary causes of pancreatitis. The following two sections address laboratory and radiological tests that should be considered in this evaluation as well as post-ERCP pancreatitis as a cause of pancreatitis.
LABORATORY TESTS FOR DETERMINATION OF ETIOLOGY There are several laboratory tests or combinations of tests that have been studied to help elucidate the etiology of AP. It is essential to be able to separate cases of acute biliary pancreatitis from nonbiliary etiologies, as the early management of these patients can differ significantly. The important consideration is whether or not the patient with biliary pancreatitis should undergo urgent ERCP with biliary sphincterotomy and stone extraction. Identifying which patients with biliary pancreatitis require urgent ERCP is discussed later in the chapter. In order to make the diagnosis of biliary pancreatitis, however, of the tests available in a common liver function panel, the most predictive is the alanine aminotransferase (ALT). An ALT level of 150 IU/L or more, which corresponds to a level of more than three times the upper limit of normal, had a positive predictive value of 95% according to one metaanalysis8. Unfortunately, the sensitivity of an elevated ALT is quite low, with only half
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Table 8-4
CAUSES OF ACUTE PANCREATITIS Autoimmune Biliary etiologies Biliary sludge Choledochocele Gallstones Microlithiasis/crystals Papillary stenosis Sphincter of Oddi dysfunction Genetic mutations CFTR SPINK Hereditary Hypercalcemia Hypertriglyceridemia Infectious Bacterial: Legionella, Leptospira, Mycoplasma, Salmonella Fungal: Aspergillus Parasites: Ascariasis, Cryptosporidium, Toxoplasma Viral: Coxsackievirus, CMV, hepatitis B, Mumps, VZV, HSV Idiopathic Medications Neoplastic Pancreas divisum Post-ERCP Pregnancy Toxins Ethanol Methanol Scorpion venom Trauma Vascular disease Atheroembolism Hemorrhagic shock Severe hypotension Vasculitis: PAN, SLE
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Table 8-5
ACQUIRED CAUSES OF HYPERTRIGLYCERIDEMIA Alcohol abuse Alstrom syndrome Diabetes mellitus Hypothyroidism Lipid administration (TPN) Medications Beta blockers Certain antifungals (itraconazole, ketoconazole) Cyclosporin Estrogens Glucocorticoids HAART therapy Sirolimus Certain SSRIs (fluoxetine, sertraline) Tamoxifen Tretinoin and related medications Nephrotic syndrome Obesity Pregnancy
of all biliary pancreatitis patients having significant elevations of this marker5. The combination of a right upper quadrant ultrasound that demonstrates stones or sludge within the gallbladder or common bile duct with an elevated ALT is the most accurate predictor of a biliary etiology. When drawn within 24 hours of admission, an ALT value of 80 IU/mL (or two times the upper limit of normal) in combination with a positive right upper quadrant (RUQ) US had a sensitivity, specificity, and positive and negative predictive value of 98%, 100%, 100%, and 96%, respectively 9. Along with gallstone pancreatitis, another major etiology of AP in the United States is alcohol-induced pancreatitis. Whereas gallstone pancreatitis is typically an acute attack upon an otherwise healthy pancreas, alcohol-induced pancreatitis can be viewed as an acute attack upon a pancreas that has become slowly chronically diseased. It is unusual for the first-time drinker to develop acute alcohol-induced pancreatitis; rather, this condition seems to afflict those who are chronic users of alcohol. AP in the alcoholic typically presents with lower levels of amylase in comparison with other etiologies, such as gallstones, and may even present with a normal amylase value. One study showed that 32% of patients with alcohol-induced AP had normal amylase levels at admission10. With the knowledge that the pancreas contains nearly five times more lipase than amylase, an increase in the ratio of serum lipase to amylase has been investigated with respect to predicting alcohol as the etiology of pancreatitis. If one uses multiples of the upper limits of normal for these laboratory tests, a ratio
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Table 8-6
REPORTED CAUSES OF HYPERCALCEMIA-ASSOCIATED PANCREATITIS Familial hypocalciuric hypercalcemia Immobilization hypercalcemia Milk-alkali syndrome Multiple myeloma Paraneoplastic syndrome associated with leiomyosarcoma associated with non-small cell bronchial carcinoma associated with renal cell carcinoma Parathyroid adenoma Primary hyperparathyroidism Sarcoidosis Vitamin D poisoning
of lipase to amylase of more than two was initially reported to be indicative of an alcohol-related etiology for AP11. A subsequent study reported that the higher the lipase to amylase ratio elevation, the greater the specificity of alcohol as the etiology of acute pancreatitis. While only 31% sensitive, a ratio of more than five had a 100% specificity in this study12 . Later studies demonstrated that there was too much overlap in lipase to mylase ratios among biliary, alcohol-related, and nonbiliary nonalcoholrelated etiologies, however, and as a result, enthusiasm for this method of determining an alcohol-related etiology has waned13,14 On the other hand, the use of carbohydrate-deficient transferrin (CDT), a marker of chronic alcoholism, may provide the clinician with a marker that is both sensitive and specific for the diagnosis of alcohol-related pancreatitis. Depending on the cutoff value used for CDT, studies have demonstrated sensitivities ranging from 75% to 87.5% and specificities of 85.2% to 100%15-17. Combining a CDT cutoff of 22.5 U/L with a serum trypsin activity >152 U/L enabled correct prediction of acute alcoholic pancreatitis in 98% of the cases in one study16. Although the measurement of CDT is reported to be easy to perform, it is not widely available and we do not use this test in our institution. Hypertriglyceridemia may be determined to be responsible for precipitating an attack of AP when the serum concentration is >1000 mg/dL. At this point, the lipemic serum will appear milky in the tube used to collect the blood and the laboratory merely serves to confirm the high pre-test suspicion of hypertriglyceridemia that arises when viewing the specimen. Simply viewing the tube of serum, although helpful, is rarely possible, as phlebotomists or nurses usually draw the blood before the clinician sees the patient. It is helpful to read the report of serum chemistries carefully when sus-
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pecting AP, however, as it will often be reported on the result sheet that the specimen appeared lipemic. It could then be inferred that the patient has hypertriglyceridemia even before measuring the level. The serum level of triglycerides may be inaccurate in the setting of acute illness and a baseline fasting measure should be drawn after the illness has resolved if no such values are available from before the onset of illness. Acquired causes of hypertriglyceridemia are reported in Table 8-5. The final laboratory test that can be helpful in determining etiology in AP is the serum calcium level. Occasionally, a patient with AP will be found to have hypercalcemia when the serum chemistries from admission are reviewed and this metabolic derangement may be the etiology that explains AP in a minority of patients. As with triglycerides, serum calcium will be altered in the setting of acute illness and hypocalcemia will actually be more prevalent as AP progresses. The possible etiologies associated with hypercalcemic AP are diverse and listed in Table 8-6.
POST-ERCP PANCREATITIS Most of the major etiologies of AP in the United States—gallstone, alcohol, medications, hypertriglyceridemia, and hypercalcemia—may be suspected based on laboratory tests that are discussed above. As we have outlined, these etiologies will usually be evident in the early stages of the evaluation from the clinical history, laboratory evaluation, and review of medications. While not yet discussed, the unfortunate patient who presents with abdominal pain, nausea, emesis, and a threefold or greater elevation in amylase following ERCP provides the clinician with yet another etiology for AP that can be readily ascertained from the clinical history post-ERCP pancreatitis. The anticipated rate of post-ERCP pancreatitis ranges from 1% to 7% according to data reviewed by the Standards of Practice Committee of the American Society of Gastrointestinal Endoscopy18. For patients with suspected sphincter of Oddi dysfunction undergoing sphincter of Oddi manometry, the risk is up to 20% to 25%19. Unfortunately, despite years of research involving the search for a medication or technique that can reliably decrease the risk of post-ERCP pancreatitis, no such panacea has been found. Efforts in the past have included studies of lidocaine sprayed onto the papilla, nitroglycerine (sublingual and transdermal), heparin, gabexate, corticosteroids, somatostatin, octreotide, nifedipine, allopurinol, IL-10 and prophylactic stents20-36. Recently, the Duke Biliary Group presented promising data at the 2003 Digestive Diseases Week on the use of synthetic secretin37. Although certain medications such as gabexate, somatostatin, and synthetic secretin have shown real promise, the problem lies in being able to correctly select which patients to treat 38. We cannot endorse the use of any of these prophylactic medications at this time and do not use any in our endoscopy suite. At the present time, a program of universal prophylaxis cannot be justified. Additional etiologies for AP are listed in Table 8-4.
Radiological Evaluation in Acute Pancreatitis In this section, we will address the radiological evaluation of patients with AP. We will cover its role in determining etiology as well as its use in the management of pancreatitis. Transabdominal ultrasound (US) is frequently performed in the setting of AP. The main role of US in AP is for establishing a biliary etiology and when positive for biliary stones in the gallbladder or bile duct, the study is quite useful. The exam’s sensitivity
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and accuracy suffers, however, due to body habitus (obesity), overlying bowel gas, and dependency on the operator’s skill level. In one prospective study of 50 consecutive patients with AP designed to evaluate the role of US in the diagnosis and prognosis of AP and the detection of a biliary origin, the pancreas could not be visualized in six patients and in 19 only partial examination was possible39. The performance characteristics of transabdominal ultrasound for the evaluation of the gallbladder itself, however, are excellent. Advantages of US include the ability to obtain results rapidly as the test is performed; it is noninvasive, requires no sedation, and has no complications. For these reasons, as well as the fact that US is relatively inexpensive compared to CT, portable, and widely available, we recommend a screening RUQ US as the initial radiological test for patients with AP when there is clinical suspicion of a biliary etiology. It is important to note that a CT scan is not an adequate study to exclude a gallstone etiology because its sensitivity is too low for the detection of gallbladder stones. In comparison, the helical abdominal CT scan with thin section scans taken through the pancreas during the administration of IV contrast (ie, the pancreas protocol CT) has become widely used for the diagnosis and risk stratification of AP. The use of IV contrast is important for evaluating whether necrosis is present. Thin cuts are primarily used to evaluate for small lesions such as tumors and are therefore crucial during the initial CT scan. Changes indicative of AP on CT scan include glandular enlargement, inflammatory stranding in the peripancreatic fat or adjacent soft tissue, and intra- or peripancreatic fluid collections. CT has undoubtedly helped many patients by diagnosing pancreatic necrosis at an earlier time, allowing aspiration for infected necrosis, earlier use of broad-spectrum antibiotics, a more timely performance of pseudocyst drainage and determination of the need for surgical debridement of infected, devitalized tissue. Some earlier data discouraged the use of CT scan early in the course of AP, fearing that the administration of IV contrast before adequate fluid resuscitation might be associated with a poorer outcome in terms of renal insufficiency. These early fears have largely been replaced by the wealth of experience demonstrating the benefits of CT scan in detecting necrosis, fluid collections, and other possible complications of AP. In fact, the Japanese Society of Abdominal Emergency Medicine has developed an evidence-based practice guideline to help clinicians with the management of AP40. This guideline gives a recommendation grade B to the use of an enhanced CT for the assessment of degree of pancreatic necrosis and inflammation. We find that many patients who are admitted through the emergency department (ED) will have already had a CT scan as part of their initial ED evaluation. This information is useful for helping to establish the diagnosis as well as for providing a baseline should the clinical course worsen over time. In terms of predicting mild versus severe AP, one study reported that the combination of the serum albumin level plus a CT scan demonstrating extrapancreatic fluid collections had a negative predictive value of 92% to 96%, positive predictive value of 67% to 100%, and was a better indicator of severity than Ranson, Glasgow, and APACHE II41. If the patient with mild pancreatitis has not already had a CT scan performed in the ED, we do not automatically perform one following admission. Instead, we allow the patient’s clinical course to dictate whether one is indicated. One retrospective study demonstrated a longer length of stay for patients with AP who underwent CT scan than those who did not despite a comparable severity of illness42 . Although these results can be criticized
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on the basis of study design and the faults inherent to a retrospective descriptive study, they still highlight the fact that abdominal CT scan is not mandatory in all patients with AP and may even have adverse consequences with regard to hospital costs (ie, length of stay) without contributing positively to outcome. In our institution, we use worsening or uncontrollable pain, especially with fever and elevated white blood cell (WBC) or signs of developing sepsis, as indicators to pursue CT scan of the pancreas. The reasons for this are to reassess the diagnosis in terms of severity and complications and especially to evaluate for pancreatic necrosis as it is now clear that patients with necrosis require broad-spectrum antibiotics and possibly antifungals to reduce morbidity from infected necrosis43-48. Magnetic resonance imaging (MRI) of the pancreas and magnetic resonance cholangiopancreatography (MRCP) have gained increasing popularity in the evaluation of hepatobiliary and pancreatic pathology. While still not widely utilized, MRI has been shown to evaluate poorly perfused areas of the pancreas in AP and discriminate areas of perinecrotic fluid from necrosis and hemorrhage that might otherwise be interpreted simply as necrosis on CT scan49. The ability to render an MRCP following MRI can supply additional information on etiology (eg, choledocholithiasis, annular pancreas, pancreas divisum) that CT may not be able to provide50. In addition, because gadolinium is a nonionic contrast agent, MRI offers a safer imaging option for patients with renal insufficiency. Unfortunately, there are disadvantages that limit the applicability of MRI. First, smaller community hospitals are much more likely to have a CT scanner than an MRI. The exam requires a more cooperative patient than CT, as it takes longer to acquire MRI than the rapid helical CT. A patient writhing in severe pain may not be able to lie still, resulting in motion artifact that renders the exam images unusable. A number of patients are claustrophobic and will resist entering the “tube”. Additionally, implanted metallic devices such as pacemakers, artificial heart valves, artificial joints, and other prostheses may prevent the patient from being able to undergo MRI. One final imaging modality worthy of mention is endoscopic ultrasound (EUS). In contrast to transabdominal ultrasound, EUS is able to detect gallstones or sludge within the gallbladder and extrahepatic bile duct regardless of body habitus. Bowel gas is not a concern and operator skill is placed in the hands of the physician, not an ultrasound technician. EUS is able to detect additional abnormalities, such as pancreas divisum and pancreatic neoplasia, which may not be apparent with other imaging modalities. The greatest utility for EUS at this time may be in helping establish a diagnosis of chronic pancreatitis or assist with finding an etiology in recurrent acute pancreatitis51,52 . A significant limitation to the use of EUS is that it is not widely available in the community practice setting. Algorithms to establish the place of this modality in the evaluation of AP have not yet been established.
Management of Pancreatitis In this section, we will address important aspects to consider when managing patients with pancreatitis. This is not intended to be an exhaustive review of management but rather a focused review of important and practical issues.
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PREDICTING SEVERITY Once a diagnosis of AP is made, one of the most important early tasks is the risk stratification of patients into the two major clinical categories: mild or interstitial pancreatitis and severe or necrotizing pancreatitis. This division is important for several reasons. First, this initial triage allows proper utilization of hospital resources. Whether clinically mild or severe, a majority of patients with AP will report pain that is 10 on a scale of 1 to 10 and so the presenting level of pain is not a helpful guide. It is imperative, however, to gain control of pain quickly and for patients with predicted severe AP we use patient controlled analgesia (PCA) with narcotics. A majority of patients with mild pancreatitis will have pain controlled with scheduled doses of narcotics with no breakthrough and some may even be well treated with an asneeded regimen. Pain is a subjective experience, though, and some patients with mild pancreatitis are eventually placed on PCA as well. It is helpful to involve the services of an anesthesia pain service for patients with complicated pain issues. Second, while values in the thousands for serum amylase and lipase will attract more attention than numbers in the hundreds, not unlike the subjective level of pain, these objective tests are also known to have a poor correlation with severity of illness. The initial task facing the clinician at the time of admission is distinguishing mild from severe and deciding which patients can be managed on “the ward” and which are more appropriately managed in a monitored setting such as the intensive care unit (ICU). In an era where patients are often held in observation units while waiting for beds to become available for admission or initially managed on a medical ward while waiting for an ICU bed, the decisions made during these early hours can truly be “life or death” for the patient with severe AP53. Finally, because early mortality in AP is usually due to multisystem organ failure, the identification of patients with severe pancreatitis as early as possible can allow for transfer to a higher level of care when such resources are available. To help guide clinicians, various predictors of severity have been developed. Some are clinically based, some are laboratory based, some can be interpreted immediately, some can be recalculated serially, and others are not valid until 48 hours into the illness. Some scoring systems are specific for pancreatitis, whereas others are for general use in severe illness. The characteristics of these various scoring systems are provided in Table 8-7.
Clinical Scoring Systems for Predicting Severity The first scoring systems that were developed to aid the clinician in determining severity in AP were clinically based. The now venerable Ranson criteria were first presented in 1974 and remained the standard until 1981, when a modified version known as the Glasgow criteria was developed. These criteria are largely derived from blood tests and are therefore easy to obtain and interpret. Unfortunately, however, application of the Ranson criteria requires laboratory data both from admission and at 48 hours to calculate severity and expected mortality. The Glasgow criteria are measured at the 48-hour mark as well. We looked at the utility of the Ranson criteria in our own institution and found that it is uncommon for clinicians to actually measure all 11 of these criteria in patients with AP. A Ranson score of >3 did indeed correlate with severe AP, though no prediction regarding outcome or mortality could be drawn from the use of the Ranson score. These latter parameters are most important to the clinician and the reason severity scales are used in the first place. As such, we agree
Acute Pancreatitis Table 8-7
CLINICAL CRITERIA SCALES Atlanta Criteria for Severe Acute Pancreatitis Organ Failure Shock: systolic blood pressure <90 mm Hg Pulmonary insufficiency: PaO2 <60 mm Hg Renal failure: serum creatinine >2 mg/dL Gastrointestinal bleeding: >500 mL/24 hr And/or Local Complications Necrosis Abscess Pseudocyst Unfavorable Early Prognostic Signs ≥ 3 Ranson’s signs (see below) ≥ 8 APACHE-II points
Ranson’s Criteria for Severity of Pancreatitis At Admission Age >55 yr White blood cells >16,000/mm3 Glucose >200 mg/dL Lactate dehydrogenase >350 IU/L Aspartate aminotransferase >250 U/L During Initial 48 hr Hematocrit decrease of >10 mg/dL Blood urea nitrogen increase of >5 mg/dL Calcium <8 mg/dL PaO2 <60 mm Hg Base deficit >4 mEq/L Fluid sequestration >6 L Mortality when score: <3 (<1%), 3-4 (16%), 5-6 (40%), >6 (100%)
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Table 8-7, continued
Bank’s Clinical Criteria for Severity of Pancreatitis Cardiac = shock, tachycardia >130, arrhythmia, EKG changes Pulmonary = dyspnea, rales PO2 <60mm Hg, adult respiratory distress syndrome Renal = urine output <50ml/h, rising blood urea nitrogen and/or creatinine Metabolic = low or falling calcium, pH; albumin decrease Hematological = falling hematocrit, disseminated intravascular coagulation Neurological = Irritability, confusion, localizing signs Hemorrhagic = on signs or peritoneal tap Tense distension = severe ileus, fluid ++ Interpretation ≥1 = severe (potentially lethal) disease
Imrie’s Prognostic Criteria for Severity of Pancreatitis (Glasgow Criteria) During initial 48 hours White blood cell count over 15,000 Blood glucose over 10 mmol/l in absence of diabetes history Serum urea over 16 mmol/l (no response to IV fluids) PO2 level below 60 mm Hg Serum calcium level below 2.0 mmol/l Lactic dehydrogenase over 600 U/l Aspartate aminotransferase/alanine aminotransferase >200µm/l Serum albumin level less than 32 g/l
Simplified Prognostic Criteria ( of Agarwal and Pitchumoni) During initial 48 hr Cardiac = BP <90 mm Hg and/or tachycardia >130 bpm Pulmonary = PO2 <60 mm Hg Renal = Urine output <50 ml/h Metabolic = Calcium < 8 mg/dl and/or albumin <3.2 g/dl
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Table 8-7, continued
CT Severity Index (Balthazar score) Grade of acute pancreatitis A: normal pancreas B: pancreatic enlargement alone C: inflammation confined to the pancreas and peripancreatic fat D: one peripancreatic fluid collection E: two or more fluid collections Degree of pancreatic necrosis No necrosis Necrosis of 1/3 of the pancreas Necrosis of ½ of the pancreas Necrosis of more than ½ of the pancreas CT Severity Index = grade points + degree of necrosis points
Points 0 I 2 3 4 0 2 4 6
Marshall Multiple Organ Dysfunction Score Organ system Respiratory (PO2/FiO2) Renal (serum creatinine umol/L) Hepatic (serum bilirubin umol/L) Cardiovascular (PAR=HR x RAP/mean BP) Hematologic (platelet count) Neurologic (Glasgow coma score)
0 >300
Score 1 2 3 226-300 151-225 76-150
<=100
101-200 201-350 351-500 >500
<=20
21-60
61-120
121-240 >240
<=10.0
10.1-15
15.1-20
20.1-30 >30
>120
81-120
51-80
21-50
<=20
15
13-14
10-12
7-9
<=6
4 <=75
Mortality = 0% for score = 0, ~25% for score 9-12, 50% for score 13-16, 75% for score 17-20 and 100% mortality for score >20
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with the conclusion of our colleagues that further testing of the utility of the Ranson criteria with respect to outcome and mortality is indicated in order to determine their true place in the present day management of AP (Sultan et al, unpublished data). A more cumbersome, but probably more versatile, tool is the Acute Physiologic and Chronic Health Evaluation (APACHE) II score. The APACHE II scoring system is not specific for pancreatitis and looks at such factors as the patient’s underlying disease and chronic health status. Additional points are added for 12 continuous physiologic variables measured within 24 hours of admission to the ICU. A more recent version, the APACHE III, looks at 17 physiologic variables as well as the illness that resulted in ICU admission. It would intuitively appear that APACHE III would be more accurate than the APACHE II, but a study comparing Ranson, APACHE II, and APACHE III did not show the APACHE III to be much better in terms of assessing severity in AP than its predecessors54. Another study evaluated 28 patients with severe AP who were admitted to the ICU from a larger cohort of 477 patients with AP55. Ranson scores, Imrie scores, APACHE II and III scores, simplified acute physiology scores, and multiple organ dysfunction scores were tabulated on these 28 patients at 1, 2, 3, 7, and 14 days after ICU admission. Balthazar’s CT severity index was available on 24 of the 28 (86%) patients. Patient age, Ranson, Imrie, APACHE III, CT, simplified acute physiology scores, multiple organ dysfunction scores and APACHE II scores before day 7 did not correlate with adverse clinical outcome. Only the APACHE II score at day 7 after ICU admission correlated with ventilator days and infectious complications. These studies demonstrate that, while clinical predictors such as the APACHE II and III are useful during the course of illness to stratify patients in terms of severity, they are not useful early enough in the course of illness to be able to predict (and thereby possibly prevent) complications such as organ failure in AP. Although not a predictor of severity, the Atlanta criteria, established during a multinational symposium in 1992, are the most widely used classification system to define severity in AP. The Atlanta criteria are listed with the other clinical scales used to predict or define severity of AP in Table 8-7.
Single Laboratory Markers as Predictors of Severity A great deal of research has been done to try and find a quick, easy to perform, accurate, specific laboratory test that could serve as a marker of severity in AP. Nonspecific markers of inflammation such as C reactive protein (CRP)56, procalcitonin and calcitonin precursors57-60, tissue necrosis factor (TNF), and cytokines such as IL-6 and IL-861 have shown promise in protocols and clinical trials but remain relegated to the realm of research tools due to their lack of availability on a wide scale commercial basis. Markers specific to the pathophysiologic events that take place with AP, ie, urinary trypsinogen activating peptide (TAP) 62 and trypsinogen-263 have not only been shown to have high sensitivity, specificity, positive predictive, and negative predictive values for predicting severe pancreatitis, but may also be available as a bedside dipstick test64. The use of the hematocrit as a marker of severity is based on the premise that an elevated hematocrit correlates with hemoconcentration, which in turn correlates with hypovolemia, reduced pancreatic perfusion, and higher risk of necrosis and organ failure. One study used a hematocrit cutoff of >/= 44% with failure to correct by 24 hours and the other used a cutoff of >47% 65,66. Both studies demonstrated a significant correlation with more severe pancreatitis. The negative predictive value at 24
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hours was 96% for necrotizing pancreatitis and 97% for organ failure in one study65. Unfortunately, if a patient has severe AP, fluid resuscitation may not be able to prevent the development of pancreatic necrosis in patients that present with hemoconcentration and whose hematocrit fails to correct by 24 hours 67. Perhaps the sequence of events that leads to necrosis in patients with hemoconcentration has already begun by the time they receive care, as the median time to presentation for patients with severe (necrotizing) pancreatitis in this study was 18 hours 67. Additionally, many patients with AP may already have a preexisting illness or condition resulting in an anemia such that a hematocrit in the range of 44% to 47% will not be seen even in the face of significant hemoconcentration. Due to this, the sensitivity of this method for predicting severity is too low to be used universally as a screening tool.
Radiographic Predictors of Severity Ranson used the enhanced pancreatic CT scan to prognosticate severity. He graded CT scans as A (normal), B (pancreatic enlargement alone), C (inflammation confined to the pancreas and peripancreatic fat), D (one peripancreatic fluid collection), and E (two or more fluid collections) 68. The drawback to this classification system was the lack of differentiation between fluid collections associated with interstitial pancreatitis and ones having areas of necrosis. To improve upon this, Balthazar added the degree of necrosis present to the preceding scale to make what is known as the CT severity index (CTSI), which has a better prognostic accuracy. Patients with necrosis had 23% mortality and an 82% complication rate, while patients without necrosis had 0% mortality and 6% morbidity. Patients with a CTSI of 0 or 1 had no morbidity or mortality, those with a CTSI of 2 had no mortality and 4% morbidity and those with a CTSI of 7 to 10 had 92% morbidity and 17% mortality69. Despite the presence of a formal scoring system, we do not use the CTSI nomenclature in our institution when interpreting CT scans of patients with AP.
The Role of ERCP in Pancreatitis We discussed earlier the importance of identifying, in the acute setting, gallstones as a cause of AP because of the potential need for urgent ERCP. The role of ERCP in the treatment of acute biliary pancreatitis has been reviewed by a recent National Institutes of Health (NIH) consensus conference70. The policy at our institution is to perform ERCP for suspected biliary pancreatitis if jaundice, cholangitis, or biliary ductal dilation is seen on imaging. If only elevated liver enzymes are present and the patient is clinically stable, we recheck the lab tests in approximately 12 hours. If the tests are normalizing, we generally recommend intraoperative cholangiogram at the time of cholecystectomy or MRCP if a more urgent, yet noninvasive, study is needed. If the liver enzymes are static or rising, we generally proceed to ERCP. An evidencebased algorithm for the endoscopic management of acute gallstone pancreatitis from our institution was published in 1999 and remain valid in 200471. It is not uncommon for the screening US to miss these stones that are small enough to pass through the cystic duct and into the common duct unannounced, only to trigger an attack of AP upon passing through the papilla. Other than biliary pancreatitis or stent placement for pancreatic duct disruption72,73, ERCP is generally avoided during AP. A high quality MRCP may show ductal disruption prior to therapeutic ERCP and is also useful to rule out structural abnormalities such as papillary tumor, pancreatic adenocarcinoma, or choledochocele
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without the risks associated with endoscopy and conscious sedation50. The role of ERCP after a patient’s first attack of pancreatitis is controversial. We do not routinely perform ERCP in this situation and in general do not feel that one is indicated. ERCP after an attack of pancreatitis has subsided does have a defined role, however, in the evaluation of recurrent acute and chronic pancreatitis. A discussion of these broad topics, however, is beyond the scope of this chapter. ERCP is often useful for the evaluation and management of complications associated with AP. This topic will be discussed further later in this chapter.
The Use of Antibiotics and the Role of Nutrition in Acute Pancreatitis Two confusing and often contentious topics in the management of AP concern the use of antibiotics and the role of nutritional support for patients. The following sections describe the approach we take with our patients and provide guidance for the clinician trying to decide how best to address these topics.
ANTIBIOTICS The issues of when to use antibiotics, which ones, and for how long have been points of controversy for many years and there is still no universally acceptable practice guideline available to help clinicians with these difficult topics. As a referral institution that receives patients from a large and diverse geographic area, we have not observed any obvious patterns in the use of antibiotics. Some providers seem to uniformly prescribe antibiotics to all of their patients with AP, while others reserve them for patients with a predicted severe course (ie, those with pancreatic necrosis) or those with acute fluid collections. The literature is just as divided. A review of the available evidence clearly demonstrates that broad-spectrum intravenous antibiotics with high pancreatic penetration have been beneficial for patients with necrosis 43. How much necrosis is required has not been universally agreed upon. Some clinicians advocate empiric antibiotics for patients with any degree of necrosis74. It has been established that intestinal permeability is increased in AP as a result of endotoxemia, offering bacterial translocation as a possible explanation for infected necrosis and gram-negative sepsis that complicates some severe cases of AP75. No one would argue that patients with a positive gram stain after aspiration of a fluid collection or pseudocyst are obvious candidates for antibiotics. As the vast majority of morbidity and mortality in AP results from the development of sepsis and multisystem organ failure, the difficulty lies in deciding how to approach the sick patient who does not have necrosis on CT76. All patients with pancreatitis will have significant pain and the majority will have a stress demargination of their WBC with a neutrophil-predominant leucocytosis. Low-grade fever due to the activation and release of inflammatory mediators will also be present in many patients. It is difficult for a clinician facing a patient with a low-grade fever and elevated WBC count to resist the urge to empirically start antibiotics, but that may be the best course of action for patients with mild pancreatitis. Patients without necrosis are not likely to have any added benefit from empiric antibiotics and concern has even been raised of fungal complications developing from indiscriminate use of broad-spectrum antibiotics44. A majority of patients with AP will have interstitial pancreatitis without necrosis
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and will have a resolution of symptoms within 4 to 7 days. For these patients, we favor aggressive hydration and close attention to the control of pain and nausea. We monitor the patient’s level of pain in addition to the laboratory parameters CBC and complete metabolic panel on a daily basis. If the patient’s pain is not responding to the narcotic regimen in the setting of an increasing WBC and fever, we will order a CT scan to evaluate for necrosis and/or fluid collections. If either of these are present on CT, we will consider requesting aspiration of the tissue before beginning antibiotics. The decision to aspirate necrosis or fluid collections is not always straightforward as some fever and elevated white cell count is common in patients with noninfected pancreatitic necrosis and aspiration should be avoided in this setting. Aspiration is performed when there is clinical concern for sepsis, a decision made easier with experience in managing patients with pancreatitis. If the aspiration cannot be performed in a timely manner (within that same day), we will begin antibiotics empirically to prevent further complication. We prefer the use of Imipenem due to its superior penetration of the pancreas.
NUTRITION One of the more difficult questions facing clinicians treating AP regards nutrition. When to feed and by which route—enteral or parenteral—has been the focus of much research, and the consensus would now favor the enteral route for the following reasons. First, the enteral route is felt to maintain the integrity of the gut mucosa and decrease the incidence of bacterial translocation. In doing so, bacterial contamination of fluid collections and other infectious complications will be reduced77. Furthermore, enteral nutrition is less expensive, easier to administer, and avoids possible complications associated with a central venous catheter. When to feed is a more difficult issue to address for some clinicians due to the unpredictability of the course of AP. All would agree that an NPO status is mandatory to put the pancreas to rest and allow healing to proceed. The difficult part is in forecasting how long the illness will persist. If a clinician knew that a patient’s AP would resolve within 2 or 3 days, there would be no problem merely withholding nutrition for that period of time while providing intravenous hydration with a dextrose-based solution. The problem arises when the course of AP begins to extend to 4 or more days. All would agree that some form of nutrition should be established at this point since patients will become increasingly more catabolic and require additional nutrients to facilitate the healing process. Even if a clinician agrees that enteral nutrition is the preferred method of delivery, persistent nausea and vomiting or severe ileus may preclude the ability to initiate feeding by this route. If this is the case, when nutrition has already been withheld for 4 or more days and the severity of illness appears to predict a prolonged hospitalization, we will use parenteral nutrition temporarily to meet the increased metabolic demands of these seriously ill patients. We will also recommend nasogastric (NG) tube for decompression only in those patients with persistent nausea and vomiting. Patients without these findings will not require an NG tube. When ileus is not an issue, we favor placement of a nasojejunal feeding tube to provide enteral nutrition. As a compromise between these two strategies, a group of Chinese investigators evaluated 96 patients with AP that were divided into two treatment groups. One group received only TPN while the other received parenteral nutrition followed by enteral nutrition in two different phases. The group that received parenteral then
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enteral nutrition in phases improved their weight and prealbumin more quickly, decreased their APACHE II scores and demonstrated a decrease in TNF-alpha, CRP and IL-6 levels more quickly than the TPN only group78. Although we favor placement of a duodenal tube beyond the ligament of Trietz under fluoroscopic guidance (or PEJ for those with complications such as pseudocyst or infected necrosis with a prolonged predicted course), some research has demonstrated that feeding through a simple nasogastric tube is both safe and effective79. For the majority of patients with mild pancreatitis, the length of stay is less then 7 days. The usual course is for a patient to be held strictly NPO for the first 48 to 72 hours until pain has resolved. As the patient’s pain resolves, appetite will return and signal that it is time to resume PO intake. We begin slowly with clears for the first day after the diet is resumed. If tolerated with no return of any significant pain, clears are advanced to a low fat diet. The patient should be able to tolerate the low fat diet with no recurrence of pain before discharge can take place. The patient does not need to be completely pain free, but should not have significant increase in pain after oral intake is introduced. One of the most common mistakes we see in the management of AP is feeding a patient too early. Although return of appetite is a good sign that the illness is resolving, the patient should not try to tolerate significant pain or nausea in an attempt at hastening discharge.
Complications One of the more worrisome complications of severe AP is the development of acute fluid collections and acute pancreatic pseudocysts. Fluid collections may resolve without sequelae or may evolve into organized fluid collections that can be difficult to distinguish from pancreatic pseudocysts when contiguous with the gland. Complicating the issue further is the concern for bacterial or fungal infection of these entities. Pseudocysts can be drained endoscopically, percutaneously, or surgically. Generally, the indications for pseudocyst are:
1. 2. 3. 4. 5.
Symptoms related to the cyst Concern about infection Concern about malignancy Complications such as hemorrhage, rupture, and obstruction Failure to resolve with conservative measures.
Symptoms related to the cyst are generally abdominal bloating, fullness, pain, nausea, weight loss or early satiety due to gastric outlet obstruction type physiology. Measures employed to help a pseudocyst resolve may include a low fat diet and pancreatic enzyme supplementation or an NPO status with prolonged enteral feeding via a jejunostomy tube and the use of octreotide to further decrease pancreatic secretion. However, in the asymptomatic patient, employing these interventions is unlikely to be met with compliance and there are not good data that it will result in improved outcome. Prolonged TPN is no longer used due to the increased risk of catheter-related complications80,81. The old standard rule of "6 and 6"—ie, a cyst size of 6 cm or more present for 6 weeks will require drainage in order to successfully resolve82 —is no longer felt to apply83. It is not unsafe or uncommon for patients who are tolerating their pseudocyst without symptoms to be able to be managed with serial imaging studies until resolution is seen84.
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When pseudocyst drainage is necessary, in addition to percutaneous and surgical options, endoscopic transpapillary drainage, cystgastrostomy, and cystenterostomy are each possible in the right setting. For endoscopic cystgastrostomy or cystenterostomy, the cyst should directly abut the stomach or small bowel with a wall that is not more than 1 cm in thickness. EUS is useful to evaluate for vascular or aneurysmal structures in the wall that could preclude endoscopic drainage. Transpapillary drainage is most successful when the cyst communicates with the main pancreatic duct as seen at ERCP85. Placement of an endoprosthesis across the papilla and into the cyst cavity was shown to be successful in two studies in the mid-1990s and has since become a useful modality for the therapeutic pancreatic endoscopists when deciding how to approach the management of pseudocysts86,87. A more recent report by Baron and colleagues reported 72% and 74% resolution rates for necrosis and acute pseudocyst following endoscopic drainage procedures88. If able to cross the ductal disruption that is feeding the cyst with a guidewire, stenting the defect until the pseudocyst resolves is preferred. It should be apparent to clinicians treating patients with these complications that endoscopic drainage should only be performed by therapeutic biliary endoscopists skilled in these maneuvers and with good surgical and radiological support. This, therefore, usually requires management in a tertiary referral center. It is beyond the scope of this chapter to attempt to describe in detail the various techniques that can be performed to accomplish successful drainage. The diagnosis of acute fluid collections is made radiographically. As discussed above, MRI is able to distinguish areas of necrosis better than CT, yet CT is the modality that will be more available to the clinician and the modality with which most clinicians will be familiar. The presence of air within a fluid collection suggests the presence of a gas-producing organism and is an absolute indication for aspiration with gram stain and the use of broad-spectrum antibiotics. Formal drainage, either percutaneously or surgically, will also likely be required. Patients with a percutaneous catheter in place who develop fever, elevation in WBC, the development of new pain, or an increase in existing pain require prompt bedside evaluation. First, the amount of the drainage fluid should be assessed. If a previously welldraining fluid collection is no longer draining, concern should focus on misplacement of the catheter. The tube may have been inadvertently pulled and no longer be in the correct position or the fluid cavity may have septations such that the remaining fluid is no longer in contact with the tip of the catheter. Both of these scenarios can be addressed and easily corrected by radiographic consultation. Next, the character of the fluid should be assessed. If the fluid was previously thin and is now purulent, thick, or frankly bloody, concern should exist for untreated infection, superimposed fungal infection, or hemorrhage, respectively. Culture and susceptibility testing of previously aspirated fluid should be available to guide existing antibiotic therapy. Blood culture or urine culture should be done to assist in evaluation if a patient already on broad-spectrum antibiotics is persistently febrile. The growth of fungal species from either of these cultures is an indication that the pancreatic fluid collection may also be infected with fungi and prompt antifungal coverage should be instituted. Organized fluid collections or pseudocysts that fail to improve with percutaneous measures are referred for surgical drainage in our institution. The medical care of these seriously ill patients requires a team approach to ensure that infectious disease, nutrition, and pulmonary issues are addressed and maximized before undergoing surgery. We convene a weekly multidisciplinary conference at our institution
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to discuss the management of complicated patients. This allows for a broad discussion from different vantage points and areas of expertise and also helps foster a more uniform standard of care in our teaching institution. Pathologists, gastroenterologists, surgeons, radiologists, and interventional radiologists attend the conference.
Summary In this part of the clinician’s guide, our discussion of acute pancreatitis has attempted to provide evidence to substantiate our recommendations to the clinician and provide a list of references for further self-review. To summarize our approach to AP, we offer the following recommendations:
1. Making the diagnosis Substantiate an appropriate clinical suspicion with an elevated amylase or lipase that is 3 times the upper limit, being aware of situations or medications that can interfere with amylase (increased triglycerides, delayed presentation, alcoholics) and lipase. a. We do not use urinary trypsinogen. b. Radiographic imaging at admission can help to substantiate diagnosis as well as severity (necrosis) and can help with etiology as well (biliary versus nonbiliary). 2. Determining etiology a. Differentiate biliary from nonbiliary as early as possible with US and liver function tests to determine need for ERCP in patients with cholangitis or progressive biliary obstruction. b. Check available records and admission labs for clues to etiology (triglycerides, LFTs, calcium, medications, alcoholism, medical history, ie, previous biliary pain, HIV, trauma, recent catheterization, etc). 3. Determining severity a. Triage into mild and severe helps mainly to allow focus on the severe i. Severe patients at higher risk for multiple system organ failure and septic complications. ii. Early antibiotics (Imipenem) and CT scan to evaluate for acute fluid collections and necrosis. b. Earliest lab markers of severity may prove to be calcitonin precursors/procalcitonin and IL-6/IL-8 though these remain investigational at this time. c. We do not use a structured scoring of Ranson/Imrie, APACHE II/III scores or CRP. 4. Treatment a. Aggressive IVF hydration to ensure adequate perfusion of the pancreatic microcirculation. b. Empiric antibiotics in severe AP.
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c. NG tubes only if nausea and vomiting are present. Remove once these issues resolve. d. Analgesia via patient controlled analgesia for severe pancreatitis. e. Use of an anesthesia pain service for complex pain issues. 5. Nutrition a. No crystal ball to predict length of stay, therefore if recovery of ability to take PO is not expected by day 4 to 6, we initiate enteral feeds with a tube placed into the jejunum. i. Patients with persistent ileus, nausea, or vomiting may need TPN then transitioned to enteral nutrition as soon as the ileus resolves. b. Milder cases are allowed clear fluids once pain has subsided with slow advancement. c. Patients should tolerate a low fat diet before discharge. 6. Management of complications a. We have a multidisciplinary meeting with our radiologists, interventional radiologists, and biliary surgeons on a weekly basis to discuss management of complicated patients and ensure uniform standard of care. b. We typically allow acute fluid collections/pseudocysts time (4 to 6 weeks) to resolve before intervening with percutaneous or surgical drainage. Intervention for asymptomatic pseudocysts that do not resolve is not routinely performed. i. Symptomatic or complicated fluid collections are dealt with more quickly. c. Fluid collections/pseudocysts that communicate with the main duct or that abut the stomach/duodenum may be treated endoscopically.
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69. Brown A, Orav J, Banks PA. Hemoconcentration is an early marker for organ failure and necrotizing pancreatitis. Pancreas. 2000;20:367-72. 70. Lankisch PG, et al. Hemoconcentration: an early marker of severe and/or necrotizing pancreatitis? A critical appraisal. Am J Gastroenterol. 2001;96:2081-5. 71. Brown A, et al. Can fluid resuscitation prevent pancreatic necrosis in severe acute pancreatitis? Pancreatology. 2002;2:104-7. 72. Ranson JH, et al. Computed tomography and the prediction of pancreatic abscess in acute pancreatitis. Ann Surg. 1985;201:656-65. 73. Balthazar EJ, et al. Acute pancreatitis: value of CT in establishing prognosis. Radiology. 1990;174:331-6. 74. Solomkin JS, Umanskiy K. Intraabdominal sepsis: newer interventional and antimicrobial therapies for infected necrotizing pancreatitis. Curr Opin Crit Care. 2003;9: 424-7. 75. Ammori BJ. Role of the gut in the course of severe acute pancreatitis. Pancreas. 2003;26:122-9. 76. Gloor B, et al. Late mortality in patients with severe acute pancreatitis. Br J Surg. 2001;88:975-9. 77. Olah A, et al. Early nasojejunal feeding in acute pancreatitis is associated with a lower complication rate. Nutrition. 2002;18:259-62. 78. Zhao G, et al. Clinical study on nutrition support in patients with severe acute pancreatitis. World J Gastroenterol. 2003;9:2105-8. 79. Eatock FC, et al. Nasogastric feeding in severe acute pancreatitis may be practical and safe. Int J Pancreatol. 2000;28:23-9. 80. Jackson MW, et al. The limited role of total parenteral nutrition in the management of pancreatic pseudocyst. Am Surg. 1993;59:736-9. 81. Shahrudin MD, Noori SM. Pancreatic pseudocyst: the controversial value of total parenteral nutrition. Hepatogastroenterology. 1997;44:559-63. 82. Yeo CJ, et al. The natural history of pancreatic pseudocysts documented by computed tomography. Surg Gynecol Obstet. 1990;170:411-7. 83. Pitchumoni CS, Agarwal N. Pancreatic pseudocysts. When and how should drainage be performed? Gastroenterol Clin North Am. 1999;28:615-39. 84. Cheruvu CV, et al. Conservative treatment as an option in the management of pancreatic pseudocyst. Ann R Coll Surg Engl. 2003;85:313-6. 85. Byrne MF, Mitchell RM, Baillie J. Pancreatic pseudocysts. Curr Treat Options Gastroenterol. 2002;5:331-338. 86. Barthet M, et al. Endoscopic transpapillary drainage of pancreatic pseudocysts. Gastrointest Endosc. 1995;42:208-13. 87. Catalano MF, et al. Treatment of pancreatic pseudocysts with ductal communication by transpapillary pancreatic duct endoprosthesis. Gastrointest Endosc. 1995;42:214218. 88. Baron TH, et al. Outcome differences after endoscopic drainage of pancreatic necrosis, acute pancreatic pseudocysts, and chronic pancreatic pseudocysts. Gastrointest Endosc. 2002;56:7-17.
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Chronic Pancreatitis Tyler Stevens, MD; Darwin L. Conwell, MD
Introduction Chronic pancreatitis (CP) is characterized by the gradual fibrotic destruction of pancreatic tissue. The resulting symptoms of abdominal pain and maldigestion are frequently complicated by malnutrition, psychosocial decline, work-loss, narcotic addiction, and large health care expenditures. Multiple diagnostic and treatment challenges require an interdisciplinary management strategy. This chapter provides a concise review of all aspects of CP.
Epidemiology The prevalence of pancreatic fibrosis ranges from 0.04% to 5% in autopsy studies1,2 . According to studies from predominantly Western countries, incidence ranges from 1.6 to 23 cases per 100,000 per year. The gradual rise in incidence observed in some studies may be attributed to increasing alcohol consumption and earlier diagnosis3,4. The substantial difference in incidence rates between geographic areas is likely related to the prevalence of heavy alcohol consumption. Chronic pancreatitis results in excess of 122,000 outpatient visits in the United States and greater than 56,000 hospitalizations per year5. The total cost of treatment of pancreatic diseases in the United States was 2.1 billion dollars in 1998. Based on these figures, CP constitutes a substantial cost burden on national health care systems.
Classification MARSEILLES CLASSIFICATION For decades, acute and chronic pancreatitis were thought to represent ends of a spectrum of inflammatory pancreatic disease. This notion was challenged in 1963, when the first Marseilles conference codified acute and chronic pancreatitis as two
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Table 9-1
TERMS USED IN MARSEILLE CLASSIFICATION SYSTEMS First Second Symposium Symposium Marseille (1963) Marseille (1984)
Third Symposium Marseille-Rome (1988)
Acute Pancreatitis
Acute pancreatitis Acute relapsing pancreatitis
Acute pancreatitis
Acute pancreatitis
Chronic Pancreatitis
Chronic pancreatitis Chronic relapsing pancreatitis
Chronic pancreatitis Chronic obstructive pancreatitis
Chronic calcifying pancreatitis Chronic inflammatory pancreatitis Chronic obstructive pancreatitis
separate entities (Table 9-1) 6. Acute pancreatitis was further subdivided into singleepisode acute and acute relapsing pancreatitis; chronic pancreatitis was classified as chronic and chronic relapsing forms. The second symposium (Marseilles, 1984) subdivided acute and chronic pancreatitis into multiple histopathological types7. Also at that conference, CP was defined as “a progressive inflammatory disease of the pancreas, characterized by irreversible morphologic changes”. A third symposium (Marseilles-Rome, 1988) eliminated the terms acute relapsing and chronic relapsing and further delineated CP as calcific, inflammatory, and obstructive8.
CAMBRIDGE CLASSIFICATION The Marseilles classification possesses limited clinical usefulness because of its reliance on histological criteria. The risk and impracticality of obtaining pancreatic biopsies has prompted radiographic classification systems designed to evaluate gland morphology and structure. The Cambridge classification is based on the severity of pancreatic duct changes encountered on endoscopic retrograde pancreatography (ERP) 9,10. Using standardized criteria, pancreatic duct changes are graded from equivocal (Class I) to severe (Class IV) (Table 9-2). Although moderate and severe ERP changes are widely accepted as diagnostic of advanced CP, equivocal and mild ERP changes are considered less reliable. Intraobserver variability, questionable specificity, and discordance with pancreatic function and histology have cast reasonable doubt on the significance of Cambridge Class I and II pancreatitis.
Normal Equivocal Mild Chronic Pancreatitis Moderate Chronic Pancreatitis Severe Chronic Pancreatitis
0 I II
Abnormal
Abnormal
Normal Normal Normal
MPD
>3
>3
None <3 3 or more
Abnormal MPDB
One or more: large cavity, obstruction, filling defects, severe dilation or irregularity
None
None None None
Additional Features
and designated as being in the head, body, or tail; if more than one third of the gland is involved, changes are classified as “diffuse”.
MPD: Main pancreatic duct, MPDB: Main pancreatic duct branches.* If pathologic changes are limited to one third or less of gland, they are classified as “local”
IV
III
Terminology
CAMBRIDGE CRITERIA FOR GRADING SEVERITY OF CHRONIC PANCREATITIS
Cambridge Classification
Table 9-2
Chronic Pancreatitis 181
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MINIMAL CHANGE CHRONIC PANCREATITIS Other terminology has been applied to CP based on the presence and severity of morphologic changes. The terms small-duct and minimal change CP imply mild or absent imaging findings. Large-duct and calcific CP signify advanced ductal and parenchymal structural changes. Although lacking major structural abnormalities, minimal change pancreatitis can be quite painful and require narcotic analgesics, nerve blockade, or surgical resection for relief. A recent study utilized pancreatic surgical resection specimens to define the histological features of minimal change pancreatitis11. The tissue showed evidence of chronic inflammation, duct proliferation, duct complex formation, adenomatous nodules, and acinar cell atrophy. Therefore, it appears that significant pathologic changes may be present in a gland lacking major structural changes on imaging tests.
ETIOLOGY-BASED CLASSIFICATIONS There have been several etiology-based classification systems of CP. Chari and Singer have proposed subclassifying chronic, calcific pancreatitis into seven categories: alcohol-induced, tropical, hereditary, idiopathic, hypercalcemic, hyperlipidemic, and analgesic-induced12 . More recently, Schneider and Whitcomb have developed the TIGAR-O classification, which places special emphasis on recent advances in understanding of the genetic basis of pancreatitis (toxic-metabolic, idiopathic, genetic, autoimmune, recurrent or severe, obstructive)13.
Pathology and Pathophysiology PATHOLOGY The gross pathological changes of CP may be focal, segmental, or diffuse. The pancreas may appear enlarged, atrophic, indurated, deformed, with or without the presence of pseudocysts. The ducts may be dilated, irregular, and contain calcifications. The histological features of chronic pancreatitis do not vary substantially based on etiology. Essential features include irregular and patchy loss of acinar and ductal tissue, chronic inflammation, ductal changes, and fibrosis (Figure 9-1)14. The lobular architecture of the parenchyma is usually preserved. Islet cells are typically unaffected until the most advanced stages of disease.
PATHOPHYSIOLOGY In the past three decades, several pathogenic theories have emerged. In addition, a large body of new knowledge has accumulated regarding cellular, genetic, and molecular mechanisms of fibrogenesis. Both the traditional theories and some of these new advances are discussed in this section.
The Oxidative Stress Hypothesis Braganza et al proposed that the root cause of pancreatic disease is the overactivity of hepatic mixed-function oxidases15. Byproducts of oxidase activity include reactive molecules capable of damaging pancreatic tissue. The pancreas may be exposed to these byproducts through the systemic circulation or by reflux of bile into the pancre-
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Figure 9-1. Histology demon-
strating inflammatory cells and extensive replacement of the pancreatic acinar complexes with fibrosis.
atic duct. Evidence comes from experiments demonstrating increased concentrations of oxidized products in the bile of patients with chronic pancreatitis16-19. Furthermore, antioxidant therapy has been found to improve pain in chronic pancreatitis20,21. High doses of antioxidants have been shown to prevent fibrosis in a rat model of CP22 . Oxidative stress is probably involved in the pathogenesis of CP, but it has never been proven to be an initiating factor.
The Toxic-Metabolic Theory Bordalo and colleagues proposed that alcohol was directly toxic to the acinar cell by changing the cellular metabolism 23. This metabolic effect produces lipid accumulation, fatty degeneration, cellular necrosis, and eventual widespread fibrosis. Evidence for this theory comes from histopathological studies that suggested a stepwise progression from fatty accumulation to fibrosis. A criticism of this theory has been the lack of proof that “steatopancreatitis” is a true precursor to fibrosis, rather than a parallel, reversible, alcohol-related lesion 24.
Stone and Duct Obstruction Theory Sarles proposed the concept that acute and chronic pancreatitis were two distinct diseases with separate pathogeneses25. Acute pancreatitis results from unregulated trypsin activation and autodigestion; CP begins within the pancreatic ductules. Alcohol must primarily modulate exocrine function to increase the lithogenicity of pancreatic juice. Lithogenic pancreatic fluid produces protein plugs, forming a nidus for stone formation. Chronic contact of the stones with the ductal epithelial cells produces ulceration and scarring, resulting in obstruction, stasis, and further stone formation. Eventually, atrophy and fibrosis develop as a result of this obstructive process. Alcohol may increase lithogenicity through several mechanisms, including a change in volume of pancreatic secretion, a decrease in citrate concentration, hypersecretion of protein, and increased fluid viscosity 26-34. Specific proteins such as pancreatic stone protein (lithostathine) and glycoprotein-2 have been implicated in stone development 35-37. Though widely espoused, stone theory falls short on several levels. Most notably, protein plugs are not found in all cases of CP and particularly not in the early stages (88% with severe fibrosis; 46% with mild fibrosis); therefore, the causative role of stone formation and duct obstruction is not established 38.
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Necrosis Fibrosis Theory In stark contrast to the stone theory, the necrosis-fibrosis hypothesis envisions the development of fibrosis from recurrent acute pancreatitis. The sequelae of inflammation from acute pancreatitis produce scarring and extrinsic compression of the ductules. Obstruction results in stasis and secondarily, stone formation. A stepwise progression of recurrent acute pancreatitis to fibrosis has been suggested by histopathological and clinical studies39-41. The recently discovered genetic mechanism of hereditary pancreatitis (HP) has provided further credence for the necrosis-fibrosis sequence. HP produces recurrent acute pancreatitis beginning in early childhood, almost invariably leading to CP in early adulthood. There has been intense debate between proponents of the stone and ductal obstruction and necrosis-fibrosis models. The primary argument is whether CP begins at the level of the acinar cells (stone theory) or at the level of the pancreatic ductule (necrosis-fibrosis). In an attempt to reconcile these viewpoints, it has been postulated that CP requires two insults: 1) the early formation of protein plugs, and 2) postnecrotic fibrosis from acute pancreatitis resulting in ductular obstruction42 .
Primary Duct Hypothesis Cavallini postulated that the primary pathogenic factor in CP was an immunologic attack of the duct epithelium43. The target of this attack is a genetic or acquired antigen within the duct. Support for this hypothesis came from several observations. Antibodies to carbonic anhydrase I and II (present in the ductal epithelium) were detected in patients with CP, suggesting a possible immune target44. Instillation of trinitrobenzene sulphonic acid into the pancreatic ducts of rats reproducibly leads to histological evidence of an immune reaction, and subsequently, changes of CP45. Finally, activation of cytotoxic cells has been demonstrated within the periductal areas of the pancreas in patients with alcoholic chronic pancreatitis 46. Based on these data, it is proposed that large-duct CP represents a primary autoimmune or inflammatory condition beginning in the pancreatic duct, analogous to primary sclerosing cholangitis47. Alcohol may initiate this sequence through some modulation of target antigens within the duct epithelium.
Pancreatic Fibrosis In the past 10 years, significant progress has been achieved in the understanding of the underlying cellular mechanisms of pancreatic fibrogenesis. A major discovery has been the primary role of stellate cells in pancreatic fibrogenesis. Long known to play an important role in hepatic fibrogenesis, the presence of stellate cells in rat and human pancreas suggests a similar role in pancreatic fibrosis48,49. When activated, stellate cells migrate to the periacinar areas and become capable of synthesizing collagen and fibronectin50. There is ample evidence to implicate pancreatic stellate cells in the deposition of collagen in the early stages of CP. Both animal and human experiments have revealed an increased number of stellate cells in areas of fibrosis within the pancreas51,52 . Furthermore, alcohol and oxidative stress have been found to stimulate pancreatic stellate cells53,54. It is known that the cytokine profile in CP is distinct from normal pancreas55. Stellate cells are stimulated by a variety of cytokines, many of which are emitted during the inflammatory phase of acute pancreatitis, suggesting a mechanism for the necrosis fibrosis sequence56-58. Transforming growth factor beta (TGF-ß1) has
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Figure 9-2. Distribution of etiology of CP.
received considerable attention in recent years as a mediator of fibrosis in pancreatic disease. Long known to play a major role in fibrogenesis in other organ systems59-61, TGF-ß1 has recently been found to mediate pancreatic fibrogenesis 62-64.
Sentinel Acute Pancreatitis Event (SAPE) Hypothesis Whitcomb and Schneider have proposed an interesting hypothesis for CP pathogenesis that incorporates these recent advances in pancreatic fibrogenesis, as well as unifying many of the previous theories65-67. The sequence of this hypothesis is summarized as follows:
1. Pancreatic acinar cells secrete specific cytokines in response to toxic-metabolic and oxidative stress from alcohol; however, fibrosis does not occur because stellate cells are not yet present within the periacinar areas. 2. The first episode of acute pancreatitis (“sentinel event”) produces a massive inflammatory response. The late, anti-inflammatory phase of this response includes the attraction of mononuclear cells capable of secreting cytokines, includingTGF-ß1. These cytokines cause the migration and stimulation of stellate cells to the periacinar areas for proper healing. 3. Once attracted, stellate cells remain in the pancreatic bed indefinitely and are capable of responding to signals of injury. 4. In the setting of continued alcohol, oxidative stress, or recurrent acute pancreatitis, stellate cells deposit collagen.
Etiology ALCOHOL In developed countries, 70% of CP is associated with heavy and prolonged alcohol intake (Figure 9-2) 68. The peak age of onset of alcohol-induced CP is 3569. Although the risk is dose-dependent, there is no clearly defined threshold of alcohol intake70. In most cases, patients have had a heavy and prolonged intake of at least 150 g/day for 5 years. Similar to alcoholic liver disease, females require less alcohol to develop CP compared to males. The typical course of alcohol-induced CP differs from nonalcohol-induced CP. Pain tends to be more severe, and calcifications and ductal changes are seen more often in alcohol-induced compared to nonalcohol-induced CP. Alcohol-induced CP progresses faster to endocrine and exocrine sufficiency compared to nonalcoholic forms.
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Most patients have had recurrent episodes of AP for several years prior to the development of CP. Interestingly, some of these patients have histological or functional changes of CP detected at the time of their first episode of AP71. Approximately 10 to 30% of patients with longstanding recurrent AP are “nonprogressors” who do not develop functional or morphological evidence of CP72 . Conversely, many patients presenting with alcohol-induced CP do not have documented preceding episodes of AP. Although pancreatic fibrosis may be detected at autopsy in 50% of alcoholics, only 10 to 20% develop clinically apparent CP73,74. Furthermore, animal models have only revealed alcohol as a potentiating rather than a causative factor in the development of CP75. These data imply the presence of cofactors that amplify the effect of alcohol74. An increased prevalence of some genetic mutations known to produce CP has been demonstrated in patients with previously diagnosed alcoholic pancreatitis76,77, while others have not 78. Dietary factors, such as high fat or high protein intake, may also have a detrimental effect 79. Smoking is associated with an increased risk for CP, independent of alcohol use80. Smoking adversely affects pancreatic bicarbonate and water secretion81,82 , induces oxidative stress83, and increases the rate of pancreatic calcification84. The interaction and interdependence of smoking and alcohol as risk factors for CP is not fully understood.
TROPICAL PANCREATITIS Tropical pancreatitis (TP) is endemic in several areas of the developing world, including India, Africa, and South America. This disease usually affects children and young adults, and rarely presents after age 40. Episodic abdominal pain is followed by a relatively speedy progression to endocrine and exocrine insufficiency. Morphological changes are often severe, including diffuse pancreatic calculi and ductal dilatation. Although not completely understood, the mechanism is most likely nutritional. Proposed pathogenic factors include dietary toxins (cyanogens in the Cassava plant) as well as micronutrient deficiencies (zinc, copper, and selenium) 85.
OBSTRUCTIVE CHRONIC PANCREATITIS Obstruction of the main pancreatic duct reproducibly produces changes of CP within weeks in several animal models86-88. The pathology of obstructive pancreatitis in humans differs somewhat from other forms. Features include uniform distribution of inter- and intralobular fibrosis and marked destruction of the exocrine parenchyma in the territory of obstruction, notably lacking the presence of plugs and calcifications89. Causes of obstructive CP include pancreatic adenocarcinoma, neuroendocrine tumors, and intrapapillary mucinous tumor (Figure 9-3). Other disorders such as sphincter of Oddi dysfunction and pancreas divisum have a more tenuous connection with CP. CP is most easily attributed to pancreas divisum when structural changes are confined to the dorsal pancreas. Intraductal hypertension is known to play a role in pathogenesis of pain, and may also have a role in fibrogenesis and glandular damage in patients with obstructive CP.
AUTOIMMUNE PANCREATITIS Autoimmune chronic pancreatitis (AIP) is a rare condition previously known as nonalcoholic duct-destructive chronic pancreatitis90. AIP may be associated with
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Figure 9-3. Examples of etiolo-
gies for obstructive CP. (A) CT scan showing ductal dilation with intraductal papillary projections suggestive of intrapapillary mucinous tumor (IPMT). (B) In same patient, endoscopic view demonstrating gaping ampulla with extrusion of mucin. (C) ERCP showing mucin as filling defect in pancreatic duct. (D) MRCP demonstrates pancreas divisum. Courtesy of John J. Vargo, MD, MPH, Cleveland Clinic Foundation.
Figure 9-4. CT scan and ERCP
appearance of autoimmune pancreatitis, before and after treatment with steroids. (A,C) Prior to steroids, the gland is enlarged and edematous, and the pancreatic duct is narrowed and irregular. (B,D) These features improve after steroid therapy. Reprinted with permission from Kluwer Academic/Plenum Publishers.
autoimmune diseases such as Sjögren’s syndrome and primary sclerosing cholangitis91-93. Patients with AIP usually have milder pain compared to other forms of CP. Laboratory features include hypergammaglobulinemia and the presence of various autoantibodies, including antinuclear, antilactoferrin, anticarbonic anhydrase I and II, and antismooth muscle. Cross-sectional imaging reveals diffuse enlargement of the pancreas and a lack of calcifications and cysts. Pancreatogram reveals pancreatic ductal irregularity and narrowing. These structural features improve rapidly with corticosteroid therapy (Figure 9-4) 94. Histopathological findings include infiltration of lymphocytes and plasmacytes with fibrosis concentrated around the pancreatic duct. The most likely pathogenesis of AIP is immune-mediated attack on the ductal cells. The increase in pancreatic CD4+ and CD8+ T-cells in patients with AIP suggests that cellular, as well as humoral immunity, is involved in ductal injury 95.
GENETIC CAUSES In the past 10 years, exciting discoveries have been made in the genetic basis of pancreatic disease. Elucidation of the genetic mechanism of hereditary pancreatitis has provided insight into pathogenesis of pancreatitis. Furthermore, myriad mutations have been plausibly linked to pancreatitis. These mutations may cause disease by themselves or interact with other environmental and genetic factors to produce pancreatitis in a given individual.
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Hereditary Pancreatitis Hereditary pancreatitis (HP) is a rare autosomal dominant disease with approximately 80% penetrance. Patients present in childhood with recurrent painful episodes of AP invariably followed by the development of CP in young adulthood. After years of painful pancreatitis, patients with HP frequently succumb to pancreatic cancer. Whitcomb and colleagues have recently discovered that HP is caused by a single point mutation in the cationic trypsinogen gene96. The mutation causes a gain-of-function of the trypsinogen molecule such that activated trypsin cannot be inactivated. The resulting loss of feedback regulation causes autodigestion and subsequent episodes of acute pancreatitis. Although R117H is the most common mutation, other trypsinogen mutations have been found to produce HP.
Cystic Fibrosis Cystic fibrosis (CF) is an autosomal recessive disease characterized by thick, dehydrated bodily secretions, resulting in recurrent lower respiratory tract infections, bronchiectasis, and pancreatic insufficiency. The pathogenic defect in CF is a mutation of the cystic fibrosis transmembrane conductance regulator gene (CFTR) located on chromosome 7. The protein is encoded by this gene is a cyclic AMP dependent chloride channel which functions in electrolyte and water transport across epithelial cell membranes97. Although 85% of CF patients have the severe form with respiratory disease and pancreatic insufficiency, the remaining 15% possess lower sweat chloride levels and may express other phenotypic features98. Recent studies have demonstrated a high prevalence of CFTR gene mutations among patients presenting with idiopathic acute and chronic pancreatitis99-101. Most patients who present with pancreatitis as the sole phenotypic feature of CF have one or two mild CFTR mutations102 .
Serine Protease Inhibitor, Kazal Type 1 Serine protease inhibitor, Kazal type 1 (SPINK-1) is the gene that encodes pancreatic secretory trypsin inhibitor. The serine protease inhibitor provides the first line of defense in the acinar cell in counteracting the effects of activated trypsin103. Mutations causing loss of function of this protein increase the risk of development of acute and chronic pancreatitis. SPINK-1 mutations are increased in frequency among patients with idiopathic pancreatitis104. SPINK-1 mutations are thought to act as disease modifiers, lowering the threshold for developing clinical pancreatitis from other combined etiologies105.
IDIOPATHIC CHRONIC PANCREATITIS Although recent genetic discoveries have caused this category to dwindle, 10% to 30% of patients with chronic pancreatitis possess no clear risk factors for the disease. Idiopathic CP has been classified as early and late onset, given its bimodal age presentation and differences in presentation106. Early-onset idiopathic CP presents in the first two decades of life with severe abdominal pain, while structural and functional changes occur later in life. Patients with late-onset idiopathic CP present in the fourth or fifth decade with minimal pain, often with pancreatic insufficiency at the time of diagnosis. Exocrine and endocrine dysfunction and pancreatic calcifications are much more likely to occur in late-onset idiopathic CP. Possible mechanisms for idiopathic CP include occult alcohol use and undiagnosed genetic defects or autoimmune disease.
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Miscellaneous Causes Severe hypercalcemia is known to trigger episodes of AP through trypsin-mediated mechanisms. Several studies have shown an association of hyperparathyroidism with CP107,108. In addition to producing acute recurrent pancreatitis, hypercalcemia increases lithogenesis in pancreatic fluid109-110. Chronic renal failure is associated with an increased prevalence of CP111. An autopsy study performed in 78 patients with end-stage renal disease (ESRD) revealed pancreatic fibrosis in 28% of patients112 . There is an increased prevalence of sonographic parenchymal changes and abnormal pancreatic function in patients with CP. The pathogenesis of CP in renal failure is not known, but suggested mechanisms include a toxic affect from uremia and inspissated pancreatic secretion and plug formation from recurrent intravascular volume depletion during hemodialysis113. Several cases of analgesic-associated CP have been reported114. Hyperlipidemia and gallstones are controversial causes of CP.
Clinical Presentation ABDOMINAL PAIN Abdominal pain is common in CP, occurring in 50 to 80% of cases115. Pain is frequently the most distressing symptom of CP, often leading to loss of work, depression, and narcotic addiction. Severe exacerbations of abdominal pain are responsible for the majority of the hospitalizations related to this illness. Pancreatic pain is dull or boring in quality, and often worsens after eating. The location is in the epigastrium with occasional radiation to the back. There may be significant nausea and vomiting associated with the pain. The pattern and severity of pain is quite variable in CP. Ammann and Muellhaupt described two distinct types of pain based on a prospective study of 207 patients with chronic alcohol-induced CP (Figure 9-5)116. Type A pain was characterized by short, relapsing pain episodes lasting days to weeks, separated by pain-free intervals lasting months. Prolonged periods of persistent, daily severe pain flares or recurrent clusters of pain characterized type B pain. Pain exacerbations may or may not include serum elevations of the pancreatic enzymes suggestive of acute pancreatic inflammation. The relentless and progressive loss of pancreatic parenchyma may lead to years of abdominal pain. Conversely, some series have shown that pain may gradually lessen over years of CP117. Parameters associated with regression of pain include the development of calcifications118, exocrine insufficiency119, or endocrine insufficiency. However, this notion of pancreatic “burnout” remains highly controversial120,121. The pattern and severity of pain may differ according to etiology. Although pain from alcohol-induced CP is typically severe and chronic, pain may not be the predominant symptom in CP of other causes. Layer et al described two distinct forms of idiopathic CP106. These investigators described patients with early-onset pancreatitis as having a long course of severe pain, with the development of morphological and functional pancreatic damage; whereas the patients with late-onset pancreatitis had a mild and ultimately painless course of CP. Multiple pathogenic mechanisms have been proposed to contribute to abdominal pain in CP. The pathophysiologic mechanism may differ according to the degree of structural change (small versus large duct disease). When severe structural disease is
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Figure 9-5. Temporal patterns of
type A and type B pancreatic pain. Reprinted with permission from Elsevier.
present (ie, main pancreatic duct dilation, ductal and parenchymal calcifications, large pseudocysts, etc), mechanical causes are thought to be the predominant cause of pain, and treatment aimed at these structural causes may offer substantial relief. In large-duct CP, an enlarged, inflamed gland or pseudocyst may produce pain through direct pressure on retroperitoneal structures. Patients with large duct CP often have intraductal and interstitial hypertension resulting from ductal stones, strictures, and decreased duct wall compliance122-125. A growing literature suggests that pain improves with surgical or endoscopic relief of obstruction126-128. Experiments in cats with obstructive CP have demonstrated not only increased pressures, but also impaired pancreatic blood flow129,130. In contrast to the normal hyperemic response, secretin administration to cats with obstructive CP produces a decrease in blood flow to the pancreas. It has been postulated that impaired blood flow and increased interstitial pressures results in a compartment syndrome. This mismatch of oxygen supply and demand results in ischemic pain and fibrosis. The causes of pain in small duct pancreatitis are less well understood. CCK may have a role in the pathogenesis of pancreatic pain. CCK levels are elevated in CP, likely resulting from loss of feedback inhibition131. Persistently elevated CCK levels produce continuous stimulation of the gland, further contributing to ductal hypertension. Despite this rationale, attempts to suppress CCK levels and improve pain through the administration of exogenous enzymes have yielded mixed results132 . Histological studies have demonstrated inflammatory changes around pancreatic sensory neurons133. The inflammatory cellular infiltrate secretes chemical mediators into the area surrounding the nerve fibers to trigger nociceptive impulses. A burgeoning of research of the specific cytokines and neuropeptides detected in the cellular milieu surrounding pancreatic sensory nerves has strengthened the concept that “neuroimmune” interactions impact the pathogenesis of pain134. A recent study of Chowdhury et al has suggested a high prevalence of gastroparesis in patients with small duct CP135. Abdominal pain is a frequently reported symptom in patients with gastroparesis136. The authors concluded that gastroparesis might be contributing to pain in these patients who lack severe structural disease. They further speculated that gastroparesis could be related to the elevated CCK levels seen in CP. The true contribution of gastroparesis to CP pain as well as the possible benefit of promotility agents in the treatment of pancreatic pain remains to be seen.
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Finally, not all pancreatic pain is visceral. It appears there is a high prevalence of somatosensory and central pain in CP. We recently analyzed the results of differential nerve blockades (DNB) of patients undergoing medical or surgical therapy for CP137. Only 5 of 23 patients (22%) had true, visceral pain detected by DNB. The remaining 18 patients (78%) had a nonvisceral origin of pain (11/23 central, 4/11 somatosensory, 3/23 mixed). Furthermore, those patients who had nonvisceral pain did not respond well to medical treatment, nerve blocks, or surgical therapy. Therefore, CP pain is a complex interaction between nociceptive impulses from the gland itself, combined with other factors, including central neural impulses, abdominal wall pain, narcotic dependence, and psychiatric disorders.
STEATORRHEA AND MALDIGESTION The intraluminal digestion of fat and protein relies on pancreatic enzyme and bicarbonate production. The gradual replacement of the pancreas with fibrosis produces a steady deterioration in enzyme output. Although exocrine changes may be detected early in the course of CP through pancreatic function testing, clinically apparent steatorrhea does not occur until 90% of pancreatic function is lost138. Overt steatorrhea is seen in 30% of patients with CP. Fat malabsorption is typically more severe and occurs earlier than protein malabsorption. Chronic biliary obstruction may worsen fat malabsorption. The time from diagnosis of CP to onset of maldigestion varies from 5.6 to 26 years, depending on the etiology of disease117. The sudden development of overt exocrine insufficiency may suggest main pancreatic duct obstruction by inflammatory strictures or ductal adenocarcinoma. Protein calorie malnutrition and vitamin deficiencies are common complications of steatorrhea and malabsorption139.
DIABETES MELLITUS Although glucose intolerance may occur early, overt diabetes typically does not occur until late in the disease course. A prospective cohort study of 500 consecutive CP patients with a mean follow-up of 7 years revealed an 83% cumulative rate of diabetes mellitus (DM) at 25 years after clinical onset of pancreatitis140. Multivariate analysis revealed distal pancreatectomy and early onset of pancreatic calcifications as the only independent predictors of diabetes. A family history of diabetes substantially increases the risk for the development of pancreatic diabetes. Pancreatic diabetes usually requires insulin as the pathogenesis relates to lack of production rather than lack of responsiveness to insulin. Furthermore, these patients are prone to severe hypoglycemia with insulin overdose because of concomitant glucagon deficiency.
WEIGHT LOSS Although severe weight loss is closely correlated with the development of steatorrhea, multiple symptoms contribute to malnutrition in CP, including abdominal pain, sitophobia, anorexia, nausea, and vomiting141. In most cases, patients are able to compensate for weight loss by eating more. Severe weight loss may signal development of a complication of chronic pancreatic fibrosis, such as gastric outlet obstruction or pancreatic cancer.
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Diagnosis The diagnosis of CP is suspected based on a combination of clinical, structural, and functional findings. Imaging tests (plain x-ray, CT scan, ultrasound, etc) are helpful for advanced, large-duct CP, however may be insufficient for detecting smallduct (minimal change) CP. More invasive imaging tests (ERCP, EUS) offer better sensitivity for early disease at the cost of increased risk. When imaging tests are negative, pancreatic function tests are helpful to confirm or rule out the presence of pancreatic insufficiency as a marker of CP. This section includes a brief description of the imaging and functional diagnostic tests for CP. As a caveat, many of the studies evaluating sensitivities of these tests are inherently flawed because they include mostly subjects with established, advanced CP. Relatively few studies have included patients with early CP. Furthermore, few tests have been compared to histology—the true gold standard.
IMAGING TESTS Abdominal Plain Films and Transabdominal Ultrasound Plain abdominal x-rays have been used for decades to detect pancreatic calcifications suggestive of underlying CP (Figure 9-6). Although pancreatic calcifications are fairly specific for CP, sensitivity ranges from 30% to 70%. Transabdominal ultrasonography (US) is another relatively noninvasive, inexpensive test of limited usefulness in diagnosis of pancreatic disease. In patients of thin body habitus, transabdominal US may detect parenchymal and ductal features suggestive of CP. The sensitivity of transabdominal US for the detection of CP ranges from 60% to 70%; specificity ranges from 80% to 90% 98. Ultrasound is also helpful in evaluating other abdominal organs for differential causes of abdominal pain142 . Despite relatively low sensitivity, abdominal x-rays and transabdominal US are reasonable in the initial work-up of CP because they are simple, noninvasive, and inexpensive.
Computed Tomography Scanning CT scan using intravenous contrast and thin-cuts through the pancreas is frequently used in the diagnosis of large-duct pancreatitis. The cardinal features are glandular atrophy, calcifications, and duct dilation (Figure 9-7)143. Glandular atrophy is fairly sensitive for advanced disease and the presence of glandular insufficiency, but may also be seen in elderly patients144. Calcifications have high specificity and may145 or may not146 correlate well with pancreatic exocrine insufficiency. The reported sensitivity for advanced CP ranges from 74% to 90%; specificity is 84 to 100%147. The sensitivity of CT for early or mild CP is considered inferior to that of ERCP and pancreatic function testing. CT is very good for detecting complications of CP, such as pseudocysts, arterial pseudoaneurysm, splenic vein thrombosis, and biliary dilatation. Pancreatic cancer may also be detected with CT, although it may be difficult to differentiate from an inflammatory mass.
Endoscopic Retrograde Cholangiopancreatography ERCP is considered the radiographic gold standard for diagnosis of CP148. ERCP may be used for diagnosis and staging of CP, as well as for evaluation of pseudocysts and underlying ductal adenocarcinoma or other obstructive causes of CP (Figure 9-8).
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Figure 9-6. Abdominal x-ray revealing pancreatic calcifications.
Figure 9-7. CT scan revealing ductal dilation and extensive pancreatic calcifications.
It is frequently employed in the presurgical evaluation of patients with large-duct CP. CP primarily affects the small ducts, followed by the main pancreatic duct. Reported sensitivities and specificities of ERCP for detecting CP are 71% to 93% and 89% to 100%, respectively 98. Although ERCP is considered by many to be the most sensitive imaging test for early CP, the diagnostic implications of early ductal changes are not completely understood. Few studies have analyzed ERP findings compared to the true gold standard-histology149. The specificity of small duct changes is lower as they may be encountered in old age or in the setting of resolving AP150,151.
Magnetic Resonance Imaging In the past decade, magnetic resonance imaging (MRI) has become increasingly utilized in the evaluation of pancreatic disease. Both the ductal and parenchymal architecture may be evaluated with MRI. MRI is comparable to CT scan for the detection of pancreatic atrophy or enlargement and pseudocysts. Calcifications are more difficult to detect on MRI and are visualized as signal voids. Enhancement with gadolinium contrast may help differentiate pancreatic cancer from an inflammatory mass.
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Figure
9-8. ERCP changes according to Cambridge classification. (A) Class I (equivocal), revealing a normal main pancreatic duct (MPD) and 1-3 small branch changes. (B) Class II (mild), revealing a normal MPD, and more extensive small duct ectasia and clubbing. (C) Class III (moderate), revealing mild dilation of the MPD. (D) Class IV (severe), showing severe irregularity and "chain of lakes" appearance of the MPD.
Interestingly, MRI may also detect the presence of pancreatic fibrosis through the presence of abnormal signal intensities. Patients with CP have lower signal intensity on T1-weighted images compared to controls152 . In addition, diminished or heterogeneous enhancement after gadolinium may be seen on fast gradient T1-weighted images153,154. The ability of MRI to detect differences in signal intensity based on the presence of fibrosis has implications for diagnosing early CP. The development of MR cholangiopancreatography (MRCP) has been a major advancement in pancreatic imaging. Heavily T2-weighted images produce bright enhancement of fluid-filled structures, including the pancreatic and biliary ducts. MRCP is a noninvasive alternative to ERCP for evaluation of the main pancreatic duct. Multiple studies have shown satisfactory agreement of MRCP with ERCP for the detection of ductal dilatation and irregularity, strictures, pancreas divisum, and pseudocysts155,156. Although MRCP is comparable to ERCP for visualizing the main pancreatic duct, it lacks sensitivity for small duct changes. Secretin-enhanced MRCP may provide improved appreciation of structure by increasing secretion and distending the pancreatic duct157. Changes in duct volume and duodenal fluid volume after secretin can provide a rough assessment of pancreatic function158. There is ongoing, intense research in the use of MRI as a noninvasive alternative for simultaneously evaluating the pancreatic ducts and parenchyma. It is hoped that combined MRI modalities will ease the diagnosis of early CP.
Endoscopic Ultrasound In recent years, pancreatic EUS has emerged as a valuable test for the evaluation of pancreatic structure. EUS is similar to MRI in its simultaneous assessment of ducts and parenchyma. Furthermore, EUS is less invasive and entails less risk than ERCP. In contrast to transabdominal US, which is frequently limited secondary to body habitus and bowel gas, EUS produces excellent images due to the close proximity of the probe to the gland. Eleven sonographic criteria have been used for the diagnosis of CP (Table 9-3). Minimizing the sonographic criteria required for diagnosis improves sensitivity while decreasing specificity. A receiver-operating curve (ROC) analysis comparing EUS to ERCP demonstrated maximum sensitivity for all CP when three criteria are present159. A high specificity and positive predictive value for moderate to severe CP was
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ENDOSCOPIC ULTRASOUND FEATURES OF CHRONIC PANCREATITIS Parenchymal
Ductal Features
Gland atrophy Hyperechoic foci Hyperechoic stranding Cysts Lobularity
Narrowing Dilation Irregularity Calculi Side branch dilation Hyperechoic walls
demonstrated when six criteria were used. Other studies of EUS using a cutoff of three sonographic criteria have shown agreement with ERCP in normals and in advanced disease, but discordance in the presence of mild and moderate changes160,161. The substantial proportion of patients with normal ERCP and pancreatic function tests and abnormal EUS amplifies the concern that EUS may be overdiagnosing CP162 . A recent study demonstrated three or more EUS criteria for CP in 46% of patients presenting with dyspepsia163. The authors suggested that underlying CP might be present in many patients presenting with chronic abdominal pain. Interestingly, 20% of asymptomatic controls had three or more criteria for CP as well.
PANCREATIC FUNCTION TESTS Pancreatic function tests (PFT) are useful for detecting exocrine insufficiency as a cause of steatorrhea and surrogate marker of CP. Pancreatic function tests are most helpful when imaging tests are negative or equivocal.
Direct Pancreatic Function Tests Direct PFTs require double-lumen gastroduodenal tubes for the collection of hormone-stimulated pancreatic fluid for biochemical analysis of enzyme and bicarbonate production (Figure 9-9). Although direct PFTs are considered the functional gold standard, innumerable permutations exist regarding the hormonal stimulants used (CCK versus secretin versus combined, IV bolus versus continuous infusion) and the fluid parameters measured (enzymes versus bicarbonate, volume versus output versus concentrations)164. Furthermore, the collection time and accepted biochemical cutoffs are variable. Direct tests are considered the most sensitive tests for the diagnosis of early CP because they detect minor changes in acinar and duct cell function prior to the development of overt steatorrhea. Whereas overt steatorrhea occurs with 90% of loss of glandular function, direct PFT may detect abnormalities with 60% to 70% loss of function165. The sensitivities of direct PFTs range from 74% to >90%147. Because of the time-consuming and cumbersome nature of these tests, direct PFTs have been
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Figure 9-9. Proper placement of Dreiling gastroduodenal collection tube for direct pancreatic function testing. The tip is past the ligament of Treiz with proximal port in gastric antrum and distal port in the second portion of the duodenum.
relegated to a few tertiary centers. The recent development of endoscopic collection methods for direct PFTs holds promise in increasing accessibility of these valuable tests166,167.
Indirect Pancreatic Function Tests There are a plethora of noninvasive, indirect tests of pancreatic function that do not require passage of collection tubes. Qualitative measurement of stool fat is an inexpensive and noninvasive screen for fat malabsorption (Figure 9-10). Stool fat lacks sensitivity for early CP because 90% of glandular function must be lost to result in fat malabsorption. Stool fat is nonspecific for pancreatic insufficiency because mucosal disease and bile deficiency can produce fat malabsorption. In this situation, the D-xylose test may be helpful in differentiating mucosal disease from pancreatic insufficiency. The measurement of fecal proteases such as chymotrypsin, trypsin, and elastase-1 are likewise sensitive for the detection of moderate and advanced CP168. The bentiromide and pancreolauryl tests involve ingestion of oral substances that are selectively cleaved by pancreatic enzymes169,170. The cleaved segments of these substances are absorbed into the systemic circulation and excreted. Measurement of the urinary metabolites allows a quantification of pancreatic exocrine function. Because indirect tests only become positive in the presence of overt malabsorption, the sensitivity of these tests is higher for moderate and severe CP than for mild CP. Several studies have compared the results of the radiographic and functional gold standards (ERCP versus secretin test)171,172 . Most of these studies have shown a good correlation in moderate and advanced disease and discordance in early disease. This may suggest that in some patients, functional changes may precede structural changes and vice versa.
Therapy Once the diagnosis and staging of CP is accomplished, therapy is directed at the symptoms and complications. Although variable in character and pattern, pain is the most common symptom of CP. The management of abdominal pain from CP is challenging because of superimposed narcotic addiction. Furthermore, nonvisceral (ie, non-pancreatic) pain may be present, which may predict a poor response to therapy directed at the pancreas. Medical therapy is usually the first line of treatment for patients with pain from CP. Surgery is an option for patients who fail medical therapy or who have advanced ductal and cystic changes amenable to surgical drainage.
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Figure 9-10. A.
Endoscopic view; B. Sudan stain showing steatorrhea in a patient with pancreatic insufficiency. For full-color version, see page CA IV of the Color Atlas.
MEDICAL THERAPY There are five principle medical options available for the treatment of pancreatic pain: abstinence from alcohol, analgesics, pancreatic enzymes, visceral nerve blocks, and endoscopic therapy. Abstinence from alcohol is a critical first step in therapy. Alcohol is known to hasten the progression of exocrine and endocrine dysfunction and increase mortality173,174. A review and meta-analysis demonstrated an increased likelihood of persistent pain in those who continued to imbibe (26% versus 53%)175. Analgesic agents are the cornerstones of therapy for the treatment of painful CP. It is best to start with non-narcotic analgesics such as nonsteroidal anti-inflammatory agents, acetaminophen, and tramadol. If pain persists, these agents may be combined with low doses of mild narcotics such as codeine or propoxyphene. Potent narcotics should be avoided if possible given the potential for dependency; however, recalcitrant pain may warrant their use in select cases. Differential nerve blockade (DNB) is helpful in ruling out nonvisceral sources of pain. Patients with somatosensory pain may benefit from anticonvulsants such as gabapentin. Patients with central pain may benefit from antidepressants and psychiatric counseling. When exocrine functional loss reaches a critical threshold, malabsorption results in steatorrhea and malnutrition. The mainstay of therapy for maldigestion from pancreatic insufficiency is exogenous pancreatic enzyme supplements. These medications are safe, well-tolerated, and produce few side effects. Several enzyme products are available and each contains different amounts of lipase, protease, and amylase (Table 9-4). Enteric coated may be more effective than uncoated preparations for treatment of maldigestion, given higher potency and better delivery to the small bowel. A minimum of 30,000 IU of lipase and 10,000 IU of protease should be administered with each meal to allow adequate intraluminal digestion of fat and protein. Successful treatment with pancreatic enzymes results in improvement in maldigestion and steatorrhea. Because gastric acid denatures exogenous enzymes, a daily proton-pump inhibitor may be added for patients refractory to therapy (Figure 9-11). Progress may be monitored through assessment of symptoms or more objectively through 72-hour stool fat quantification. Studies of the effects of pancreatic enzymes on abdominal pain have yielded mixed results. The supposed mechanism of pain relief relates to the breakdown of CCK-releasing peptide (CCK-RF) by exogenous enzymes within the duodenal lumen.
Enteric-coated Micro-tablets
Enteric-coated Micro-tablets
Pancrease MT 4/10/16/20
Ultrase MT6/12/16/20
Enteric-coated Micro-spheres
Capsule Tablet Tablet
Rapid Release Cotazym Pancreatin Viokase
Delayed Release Creon 5/10/20
Form
6,000 12,000 18,000 20,000
4,000 10,000 16,000 20,000
5,000 10,000 20,000
8,000 12,000 8,000
Lipase
19,500 39,000 58,500 65,000
12,000 30,000 48,000 44,000
18,750 37,500 75,000
30,000 60,000 30,000
Protease
19,500 39,000 58,500 65,000
12,000 30,000 48,000 56,000
16,600 33,200 66,400
30,000 60,000 30,000
Amylase
Enzyme Content (USP Units)
PANCREATIC ENZYME PREPARATIONS
Preparation
Table 9-4
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Figure 9-11. Management algorithm for maldigestion in pancreatic insufficiency.
Digestion of CCK-RF attenuates serum CCK levels and pancreatic stimulation. Oral pancreatic enzymes appear to decrease pain in some patients with CP176. However, a recent meta-analysis of six randomized placebo-controlled trials did not reveal a statistically significant benefit for supplemental pancreatic enzyme therapy for pain relief (Figure 9-12)132 . A major criticism with this study was the substantial methodological variability among the included studies, most importantly the mixture of coated and uncoated preparations. Uncoated preparations are better for pain relief as they are most effectively delivered to the proximal small bowel to inhibit CCK. Although the role of exogenous enzyme supplementation for pain relief is not completely understood, they are worth trying in all patients because of their safety and minimal side effects. Endoscopic modalities of treatment of CP include duct decompression, drainage of pseudocysts, and EUS-guided celiac plexus block. Patients with large-duct CP who are ineligible for surgery and have distal pancreatic duct strictures or stones may be suitable for endoscopic duct-decompression therapy. Techniques include endoscopic pancreatic sphincterotomy, balloon dilatation of strictures, mechanical or extracorporeal sound wave lithotripsy, and placement of pancreatic duct stents (Figure 9-13). Multiple studies have suggested that endoscopic therapy is effective for pain relief. For example, a study by Cremer et al noted a significant decrease in pain in 94% of patients who underwent pancreatic duct stenting with a 12-month average duration of pain relief177. Pain relief was sustained at 3 years in 55% of the patients. Most other trials have shown a more modest treatment effect. Unfortunately, few randomized trials comparing endoscopic to surgical or medical therapy have been performed178.
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Figure 9-12. Results of meta-analysis of pancreatic enzyme therapy for pain relief in CP. Reprinted with permission from Blackwell Publishers.
The benefit of endoscopic therapy must be weighed against the immediate risk of acute pancreatitis and the long-term risk of stent-induced strictures. These procedures should only be performed in high volume centers by experienced endoscopists. Patients who fail initial medical therapy are candidates for celiac plexus blockade (CPB) (Figure 9-14). Appropriate candidates include patients with small-duct disease or patients with large duct disease who fail to respond to surgical or endoscopic duct decompression. Nerve blocks are less effective in CP compared to pancreatic cancer, but should still be considered as an option for patients with recalcitrant pain179. When CPB is effective, the duration of effect is usually 2 to 4 months and may need to be repeated. In contrast to malignant disease, corticosteroid injections are favored over alcohol injections in CP because of the risk of paraplegia with alcohol. Although CPB is usually performed under CT-guidance, EUS-guided CPB has recently emerged as an effective method. One report showed a higher rate of pain relief for EUS versus CTguided CPB180. When patients do not respond to CPB, there may be nonvisceral pain contributing to their symptoms. CPB is discussed in further detail in Chapter 15.
SURGICAL THERAPY Surgical therapy is most beneficial in patients with severe pain and large duct CP. A Roux-en-Y side-to-side pancreaticojejunostomy (Puestow procedure) to drain the entire pancreas is indicated for patients with pancreatic duct dilatation greater than 7 mm. Large pseudocysts may be surgically drained at the time of duct decompression
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Figure 9-13. Endoscopic therapy for CP. A. Stone extraction using mechanical lithotripsy; B, C. Pancreatic duct stricture, pre- and post-stent placement.
through cyst-gastrostomy, cyst-duodenostomy, or cyst-jejunostomy. Most studies have shown favorable immediate success in 80% to 90% of patients. The results are often not durable, as long-term relief is seen in only 40% to 50% of patients181. It has not been established whether duct decompression surgery preserves pancreatic exocrine and endocrine function. Patients who have small-duct disease and pain unresponsive to medical therapy may undergo resection of diseased areas of the pancreas. Resection of large portions of the pancreas may produce brittle diabetes and metabolic derangements.
Complications PSEUDOCYSTS Pseudocysts are collections of pancreatic secretions that develop as a result of inflammation. Pseudocysts are the most common cysts of the pancreas; however, they differ from other pancreatic cysts in that they lack an epithelial lining. Pseudocysts may arise in either acute or chronic pancreatitis, although the mechanisms differ182 . In acute pancreatitis, pseudocysts are thought to develop from severe inflammation and liquefaction necrosis. In CP, pseudocysts result from ductal obstruction leading to upstream dilation and cyst formation. ERCP frequently shows a communication
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Figure 9-14. Celiac plexus block for visceral pancreatic pain.
of the cyst with the pancreatic duct. Most pseudocysts develop in the body and tail of the pancreas183. The most common clinical presentation is worsening abdominal pain in known CP, or several weeks after an episode of acute pancreatitis. There is often an associated elevation in the serum amylase and lipase. The natural history may include spontaneous resolution or progressive increase in size184. Pseudocysts arising in CP rarely rupture, become infected, or hemorrhage. Treatment may be conservative for small cysts, but endoscopic drainage (transmural or transpapillary) or surgical resection is required for enlarging or symptomatic cysts (Figure 9-15).
GASTRIC OUTLET AND BILIARY OBSTRUCTION Biliary obstruction and gastric outlet obstruction are relatively infrequent complications, most commonly occurring in advanced alcoholic pancreatitis. Gastric outlet obstruction from duodenal compression occurs in approximately 5% of cases, and may arise from severe fibrosis in the head of the gland, pseudocysts, or pancreatic cancer. Patients present with increased abdominal pain, vomiting, and inability to tolerate oral intake. Diagnosis may be established with barium upper GI x-ray, endoscopy, or CT scan. Biliary obstruction occurs in 10% and presents with jaundice. Although extensive fibrosis or enlarging pseudocysts are the most common causes, the development of jaundice in CP should raise concern for pancreatic cancer. Diagnosis is based on ERCP, which characteristically reveals a long, tapered stricture. A “double duct” sign may be present in the setting of large duct CP, presenting diagnostic uncertainty as to the presence of underlying ductal cancer. Surgery is most often required for management of both of these obstructive complications.
PANCREATIC ADENOCARCINOMA CP is a known risk factor for pancreatic cancer; conversely, pancreatic cancer can cause obstructive CP. Pancreatic cancer contributes substantially to mortality of pancreatitis, developing in 4% of patients with a 20-year duration of CP173. Diagnosis of pancreatic cancer in CP is difficult. It should be suspected with the development
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Figure 9-15. A. CT scan showing pancreatic pseudocyst in a patient with CP; B. Endoscopic transmural drainage of pseudocyst.
of acute worsening in abdominal pain, weight loss, or functional decline. Imaging tests often produce uncertainty in differentiating cancer from inflammatory masses and brushings are frequently nondiagnostic. Definitive diagnosis is often reserved for pathologic examination of the surgical explant.
PANCREATIC FISTULAE AND ASCITES Both internal and external fistulas may develop as a consequence of CP, usually arising from communications of pancreatic pseudocysts with adjacent cavities or from duct disruption. Communications with the peritoneal and pleural cavities produce refractory ascites and pleural effusions. Diagnosis is based on fluid analysis, which reveals elevated amylase content. Endoscopic stent placement across the region of ductal disruption may be effective for treatment of these conditions185.
SPLENIC VEIN THROMBOSIS AND SPLENIC ARTERY PSEUDOANEURYSM Splenic vein thrombosis occurs in 45% of patients with CP, but most are asymptomatic186. When morbidity occurs, it is the result of bleeding from secondary gastric varices. Splenectomy is the preferred management for recurrent bleeding from this condition. Splenic artery pseudoaneurysm is a disastrous complication arising from pancreatic inflammation and necrosis in the vicinity of the splenic artery. Pseudoaneurysms may rupture into adjacent pseudocysts resulting in hemobilia, or into the peritoneal cavity resulting in intraperitoneal hemorrhage. The mortality associated with this complication is 40% to 60%. Splenic artery pseudoaneurysms should be repaired surgically unless limiting comorbidities exist187. Endovascular therapy may also show promise in the management of this problem188.
Prognosis A multicenter study of 2,015 patients demonstrated a mortality rate for CP 3.6fold higher than for those without pancreatitis189. The 10-year survival rate was 79%
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for CP compared to 93% for patients without pancreatitis. The prognosis of CP is strongly dependent on the presence of alcohol abuse. The life expectancy is shorter for alcohol-induced compared to nonalcohol-induced CP. Other poor prognostic indicators include smoking, increased age, and concomitant cirrhosis190. Medical or surgical therapy has not been shown to impact morality. Death is frequently related to nonpancreatic causes in most patients regardless of etiology of CP. In a study of 315 patients with CP, Layer et al found that the cause of death was related to pancreatitis or pancreatic cancer in only 15% of alcohol-related and 3% of nonalcohol-related CP106.
APPROACH TO THE DIAGNOSIS OF CHRONIC PANCREATITIS Because of the significant challenges inherent in the management of this disease, we have developed a multidisciplinary approach191. All patients referred to our pancreas clinic first undergo a complete diagnostic and staging evaluation (Figure 9-16). Imaging tests are obtained to accurately determine the morphology of disease, often consisting of a pancreatic CT scan to assess gross parenchymal abnormalities (cysts, calcifications, and cancer) and an MRCP to evaluate the main pancreatic duct. If these tests do not reveal advanced structural changes, secretin-stimulated direct PFT, ERCP, and EUS are used to diagnose early CP. Most patients are referred for psychological and chemical-dependency evaluation to uncover contributing factors to the pain syndrome. After the diagnosis has been firmly established, patients with severe pain refractory to initial conservative management are referred for a differential nerve blockade (Figure 9-17). This procedure clarifies the origin of abdominal pain and may identify patients with nonvisceral pain who are less likely to respond to aggressive medical and surgical therapy directed at the pancreas. Patients with nonvisceral pain are first given a trial of conservative therapy (non-narcotic analgesics and abstinence from alcohol). If this fails, they are referred for psychotherapy and chemical dependency treatment. If there is somatosensory pain, a trial of gabapentin is attempted. Patients with visceral pain are also given a trial of conservative medical management. Further therapy is directed based on the morphology of disease (large-duct versus small-duct). Patients with large-duct disease or large pseudocysts are referred for surgical evaluation, or for a trial of endoscopic therapy. Patients with small-duct disease are referred for a CBP trial. Minimal change disease that fails to respond to nerve blocks may be considered for resection or experimental drug trials.
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Figure 9-16. Approach to the diagnosis of CP.
Figure 9-17. Approach to the management of pain in CP.
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141. Apte MV, Keogh GW, Wilson JS. Chronic pancreatitis: Complications and management of pain. J Clin Gastroenterol. 1998;29:225-240. 142. Clain JE, Pearson RK. Diagnosis of chronic pancreatitis: Is a gold standard necessary? Surg Clin N Am. 1999;79:829-843. 143. Remer EM, Baker ME. Imaging of chronic pancreatitis. Radiol Clin N Am. 2002;40:1229-1242. 144. Balthazar E. Pancreatitis. In: Levine M, ed. Textbook of Gastrointestinal Radiology, Volume 2. Philadelphia: WB Saunders; 2000:1767-1795. 145. Scuro LA, Cavallini G, Benini L, et al. Pancreatic calcifications in patients with chronic pancreatitis: a sign of long-lasting or severe disease? Int J Pancreatol. 1990;6:139-150. 146. Lankisch PG, Otto J, Erkelenz I, Lembcke B. Pancreatic calcifications: no indicator of severe exocrine pancreatic insufficiency. Gastroenterology. 1986;90:617-621. 147. Niederau C, Grendell JH. Diagnosis of chronic pancreatitis. Gastroenterology. 1985;88:1973-1995. 148. Axon ATR, Classen M, Cotton P, et al. Pancreatography in chronic pancreatitis. International definitions. Gut. 1984;25:1107-1112. 149. Kizu M, Newmann J, Cotton PB, et al. Histological correlation with pancreatography in necropsy specimens. Gut. 1977;18:399-400. 150. Cavallini G, Riela A, Angelini GP, et al. Limitations in the interpretation of endoscopic retrograde pancreatography findings in chronic pancreatitis. In: Malfertheiner P, Ditschuneit H, eds. Diagnostic Procedures in Pancreatic Disease. Berlin: SpringerVerlag; 1985:175-184. 151. Forsmark CE, Toskes PP. What does an abnormal pancreatogram mean? Gastrointest Endosc Clin N Am. 1995;5:105-123. 152. Semelka RC, Shhoenut JP, Kroeker MA, et al. Chronic pancreatitis: MR imaging features before and after administration of gadopentetate dimeglumine. J Magn Reson Imaging. 1993;3:79-92. 153. Zhang XM, Shi H, Parker L, et al. Suspected early or mild chronic pancreatitis: enhancement patterns on gadolinium chelate dynamic MRI. J Magn Reson Imaging. 2003;17:86-94. 154. Sica GT, Miller FH, Rodriguez G, et al. Magnetic resonance imaging in patients with pancreatitis: evaluation of signal intensity and enhancement changes. J Magn Reson Imaging. 2002;15:275-284. 155. Sica GT, Braver J, Coonehy MJ, et al. Comparison of endoscopic retrograde cholangiopancreatography with MR cholangiopancreatography in patients with pancreatitis. Radiology. 1999;210:605-610. 156. Takehara Y, Ichijo K, Tooyama N, et al. Breath-hold MR cholangiopancreatography with a long-echo-train fast spin-echo sequence and a surface coil in chronic pancreatitis. Radiology. 1994;192:73-78. 157. Matos C, Metens T, Deviere J, et al. Pancreatic duct: morphologic and functional evaluation with dynamic MR pancreatography after secretin stimulation. Radiology. 1997;203:435-441. 158. Cappeliez O, Delhaye M, Deviere J, et al. Chronic pancreatitis: evaluation of pancreatic exocrine function with MR pancreatography after secretin stimulation. Radiology. 2000;215:538-564.
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159. Sahai AV, Zimmerman M, Aabakken L, et al. Prospective assessment of the ability of endoscopic ultrasound to diangose, exclude, or establish the severity of chronic pancreatitis found by endoscopic retrograde cholangiopancreatography. Gastrointest Endosc. 1998;48:18-25. 160. Nattermann C, Goldschmidt AJ, Dancgier H. Endosonography in chronic pancreatitis-a comparison between endoscopic retrograde pancreatography and endoscopic ultrasonography. Endoscopy. 1993;25:555-564. 161. Wiersma MJ, Hawes RH, Lehman GA, et al. Prospective evaluation of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography in patients with chronic abdominal pain of suspected pancreatic origin. Endoscopy. 1993;25:555564. 162. Forsmark CE. The diagnosis of chronic pancreatitis. Gastrointest Endosc. 2000;52:293298. 163. Sahai AV, Mishra G, Penman ID, et al. EUS to detect evidence of pancreatic disease in patients with persistent or nonspecific dyspepsia. Gastrointest Endosc. 2000;52:153159. 164. Lankisch PG. Exocrine pancreatic function tests. Gut. 1982;123:777-785 165. Toskes PP. Diagnosis of chronic pancreatitis and exocrine insufficiency. Hosp Pract. 1985;97-108. 166. Conwell DL, Zuccaro G, Vargo JJ, et al. An endoscopic pancreatic function test with synthetic porcine secretin for the evaluation of chronic abdominal pain and suspected chronic pancreatitis. Gastrointest Endosc. 2003; 57: 37-40. 167. Conwell DL, Zuccaro G, Vargo JJ, et al. An endoscopic pancreatic function test with cholecystokinin-octapeptide for the diagnosis of chronic pancreatitis. Clinical Gastroenterology Hepatology. 2003;1:189-194. 168. Ammann RW, Tagwercher E, Dashiwagi H, et al. Diagnostic value of fecal chymotrypsin and trypsin assessment for detection of pancreatic disease. Am J Dig Dis. 1968;13:123-146. 169. Lankisch PG, Schreiber A, Otto J. Pancreolauryl test: evaluation of a tubeless pancreatic function test in comparison with other indirect and direct tests for exocrine pancreatic function. Dig Dis Sci. 1983;28:490-493. 170. Toskes PP. The bentiromide test for pancreatic exocrine insufficiency. Pharmacotherapy. 1984;4:74-83. 171. Branganza JM, Hunt LP, Warwich R. Relatinoship between pancreatic exocrine function and ductal morphology in chronic pancreatitis. Gastroenterology. 1982;82:13411347. 172. Malfertheiner P, Buchler M, Stanescu A, et al. Exocrine pancreatic function in correlation to ductal and parencymal morphology in chronic pancreatitis. Hepatogastroenterology. 1986;33:110-114. 173. Lowenfels AB, Maisonneuve P, Cavillini G, et al. Pancreatitis and the risk of pancreatic cancer. N Engl J Med. 1993;328:1422-1427. 174. Gullo L, Barbara L, Labo G. Effectg of cessation of alcohol use on the course of pancreatic dysfunction in alcoholic pancreatitis. Gastroenterology. 1998;95:1063-5. 175. Strum WB, Spiro HM. Chronic pancreatitis. Ann Intern Med. 1971;74:264-71. 176. Isaksson G, Ihse I. Pain reduction by an oral pancreatic enzyme preparation in chronic pancreatitis. Dig Dis Sci. 1983;28:97-102. 177. Cremer M, Deviere J, Delhaye M, et al. Stenting in severe chronic pancreatitis: results of medium term follow up in seventy-six patients. Endoscopy. 1991;23:171-176.
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Pancreatic Ductal Complications Ali Fazel, MD
Introduction Benign and malignant pancreatic diseases produce a variety of pancreatic duct (PD) abnormalities. Potential complications of the pancreatic duct include strictures, stones, and leaks. Abnormalities found on endoscopic retrograde pancreatogram characterize pancreatic ductal complications. Strictures present as a narrowing of the PD, which most often occurs in the setting of pancreatitis or pancreatic cancer. Stones almost always occur in the setting of chronic pancreatitis and can be seen as filling defects within the opacified PD. Pancreatic duct leaks are characterized by extravasation of contrast media from the pancreatic duct and into surrounding tissues. Pancreatic duct leaks can lead to pseudocysts, fistula formation, and ascites (Table 10-1). This chapter reviews the clinical manifestations, diagnostic approach, and management strategies for these complications.
Pancreatic Duct Strictures Pancreatic duct strictures are defined by a significant narrowing of the pancreatic duct on pancreatogram. Pancreatitis and pancreatic cancer cause the vast majority of pancreatic duct strictures. The diagnostic work-up revolves around the differentiation of a benign from a malignant stricture. This vital distinction leads to the consideration of surgical pancreatic resection for malignant disease, while benign strictures can often be managed by nonsurgical means (Table 10-2).
DIAGNOSTIC EVALUATION The basic challenge is to identify and operate on patients with malignancy when they are still respectable, while trying to avoid surgery in those with benign disease. Malignant cytological findings on endoscopic brushing of a stricture definitively establish the diagnosis of malignancy. Unfortunately, brushing of malignant strictures yields positive cytological findings in less than one-half of patients. In the absence of
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Table 10-1
PANCREATIC DUCTAL COMPLICATIONS Stricture Stone Leak
Table 10-2
ETIOLOGIES OF PANCREATIC DUCT STRICTURES Neoplastic • • •
Adenocarcinoma Neuroendocrine tumors Cystic neoplasms
Pancreatitis • • •
Chronic pancreatitis Acute pancreatitis Pseudocyst
Blunt abdominal trauma Stent-induced Idiopathic
positive findings on brushings, one must fall back on alternative methods to judge the likelihood of malignancy. Parameters to be considered include clinical presentation, pancreatography findings, endoscopic ultrasound, and serum Ca 19-9 (Table 10-3).
CLINICAL PRESENTATION Individuals with pancreatic strictures often present with symptoms of acute pancreatitis, acute recurrent pancreatitis, chronic pancreatitis, or pancreatic malignancy. Abdominal pain is the primary symptom of acute pancreatitis. The pain is located in the upper abdomen and often radiates to the back. This can be associated
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Table 10-3
DIAGNOSTIC TOOLS FOR THE EVALUATION OF PANCREATIC DUCT STRICTURES Clinical presentation ERCP • Pancreatography • Cytology
Endoscopic ultrasound (EUS) with FNA Serum Ca-19-9 with nausea, vomiting, and abdominal distention. In chronic pancreatitis, the upper abdominal pain becomes chronic and is often associated with steatorrhea or diabetes mellitus. The latter manifestations result from exocrine and endocrine insufficiency of the pancreas. The cardinal manifestation of pancreatic malignancy is upper abdominal pain and weight loss. This is associated with jaundice in one-half of cases. Progressive weight loss and painless jaundice strongly suggest malignancy.
ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAM Close examination of the cholangiopancreatogram provides important clues to the cause of a pancreatic duct stricture. A single irregular stricture with proximal dilation and normal distal anatomy is suggestive of malignancy (Figure 10-1). Contiguous strictures of the pancreatic duct and common bile duct carry a positive predictive value of 85% for the presence of pancreatic cancer (Figure 10-2). This “double duct sign” indicates a high likelihood of malignancy but can also be seen in the setting of chronic pancreatitis. In chronic pancreatitis, dilation of the main pancreatic duct and abnormal side branches may be seen both proximal and distal to benign strictures. Chronic pancreatitis can also present with multiple strictures and intervening areas of ductal dilation (chain of lakes appearance) (Figure 10-3). Six percent of pancreatic malignancies develop in the setting of chronic pancreatitis. Consequently, a pancreatogram consistent with chronic pancreatitis does not entirely exclude the possibility of malignancy. The diagnosis of a benign stricture must be supported by other clinical findings as well. Faulty pancreatogram technique and anatomic variation can be mistaken for the presence of a PD stricture. Underfilling of the PD creates the appearance of ductal irregularity and narrowing. An adequate injection of contrast that fills the entire main PD and secondary side branches reverses this irregular appearance. Inadvertent injec-
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Figure 10-1. A malignant ductal stricture located in the pancreatic body. Upstream to the stricture significant dilation of the pancreatic duct and side branches is seen. Downstream to the stricture the pancreatic duct appears normal.
Figure 10-2. Contiguous strictures of the pancreatic duct and common bile duct causing proximal dilation of both ducts. A “double duct sign” indicates a high likelihood of malignancy but can also be seen in chronic pancreatitis.
tion of air into the PD can create the false appearance of a PD cutoff. Advancing the catheter into the pancreatic body and gently injecting contrast into the proximal PD resolves this false appearance. Most variants are of no clinical significance and familiarity with these possibilities helps avoid unnecessary work-up. Ventral-dorsal ductal malfusions such as pancreas
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Figure 10-3. Multiple ductal stictures are separated by intervening areas of ductal dilation (chain of lakes appearance). This appearance is consistent with advanced chronic pancreatitis.
divisum and incomplete pancreas divisum can be mistaken for occlusion or stricture of the PD. Atypical configurations of the PD most often include an ansa loop or spiral loop of the ventral duct in the pancreatic head.
ENDOSCOPIC ULTRASOUND Endoscopic ultrasound (EUS) is the most sensitive method for the detection of small pancreatic masses, particularly when they are smaller than 2 cm in size. Pancreatic malignancies appear as a relatively hypoechoic area that encompasses the pancreatic duct at the site of the stricture. Fine-needle aspiration (FNA) biopsy of these focal abnormalities can definitively confirm the presence of malignancy in 80% to 90% of cases. Unfortunately, in the setting of chronic pancreatitis, the sensitivity of FNA biopsy decreases to 50%. Although EUS has proven very useful for the overall early diagnosis of pancreatic cancer, this utility has not been well studied in the setting of patients presenting with pancreatic duct strictures.
SERUM CA 19-9 Ca 19-9 is the only tumor marker of practical utility in the evaluation of PD strictures. The positive predictive value (PPV) and negative predictive value (NPV) of this marker for the diagnosis of pancreatic cancer varies depending on the cutoff value chosen. A cutoff of 37 U/mL provides a sensitivity of 80% and NPV of 90%. A cutoff of 1000 U/mL provides a specificity of 100%. Thus a value of greater than 1000 U/mL strongly supports the diagnosis of malignancy. Milder elevations can be seen in jaundiced patients without pancreatic cancer. Ca 19-9 levels can be normal in
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early pancreatic cancers, and thus low levels of this tumor marker cannot effectively exclude the possibility of pancreatic cancer1.
MANAGEMENT OF THE CYTOLOGY NEGATIVE PANCREATIC DUCT STRICTURE The management options for a newly diagnosed cytology negative PD stricture include proceeding with a pancreatic resection on the assumption that the stricture is malignant, or treating the lesion as a benign stricture. To proceed with a blind resection, a break-even point must be reached where the benefits outweigh the risks of surgery. The mortality associated with a pancreaticoduodenectomy is approximately 5% and major morbidity occurs in another 5% to 10%. Half of the patients undergoing successful resection of their tumor will experience long-term disease-free survival. Consequently, the benefits of blind resection outweigh the risks when the ultimate likelihood of a resectable pancreatic cancer is greater than 20%. Vigilant followup is needed in cases where strictures are presumed to be benign. Periodic clinical evaluation and abdominal imaging (transabdominal ultrasound, abdominal CT, or EUS) should be performed to rule out any changes that would suggest a previously undetected malignancy. Findings of particular concern include a new or evolving pancreatic mass or progressive ductal dilation.
TREATMENT OF THE BENIGN PANCREATIC DUCT STRICTURES Given the presumed role of ductal hypertension in the genesis of symptoms in patients with PD strictures, measures to bypass or traverse the stricture to relieve the increased pressure are undertaken. These measures can be medical, endoscopic, or surgical. Therapies are primarily directed at the relief of pain and the prevention of recurrent bouts of acute pancreatitis. Asymptomatic strictures do not require treatment once the possibility of malignancy has been adequately excluded. Mildly symptomatic patients respond well to conservative therapy consisting of analgesics and/or pancreatic enzymes. When conservative therapy fails, consideration is given to endoscopic or surgical intervention.
ENDOSCOPIC THERAPY OF BENIGN STRICTURES Endoscopic therapy is appropriate in symptomatic benign PD strictures. Significant strictures can present with pain and/or pancreatitis. Pancreatic malignancy must be adequately excluded prior to embarking on a course of endoscopic therapy. Endoscopic therapy often requires multiple treatment sessions necessitating significant motivation and compliance on the part of the patient. Endoscopic therapy of benign pancreatic strictures includes pancreatic sphincterotomy, stricture dilation, and/or stenting of the PD. Often multiple treatment sessions are required over an interval of 6 to 12 months. In the presence of ductal stones or pseudocyst, stone extraction and pseudocyst drainage can facilitate the treatment of PD strictures.
Pancreatic Sphincterotomy Pancreatic sphincterotomy increases the size of the pancreatic duct orifice and facilitates the insertion of endoscopic accessories. The methods for pancreatic sphincterotomy include standard pull-type sphincterotomy and needle knife sphincterotomy. Standard pull-type pancreatic sphincterotomy requires initial
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Figure 10-4. A schematic representation of a pancreatic sphincterotomy: A. Cannulation of the bile duct is obtained with a pull-type sphincterotome; B. A biliary sphincterotomy is performed exposing the pancreaticobiliary septum covering the intramural portion of the pancreatic duct; C. Deep cannulation of the pancreatic duct is obtained and a pancreatic sphincterotomy is performed in the 12 o’clock position along the full length of the pancreaticobiliary septum.
cannulation of the bile duct with a pull-type sphincterotome. A biliary sphincterotomy exposes the pancreaticobiliary septum covering the intramural portion of the PD. The pancreatic orifice can be identified near the 3 to 6 o’clock margin of the biliary sphincterotomy. Deep cannulation of the pancreatic duct is then obtained with a pull-type sphincterotome. The pancreatic sphincterotomy is performed in the 12 o’clock position along the full length of the pancreaticobiliary septum (Figure 10-4). Occasionally, cannulation of a stenotic PD orifice necessitates the use of a taper tipped catheter for cannulation. Needle knife pancreatic sphincterotomy requires the placement of a stent into the distal PD. The PD stent serves as a guide for the direction and extent of the needle knife incision and provides prophylaxis against the development of postsphincterotomy pancreatitis. The needle knife consists of a plastic catheter with a protruding bare cutting wire that delivers electrocautery current. The needle knife cut is begun at the papillary orifice and is extended along the intramural portion of the PD by following the course of the stent. This technique often cannot be used because strictures or stones in the pancreatic head can impede initial placement of the stent. Early complications of pancreatic sphincterotomy include pancreatitis, bleeding, perforation, and pancreaticobiliary sepsis. These can occur in 10% to 13% of cases. The vast majority of early complications are related to post-ERCP pancreatitis, which can develop in 7% to 13% of pancreatic sphincterotomies. Placement of a pancreatic stent decreases the risk of pancreatitis and is effective in preventing the more severe forms of post-ERCP pancreatitis. Late complications of pancreatic sphincterotomy consist of stricture at the sphincterotomy site. This has been reported to occur in up to
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14% of cases and can be treated with repeat sphincterotomy. This significant stenosis rate has led to the use of pure cut current for pancreatic sphincterotomies.
Stricture Dilation Dilation can be performed with dilation balloons or catheters. Dilation balloons are available in 4, 6, and 8 mm diameters. The diameter of the stricture and the overall diameter of the pancreatic duct determine the size of balloons used. A guidewire must be able to traverse the stricture. The dilating device is then passed over the guidewire and through the area of narrowing. The dilating balloon is 2 cm long and is located on the distal tip of a 5 to 7 French catheter. Radio-opaque markers at the distal and proximal ends of the balloon allow accurate positioning of the balloon across the stricture site. The balloon is inflated to a predetermined pressure until there is obliteration of the balloon waist at the site of narrowing. The entire procedure is performed under fluoroscopic guidance. Tight strictures that cannot be traversed with a balloon catheter can be dilated by passing a graduated dilating catheter across the stricture. This catheter is delivered over a guidewire and ranges from 3 to 10 Fr in size. The success of graduated dilation may be limited by the amount of force that can be applied to pass the dilating catheter through the stricture.
Pancreatic Stent Placement Pancreatic stent placement maintains stricture patency after dilation. The best candidates for pancreatic duct stenting appear to be those patients with a stricture in the pancreatic head and “upstream” dilation. The technique for placing a stent in the pancreatic duct is similar to that used for placing a biliary stent. In some patients, a pancreatic sphincterotomy (with or without a biliary sphincterotomy) is performed to facilitate placement of accessories and stents. The stent is advanced over a guidewire, which must traverse the stricture, and across the stricture using a “pushing catheter” under fluoroscopic guidance. Stent diameter, which ranges from 5 to 10 French, is determined by the size of dilator used and the diameter of the pancreatic duct (Figure 10-5). In general, the stent diameter should not exceed the downstream duct diameter. Flaps located on both ends of the stent prevent stent migration. Stent length should be chosen such that one flap is located just outside the papilla and the other flap is positioned beyond the stricture. High-grade strictures may require dilation prior to placement of endoprosthesis. Reported initial outcomes of endoscopic therapy of benign PD strictures have been promising. Stent insertion is technically possible in 72% to 100% of cases. Difficulty in stent insertion occurs primarily in the setting of pancreas divisum. Subsequent to stent insertion, symptomatic relief occurs in 75% to 95% of cases. This symptomatic improvement continues after stent removal in 47% to 70%. Longer term follow-up, ranging from 1 to 2 years, has shown that long-term stricture resolution occurs in 20% to 40% of patients2-5. This success has been tempered by several concerns. Long-term resolution of strictures occurs in only 20% to 40% of patients. Stent occlusion can lead to recurrent pancreatitis and pancreatic sepsis. Finally, increasingly recognized is the potential for focal pancreatitis and even stricture formation elicited by the presence of a pancreatic stent itself. Avoidance of stent-induced complications may be reduced by shortening the stent exchange intervals and limiting the duration of overall endoscopic therapy of strictures.
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Figure 10-5. Above a balloon dilation catheter, graduated dilation catheter and a pancreatic duct stent can be seen.
SURGICAL THERAPY OF BENIGN STRICTURES Surgical therapy is indicated when medical and endoscopic interventions fail to provide adequate relief. Three types of surgical procedures can be performed: 1) ductal drainage, 2) pancreatic resection, and 3) combined drainage and resection. Pancreatic duct anatomy, the presence of concomitant biliary or duodenal stricture, the presence of pseudocysts, and significant concern for malignancy influence the type of surgical procedure performed. A pancreatic head stricture associated with a biliary or duodenal stricture, a small pancreatic duct, or significant pancreatic head enlargement would necessitate a pancreatic head resection (Whipple procedure or pancreaticoduodenectomy). A pancreatic head stricture with a diffusely dilated upstream pancreatic duct and mid-body pseudocyst could be best addressed with a side-to-side pancreaticojejunostomy (Puestow procedure). A stricture in the pancreatic body or tail and pancreatitis isolated to the distal pancreas can be treated with a distal pancreatectomy. Surgical outcomes have been favorable in the setting of chronic pancreatitis. The Puestow procedure provides initial pain relief in 65% to 80% of patients. On longterm follow-up, one-third of patients experience lasting pain relief. The more extensive Whipple procedure provides pain relief in 80% to 90%. Enthusiasm for this extensive operation is tempered by the acute and chronic morbidity associated with the procedure. There are no studies comparing medical, endoscopic, and surgical therapies for treatment of benign pancreatic duct strictures.
Pancreatic Duct Stones PATHOGENESIS Pancreatic stones develop in the setting of chronic pancreatitis in over one-half of patients. Pancreatic stones develop within the pancreatic ductal system and primarily consist of precipitated calcium carbonate crystals. Pancreatic secretions consist of water, electrolytes, and digestive enzymes. These electrolytes include supersaturated concentrations of calcium and bicarbonate. Normal pancreatic secretions contain a number of factors that inhibit calcium carbonate crystal formation and aggregation.
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The acinar cells produce and secrete a “lithostatin” protein. This protein is stored in acinar zymogen granules and upon release into the pancreatic ducts inhibits the precipitation and crystallization of calcium carbonate. Citrate also plays an antilithogenic role through the chelation of calcium. Chronic pancreatitis leads to changes in pancreatic juice flow and a decrease in antilithogenic factors such as lithostatin and citrate. Changes in these poorly understood antilithogenic factors contribute to calcium carbonate stone formation in the setting of chronic pancreatitis.
CLINICAL PRESENTATION Pancreatic stone formation can aggravate the clinical course of chronic pancreatitis, manifested as increased abdominal pain, worsening pancreatic insufficiency, pseudocyst formation, or recurrent attacks of acute pancreatitis. Stones form in the main pancreatic duct as well as primary and secondary duct side branches. The rationale for intervention is based on the premise that stones that obstruct the PD and impede drainage of pancreatic secretions lead to increased ductal and parenchymal pressure. Increased pressure impairs pancreatic blood flow and leads to ischemia and pain.
DIAGNOSTIC EVALUATION The possible presence of pancreatic stones should be sought in patients with chronic pancreatitis who have worsening or refractory symptoms. The evaluation must identify pancreatic stones and their anatomic location relative to the main PD. Stones within the main PD should be extracted to remove any impediment to the flow of pancreatic juice. In contrast, stones in PD branches generally do not require extraction as long as they do not impair the overall drainage of pancreatic secretions. The various imaging modalities available to diagnose pancreatic duct stones include noninvasive imaging methods such as radiographs, CT scan, and MRCP, and invasive methods such as ERCP and EUS.
Noninvasive Imaging Most PD stones are visible on plain abdominal radiographs as focal calcified densities within the pancreas. Although the plain radiograph identifies the presence of stones, it does not provide information about the relationship of the stone to the pancreatic duct (Figure 10-6). The most sensitive modality for the detection of pancreatic calcification is CT scan. Small stones that are not visible on plain radiographs are clearly visualized on CT scan. Occasionally, the stone can be seen to be located within the main PD, causing upstream dilation of the duct. MRCP has become the noninvasive modality of choice for detection of stones and mapping of their relationship to the PD. MRI/MRCP provides images of the PD analogous to ERCP and cross-sectional images of the parenchyma similar to CT scan. The administration of secretin during MRCP enhances delineation of the PD and its branches.
Invasive Imaging When ductal anatomy and the precise location of pancreatic stones cannot be defined by noninvasive means, the method of choice is ERCP (Figure 10-7). As MRCP imaging improves, ERCP will probably become limited to cases where endoscopic therapy is planned. ERCP allows the detection of strictures and ductal
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Figure 10-6. Pancreatic duct stones (arrows) seen as focal calcified densities within the pancreas on plain abdominal radiographs. The pancreas extends across the L-1 and L-2 vertebral bodies. tortuosity downstream from the stone. Impacted stones characteristically are immobile and impede the injection of contrast or the passage of guidewires beyond their location. On EUS examination, pancreatic stones appear as hyperechoic foci with distal shadowing. EUS also provides helpful information in regards to the location of the stone relative to the main pancreatic duct. Endosonography also helps exclude the presence of a pancreatic mass at the site of any associated ductal strictures.
CHOICE OF THERAPEUTIC MODALITIES Therapeutic options for the treatment of pancreatic stones include extracorporeal shock wave lithotripsy, endoscopic extraction, and surgery. The information obtained from pancreatic imaging dictates the therapy that can be used for optimal effect. Issues that require special attention include the stone size, number, location, and degree of impaction. The presence of PD strictures and ductal tortuosity downstream from the stones also greatly influences the possibility of endoscopic extraction (Table 10-4).
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Figure 10-7. The filling defect in the main pancreatic duct of the pancreatic head (arrow)
represents a ductal stone. The stone is not impacted and contrast freely flows beyond the stone and into the proximal pancreatic.
ENDOSCOPIC THERAPY OF PANCREATIC STONES A pancreatic sphincterotomy is usually performed to both facilitate the insertion of stone retrieval devices and for stone extraction. The need for a simultaneous biliary sphincterotomy is not necessary. Standard biliary stone retrieval devices (baskets and balloons) are the most common accessories used to remove PD stones. An extraction balloon can be advanced past nonimpacted stones. Balloon inflation and withdrawal can successfully remove smaller stones in the pancreatic head. This technique is limited by the tendency of the balloon to force stones into side branches of the PD. Alternatively, stones can be grasped and extracted using baskets. Nonimpacted stones in the pancreatic head or body are often successfully removed with this technique. Stones of larger size that cannot be extracted with a balloon or basket can be initially fragmented with mechanical lithotripsy. The use of mechanical lithotripsy is usually limited to the pancreatic head due to the relative rigidity of the mechanical lithotripter. Downstream strictures usually require dilation prior to attempting stone extraction. Guidewires, balloons, and baskets often cannot be advanced past stones impacted in
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Table 10-4
SELECTION OF THERAPEUTIC APPROACH The selection of the therapeutic approach is dictated by the stone size, number, location, impaction, and the status of downstream pancreatic duct.
ERCP extraction alone • • • •
<10 mm in size Less than 3 in number Located in pancreatic head Not impacted, no downstream strictures
ESWL followed by ERCP extraction • • • •
>10 mm in size Greater than 3 in number Located in pancreatic body or tail Stone impaction, downstream ductal stricture, or tortuosity
Surgery • Failed endotherapy • Presence of inflammatory mass with concern for malignancy
the PD duct lumen. When a PD stone cannot be removed on initial ERCP, extracorporeal shock wave lithotripsy (ESWL) should be performed to fragment the stone and facilitate endoscopic removal. Stone clearance has been reported in 70% to 80% of cases. In individuals whom stone clearance succeeds, immediate pain relief occurs in 80% to 100% of cases. When patients have been followed for up to 5 years, this pain relief has continued in 55% to 85% of cases 6-10. Complications of endoscopic stone extraction occur in 5% to 15% of cases and are often related to the pancreatic sphincterotomy. These complications include pancreatitis, bleeding, cholangitis, and in rare instances, perforation.
EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY Since its introduction in 1987, ESWL has become a safe and accepted modality for the management of PD stones. Shockwaves are generated by electrohydraulic (Dornier, Erlangen, Germany) or electromagnetic (Siemens, Munich, Germany) generators and are focused onto the targeted stone. Accurate targeting of the stone through fluoroscopic guidance is very important for successful lithotripsy. The delivery of shockwaves causes cavitation of the dissolved gases in the fluid around the stone.
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The resultant force fragments the stone into smaller particles. Most radio-opaque calcium-containing stones will easily fragment, while radiolucent stones can be resistant. The procedure is performed under conscious sedation. ERCP is performed within 24 hours of ESWL to remove the resultant stone fragments. These fragments can then be removed with balloon or basket extraction devices or will pass spontaneously. Most patients require 1 to 3 sessions, depending on the number and size of stones present. Lithotripsy is associated with little morbidity. Successful fragmentation can be confirmed on fluoroscopy. Radiographic findings sometimes can be limited to slight mottling and heterogeneity of the stone, which can be difficult to detect. Stone fragmentation rates of over 90% have been reported. Complications include skin petechiae and gastroduodenal erosions. Significant morbidity is rare, and no mortalities have been reported in large series. Combined ESWL and endoscopic therapy leads to complete clearance of the PD in 50% to 75% of cases and partial clearance in an additional 5% to 30%. Studies have demonstrated clinical improvement, defined as complete or partial pain relief, increase in body weight, and improvement of exocrine function in 62% to 86% of cases. Surgery was necessary in only 5% to 15% of patients. Combined ESWL and endoscopic therapy has been most successful in individuals with earlier stages of chronic pancreatitis, and stones in the prepapillary location without any distal PD strictures7,11.
Pancreatic Duct Leaks Extravasation of contrast media from the PD on endoscopic retrograde pancreatogram establishes the diagnosis of PD leak (Figure 10-8). Leakage of pancreatic secretions from defects in the PD into the peripancreatic tissues and organs can lead to pseudocysts, fistula formation, pleural effusion, and ascites. The leak originates from a defect in the PD that can be a consequence of acute necrotizing pancreatitis, chronic pancreatitis, or penetrating abdominal trauma. Obstructive lesions of the distal PD such as strictures or stones can perpetuate and aggravate PD leaks by forcing pancreatic secretions through PD defect and into the peripancreatic area (Table 10-5).
PANCREATIC PSEUDOCYSTS Pancreatic duct defects that arise in the setting of acute or chronic pancreatitis often lead to the collection of pancreatic secretions and inflammatory debris in the peripancreatic area (Figure 10-9). Over a period of 4 to 6 weeks, this collection develops a fibrous capsule. This fibrous capsule does not have an epithelial lining, hence the term “pseudocyst”. Pseudocysts may complicate 7% to 15% of episodes of acute pancreatitis and 20% to 25% of chronic pancreatitis cases. Although pseudocysts can be asymptomatic, they may cause abdominal pain, nausea, or vomiting. Pseudocysts can also be complicated by infection or hemorrhage. Most asymptomatic pseudocysts resolve spontaneously and do not require therapeutic intervention. However, pseudocysts that are symptomatic, demonstrate progressive enlargement, or are infected require intervention. Increasingly, the method of choice for pseudocyst drainage is endoscopic. Often radiological or surgical drainage is performed when endoscopic drainage has failed or is not technically possible. The decision to drain a pseudocyst should be made independent of the intervention chosen.
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Figure 10-8. Extravasation of contrast media from the pancreatic duct in the mid-pancreas. Contrast can be seen leaking from an otherwise normal pancreatic duct in a patient with penetrating abdominal trauma. The contrast extravasating from the pancreatic body leaks into the peripancreatic space.
DIAGNOSTIC EVALUATION Several diagnostic issues may need to be considered before proceeding with pseudocyst drainage:
1. Has the presence of a cystic neoplasm been adequately excluded? This possibility is of greatest concern in individuals who do not have a clear history of acute or chronic pancreatitis. Diagnostic sampling of cyst fluid through EUS-FNA can help exclude a neoplastic process through cytological examination and measurement of tumor markers. Pseudocyst fluid cytology shows abundant debris and inflammatory cells. Columnar cells with intracellular mucin or significant amounts of background mucin are often seen in mucinous cystic neoplasia. Fluid CEA and amylase levels can complement the diagnostic utility of cytology. In pseudocysts amylase levels are consistently high. A high cyst fluid CEA level strongly suggests a mucinous neoplasm.
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Table 10-5
CAUSES AND CONSEQUENCES OF PANCREATIC DUCT LEAKS Causes • Acute pancreatitis • Chronic pancreatitis • Abdominal trauma
Consequences • Pseudocyst • Pancreatic fistulas • Ascites
2. Is an underlying pancreatic duct obstructive lesion contributing to the pseudocyst? Obstructive lesions such as stricture or stones are most often seen in individuals with chronic pancreatitis, and if left untreated can lead to recurrence after pseudocyst drainage. ERCP identifies these lesions and allows endoscopic therapy. Dilation and stenting of strictures can be performed and stones extracted.
ENDOSCOPIC PSEUDOCYST DRAINAGE Transmural and transpapillary approaches can be employed in the endoscopic treatment of pseudocysts. In transmural drainage, a stent is placed across a communication tract created between the pseudocyst cavity and the bowel lumen (cystogastrostomy or cystoduodenostomy). This allows drainage of the fluid collection into the gastroduodenal lumen. In transpapillary drainage, a stent is placed across the papilla into the pancreatic duct. This allows drainage of the cyst fluid through the PD and papilla. The choice of therapy depends on whether the cyst communicates with the PD or is in close apposition to the gut lumen.
Transmural Drainage Transmural drainage can be performed with a standard side viewing endoscope or a therapeutic linear array echoendoscope. Standard endoscope requires the presence of a gastroduodenal wall bulge for selection of a drainage site. The therapeutic linear array echoendoscope allows the localization and drainage of nonbulging pseudocysts through ultrasound imaging. Ultrasound imaging has the additional benefit of identifying intervening blood vessels and the distance between the gastroduodenal lumen and the pseudocyst lumen. The gastroduodenal site selected for drainage should be free of significant blood vessels to decrease the risk for bleeding. The distance between the pseudocyst cavity and the gastroduodenal lumen should be less than 1 cm. This finding further ensures adequate adherence of the enteric wall to the pseudocyst wall and lowers the possibility of perforation and intraperitoneal contamination.
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Figure 10-9. Contrast leakage can be seen extravasating from the tail of the pancreatic duct and into an adjacent pseudocyst cavity (arrow).
A 19-gauge needle is advanced into the pseudocyst cavity through the selected site in the stomach or duodenum. Many authorities advocate diathermic needle cautery to create a fistula between the gut lumen and the cyst. A 0.35-inch guidewire is advanced into the pseudocyst cavity, allowing passage of other accessories over the guidewire, across the communicating tract, and into the pseudocyst. The communicating tract is enlarged using a dilation balloon (4 to 10 mm size) that is advanced over the guidewire. One or more double pigtail stents are then placed in the tract. These stents extending from the pseudocyst cavity into the gastroduodenal lumen maintain the patency of the communicating tract and provide internal drainage of the pseudocyst fluid. Pseudocyst contents containing thick fluid and significant debris benefit from the additional placement of a 7 French nasocystic catheter. The nasocystic drain allows irrigation of the pseudocyst cavity over a period of several days with the intention of clearing the cavity of all significant debris. The technical success rate of transmural drainage ranges from 90% to 100%. Transmural drainage leads to pseudocyst resolution in 80% to 100% of cases. However, pseudocyst recurrence can occur in 10% to 15% of cases12-19.
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Bleeding, perforation, and infection can occur after pseudocyst drainage. EUS imaging is thought to reduce the risk of bleeding and perforation through more careful selection of the gastroduodenal drainage site. Due to the significant risk of complications, patients are admitted for overnight inpatient observation. Due to the infection risk, intravenous prophylactic antibiotics should be administered during the procedure and continued orally for 2 to 4 weeks. Abdominal CT scans should be performed every 8 weeks to assess for resolution of the pseudocyst cavity. Radiographic resolution of the pseudocyst allows endoscopic removal of the stents. This usually occurs after 8 to 12 weeks. If the pseudocyst cavity persists, the transmural stents should be exchanged every 8 weeks to avoid occlusion of the drainage tract.
Transpapillary Drainage When the small size or anatomic location of a pseudocyst precludes transmural drainage, transpapillary drainage provides an alternative approach. This approach requires the presence of communication between the pseudocyst cavity and the PD. Any stones or strictures encountered should be treated with extraction and dilation. Failure to treat these associated pancreatic ductal diseases may result in recurrence of the pseudocyst. Depending on the size of the pancreatic duct, a 7 to 10 French stent is placed extending from the duodenum into the PD proximal to the site of ductal leakage. If the upstream PD cannot be opacified, the stent can be advanced though the PD defect into the pseudocyst cavity. Abdominal CT scans should be performed every 8 weeks to follow resolution of the pseudocyst cavity. The PD stent is exchanged every 8 weeks until complete radiographic resolution of the pseudocyst cavity. The transpapillary approach carries a lower risk of bleeding but an increased infection rate when compared to transmural drainage. Transpapillary endoscopic drainage carries a technical success rate of 94% and a complication rate of 12%. Pseudocyst recurrence occurs in 15% of patients after endoscopic drainage. The morbidity and mortality rate of endoscopic drainage are 5% to 20% and 1% to 2%, respectively12-19. Complications of endoscopic drainage include pancreatitis and infection.
PERCUTANEOUS DRAINAGE Percutaneous drainage involves the advancement of catheters into the pseudocyst cavity under CT guidance. Percutaneous drainage is the treatment of choice for the infected pseudocyst. Endoscopic drainage can further aggravate infection and is best avoided in this setting. Infection and cutaneous fistulas are the most common complications. To avoid the development of cutaneous fistulas, external drainage should not be performed in individuals with PD strictures or defects. Percutaneous drainage carries a failure rate of 16%, recurrence rate of 7%, and a complication rate of 18%.
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SURGERY DRAINAGE Multiloculated pseudocysts, pseudocysts containing significant necrotic debris, and pseudocysts associated with complete disruption of the PD are best managed with surgery. Surgery most commonly involves either internal drainage or excision of the pseudocyst cavity. Techniques for internal drainage include cystgastrostomy, cystduodenostomy, and Roux-Y cystojejunostomy. After surgery the pseudocyst recurrence rate is 10% to 20%. The morbidity and mortality rates are 20% and 1% to 2%, respectively.
PANCREATIC ASCITES AND PLEURAL EFFUSION After a ductal disruption, pancreatic fluid can occasionally leak into the peritoneal cavity. Pancreatic fluid may also enter the peritoneal cavity via disruption of a pseudocyst. The presence of pancreatic secretions elicits an oxidative response, resulting in the collection of ascitic fluid that contains very high amylase content (usually over 100,000 U/L) and protein concentration over 3 g/dL. In addition, this process may spread in the cephalad direction into the pleural cavities as well, leading to a pleural effusion with similar characteristics. Pancreatic ascites most commonly develop in the setting of chronic pancreatitis or abdominal trauma, but can occasionally be idiopathic in nature. The clinical presentation consists of increasing abdominal girth, abdominal pain, and weight loss. A variety of therapeutic options have been reported with varying success. Conservative therapy consists of NPO status, parenteral nutrition, and octreotide, with the intention of decreasing pancreatic secretions and in turn facilitating fistula closure. When conservative therapy fails, endoscopic and surgical intervention are most often successful. Endoscopic therapy consists of pancreatic sphincterotomy with placement of a PD stent. The intention is to create a path of least resistance for pancreatic drainage into the duodenum. This preferential duodenal drainage leads to closure of the pancreatic fistula. Surgical treatment consists of a Roux-en-Y jejunal anastomosis to the fistula site or an associated pseudocyst cavity. Surgical therapy succeeds in over 80% of patients when the site of PD leak has been accurately localized on ERCP20.
Conclusion The gastroenterologist, surgeon, and radiologist all contribute significantly to the management of pancreatic ductal complications. Improvements in technology and instrumentation have led increasingly toward an endoscopic approach to treatment of these cases. The expanding role of ERCP and EUS in the evaluation and treatment of pancreatic duct strictures, stones, and pseudocysts awaits confirmation from large randomized prospective studies.
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References 1. Steinberg W. The clinical utility of the CA 19-9 tumor-associated antigen. Am J Gastroenterol. 1990;85:350-355. 2. Smits ME, Badiga SM, Rauws EA, et al. Long term results of pancreatic stents in chronic pancreatitis. Gastrointest Endosc .1995;42:461-467. 3. Binmoeller KF, Jue P, Seifert H. Endoscopic pancreatic stent drainage in chronic pancreatitis and a dominant stricture: Long term results. Endoscopy. 1995;27:638644. 4. Cremer M, Deviere J, Delhaye M, et al. Stenting in severe chronic pancreatitis: results of medium term follow-up in 76 patients. Endoscopy. 1991;23:171-176. 5. Ponchon T, Bory R, Hedelius F, et al. Endoscopic stenting for pain relief in chronic pancreatitis: results of a standardized protocol. Gastrointest Endosc. 1995;42:452456. 6. Bittencourt PL, Delhaye M, Deviere J, et al. Immediate and long-term results of pancreatic ductal drainage in severe painful chronic pancreatitis [abstract]. Gut. 1996;39: A99. 7. Delhaye M, Vandermeeren A, Baize M, et al. Extracorporal shock wave lithotripsy of pancreatic duct calculi. Gastroenterology. 1992;102:610-620. 8. Dumonceau JE, Deviere J, LeMoine O, et al. Endoscopic pancreatic drainage in chronic pancreatitis associated with ductal stones: long-term results. Gastrointest Endosc. 1996;43:547-555. 9. Sherman S, Lehman GA, Hawes RH, et al. Pancreatic ductal stones: frequency of successful endoscopic removal and improvement in symptoms. Gastrointest Endosc. 1991; 37:511-517. 10. Smits ME, Rauws EA, Tytgat GNJ, et al. Endoscopic treatment of pancreatic stones in patients with chronic pancreatitis. Gastrointest Endosc. 1996;43:556-560. 11. Adamek HE, Jakobs R, Buttman A, et al. Long term follow-up of patients with chronic pancreatitis and pancreatic stones treated with extracorporeal shock wave lithotripsy. Gut. 1999;45:402-405. 12. Barthet M, Sahel J, Bodiou-Bertel C, et al. Endoscopic transpapillary drainage of pancreatic pseudocysts. Gastrointest Endosc. 1995;42:208-213. 13. Binmoeller KF, Seifert H, Walter A. Transpapillary and transmural drainage of pancreatic pseudocysts. Gastrointest Endosc. 1995;43:219-224. 14. Cremer M, Deviere J, Engelholm L. Endoscopic management of cysts and pseudocysts in chronic pancreatitis: long-term follow-up after 7 years of experience. Gastrointest Endosc. 1989;35:1-9. 15. Grimm H, Meyer WH, Nam VC, et al. New modalities for treating chronic pancreatitis. Endoscopy. 1989;21:70-74. 16. Howell DA, Lehman GA, Baron TH, et al. Endoscopic treatment of pancreatic pseudocysts: a retrospective multicenter analysis [abstract]. Gastrointest Endosc. 1995;41:424A. 17. Howell DA, Elton E, Parsons WG. Endoscopic management of pseudocysts of the pancreas. Gastrointest Endosc Clin N Am. 1998;46:143-162. 18. Kozarek RA, Ball TJ, Patterson DJ, et al. Endoscopic transpapillary therapy for disrupted pancreatic duct and parapancreatic fluid collection. Gastroenterology. 1991; 100:1362-1370. 19. Smits ME, Rauws EAJ, Tytgat GNJ, et al. The efficacy of endoscopic treatment of pancreatic pseudocysts. Gastrointest Endosc. 1995;42:202-207.
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20. Gomez-Cerezo J, Barbado Cano A, et al. Pancreatic ascites: study of therapeutic options by analysis of case reports and case series between the years 1975 and 2000. Am J Gastroenterol. 2003;98:568-577.
Suggested Reading Forsmark CE, Toskes PP. What does an abnormal pancreatogram mean? Gastrointest Endosc Clinics N Am. 1995;5:105-123. Hunt GC, Faigel DO. Assessment of EUS for the diagnosis, staging and determining the resectability of pancreatic cancer: A review. Gastrointest Endosc. 2002;55:232. Harewood GC, Wiersema MJ. Endosonography guided fine needle aspiration biopsy in the evaluation of pancreatic masses. Am J Gastroenterol. 2002;97:1386. Jowell PS. Assessment of pancreatic duct strictures. Gastrointest Endosc Clinics N Am. 1995;5:125-143. Haber GB. Endoscopic management of pancreatic stones. Techniques in Gastrointestinal Endoscopy. 1999;1:180-185. Delhaye M, Matos C, Deviere J. Endoscopic management of chronic pancreatitis. Gastrointest Endosc Clinics N Am. 2003;13:717-742. Baron TH, Harewood GC, Morgan DE, et al. Outcome differences after the endoscopic drainage of pancreatic necrosis, acute pancreatic pseudocysts and chronic pancreatic pseudocysts. Gastrointest Endosc. 2002;56:7-17. Gomez-Cerezo J, Barbado Cano A, Suarez I, Soto A, Rios JJ, Vazquez JJ. Pancreatic ascites: study of therapeutic options by analysis of case reports and case series between the years 1975 and 2000. Am J Gastroenterol. 2003;98:568-577.
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Solid Pancreatic Tumor Shyam Varadarajulu, MD; Mohamad A. Eloubeidi, MD, MHS, FACP, FACG
Introduction Ductal adenocarcinoma of the pancreas accounts for 90% of pancreatic cancers. In the United States, pancreatic cancer kills more than 26,000 persons per year, is the fourth and the fifth most common cancer in men and women, respectively1, and has the lowest 5-year survival rate of any cancer. The national 5-year survival rate has increased from 1% to 3% in whites and from 3% to 5% in blacks in the past decade1. The dismal survival of patients with pancreatic cancer is a result of the late diagnosis and low resection rates; only 10% to 20% of patients are eligible for curative resection. According to the 1995 National Cancer Data Base Report on Pancreatic Cancer 2 , 52% of 17,490 patients with pancreatic cancer had stage IV disease at diagnosis, and the overall curative resection rate (pancreatectomy) was only 14%. The specific objectives of this chapter are to discuss the presentation, diagnosis, staging, and the role of endoscopy in the management of suspected pancreatic adenocarcinoma and the evaluation of solid pancreatic tumors. Surgical management of pancreatic cancer will be discussed elsewhere in this textbook.
Clinical Presentation The suspicion of pancreatic cancer arises because of symptoms of pain, jaundice, anorexia, early satiety, or weight loss. Some symptoms may predict tumor location3 and prognosis4. Painless jaundice is the most common presentation in patients with a potentially resectable and curable lesion (52% of patients with a resectable lesion). However, pain is the most frequent symptom, seen in 80% of all patients, and present in 80% and 85% of patients with locally unresectable and advanced cancer, respectively4. The combination of pain and jaundice is present in 50% of patients with a locally unresectable lesion3. In another study of patients who underwent curative resection, preoperative steatorrhea was associated with prolonged survival, and back pain was associated with shortened survival4. It has recently been shown that onset of
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diabetes mellitus may herald the appearance of pancreatic cancer, particularly if diabetes occurs during or beyond the sixth decade of life5. Diabetes mellitus is seen in 60% to 80% of patients with pancreatic cancer, and the majority of patients received the diagnosis within 2 years of recognition of pancreatic cancer6,7. In a recent study, 72% of patients with pancreatic cancer had diabetes (all noninsulin dependent); 56% had diabetes diagnosed concomitantly with the tumor; and 16% received the diagnosis of diabetes 2 years before the diagnosis of the cancer6. Sixty-six percent of patients with pancreatic cancer and diabetes have no family history of diabetes5.
Diagnosis and Staging TUMOR MARKERS The serum concentrations of several tumor markers have been studied in pancreatic cancer. However, none has been shown to be particularly sensitive or specific in the diagnosis of pancreatic cancer8. In a review of tumor markers, cancer-associated antigen 19-9 (CA 19-9), with a cutoff value of 70 U/mL, was found to have the greatest sensitivity (70%) and specificity (87%) for diagnosis of pancreatic cancer 9,10. In other studies, with a lower cutoff of 37 U/mL, sensitivity was somewhat higher (86%) and specificity was identical (87%)11. CA 19-9 levels may also be elevated in patients with biliary tract obstruction caused by a lesion other than cancer12 . CA 19-9 can be a useful marker to monitor response to therapy. As 60% to 80% 6,7 of patients with pancreatic cancer develop glucose intolerance within 2 years before the diagnosis of pancreatic cancer, elevated plasma concentrations of islet amyloid polypeptide (IAPP), which appears to be secreted by pancreatic beta cells, have the potential for detecting early pancreatic cancer13. Compared to normal subjects, patients with other cancers, and patients with either insulin-dependent or noninsulin-dependent diabetes mellitus, concentrations of IAPP have been shown to be elevated in patients with pancreatic cancer13. The sensitivity of this test, however, is poor and it is not widely available14.
GENETIC MARKERS Genetic markers may detect pancreatic cancer, but it is unknown whether they are of value for detection of early stage pancreatic cancer. The most common gene abnormality is a codon 12 K-ras mutation, seen in around 90% of patients with pancreatic cancer15-17. K-ras mutations have been detected in plasma, in pancreatic juice, duodenal fluid, and stool, as well as in pancreatic cancer cells obtained by percutaneous needle aspiration for cytological examination. However, K-ras mutations have also been detected in patients with chronic pancreatitis18. Mutations of the p53 tumor cell suppressor gene and reduced expression of the DCC gene are also found in 50% to 70% of pancreatic cancers19,20. Further studies are required before a definitive role for genetic markers can be established in the evaluation of patients with pancreatic cancer.
COMPUTED TOMOGRAPHY Spiral computed tomography (CT) is the primary imaging study for evaluating patients presenting with symptoms suggestive of pancreatic cancer. CT is an appropri-
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ate initial imaging test because it detects tumors in the pancreas and can be used to stage for resectability and to detect liver metastases. The sensitivity of conventional CT for the diagnosis of tumors of <3 cm is 53% 21, but the sensitivity of dual-phase spiral CT for resectable tumors is as high as 85% to 95% 22-24. However, the sensitivity of dual-phase spiral CT is related to the size of the tumor; the sensitivity for tumors of 0 to 15 mm is 67%, compared with 100% for tumors of >15 mm 23. Percutaneous fine needle aspiration (FNA) biopsy of a pancreatic mass can be performed using CT guidance. Although sensitivity and specificity in the range of 80% to 90% and 98% to 100%, respectively, have been reported 24, the diagnostic accuracy to a large extent depends on tumor size and the expertise of the operator. Also, a theoretical concern is that percutaneous FNA biopsy of the pancreas may disseminate tumor cells within the peritoneal cavity or along the needle path in patients who are believed to be candidates for potentially curative resection. Recent advances in CT technology, including the development of spiral scanners and more recently multidetector CT (MDCT) scanners, and the development of three-dimensional (3D) imaging software have improved the ability of CT to image the pancreas and to evaluate a wide range of pancreatic pathology. In most of the published series, older dynamic scanners or single-row spiral scanners were used, and 3D imaging was not included. With the narrow collimation and faster scanning possibilities with new MDCT scanners, it is likely that the CT accuracy for detecting pancreatic tumor will improve. In a recently published study using MDCT, 27 of 28 pancreatic cancers were detected 25. This progress will continue as manufacturers introduce the next generation of scanners, which can acquire up to 32 slices per second with even faster scan times. The impact of these new scanners on diagnostic accuracy will need to be carefully evaluated.
MAGNETIC RESONANCE IMAGING Magnetic resonance imaging (MRI) is gaining popularity as an imaging tool for diagnosis. Although MRI is no more accurate than CT for the diagnosis of pancreatic cancer, it may demonstrate a definite mass in patients who have indeterminate head enlargement on CT. In a study of 16 patients with indeterminate head enlargement on spiral CT, a definitive tumor was seen with MRI in 1026. Tumors are viewed as low-signal masses against the high-signal background of normal pancreatic parenchyma. Pancreatic masses, ductal dilation, and liver metastasis can be demonstrated in exquisite detail. Additionally, MR angiography and MR venography techniques using gadolinium contrast can demonstrate vascular involvement with tumor and obviate the need for conventional angiography. As opposed to CT, MRI does not involve radiation and employs an iodine-free contrast agent with rare renal toxicity. Limitations of MRI are related to cost, availability, and clinicians’ familiarity and predilection for CT imaging. Magnetic resonance cholangiopancreatography (MRCP) can also be obtained at the time of MRI. In a recent prospective, controlled study, MRCP was found to be as sensitive as endoscopic retrograde cholangiopancreatography (ERCP) in detecting pancreatic carcinomas27. MRCP uses heavy T2-weighted images that emphasize fluid-containing structures such as ducts, cysts, and peripancreatic fluid collections. Images obtained are highly comparable to those after ERCP and readily demonstrate pancreatic ductal obstruction, ectasia, and calculi.
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Figure 11-1. Biliary stricture secondary to a pancreatic head mass as seen on cholangiogram.
ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY ERCP is most useful for patients in whom CT or ultrasound does not reveal a mass lesion within the pancreas, and in those in whom the differential diagnosis includes chronic pancreatitis. ERCP has a sensitivity and specificity of 90% to 95% for diagnosing pancreatic cancer 28. Findings suggestive of a malignant tumor include superimposable strictures or obstruction of the common bile and pancreatic ducts (the “double duct” sign), a pancreatic duct stricture in excess of 1 cm in length, pancreatic duct obstruction, and the absence of changes suggestive of chronic pancreatitis (Figure 11-1). In the experience of the authors, ERCP brushings yield a definitive diagnosis in only 30% to 40% of patients and further work-up is required if tissue acquisition is desired prior to surgical intervention or if chemotherapy or radiation therapy is contemplated.
ENDOSCOPIC ULTRASOUND Endoscopic ultrasound (EUS) staging of pancreatic and other tumors follows the TNM system (Table 11-1) of the American Joint Committee on Cancer (AJCC). In 2002, the AJCC modified the T staging system for pancreatic cancer to classify tumors invading the portal venous (superior mesenteric vein or portal vein) system as T3 (these were previously staged as T4) (Figure 11-2) and tumors invading the celiac or superior mesenteric artery as T4. Although this change is likely to result in decreased reported accuracy for EUS, it remains unclear if surgical therapy is beneficial compared to radiochemotherapy for tumors invading the portal venous system. Most literature is based on the previous AJCC staging system in which all mesenteric vascular invasions (venous or arterial) were staged T4.
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Table 11-1
TNM STAGING OF PANCREATIC CANCER BY THE AMERICAN JOINT COMMITTEE ON CANCER (AJCC) Primary Tumor (T) TX: Primary tumor cannot be assessed T0: No evidence of primary tumor Tis: Carcinoma in situ T1: Tumor limited to the pancreas, 2 cm or less in greatest dimension T2: Tumor limited to the pancreas, more than 2 cm in greatest dimension T3: Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery T4: Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor)
Regional Lymph Nodes (N) NX: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Regional lymph node metastasis
Distant Metastasis (M) MX: Distant metastasis cannot be assessed MO: No distant metastasis M1: Distant Metastasis
AJCC Stage Groupings Stage Stage Stage Stage Stage Stage Stage
0: Tis, N0, M0 IA: T1, N0, M0 IB: T2, N0, M0 IIA: T3, N0, M0 IIB: T1, N1, M0, T2, N1, M0, T3, N1, M0 III: T4, any N, M0 IV: Any T, any N, M1
Many large series have found EUS T stage accuracy to range from approximately 78% to 94% and nodal (N) stage accuracy between 64% and 82% 29-32 . However, lower accuracy has also been described. In a study of 89 patients in whom EUS was compared to surgical and histopathologic TNM staging 33, the overall accuracy of EUS for T and N staging were 69% and 54%, respectively. Furthermore, only 46% of
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Figure 11-2. Mass in the pancreatic head invading the superior mesenteric vein as seen using a radial echoendoscope (Olympus GF-UM 130).
tumors believed to be resectable by EUS were actually found to be resectable during laparotomy. Staging accuracy of EUS can be influenced by several factors, including the experience level of the endosonographer, imaging artifacts, and the endosonographer’s knowledge of the results of previous imaging tests. In general, T stage accuracy for EUS is highest in patients with smaller tumors, whereas helical CT is more accurate in staging larger tumors34-36. The accuracy of EUS for detecting invasion into the superior mesenteric artery and vein is lower than that for detecting portal or splenic vein invasion37,38. A recent review39 that pooled data from four studies comparing the accuracy of EUS with helical CT in the evaluation of pancreatic cancer found that EUS detected more tumors (97% versus 73%), was more accurate for determining tumor resectability (91% versus 83%), and was more sensitive for detecting vascular invasion (91% versus 64%). However, when the data were interpreted individually, two of the reports concluded that CT and EUS were approximately equivalent in detecting the primary tumors34,40, while the other two found EUS to be superior41,42 . Several features of the individual reports may account for these variable conclusions, including differences in the gold standards, variations in the specific techniques used for helical CT, and the proportion of patients with advanced disease in each study. A reasonable conclusion from these data and from clinical experience is that EUS and helical CT are complementary for staging pancreatic cancer. EUS is a more accurate modality for local T staging and for predicting vascular invasion, especially in tumors less than 3 cm, while helical CT is better for the evaluation of distant metastasis and for staging larger tumors. Similar to CT, studies comparing MRI with EUS suggest that EUS may be more sensitive for detecting small tumors, while providing complementary information regarding resectability43. Several studies have compared the accuracy of angiography and EUS for determining vascular invasion37,38,44. Although the results varied, a general conclusion is that EUS is as accurate or more accurate for determining vascular invasion, with
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Figure 11-3. Fine-needle aspiration of a pancreatic head mass using the curvilinear array echoendoscope (Olympus UC 30 P).
the exception of some tumors that invade the superior mesenteric artery. In a study of 21 patients with pancreatic cancer who underwent EUS and angiography prior to an attempt at curative resection, EUS was much more sensitive than angiography for detecting vascular invasion (86% versus 21%). The specificity and accuracy of EUS were 71% and 81%, respectively, compared with 71% and 38% for angiography43.
ENDOSCOPIC ULTRASOUND-GUIDED FINE-NEEDLE ASPIRATION EUS has an important role in guiding a biopsy needle into lesions that are too small to be identified by CT or MRI or too well encased by surrounding vascular structures to safely allow percutaneous biopsy (Figures 11-2 and 11-3)44. The impact of EUS-FNA was studied by Chang et al in a series of 44 patients 45. EUS-FNA had an accuracy rate of 95% for pancreatic lesions and 88% for lymph nodes. Three patients had enlarged celiac nodes on EUS that showed malignancy on FNA. Overall, FNA precluded surgery in 41% of patients, avoided the need for further diagnostic tests in 57%, and influenced clinical decisions in 68% of patients, thus providing substantial cost savings. Gress et al examined the role of EUS-FNA in patients with suspected pancreatic cancer after a negative CT-guided FNA or ERCP brush cytology44. In 102 patients, 57 had positive cytology on EUS-FNA and 37 had negative cytology. The examination was inconclusive in 8 patients. After a median follow-up of 24 months, all 57 patients with positive cytology on EUS-FNA had verification of the diagnosis of pancreatic cancer. Of the 45 patients with negative or inconclusive cytology on EUSFNA, 41 had no evidence of pancreatic malignancy at follow-up. One particularly important application of EUS-FNA is the detection of malignant lymph nodes. FNA has been demonstrated to increase the accuracy of lymph node staging and thereby reduce the number of unnecessary surgical explorations by identifying patients with surgically incurable disease45. Lesions located in the uncinate process of the pancreas are the most difficult to puncture. To access a mass in the uncinate process, the echoendoscope must be
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Table 11-2
INDICATIONS FOR EUS-FNA •
•
• •
To document a diagnosis of malignancy in a patient with an unresectable mass as a prerequisite for adjuvant chemotherapy or radiation therapy. To exclude other tumor types such as lymphoma, small-cell metastasis, or neuroendocrine cancer that may require a different management strategy. To determine a diagnosis in patients who are reluctant to undergo major surgery without a definitive diagnosis. To document the absence of malignancy when the pretest probability of malignancy is low.
advanced into the duodenal C-loop in the “long” position. This exerts substantial angulation and torque on the FNA needle. The needle is more difficult to advance and also causes a “bowed shape.” This altered shape can result in mistargeting. Also, lesions in the pancreatic isthmus pose a similar challenge in that the echoendoscope is usually in the “long” scope position with the tip in the gastric antrum. A transgastric approach can be more difficult than the transduodenal approach due to the laxity and redundancy of the gastric wall, as well as the capaciousness of the stomach. Lacking anchorage, the echoendoscope tends to displace during advancement of the FNA needle. A controversial issue is identifying who should undergo EUS-FNA (Table 11-2). There is general consensus that it is reasonable to obtain a tissue diagnosis in patients suspected of having pancreatic cancer who are poor surgical candidates. Histologic confirmation in such patients can be helpful in deciding on chemotherapy or radiotherapy. More controversial is the role of EUS-guided FNA in patients suspected of having pancreatic cancer who appear to be resectable on other imaging studies. One view is that a tissue diagnosis will not alter management and is therefore unnecessary. This argument is supported by the recognition that the sensitivity of EUS-guided FNA is in the range of 85% to 90%, potentially leading to false negative results in up to 15% of patients. However, an argument can be made for EUS-guided FNA in such patients when the establishment of a histologic diagnosis before surgery may alter management, as other types of malignancy involving the pancreas can mimic adenocarcinoma (eg, lymphoma). Therapy for these tumors may not include surgery. Some patients and physicians want to know definitively whether cancer is present before undergoing a surgical resection. When the FNA is negative, some patients may be willing to accept the 15% chance of missing a diagnosis of cancer rather than undergoing surgery. This is especially true when there is concurrent acute or chronic pancreatitis that may mimic a focal pancreatic cancer.
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The safety of EUS-FNA for evaluating pancreatic lesions is well established46,47. Rare complications include pancreatitis, infection, and bleeding. In a multicenter study evaluating the safety of EUS-FNA of solid pancreatic masses, 14 of 4,909 (0.29%) patients developed pancreatitis46. In another study involving EUS-FNA of pancreatic cystic lesions, 1 of 81 patients developed an infected cystadenoma after EUS-FNA47. This patient did not receive prophylactic antibiotics prior to the procedure. Current standard of care includes routine administration of antibiotics for patients undergoing FNA of pancreatic cystic lesions. Patients with solid pancreatic masses do not require antibiotics prior to EUS-FNA.
Management Appropriate treatment of patients with pancreatic cancer depends on accurate preoperative staging. With the current data, we recommend using dual-phase spiral CT as the initial test to diagnose and stage pancreatic tumors. EUS is particularly useful in patients suspected of having a small resectable tumor that was not seen on CT and in patients in whom tissue acquisition by FNA is desired for definitive diagnosis (preoperatively or for palliative chemoradiation). Laparoscopy is used in some centers for staging because small hepatic and/or peritoneal metastases can be seen that are not visualized by less invasive tests. Although laparoscopy should not be done in all patients, it is indicated if there is a high likelihood of unresectability that has not been confirmed by imaging tests48. The major drawbacks of laparoscopy are the additional time required for the procedure and the inability to determine the presence of vascular invasion. The latter requires more extensive dissection and is aided by the tactile senses available only during laparotomy. The advantage of finding unresectable disease by laparoscopy is that laparotomy and its attendant morbidity and expense are not needed. If patients require laparotomy for palliative biliary and/or gastric bypass, laparoscopy is contraindicated. The authors recommend that helical CT be performed initially to evaluate for the presence of a pancreatic mass (Figure 11-4). If metastatic disease is clearly evident, an EUS-guided biopsy can confirm the diagnosis. When the helical CT is negative for metastatic disease or an obvious mass, EUS should be performed to further evaluate the pancreas (if the clinical suspicion is high for pancreatic cancer) followed by EUS-guided FNA of any apparent mass noted. Those who are found to have T1-3, N0/1 disease generally undergo exploration (with or without chemoradiation), while those who are found to have unresectable disease (T4 or M1) should be managed palliatively. Endoscopic management is indicated mainly for controlling symptoms of unresectable pancreatic cancer such as relief of obstructive jaundice, gastric outlet obstruction, and pain. Surgical and medical management of pancreatic cancer are discussed elsewhere in this book.
JAUNDICE Palliation of jaundice in patients who are not undergoing an attempt at surgical resection is usually accomplished by placement of an expandable metal stent. Surgery is generally reserved for those in whom stent placement is not possible due to technical reasons and those in whom a surgical gastric bypass for outlet obstruction is contemplated as a combined procedure.
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CT
Unresectable mass
No mass/ Resectable mass
EUS
Tissue by EUS-FNA
FNA for diagnosis
Resectable
Unresectable
Palliation
Surgery Figure 11-4. Algorithm for management of pancreatic cancer.
EXPANDABLE METAL STENTS Endoscopically placed expandable metal stents can provide minimally invasive effective palliation of jaundice. Randomized trials have shown no difference in survival between endoscopic stent placement and surgical bypass for malignant obstructive jaundice; patients who undergo stent placement have more frequent readmissions for stent occlusion, recurrent jaundice, and cholangitis, but lower morbidity and procedure-related mortality49-52 . Although metal stents can also be placed percutaneously, at least one controlled trial that included 75 patients with malignant bile duct obstruction demonstrated that patients treated with an endoscopic stent had a higher success rate for relief of jaundice (81% versus 61%) and a significantly lower 30-day mortality rate (15% versus 33%)51. Metal stents are preferred compared to plastic stents because they are much less likely to become clogged by debris or tumor in growth53. Choice of stent is operator-dependent and typically is based on predicted likelihood of survival of the evaluated patient.
SURGERY The surgical options for achieving biliary decompression include an anastomosis between the gallbladder and jejunum (cholecystojejunostomy) or common bile duct
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and jejunum (choledochojejunostomy). Drainage is successful in returning the serum bilirubin concentration in approximately 90% of patients54. One advantage of surgical bypass is the ability to perform prophylactic or therapeutic gastrojejunostomy to avoid gastroduodenal obstruction. However, in one report, the postoperative mortality and perioperative morbidity rates were 3.1% and 22%, respectively, and the median survival was 6.5 months55.
DUODENAL OBSTRUCTION Approximately 20% of patients with pancreatic cancer will develop duodenal obstruction leading to gastric outlet obstruction56. Management can be either endoscopic by means of enteral stenting or surgical by means of palliative bypass.
Enteral Stenting Recent data suggest that enteral stenting has a similar success rate as surgical palliation (with approximately 90% of patients improving clinically) but is associated with less morbidity, procedure-related mortality, and cost57,58. Despite initial success, 15% to 40% of patients require reintervention for recurrent symptoms or biliary obstruction. In contrast, in at least one report, no patient undergoing surgical decompression (ie, gastrojejunostomy) required reintervention for obstructive symptoms59. Furthermore, some patients may not improve even after successful stent placement, because of unidentified sites of malignant obstruction, diffuse peritoneal carcinomatosis with bowel encasement, or functional gastric outlet obstruction from neural (celiac axis) tumor involvement60. Several complications can occur during or after placement of the stents. Intraprocedural complications include complications of conscious sedation, pulmonary aspiration, stent malposition, perforation, and bleeding. Late complications include distal stent migration, bleeding, and perforation, as well as fistula formation.
Surgical Palliation To avoid gastric outlet obstruction, some surgeons create a prophylactic palliative gastrojejunostomy with a biliary bypass in those who are deemed to be unresectable at exploration. The benefit of a prophylactic gastrojejunostomy was shown in a prospective randomized trial in which 87 patients with an unresectable periampullary malignancy who were believed not to be at risk for duodenal outlet obstruction were randomly assigned to receive or not receive a prophylactic gastrojejunostomy59. Although the group undergoing prophylactic surgery had a similar mean survival (8.3 months), rate of postoperative complications, and length of hospital stay, therapeutic intervention for late gastric outlet obstruction occurred significantly less often (0 versus 19%). However, the real benefit of this procedure in patients with unresectable pancreatic cancer has been questioned: delayed gastric emptying is a frequent result of prophylactic gastrojejunostomy, occurring in almost 50% of patients 61, and a substantial number of those who have the procedure for symptom control die either during or within 30 days of the procedure 62 . The authors prefer surgical palliation as an initial approach in those patients who experience symptomatic outlet obstruction but are deemed fit to undergo a major surgery. In those with comorbid illnesses, terminal disease, and poor surgical candidates, enteral stenting is the preferred method of palliation.
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Figure 11-5. Celiac plexus block being performed using the curvilinear array echoendoscope.
PAIN Pain related to pancreatic cancer is often poorly controlled. Celiac plexus neurolysis (CPN) is a chemical splanchnicectomy of the celiac plexus, which ablates the afferent nerve fibers that transmit pain from intra-abdominal viscera. EUS guidance offers the most direct access to the celiac plexus of all the CPN techniques short of surgical intervention. The celiac ganglia are located at the origin of the celiac artery, which is easily identified at endosonography (Figure 11-5). The relative proximity of the celiac ganglia to the posterior gastric wall ensures an accurate passage of the injecting needle into the ganglia, thereby minimizing the risk of complications and potentially increasing the effectiveness of the block. Bupivacaine and absolute ethanol are commonly used for performing CPN. EUS-CPN performed for the palliation of pancreatic cancer pain appears to be as safe and effective as CPN performed by other techniques. An added advantage of the EUS approach is that it can be performed during staging and biopsy of the tumor. In a pilot study, pain relief lasting for a median of 10 weeks was achieved in 88% of 25 patients undergoing EUS-CPN63. Similar results were observed in a later prospective study involving 58 patients; pain scores were significantly lower than baseline in 78% of patients 2 weeks after the procedure and were sustained for 24 weeks 64. On multivariate analysis, the benefit of EUS-CPN was independent of morphine use, chemotherapy, and radiation.
Neuroendocrine Tumors CONFRONTING ISSUES Pancreatic endocrine tumors are often small and hard to detect by radiologic techniques. Since the original description of gastrinomas in 1955 by Zollinger and
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Ellison65, multiple imaging modalities have been evaluated to localize pancreatic neuroendocrine lesions for surgical resection. Studies have shown that CT, MRI, and conventional US detect tumors in less than 50% of patients 66. Somatostatin receptor scintigraphy (SRS) is reported to have the highest sensitivity for gastrinomas but is less accurate for detecting insulinomas 67. The optimal algorithm for staging pancreatic neuroendocrine tumors is unknown. Issues important for clinical management include:
1. Is the tumor localized to the region of the pancreas (including gastrinoma triangle) or metastatic? 2. Is it unifocal or multifocal within the pancreas? 3. Is it functional or non-functional, benign or malignant?
WORK-UP To determine whether a tumor is localized or metastatic, cross-sectional imaging and SRS are likely more accurate than EUS due to their ability to image broad areas67. For imaging within the pancreas, EUS provides superior resolution and accuracy relative to CT scan. In a study of 82 patients, Anderson et al identified 100 tumors in 54 patients, emphasizing the frequency of multifocal tumors 68. EUS accurately localized the tumor in 93% of patients and had a specificity of 95%, which was higher than CT or transabdominal US. EUS was not reliable for detection of extrapancreatic tumors. Zimmer et al compared EUS to CT, SRS, US, and MRI in 40 patients with neuroendocrine tumors 69. EUS had the highest overall accuracy for both gastrinomas and insulinomas but missed 50% of extrapancreatic tumors. In one report of patients who had negative ultrasonography and CT scans, EUS detected endocrine tumors in the pancreas with high sensitivity (82%) and specificity (95%) 70. In patients with nonfunctioning neuroendocrine tumors where the risk of surgery is elevated, it would be useful to distinguish benign from malignant neuroendocrine tumors. In two studies71,72 , EUS was able to accurately distinguish malignant lesions based on the presence of an irregular inhomogeneous hypoechoic mass or on invasion and obstruction of the pancreatic duct. Tumors without these features were almost always benign.
Intraductal Endoscopic Ultrasonography Intraductal endoscopic ultrasonography (IDUS) involves the insertion of an ultrathin (2 mm) US probe directly into the pancreatic duct during ERCP. Preliminary experience suggests that it may be more accurate than standard EUS for the detection of neuroendocrine tumors. Although experience with IDUS is limited, initial data suggest that IDUS may improve the evaluation of these patients and lead to the identification of tumors arising within the pancreas that have gone unrecognized by other techniques73,74. In one study, IDUS was able to identify the presence of an islet cell tumor in seven of seven patients74. In one of these patients who had multifocal disease, IDUS accurately determined the number of tumors while EUS failed to detect all lesions. The distance from the tumors to the main pancreatic duct was accurately determined, thus aiding preoperative planning of wedge resection, which was possible in two patients. EUS can also be useful for preoperative localization of pancreatic endocrine tumors by its ability to tattoo lesions by fine-needle injection using India ink 75. This may
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shorten operative time because it obviates the need to localize the tumor by palpation and intraoperative US. This technique may have the potential to facilitate tumor resection by less invasive methods, such as laparoscopic enucleation. These data suggest that EUS serves an important role in localizing tumors within the pancreas, detecting multifocal tumors, and distinguishing benign from malignant tumors. In addition, EUS should be used with cross-sectional imaging and SRS to identify extrapancreatic tumors or metastases.
MANAGEMENT Management is based on the nature of the underlying neuroendocrine tumor. In general, patients with localized disease (sporadic lesions) should be managed by laparotomy with a curative intent. Patients with tumors that are part of a syndrome such as multiple endocrine neoplasia may be managed medically as the tumors are multifocal in these patients. The clinical course of patients with metastatic pancreatic neuroendocrine tumors is highly variable. Some patients with indolent tumors may remain symptom-free for years, even without treatment. Others have symptomatic metastatic disease, either from tumor bulk or hormonal hypersecretion, and require therapy. Several options are available for the treatment of metastatic neuroendocrine tumors including somatostatin analogs, interferon alfa, cytotoxic chemotherapy, surgical resection, hepatic artery embolization, and possibly orthotopic liver transplantation in highly selected patients.
Future Trends The efficacy of direct antitumor therapy has recently been reported in clinical trials. Therapy involves dose-dependent injection of a modified adenovirus (TNFerade) that is capable of preferentially replicating in and destroying tumor cells. In a study of 37 patients76 with locally advanced pancreatic cancer treated with TNFerade (administered by either EUS or CT-guidance) and concomitant chemoradiation, 74% achieved tumor stabilization, 11% more than 50% reduction in tumor size, and five underwent tumor resection (four had negative surgical margins). The treatment is safe and only minimal adverse events were reported. The effect of TNFerade on metastatic disease and its long-term efficacy remains unclear. This exciting trial is still underway and the final results are awaited.
References 1. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics 1996. CA Cancer J Clin. 1996;46:5-27. 2. Niederhuber JE, Brennan MF, Menck HR. The National Cancer Data Base report on pancreatic cancer. Cancer. 1995;76:1671-167. 3. Kalser MH, Barkin J, MacIntyre JM. Pancreatic cancer. Assessment of prognosis by clinical presentation. Cancer. 1985;56:397-402. 4. Mannell A, van Heerden JA, Weiland LH, Ilstrup DM. Factors influencing survival after resection for ductal adenocarcinoma of the pancreas. Ann Surg. 1986;203:403407. 5. Gullo L, Pezzilli R, Morselli-Labate AM. Diabetes and the risk of pancreatic cancer. Italian Pancreatic Cancer Study Group. N Engl J Med. 1994;331:81-84.
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6. Permert J, Larsson J, Westermark GT, et al. Islet amyloid polypeptide in patients with pancreatic cancer and diabetes. N Engl J Med. 1994;330:313-8. 7. Schwarts SS, Zeidler A, Moossa AR, et al. A prospective study of glucose tolerance, insulin, C-peptide, and glucagon responses in patients with pancreatic carcinoma. Am J Dig Dis. 1978;23:1107-14. 8. Metzgar RS, Asch HL. Antigens of human pancreatic adenocarcinomas: their role in diagnosis and therapy. Pancreas. 1988;3:352. 9. Posner MR, Mayer RJ. The use of serologic tumor markers in gastrointestinal malignancies. Hematol Oncol Clin North Am. 1994;8:533-53. 10. Pleskow DK, Berger HJ, Gyves J, Allen E, McLean A, Podolsky DK. Evaluation of a serologic marker, CA19-9, in the diagnosis of pancreatic cancer. Ann Intern Med. 1989;110:704-9. 11. Safi F, Schlosser W, Falkenreck S, Beger HG. CA 19-9 serum course and prognosis of pancreatic cancer. Int J Pancreatol. 1996;20:155-61. 12. Albert MB, Steinberg WM, Henry JP. Elevated serum levels of tumor marker CA19-9 in acute cholangitis. Dig Dis Sci. 1988;33:1223-5. 13. Westermark P, Wilander E, Westermark GT, Johnson KH. Islet amyloid polypeptidelike immunoreactivity in the islet B cells of type 2 (non-insulin-dependent) diabetic and non-diabetic individuals. Diabetologia. 1987;30:887-92. 14. Chari ST, Klee GG, Miller LJ, Raimondo M, DiMagno EP. Islet amyloid polypeptide is not a satisfactory marker for detecting pancreatic cancer. Gastroenterology. 2001; 121(3):640-645. 15. Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M. Most carcinomas of the exocrine pancreas contain mutant c-Kras genes. Cell. 1988;53:549-54. 16. Hruban RH, van Mansfeld AD, Offerhaus GJ, et al. K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol. 1993;143(2):545-54. 17. Lemoine NR, Jain S, Hughes CM, et al. K-ras oncogene activation in preinvasive pancreatic cancer. Gastroenterology. 1992;102:230-6. 18. Rivera JA, Rall CJ, Graeme-Cook F, et al. Analysis of K-ras oncogene mutations in chronic pancreatitis with ductal hyperplasia. Surgery. 1997;121:42-49. 19. Redston MS, Caldas C, Seymour AB, et al. p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res. 1994;54(11):3025-33. 20. Hohne MW, Halatsch ME, Dahl GF, Winel RJ. Frequent loss of expression of the potential tumor-suppressor gene DCC in ductal pancreatic adenocarcinoma. Cancer Res. 1992;52:2616-19. 21. Muller MF, Meyenberger C, Bertschinger P, Schaer R, Marincek B. Pancreatic tumors: Evaluation with endoscopic US, CT, and MR imaging. Radiology. 1994;190 (3):745-51. 22. Bluemke DA, Cameron JL, Hruban RH, et al. Potentially resectable pancreatic adenocarcinoma: Spiral CT assessment with surgical and pathologic correlation. Radiology. 1995;197:381-5. 23. Legman P, Vignaus O, Dousser B, et al. Pancreatic tumors: comparison of dual-phase helical CT and endoscopic sonography. Am J Radiol. 1998;170:1315. 24. Johnson DE, Pendurthi TK, Balshem AM, et al. Implications of fine-needle aspiration in patients with resectable pancreatic cancer. Am Surg. 1997;63:675-9.
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25. McNulty NJ, Francis IR, Platt JF, et al. A multi-detector row helical CT of the pancreas: effect of contrast-enhanced multiphasic imaging on enhancement of the pancreas, peri-pancreatic vasculature, and pancreatic adenocarcinoma. Radiology. 2001;220:97-102. 26. Semelka RC, Kelekis NL, Molina PL, Sharp TJ, Calvo B. Pancreatic masses with inconclusive findings on spiral CT: is there a role for MRI? J Magn Reson Imaging. 1996;6(4):585-8. 27. Adamek HE, Albert J, Breer H, et al. Pancreatic cancer detection with magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography: A prospective controlled study. Lancet. 2000;356:190-193. 28. Freeny PC. Radiologic diagnosis and staging of pancreatic ductal adenocarcinoma. Radiol Clin North Am. 1989;27:121-128. 29. Rosch T, Lorenz R, Braig C, et al. Endoscopic ultrasound in pancreatic tumor diagnosis. Gastrointest Endosc. 1991;37:347-352. 30. Palazzo L, Roseau G, Gayet B, et al. Endoscopic ultrasonography in the diagnosis and staging of pancreatic adenocarcinoma: results of a prospective study with comparison to ultrasonography and CT scan. Endoscopy. 1993;25:143-150. 31. Gress FG, Hawes RH, Savides TJ, et al. Role of EUS in the preoperative staging of pancreatic cancer: a large single-center experience. Gastrointest Endosc. 1999;50:786791. 32. Yasuda K, Mukai H, Nakajima M, et al. Staging of pancreatic carcinoma by endoscopic ultrasonography. Endoscopy. 1993;25:151-155. 33. Ahmad NA, Lewis JD, Ginsberg GG, et al. EUS in preoperative staging of pancreatic cancer. Gastrointest Endosc. 2000;52:463-468. 34. Legmann P, Vignaux O, Dousset B, et al. Pancreatic tumors: comparison of dual phase helical CT and endoscopic sonography. AJR Am J Roentgenol. 1998;170:13151322. 35. Yasuda K, Mukai H, Fujimoto S, et al. The diagnosis of pancreatic cancer by endoscopic ultrasonography. Gastrointest Endosc. 1988;34:1-8. 36. Nakaizumi A, Uehara H, Iishi H, et al. Endoscopic ultrasonography in diagnosis and staging of pancreatic cancer. Dig Dis Sci. 1995;40:696-700. 37. Rosch T, Dittler HJ, Strobel K, et al. Endoscopic ultrasound criteria for vascular invasion in the staging of cancer of the head of the pancreas: a blind reevaluation of videotapes. Gastrointest Endosc. 2000;52:469-477. 38. Brugge WR, Lee MJ, Kelsey PB, et al. The use of EUS to diagnose malignant portal venous system invasion by pancreatic cancer. Gastrointest Endosc. 1996;43:561-567. 39. Hunt GC, Faigel DO. Assessment of EUS for diagnosing, staging, and determining resectability of pancreatic cancer: a review. Gastrointest Endosc. 2002;55:232-237. 40. Midwinter MJ, Beveridge CJ, Wilsdon JB, et al. Correlation between spiral computed tomography, endoscopic ultrasonography and findings at operation in pancreatic and ampullary tumours. Br J Surg. 1999;86:189-193. 41. Mertz HR, Sechopoulos P, Delbeke D, et al. EUS, PET, and CT scanning for evaluation of pancreatic adenocarcinoma. Gastrointest Endosc. 2000;52:367-371. 42. Harewood GC, Wiersema MJ. Endosonography-guided fine needle aspiration biopsy in the evaluation of pancreatic masses. Am J Gastroenterol. 2002;97:1386-1391. 43. Ahmad NA, Lewis JD, Siegelman ES, et al. Role of endoscopic ultrasound and magnetic resonance imaging in the preoperative staging of pancreatic adenocarcinoma. Am J Gastroenterol. 2000;95:1926-1931.
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44. Gress F, Gottlieb K, Sherman S, et al. Endoscopic ultrasonography-guided fine-needle aspiration biopsy of suspected pancreatic cancer. Ann Intern Med. 2001;134:459464. 45. Chang KJ, Nguyen P, Erickson RA, et al. The clinical utility of endoscopic ultrasound-guided fine-needle aspiration in the diagnosis and staging of pancreatic carcinoma. Gastrointest Endosc. 1997;45:387-393. 46. Eloubeidi MA, Gress FG, Savides TJ, et al. Acute pancreatitis after EUS-guided FNA of solid pancreatic masses: A pooled analysis from EUS centers in the United States. Gastrointest Endosc. 2004;60:385-389. 47. Fickling W, Madani N, Hoffman B, et al. Endoscopic ultrasound fine-needle aspiration of cystic lesions of the pancreas: a safe procedure? [Abstract.] Gastrointest Endosc. 2002;56:150. 48. Gloor B, Todd KE, Reber HA. Diagnostic workup of patients with suspected pancreatic carcinoma: the University of California-Los Angeles approach. Cancer. 1997;79:1780-6. 49. Andersen JR, Sorensen SM, Kruse A, Rokkjaer M, Matzen P. Randomised trial of endoscopic endoprosthesis versus operative bypass in malignant obstructive jaundice. Gut. 1989;30:1132-5. 50. Smith AC, Dowsett JF, Russell RC, Hatfield AR, Cotton PB. Randomised trial of endoscopic stenting versus surgical bypass in malignant low bile duct obstruction. Lancet. 1994; 344(8938):1655-60. 51. Speer AG, Cotton PB, Russell RC, et al. Randomised trial of endoscopic versus percutaneous stent insertion in malignant obstructive jaundice. Lancet. 1987;2(8550):5762. 52. Shepherd HA, Royle G, Ross AP, et al. Endoscopic biliary endoprosthesis in the palliation of malignant obstruction of the distal common bile duct: a randomized trial. Br J Surg. 1988;75(12):1166-8. 53. Prat F, Chapat O, Ducot B, et al. A randomized trial of endoscopic drainage methods for inoperable malignant strictures of the common bile duct. Gastrointest Endosc. 1998;47(1):1-7. 54. Singh SM, Longmire WP Jr, Reber HA. Surgical palliation for pancreatic cancer. The UCLA experience. Ann Surg. 1990;212(2):132-9. 55. Sohn TA, Lillemoe KD, Cameron JL, Huang JJ, Pitt HA, Yeo CJ. Surgical palliation of unresectable periampullary adenocarcinoma in the 1990s. J Am Coll Surg. 1999; 188(6):658-66; discussion 666-9. 56. Adler D, Baron TH. Endoscopic palliation of malignant gastric outlet obstruction using expanding metal stents: experience in thirty-six patients. Am J Gastroenterol. 2002;97:72. 57. Mauro MA, Koehler RE, Baron TH. Advances in gastrointestinal intervention: the treatment of gastroduodenal and colorectal obstructions with metallic stents. Radiology. 2000;215(3):659-69. 58. Yim HB, Jacobson BC, Saltzman JR, Johannes RS. Clinical outcome of the use of enteral stents for palliation of patients with malignant upper GI obstruction. Gastrointest Endosc. 2001;53:329-32. 59. Lillemoe KD, Cameron JL, Hardacre JM, et al. Is prophylactic gastrojejunostomy indicated for unresectable periampullary cancer? A prospective randomized trial. Ann Surg. 1999;230(3):322-8. 60. Yates MR III, Morgan DE, Baron TH. Palliation of malignant gastric and small intestinal strictures with self-expandable metal stents. Endoscopy. 1998;30:266-72.
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61. Doberneck RC, Berndt GA. Delayed gastric emptying after palliative gastrojejunostomy for carcinoma of the pancreas. Arch Surg. 1987;122:827-29. 62. Weaver DW, Wiencek RG, Bouwman DL, Walt AJ. Gastrojejunostomy: is it helpful for patients with pancreatic cancer? Surgery. 1987;102(4):608-13. 63. Wiersema MJ, Wiersema LM. Endosonography-guided celiac plexus neurolysis. Gastrointest Endosc. 1996;44:656-662. 64. Gunaratnam NT, Sarma AV, Norton ID, et al. A prospective study of EUS-guided celiac plexus neurolysis for pancreatic cancer pain. Gastrointest Endosc. 2001;54:316324. 65. Zollinger RM, Ellison EH. Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann Surg. 1955;142:709-723. 66. Prinz RA. Localization of gastrinomas. Int J Pancreatol. 1996;19:79-91. 67. Jensen RT, Gibril F, Termanini B. Definition of the role of somatostatin receptor scintigraphy in gastrointestinal neuroendocrine tumor localization. Yale J Biol Med. 1997;70:481-500. 68. Anderson MA, Carpenter S, Thompson NW, et al. Endoscopic ultrasound is highly accurate and directs management in patients with neuroendocrine tumors of the pancreas. Am J Gastroenterol. 2000;95:2271-2277. 69. Zimmer T, Scherubl H, Faiss S, et al. Endoscopic ultrasonography of neuroendocrine tumors. Digestion. 2000;62(Suppl 1):45-50. 70. Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med. 1992;326:1721-1726. 71. Sugiyama M, Abe N, Izumisato Y, et al. Differential diagnosis of benign versus malignant nonfunctioning islet cell tumors of the pancreas: the role of EUS and ERCP. Gastrointest Endosc. 2002;55:115-119. 72. Kann P, Bittinger F, Engelbach M, et al. Endosonography of insulin-secreting and clinically non-functioning neuroendocrine tumors of the pancreas: criteria of benignancy and malignancy. Eur J Med Res. 2001;6:385-390. 73. Furukawa T, Oohashi K, Yamao K, et al. Intraductal ultrasonography of the pancreas: development and clinical potential. Endoscopy. 1997;29:561-569. 74. Menzel J, Domschke W. Intraductal ultrasonography may localize islet cell tumours negative on endoscopic ultrasound. Scand J Gastroenterol. 1998;33:109-112. 75. Gress FG, Barawi M, Kim D, et al. Preoperative localization of a neuroendocrine tumor of the pancreas with EUS-guided fine needle tattooing. Gastrointest Endosc. 2002;55:594-597. 76. Chang KC, Senzer N, Chung T, et al. A novel gene transfer therapy against pancreatic cancer (TNFerade) delivered by endoscopic ultrasound (EUS) and percutaneous guided fine needle injection (FNI). Gastrointest Endosc. 2004;59: AB92.
Color Atlas
Figure 1-11. Choledochal cyst. Intraoperative image of choledochal cyst in a 14-yearold girl. Also shown on page 16.
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Figure 3-4. Endoscopic
sphincterotomy performed via the standard pull technique. Also shown on page 56.
Figure 3-5. Four choles-
terol gallstones removed from the common bile duct using an extraction balloon. Also shown on page 59.
CA III Figure
5-1.
Endoscopic snare resection of a villous adenoma of the ampulla of Vater. Here, the ampulla of Vater is visualized with a side viewing duodenoscope. Note the fungating appearance of the ampullary orifice. Also shown on page 97.
Figure 5-2. Dual
sphincterotomies of the pancreatic and biliary orifices have been performed. The pancreatic duct has been stented with a short, narrow caliber stent in preparation for snare ampullectomy. Also shown on page 98.
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Figure 7-3. A. Ascaris in ampulla. B. Worm removed by dormia basket. Reprinted with permission from Al-Karawi M, Sanai FM, Yasawy MI, et al. Biliary strictures and cholangitis secondary to ascariasis: endoscopic management. Gastrointest Endosc. 1999;50:695-697. Obtained with permission. Also shown on page 132.
Figure 9-10. Endoscopic view (A) and Sudan stain (B) showing steatorrhea in a patient with pancreatic insufficiency. Also shown on page 197.
chapter
12
Pancreatic Cystic Lesions David G. Forcione, MD; Brenna C. Bounds, MD
Introduction The advent of widely available cross-sectional imaging has given rise to an impressive, ever-expanding list of pancreatic cystic lesions including benign, inflammatory (pseudocysts), and neoplastic cysts (Table 12-1). Pseudocysts are considered the most common, accounting for approximately 75% to 80% of pancreatic cystic lesions. Benign cysts, including congenital cysts, lymphoepithelial cysts, and retention cysts, are uncommon, accounting for 5% of pancreatic cystic lesions. Although accounting for only 10% to 15% of lesions, the cystic neoplasms of the pancreas have become increasingly recognized as an important subset of pancreatic disease, with a histopathologic spectrum ranging from benign to malignant. Advances in endoscopic tissue acquisition with cytologic and biomarker evaluation have resulted in improvements in diagnosis, staging, and therapeutic strategies. In particular, cyst fluid analysis has become increasingly used to distinguish cystic lesions and provide some information on malignant potential. This chapter will focus on an overview of the clinicopathologic spectrum of cystic lesions of the pancreas, with a particular focus on clinical evaluation and management.
Pseudocysts DEFINITIONS AND EPIDEMIOLOGY A pseudocyst is an inflammatory cystic cavity that develops in the setting of pancreatitis or traumatic pancreatic injury. These cystic lesions most commonly are extrapancreatic in location. Pseudocysts are not true cysts as the lining is not epithelial but is composed of inflammatory cells and fibrinous debris. This inflammatory lining is often tightly adherent to adjacent viscera (colon, stomach). The cyst contains amylase-rich fluid, often in association with a variable amount of necrotic debris. The pseudocyst exists within a radiologic and pathologic spectrum of fluid collections
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Table 12-1
CYSTIC LESIONS OF THE PANCREAS I. Non-neoplastic Inflammatory Pseudocysts Noninflammtory Lymphoepithelial cysts Enteric duplication cysts Endometrial cysts Hydatid cysts Retention cysts Congenital cysts True (simple) cysts Autosomal dominant polycystic kidney disease Cystic fibrosis von-Hippel Lindau syndrome Acinar cell cystadenoma II. Neoplastic Common Solid pseuodopapillary tumor Serous cystic neoplasms Microcystic serous cystadenoma Macrocystic (oligocystic) serous cystadenoma Mucinous cystic neoplasms Mucinous cystadenoma Mucinous cystadenocarcinoma Intraductal papillary mucinous neoplasm Uncommon Cystic neuroendocrine tumors Acinar cell cystic neoplasm Ductal adenocarcinomas Lymphoma Leiomyosarcoma Schwannoma Malignant fibrous histiocytoma Metastatic deposits (renal cell and melanoma) Paragangliomas Dermoid cysts (cystic teratomas)
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Table 12-1, continued
Vascular tumors Lymphangioma Hemangioma Hemolymphangioma Hemangiopericytoma Hemangioblastoma Hemangiosarcoma associated with both acute (AP) and chronic pancreatitis (CP). It is important, from both a diagnostic and therapeutic perspective, to stratify peripancreatic fluid collections arising from AP, CP, or pancreatic trauma as an acute fluid collection, acute pseudocyst, chronic pseudocyst, or pancreatic abscess (Atlanta Consensus Conference classification) (Table 12-2). Approximately 30% to 60% of cases of AP are associated with acute fluid collections, typically located in the potential space of the lesser omentum (lesser sac) or the anterior pararenal space. Most often, these fluid collections develop within the lesser sac and are anatomically limited anteriorly by the stomach, inferiorly by the transverse mesocolon, laterally by the spleen, and by splenic flexure on the left and the duodenum on the right. The majority of acute fluid collections (80%) will resolve spontaneously, and the remainder will undergo organization to form pseudocysts. This translates into an estimated 5,000 to 7,000 new cases of pancreatic pseudocysts being discovered each year in the United States in the clinical setting of AP. Clinical observation has demonstrated that most acute fluid collections will organize into pseudocysts within 6 weeks, although this time course remains variable among patients.
ETIOLOGY AND PATHOGENESIS Approximately 5% to 15% of all episodes of AP will result in the formation of a pancreatic pseudocyst, with about half of these pseudocysts resolving or stabilizing spontaneously (remaining asymptomatic). In line with the epidemiology of AP, most acute pseudocysts develop in the setting of alcohol or gallstone mediated pancreatic injury. Epidemiologic studies performed in the United States have favored a much greater contribution from alcohol in this regard, with reports of 70% to 80% of pancreatic pseudocysts arising in the setting of acute or chronic alcoholic pancreatitis. In contrast, French studies have noted that gallstone pancreatitis accounts for the majority of their acute pancreatic pseudocysts (45%), whereas alcoholic pancreatitis contributed to the majority of chronic pancreatic pseudocysts (94%). Although the natural history data remain limited, it appears that pseudocysts are significantly more common among patients with CP, with an estimated incidence of 20% to 40%. Several mechanisms may account for the development of a pancreatic pseudocyst. An acute inflammatory necrosis of peripancreatic tissue, in association with leakage of pancreatic juice from an inflamed surface of the pancreas, leads to the formation of an
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Table 12-2
ATLANTA CONSENSUS CONFERENCE CLASSIFICATION OF PERIPANCREATIC FLUID COLLECTIONS Acute Fluid Collections: These fluid collections develop early in the course of acute pancreatitis in the setting of liquefaction necrosis. These collections lack a defined wall. Acute Pseudocysts: Amylase-rich fluid collections with a defined lining of inflammatory cells and fibrinous debris. Chronic Pseudocysts: Amylase-rich fluid collections with a defined lining of inflammatory cells and fibrinous debris, which develop in the setting of chronic pancreatitis (in the absence of a clear episode of acute pancreatitis). Pancreatic Abscess: A circumscribed intra-abdominal collection of pus in proximity with the pancreas arising as the consequence of acute pancreatitis, trauma, or chronic pancreatitis. amylase-rich cavity (with or without communication with the main pancreatic duct). Pancreatic parenchymal necrosis and associated main pancreatic duct disruption, with gross leakage of pancreatic juice into the surrounding peripancreatic space, results in peripancreatic tissue necrosis and cyst formation. The head of the pancreas is the most common site of main duct disruption (50%), followed by the body (30%) and tail (20%). Pseudocysts may also form in the setting of an acute exacerbation of CP. Additionally, pseudocysts may form as a result of pancreatic ductal obstruction due to stricture formation, proteinacious plugging, or intraductal calculi. Finally, disruption of the pancreatic duct in the setting of acute abdominal trauma (penetrating or blunt) may result in extravasation of pancreatic juice, local tissue necrosis, and subsequent pseudocyst formation. Trauma is the most common cause of pseudocyst formation among children.
CLINICAL FEATURES It is estimated that only 50% of all pseudocysts will result in clinical symptoms, while the remainder will either spontaneously resolve or remain clinically quiescent. Pseudocysts may present clinically in one of several ways. The most common presentation is that of abdominal pain, which may develop in the setting of adjacent visceral obstruction (biliary tree, bowel, vasculature, urinary tract) due to expansion of the cyst. Pancreatic fluid may fistulize to the pleural or peritoneal spaces with ensuing pleural effusions or ascites, respectively. True spontaneous infection of pseudocysts has been reported to occur in up to 10% of cases, and likely stems from surrounding gut flora in the acute fluid collection stage. Perhaps the most common reason for the development of an infected pseudocyst
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Figure 12-1. Pseudocyst.
is from contamination during transcutaneous or transenteric needle aspiration. The most feared complication of a pseudocyst is the development of a pseudoaneurysm, which may develop from localized, enzymatic erosion into an adjacent vascular structure. Pseudoaneurysms develop in 5% to 10% of patients with pseudocysts. The most commonly affected vessels are the splenic artery, gastroduodenal, and pancreaticoduodenal arteries. These may present with abdominal pain due to acute hemorrhage into the cyst cavity or with acute gastrointestinal bleeding due to hemorrhage into the pancreatic duct (hemosuccus pancreaticus).
DIAGNOSIS Most pseudocysts are diagnosed with transabdominal ultrasound (US) or computed tomography (CT) (Figure 12-1), either in follow-up of a known fluid collection discovered at the onset of AP (an acute fluid collection) or in evaluation of abdominal pain with or without a known previous history of pancreatitis or trauma. In one series of acute pseudocysts, 39% were located in the lesser sac (or omental bursa), 31% in the anterior pararenal space, 10% within the substance of the liver, and 20% in other sites. Pseudocysts may be intra- or extrapancreatic in location, although most clinically relevant pseudocysts are extrapancreatic. Intrapancreatic pseudocysts are most frequently located in the head of the pancreas. Pseudocysts may vary in size, ranging from 1 to 35 cm, with the mean size at 9 +/- 1 cm in one study. Cyst fluid contents may measure as high as 6000 mL. The fluid appearance is typically a turbid brown, although it may also be clear or hemorrhagic in nature. Approximately 80% to 90% of affected patients will have a single pseudocyst. Multiple pseudocysts are usually found in those patients with underlying alcoholic pancreatitis, presumably due to the diffuse nature of the pancreatic injury. Communication with the pancreatic duct is reported to range from 6% to 60% of cases, with the broad variability likely reflecting differences in imaging techniques. Although pseudocysts are the most common cystic lesions of the pancreas, it is important to consider a broad differential diagnosis in the evaluation, including both
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Table 12-3
CLUES FAVORING A PANCREATIC PSEUDOCYST IN THE EVALUATION OF A PANCREATIC CYSTIC LESION • Antecedent history of pancreatitis, abdominal trauma, or abdominal • • • • • •
surgery. Clinical or radiologic evidence of chronic pancreatitis. Communication of the cyst with the main pancreatic duct. Peripancreatic inflammatory changes on abdominal computed tomography. Extrapancreatic location of the cyst. Absence of internal septae within the cyst. Cyst fluid evaluation demonstrating a very high amylase (>10,000 U/mL), low CEA (<100 U/mL), and cytology demonstrating foamy histiocytes and inflammatory cells without epithelial elements or mucin.
benign pancreatic cysts and cystic neoplasms. When considering these possibilities, several clues may favor a diagnosis of a pancreatic pseudocyst (Table 12-3). One must always consider the possibility of a pseudoaneurysm, as this may be a potentially life-threatening complication of the pseudocyst. This should be suspected when the patient presents with acute worsening of abdominal pain associated with hemodynamic instability, acute decrease in hematocrit, or with evidence of acute gastrointestinal bleeding. Abdominal CT with dynamic bolus to enhance the arterial phase is a reliable means for evaluation of a suspected pseudoaneurysm. However, angiography remains the gold standard and also affords concomitant therapeutic intervention using coil and chemical embolization.
NATURAL HISTORY Historically, it has been taught that no cyst persisting more than 6 weeks following an attack of AP resolved. This dictum was based on several studies in the late 1970s and early 1980s. Interestingly, in these same series, pseudocyst size did not seem to affect frequency of resolution. In addition to lack of clinical resolution, the reported complication rate associated with pseudocysts rose sharply with time from cyst development. In one series, 20% of patients developed complications at <6 weeks compared to 46% with pseudocysts persisting 7 to 12 weeks, and 75% with those >13 weeks. These results have been challenged by more recent natural history surveys, which suggest that pseudocyst size, rather than interval of time from development, is the most important factor for predicting resolution. These studies demonstrate that 65% of pseudocysts resolve within 1 year of identification, with some resolving out as far as 28 months. The mean diameter of pseudocysts that resolved was 4 +/-1 cm as compared to 9 +/-1 cm for those that did not resolve. Recent studies demonstrate a lower
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Table 12-4
INDICATIONS FOR PSEUDOCYST INTERVENTION • • • •
Concern for a cystic neoplasm Increasing size of pseudocyst on serial cross-sectional imaging Abdominal pain Pseudocyst complications: infection, bleeding, obstruction
complication rate associated with pseudocyst persistence, with approximately 10% of patients developing life-threatening complications at up to 46 months of follow-up, with most occurring in the first 8 weeks following diagnosis. Additional factors have also been demonstrated to predict persistence of pseudocysts. These include development after AP, multiple cysts, cyst location in the tail of the pancreas, thicker cyst wall, lack of demonstrated communication with the main pancreatic duct, an associated proximal stricture of the pancreatic duct, increase in size on follow-up examination, postoperative etiology of pancreatitis, and short duration of symptoms due to the pseudocyst.
TREATMENT The management of pseudocysts continues to evolve as we develop a better appreciation of the natural history of these lesions and mature in the use of less invasive drainage techniques. The historical dictum of performing surgical cyst-enterostomy for all pseudocysts persisting for more than 6 weeks or for all cysts >6 cm in size is no longer an absolute. Current treatment strategies rely more on the clinical and radiologic behavior of the pseudocyst to determine the need for intervention (Table 12-4). Surgical, radiologic, and endoscopic methods have all been employed to drain pseudocysts (Table 12-5). Care must be taken to exclude a complicating pseudoaneurysm, as this will need to be angiographically embolized prior to any drainage attempts. Traditional surgical cyst-gastrostomy and cyst-enterostomy are now reserved for multiloculated pseudocysts, those without close apposition to an accessible duodenal or gastric wall, and for those that have failed nonsurgical techniques. A distal pancreatectomy (often with splenectomy) may be performed in patients with pseudocysts isolated to the tail of the pancreas. Morbidity and mortality rates are reported at 10% to 30% and 1% to 5%, respectively. Recurrence rate is approximately 10% to 15%. Radiologic (percutaneous) drainage is generally used for cystic lesions that are not amenable to endoscopic drainage due to location or in suspected infected collections. Persistence of a pancreaticocutaneous fistula may complicate percutaneous drainage, particularly if there is a ductal obstruction associated with the pseudocyst. Parenteral octreotide may be required to reduce flow rate through the drain prior to removal to minimize the chances of fistula formation. Following a mean of 42 days of catheter drainage, approximately 80% to 90% of pseudocysts will be adequately treated. The reported complication rates are 15% to 20%, including bleeding and drain track infection.
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Table 12-5
TECHNIQUES FOR PSEUDOCYST DRAINAGE Surgical • • •
Cyst-gastrostomy Cyst-enterostomy Segmental pancreas resection (distal pancreatectomy)
Radiologic •
Percutaneous catheter drainage
Endoscopic • •
Transpapillary stenting Transgastric or transduodenal drainage
There has been increasing interest in the use of endoscopic drainage techniques. These include transpapillary and transmural drainage. The former employs the use of a pancreatic stent through the papilla to bridge the main pancreatic duct disruption, which communicates with the pseudocyst. In some cases, the transpapillary stent can be placed through the pancreatic duct into the cavity of the pseudocyst. For infected pseudocysts or frank pancreatic abscesses, direct transmural drainage of the collection may be performed endoscopically. Transmural drainage of pancreatic pseudocysts can be performed with or without the aid of endoscopic ultrasound (EUS) (Figure 12-2). Lesions best suited for transmural drainage are those closely associated with the gastric or duodenal wall, causing a characteristic endoscopic bulge or those with a cyst wall <10 mm in size by EUS. In addition to the placement of multiple stents for adequate drainage, this technique allows for endoscopic pseudocyst debridement and nasocystic lavage for infected cavities. The use of EUS-guided transmural drainage may be associated with fewer complications, such as bleeding from cyst wall vessels or gastric or duodenal varices, and may permit for an expanded role of endoscopic drainage for those cysts not associated with a clear luminal bulge. At this time, over 600 patients have been treated with transmural endoscopic drainage, with an overall complication rate of 17% and a long-term success rate 65% to 89%. These data have established a clear role for endoscopic management of pancreatic pseudocysts. Progress is being made with the development of echoendosope compatible pseudocyst drainage systems, which will afford greater efficiency in the endoscopist’s performance of transmural pseudocyst drainage.
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Figure 12-2. Endoscopic ultrasound.
Non-neoplastic Pancreatic Cysts A variety of non-neoplastic pancreatic cystic lesions have been described in the literature. Preoperative diagnosis of these lesions remains challenging owing to their rarity and often nonspecific clinical and radiologic presentations.
LYMPHOEPITHELIAL CYSTS The lymphoepithelial cyst (LEC) is a rare pancreatic cystic lesion with <100 cases described in the literature. Most reported cases have been incidental discoveries on cross-sectional imaging, although some patients were diagnosed while undergoing evaluation for abdominal pain or a palpable mass. LECs occur with a 3:1 male predominance, with a mean age of 56 (range 35 to 72 years). The cysts may be located anywhere in the pancreas, without predilection, and range in size from 2 to 17 cm (mean 4.8 cm). Over half are multilocular. The cysts are well demarcated from the pancreatic parenchyma and do not communicate with the main pancreatic duct. Fine needle aspiration (FNA) yields a gray-white pasty material, largely composed of keratin. An LEC has a characteristic lining of keratinizing squamous epithelium overlying a small layer of lymphoid tissue. The absence of teratoid or mesenchymal features distinguishes these lesions from dermoid cysts of the pancreas. The origin of the LEC remains elusive. Unlike parotid gland LEC, there has been no identifiable association with the Epstein-Barr virus. On CT and magnetic resonance imaging (MRI), the finding of a lipid component may favor the diagnosis of a LEC. Preoperative FNA (including EUS-guided) can be performed but requires identification of both squamous and lymphoid elements to make the diagnosis. To add to the complexity of preoperative diagnosis, some patients with a LEC have been found to have markedly elevated serum and cyst CA 19-9 and CEA levels, raising concern for an underlying malignancy. For this reason, although there have been no reported cases of malignant degeneration, many patients undergo surgical resection to provide a definitive histologic diagnosis.
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ENTERIC DUPLICATION CYSTS Duplication cysts are uncommon, benign cystic anomalies that arise during early embryonic development of the gastrointestinal tract. Enteric duplication cysts are most often found in the proximal small intestine, but may be seen throughout the gastrointestinal tract. These cysts may be intraluminal or extraluminal in location, with rare reports of completely isolated cysts. An intrapancreatic location may be seen in association with cysts arising from the stomach or duodenum. Duplication cysts may be lined with stratified, ciliated, or columnar epithelium and will often contain a mucoid fluid. Cysts lined with ectopic pancreatic tissue have also been reported. In keeping with the gastrointestinal origin of these cysts, the mucosa overlies a smooth muscle layer. Although most often asymptomatic, incidental discoveries, enteric duplication cysts have been reported to present with clinical symptoms. These include: dysphagia, acute gastrointestinal bleeding in association with ectopic gastric mucosa, peritonitis due to rupture, and both acute and acute recurrent pancreatitis either due to communication with the pancreatic duct (mostly reported in children) or obstruction of the pancreatic duct orifice at the major or minor papilla. Treatment is expectant for all but symptomatic enteric duplication cysts. Rare reports of malignant degeneration have led some investigators to recommend surgical excision. Endoluminal cysts may be amenable to endoscopic therapy. This is performed with a needle-knife device used to unroof the lesion.
ENDOMETRIAL CYSTS Focal cystic endometriosis was originally described in 1984. Since that time, several cases have been reported. Focal cystic endometriosis is composed of ectopic foci of endometrial cells and stroma. Age at presentation may range from 21 to 47 years. Clinical presentations include AP, abdominal pain, anemia, and weight loss. There is one case report in the literature of a cystic endometrioma of the pancreatic tail presenting as a renal mass. Preoperative diagnosis of these rare lesions is challenging due to the cyclic nature of the endometrial lining of the cysts, which occurs concomitant with menses. Significant hemorrhagic transformation of the cyst resulting in anemia has been described. Pancreatic endometrial cysts occur most commonly in the tail of the gland. Imaging studies demonstrate a mixed solid and cystic lesion. Segmental pancreatectomy is the treatment of choice, simultaneously providing both definitive and histologic diagnosis and symptomatic relief.
RETENTION CYSTS Retention cysts result from non-neoplastic, cystic dilation of the pancreatic duct due to focal obstruction. These cysts are often mistaken for pancreatic pseudocysts due to communication with the main pancreatic duct. The presence of a ductal epithelium (with variable degree of inflammatory infiltrate) lining the retention cyst distinguishes the two lesions. Retention cysts may be located anywhere within the pancreas and may present with abdominal pain, a palpable mass, obstructive jaundice, and rarely occult gastrointestinal bleeding (from local vascular erosion).
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Retention cysts may arise in obstructing ductal lesions such as ductal adenocarcinoma, mucinous obstruction (due to cystic fibrosis or intraductal papillary mucinous neoplasm), and CP associated with ductal obstruction due to proteinacious plugging, structuring, or calculi. There are rare reports of retention cysts resulting from minor papillary stenosis in pancreas divisum. Retention cysts have also been reported as a cause of hemobilia due to erosion into adjacent vessels. Surgical treatment involves the creation of a cyst-enterostomy.
CONGENITAL CYSTS Congenital cysts of the pancreas are rare, and may be stratified into those associated with known genetic syndromes (cystic fibrosis, autosomal dominant polycystic kidney disease, and von Hippel-Lindau syndrome) and true (idiopathic) pancreatic cysts. True (idiopathic) congenital pancreatic cysts are rare, comprising 0.78% of all pancreatic cysts, and are believed to result from a developmental anomaly of the pancreatic ductal system. These solitary cysts are most common in children less than 2 years of age, predominantly infant girls. Antenatal diagnosis via fetal ultrasound has been reported. There are less than 20 case reports describing idiopathic congenital pancreatic cysts presenting in adulthood. Clinical symptoms primarily consist of abdominal pain due to mass effect on adjacent viscera. The cyst may communicate with the pancreatic duct, giving rise to high amylase levels in the cyst. Histologically, the cysts are characterized by the presence of a cylindrical epithelium. Surgical management is indicated for symptomatic cysts, and provides definitive histologic diagnosis. Autosomal dominant polycystic kidney disease (ADPKD) is a relatively common congenital disorder, occurring in approximately 1 in every 400 to 1000 live births. However, it is estimated that over 50% of cases will go undiagnosed given the propensity for the asymptomatic presentation. In addition to being associated with multiple bilateral renal cysts, patients often have asymptomatic cysts in the liver and pancreas. Other major extrarenal complications of ADPKD include cerebral aneurysms, abdominal wall and inguinal hernias, colonic diverticula, and cardiac valvular abnormalities. Abdominal, flank, or back pain occurs in about 60% of patients with ADPKD, and is usually considered to be a consequence of intracystic hemorrhage or infection within kidney or liver cysts. Chronic renal failure develops in 45% of patients with ADPKD by the age of 60. The prevalence of pancreatic cysts in patients with ADPKD has been estimated to be 10% in autopsy series. This represents the second most common extrarenal cystic complication of ADPKD (after hepatic cysts). The cysts typically do not communicate with the pancreatic ductal system, and are generally diminutive, most <8 mm in size. Pancreatic cysts in ADPKD are seen most frequently in patients over 40 years of age. Complications of pancreatic cysts in ADPKD have rarely been reported, including obstructive pancreatitis from compression due to intracystic hemorrhage. Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized by benign and malignant tumors affecting multiple organs. The characteristic lesions are CNS hemangioblastomas, renal cysts and carcinomas, retinal angiomas, and pheochromocytomas. Pancreatic lesions are common in VHL, having been reported in up to 93% of cases. The pancreas may be the only organ affected in up to 7.6% of patients. In one series of 158 patients with VHL, pancreatic involvement
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was observed in 122 patients (77.2%) and included simple cysts (91.1%), serous cystadenomas (12.3%), neuroendocrine tumors (12.3%), or combined lesions (11.5%). There are rare reports of VHL associated renal cell cancer presenting as metastatic disease to the pancreas. No specific gene mutation has been found in association with pancreatic involvement. Pancreatic cysts associated with VHL present with a mean age of 41 years, although they can occur from the 2nd through the 6th decade of life. The cysts are often multiple and are present throughout the pancreas, although the tail is the most common location. Although frequently asymptomatic (95% cases), complications may be seen and include biliary obstruction, small bowel obstruction, pancreatic duct obstruction, pancreatic exocrine insufficiency, and diabetes mellitus (often seen with microcystic adenomas replacing the pancreas). Specific treatment of pancreatic cystic lesions in VHL is indicated for the 10% of cases with symptomatic cysts or for resection of large neuroendocrine tumors (>3 cm).
HYDATID CYSTS Primary pancreatic involvement is found in less than 0.20% of cases of hydatidosis, caused by the Echinococcus granulosus parasite of the dogs. The eggs of the worm are excreted with the infected dogs’ feces. Cows, sheep, pigs, and human beings are among the intermediate hosts. Hatching in the superior portion of the jejunum, the larvae cross the intestinal mucosa to the portal system and in more than 50% of cases their final destination is the liver. Other locations, in descending order of frequency, are lungs, spleen, bone, and brain; very rarely, breast, muscles, and pancreas are involved. Usually the resultant cysts grow slowly, at 0.25 to 1.0 cm a year, and for a long time they may cause no symptoms. Rare reports describe patients who have developed obstructive jaundice in the setting of a large cyst in the head of the pancreas, mimicking pancreatic malignancy. Surgery (simple drainage, marsupialization, cyst excision, or segmental pancreatectomy) is the recommended treatment of choice for symptomatic cysts.
ACINAR CYSTIC TRANSFORMATION (ACINAR CELL CYSTADENOMA) Acinar cystic transformation (also known as an acinar cell cystadenoma) is a rare, recently described pancreatic cystic lesion. These are typically multilocular cystic lesions that are lined by normal appearing acinar cells with no atypia. The lining cells stain positively for amylase and lipase, demonstrate evidence of low proliferative activity (Ki-67 index) and exhibit expression of cytokeratin-7 (CK7) (normal acinar cells express only CK8 and CK18). The cystic spaces contain a nonmucinous fluid. Although not well defined, the histopathogenesis of these lesions is believed to be cell differentiation failure leading to a cystic transformation of single acini or clusters of acini. With time, pooling of secretions may result in cyst expansion. Predominant in women with an age range of 16 to 66 years, approximately 50% present with abdominal pain or discomfort. The cysts may be found throughout the pancreas, with a size ranging up to 15 cm. Only rarely do these cysts communicate with the pancreatic duct system. Small series of patients, with follow-up of up to 7 years, demonstrate that these cystic lesions behave in a benign fashion. Many patients undergo resection of these lesions to provide a definitive histologic diagnosis, as many patients are initially diagnosed with a mucinous cystic neoplasm based on radiologic
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findings. Although it is tempting to consider acinar cystadenomas as the precursor lesion of the acinar cell cystadenocarcinoma, there have been no specific reports demonstrating malignant degeneration of this cystadenoma.
Common Cystic Neoplasms of the Pancreas It is critical that all cystic lesions of the pancreas be evaluated as possible cystic neoplasms. There is a wide histopathologic spectrum of cystic neoplasms, including intrinsic pancreatic lesions (solid pseudopapillary neoplasm, serous cystic neoplasm, mucinous cystic neoplasm, and intraductal papillary mucinous neoplasm), cystic degeneration of ductal adenocarcinoma and neuroendocrine tumors, cystic metastases, and uncommon lesions such as hemangiomas and dermoid cysts. Over 90% of cystic neoplasms of the pancreas can be accounted for by serous, mucinous, and intraductal papillary mucinous neoplasms. Among the intrinsic pancreatic lesions, one can see a broad array of malignant potential ranging from benign (serous cystic neoplasm) to pre-malignant (intraductal papillary mucinous neoplasm) (Table 12-6). Our collective understanding of the intrinsic cystic neoplasms of the pancreas has come a long way since Compagno’s and Oertel’s seminal work in 1978 in which the basic framework for histologic differentiation of serous and mucinous cystic neoplasms of the pancreas was reported. Improved technology and increased availability of cross-sectional abdominal imaging have resulted in a broader awareness of pancreatic cystic neoplasms, as well as provided critical information in regards to the varied, and not yet fully understood, biologic behaviors. In one series, 28% of pancreatic cystic lesions diagnosed between 1998 and 2000 were cystic neoplasms as compared to 15% in the early 1990s. In a large series of 327 cystic pancreatic lesions, cystic neoplasms were actually more common than pseudocysts (22%), and this may be a reflection of referral center bias. We are seeing many more patients with incidentally discovered cystic pancreatic lesions due to increasing use of cross-sectional imaging. These present a particular clinical challenge for the provider, as treatment decisions will require specific information about the nature of the cystic lesion rather than the patient’s symptomatology. There are increasing data suggesting that even asymptomatic pancreatic cystic lesions must be carefully evaluated. A recent study examined the outcome of 212 patients with pancreatic cystic lesions. These patients were evaluated by surgeons at a single tertiary care center over a 5-year interval. Of these, 78 patients had incidentally discovered cystic pancreatic lesions. The mean age at diagnosis was 65 +/- 13 years. The mean size of the lesions was 3.3 +/- 1.9 cm. Of these, 78% underwent operative evaluation. A broad spectrum of lesions was identified, including mucinous cystic neoplasms (28%), intraductal papillary neoplasm (27%), serous cystadenoma (17%), pseudocyst (3%), and pancreatic adenocarcinoma (2.5%). The remaining 22% were either “indeterminate” or “other” cystic neoplasms. Furthermore, nearly 60% of asymptomatic patients had histologic findings demonstrating in-situ or invasive cancer, or premalignant epithelial changes. In contrast, among the 134 symptomatic patients, the cystic lesions were larger (4.6 +/- 2.7 cm) and the patients were younger (56 +/- 15 years). Nearly 50% of lesions in this group were either mucinous cystic neoplasms or intraductal papillary mucinous neoplasms. Pseudocysts accounted for nearly 20% of lesions. In this study, among asymptomatic patients, a cystic mass size cut-off of 2 cm appeared to help discriminate malignant and benign lesions, with only 3.5% of smaller lesions harboring malignancy.
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Table 12-6
INTRINSIC CYSTIC NEOPLASMS OF THE PANCREAS Type
Mean Age
Gender Predilection
Anatomic Location
Solid pseudopapillary neoplasms
26 yrs
(F:M) 9-10:1
Serous cystic neoplasms
61 yrs
3-4:1
Body/tail > head
Mucinous cystic neoplasm
49 yrs
9:1
Body/tail >>head
Intraductal papillary mucinous cystic neoplasm
68 yrs
1:2
Head >> body/tail (side branch) Body/tail =head (main duct)
Body/tail = head
Type
Histology
Fluid Characteristics
Malignant Potential
Solid pseudoneoplasms
Pseudopapillary projections
Non-mucinous debris
Low
Serous cystic neoplasms
Simple cuboida epithelial
Thin, non mucinous Low amylase Low CEA
Rare
Mucinous cystic neoplasm
Flat mucinous epithelial
Viscous, mucinous Low amylase High CEA
High
Intraductal papillary mucinous cystic neoplasm
Papillary projections of mucinous epithelium
Viscous, mucinous High amylase High CEA
Moderate
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SOLID-PSEUDOPAPILLARY NEOPLASM Solid-pseudopapillary neoplasms (SPN) of the pancreas are uncommon benign or low-grade malignant epithelial neoplasms of the pancreas with cystic features. Primarily affecting young women, solid-pseudopapillary neoplasms account for 1% to 2% of all exocrine pancreatic tumors and approximately 12% of cystic neoplasms of the pancreas. The mean age of diagnosis is 26, with a reported range of 2 to 72 years. On average, male patients tend to be older than female patients (31.4 years versus 25.5 years). In all series, there is a striking female preponderance (9-10:1). First reported by Frantz in 1959, this cystic neoplasm has been classified in the literature under multiple names, including solid-cystic tumor of the pancreas, papillarycystic tumor of the pancreas, solid and papillary epithelial neoplasm, solid and cystic acinar neoplasm, Frantz’s tumor, and pancreatic embryonic tumor. With more than 500 cases now reported in the English literature, both the World Health Organization and the Armed Forces Institute of Pathology have formally categorized this lesion as a solid-pseudopapillary neoplasm. The cell of origin for this tumor remains unknown. Some investigators have cited a possible stem cell origin given the diverse immunostaining patterns (endocrine, epithelial, and mesenchymal). Cytogenetic studies have demonstrated variable rates of loss of XX and trisomy 3. Abnormalities of the Wnt pathway (involved in beta catenin and cyclin D1) have been found in over 80% of these neoplasms. Neither the K-ras nor p53 pathways seem to play a major role in the evolution of the solid pseudopapillary neoplasm. Many patients with particularly large solid-pseudopapillary neoplasms present with abdominal pain, a palpable mass, weight loss, and/or nausea and vomiting. Most frequently, however, the tumor is discovered incidentally when the abdomen is being imaged for other reasons, including after blunt abdominal trauma. There are rare case reports of significant hemoperitoneum occurring due to capsular rupture (2% to 3% of cases). Jaundice and pancreatitis are distinctly unusual. There have been no reported cases of a solid-pseudopapillary neoplasm presenting with an endocrinopathy. The diagnosis of a SPN must be considered in the differential diagnosis of a new solid-cystic mass, particularly in a young woman. SPN are well-demarcated pancreatic tumors, with rare reports of extrapancreatic or ectopic (liver, inguinal canal, retroperitoneum) sites. They tend to be large, round tumors with a size ranging from 1 to 30 cm, with a mean size at diagnosis of approximately 9 cm. Any region of the pancreas may be affected, though with greatest frequency in the body and tail. There are rare reports of synchronous tumors in the head and tail of the pancreas. The majority of SPN are mixed solid and cystic lesions, with a minority (5.6%) demonstrating only solid features. A number of different imaging modalities have been used to evaluate this lesion. Plain abdominal films may demonstrate calcifications of the tumor pseudocapsule in up to 30% of patients. Transabdominal ultrasound and CT reveal these to be welldefined mixed solid and cystic mass lesions, particularly in the body and tail of the pancreas. They may masquerade as pseudocysts with significant internal debris. On MRI, these lesions tend to demonstrate heterogeneous high signal intensity on T2weighted images with early peripheral heterogeneous enhancement with progressive fill-in on gadolinium enhanced dynamic imaging. Angiography usually demonstrates
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Figure 12-3. EUSguided FNA.
SPNs as hypovascular tumors. As SPNs do not communicate with the pancreatic duct, ERCP is typically normal or may demonstrate displacement of the pancreatic duct due to extrinsic mass effect. There are now case reports of identification and diagnosis of SPNs of the pancreas with EUS-guided FNA (Figure 12-3). Serum CEA and CA 19-9 are normal in patients with SPNs. On gross pathologic examination, the cut surface reveals lobulated, yellow tissue and cyst formation arising out of varying degrees of hemorrhage and necrosis, particularly in the center of the lesion. There is usually a distinct fibrous capsule separating the tumor from the remainder of the pancreas. On microscopy, there is a pseudopapillary architecture with cells around a delicate microvascular network. The cells lining the cyst have eosinophillic cytoplasm, which may or may not contain PAS-positive, diastase-resistant intracytoplasmic globules. There is distinct absence of mucin or glycogen staining. These features provide for a highly characteristic cytologic appearance, allowing the pathologist to distinguish the SPN from other cystic neoplasms of the pancreas. The treatment of choice is surgical resection, including for those lesions identified incidentally. Over 85% of patients (males and females equally) will have an excellent prognosis following surgery, supporting the overall benign phenotype of these lesions. Nonetheless, these tumors are best classified as having borderline malignant potential, with an infrequent but well-documented incidence of the development of invasive or metastatic lesions. Based on large series, approximately 15% of SPNs display a malignant phenotype with development of metastatic deposits or local invasion. Reported sites of metastases include (in order of decreasing frequency): liver, peritoneum, and regional lymph nodes. Direct invasion into adjacent viscera may also be seen in rare instances. Predictors of malignant potential include the presence of perineural or vascular invasion, nuclear atypia, mitotic index, and prominence of necrobiotic rests on microscopy. Metastatic deposits are more likely to have distinct cytogenetic abnormalities including aneuploidy, unbalanced chromosome 17;13 translocations, and trisomy 3.
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Several small series have highlighted the importance of being aggressive with surgical resection in all patients, including those with evidence of local invasion, metastatic deposits, and tumor recurrences. Recurrences as far out as 8 years have been reported in patients who have undergone primary resection. Therefore, patients must be followed closely for the development of new or changing abdominal symptoms. Of interest, a number of patients have now been reported with long-term survival even with known metastatic deposits, highlighting the slow tumor doubling rate (estimated at 765 days by serial CT scans). A possible survival benefit has been suggested in some series in which children with metastatic disease at the time of initial resection are treated with adjuvant chemotherapy. As one might expect, however, there are rare reports of fatalities in the face of disease progression.
SEROUS CYSTIC NEOPLASMS Serous cystic neoplasms (serous cystadenomas and serous cystadenocarcinomas) are generally benign cystic lesions of the pancreas characterized by an epithelial lining of glycogen-containing cuboidal cells. The most common serous cystic neoplasm is the microcystic serous cystadenoma, accounting for 70% of lesions. The less common variants include the macrocystic (or oligocystic) serous cystadenoma, ill-demarcated serous cystadenoma, and the solid serous cystadenoma. Serous cystadenocarcinomas are rare cystic neoplasms, presumably reflecting the uncommon phenomenon of malignant degeneration of a serous cystadenoma. Depending on the series, serous cystic neoplasms account for 10% to 36% of all cystic neoplasms of the pancreas. Compagno and Oertel first described serous cystic neoplasms of the pancreas as a clinicopathologic identity in 1978, classifying the distinct histopathology that distinguishes serous cystic neoplasms from mucinous cystic neoplasms. There is again a female preponderance, on the order of 3-4:1, although this is less consistent in the case of the macrocystic serous cystadenoma. The mean age of patients at the time of diagnosis is 61, with an age range from 34 to 91 years. There are scattered reports of children as young as 4 years with a serous cystic neoplasm. Most lesions (75%) are located in the body or tail of the pancreas. The macrocystic variant is more commonly found in the head and body of the pancreas. There is growing knowledge regarding the pathogenesis of serous cystic neoplasms. As previously noted, patients with VHL syndrome have a high frequency of serous cystadenomas. Among these patients, there is no gender predilection and the age at diagnosis tends to be younger (mean age, 42 years). Unlike sporadic cases, VHL associated serous cystic neoplasms may involve the entire pancreas. In sporadic cases, up to 70% of patients will demonstrate loss of heterozygosity (LOH) at chromosome 3p25, the location of the VHL gene. In addition, up to 50% of patients will have LOH at chromosome 10q. The majority of patients are found to have a serous cystic neoplasm incidentally, discovered through abdominal imaging or surgery. When symptomatic (up to 50% of patients), the most common clinical presentations of serous cystic neoplasms include those resulting from mass effect on the gastrointestinal lumen (nausea, vomiting, abdominal pain, bloating) and rarely obstructive jaundice from common bile duct compression (eight reported cases in the literature). There are rare reports of serous cystic neoplasms in association with hemoperitoneum, gastrointestinal bleeding, and esophageal varices due to arterial-portal shunting.
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Figure 12-4. Oligocystic pattern.
Making a correct diagnosis of a serous cystic neoplasm is vital, as it generally allows for nonoperative, expectant management in all but symptomatic patients. A number of imaging modalities have been used to characterize these lesions. These cystic masses are typically round lesions, from 1 to 25 cm in size, with a mean size of 8 cm. Plain abdominal radiographs may reveal calcifications. The classic finding on abdominal CT is that of a microcystic mass in the body or tail of the pancreas. Thin cut CT protocols may demonstrate innumerable cystic spaces within the lesion separated by thin septae. In up to 20% of cases, a central scar containing a “starburst” calcification may be seen. Additionally, the lesion is typically intense on T1-weighted and hyperintense on T2-weighted MRI, particularly in the case of a macrocystic serous cystic neoplasm. Given the lack of communication with the main pancreatic duct, ERCP may be normal or show evidence of displacement from extrinsic compression. Angiography typically demonstrates these lesions to be hypervascular in nature. One series compared the accuracy of transabdominal ultrasound (US), abdominal CT, and MRI for the diagnosis of serous cystic neoplasms. Both US and abdominal CT fared similarly, with nearly 1/3 of cases being incorrectly diagnosed and up to 16% being nondiagnostic studies. MRI performed the best of the three with an overall accuracy of 74%. EUS classically demonstrates a single, large multicompartmental cystic mass, often with larger cysts on the periphery of the lesion, or in the case of the macrocystic serous cystadenoma, an oligocystic pattern (Figure 12-4). The septae are notably thin (2 to 4 mm). The oligocystic nature of the macrocystic serous cystic neoplasm presents particular difficulties, as it may resemble a mucinous cystic neoplasm if there are one or two compartments. A central scar with calcification is a variable finding. Mural nodules and calcifications are noticeably absent in the vast majority of these lesions. EUS-FNA may provide an additional level of diagnostic insight to the ultrasound morphologic features. EUS-FNA of the cyst is most useful to obtain a cytologic sampling of the cuboidal lining and to obtain cyst fluid for analysis of biomarkers. There are several challenges facing the endoscopist performing EUS-FNA of serous cystadenoma including the hypervascular nature of the lesion, which may result in a cytology sample overly contaminated with blood. In addition, the cystic spaces may be quite small, making adequate fluid aspiration difficult. Finally, cytologic yields may
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fail to provide a diagnosis in up to 60% of cases. The aspirated cyst fluid is typically a thin, clear, or yellow-tinged fluid with minimal viscosity (reflecting the absence of mucin). Hemorrhagic aspirates are sometimes seen due to the hypervascular nature of the lesion. The cyst fluid amylase, CEA, and CA 72-4 should all be low (CEA <10 ng/mL) consistent with lack of ductal communication (amylase) and mucinous epithelium (CEA and CA 72-4). Therefore, both the morphologic findings of EUS and the results of FNA help provide diagnostic information, and in the correct clinical setting, may help defer surgical investigation. EUS with FNA is therefore the imaging modality of choice for the evaluation of serous cystic neoplasms. On gross pathology, the microcystic serous cystic neoplasm is characterized by a honeycombed appearance with numerous small cystic spaces separated by thin septae. A central scar with calcification may be seen. They are usually well-demarcated in the pancreatic parenchyma. The cells lining the cyst spaces are uniform, flat cuboidal epithelium generously containing PAS-positive, diastase material consistent with glycogen. Mucin expression is not observed. The cytoplasm is clear and the nuclei do not demonstrate atypia. Mitoses are extremely infrequent. The lining cells are supported by a loose collagenous stroma. Immunophenotyping, though rarely done, may demonstrate cytokeratin, and characteristically is negative for neuroendocrine and exocrine markers. In contrast to mucinous cystic neoplasms, which are known to have significant malignant potential, serous cystic neoplasms are generally considered to have benign biologic behaviors. One study from Heidelberg estimated that the prevalence of cancer among serous cystic neoplasms reported in the literature, since the first reported case in 1989, to be 3%. In this same analysis, the median age of presentation of patients with serous cystadenocarcinoma was found to be 5 years later than that of serous cystadenomas (66 years versus 61 years). Patients with serous cystadenocarcinomas tended to have more abdominal symptoms than their benign counterparts. In 38% of cases, one could not distinguish the two lesions on the basis of standard pathologic examination. In 25% of cases, a diagnosis of serous cystadenocarcinoma could only be made after the development of metachronous metastases. These authors cited nuclear atypia, the presence of papillary structures on histology, and elevations in proliferation markers (Ki-67 index and p53 expression) as features associated with an increased risk of malignant behavior. Given the benign nature and excellent prognosis, expectant management follows in the majority of patients in whom a diagnosis of a serous cystadenoma is believed to be certain on the basis of consistent features by radiology, cytology, and/or cyst fluid tumor markers. Therefore, a meticulous evaluation, including the use of EUS-FNA for cytologic and cyst fluid biomarkers (CEA, CA 72-4, and amylase) is essential in providing an accurate and timely diagnosis. Surgical resection is the mainstay of treatment for those patients with symptomatic serous cystic neoplasms (obstruction or pain), for patients in whom definitive histopathologic diagnosis is desired or in cases where the preoperative diagnosis remains uncertain, and in those rare patients with clinical, radiographic, endoscopic, or cytologic concern for malignant degeneration. In addition, because of the difficulty in excluding a mucinous neoplasm on the basis of morphologic criteria, many patients with macrocystic (oligocystic) serous cystadenomas undergo operative resection.
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MUCINOUS CYSTIC NEOPLASMS The mucinous cystic neoplasms (MCNs) of the pancreas include the mucinous cystadenoma and cystadenocarcinoma. These are considered the most aggressive of the cystic neoplasms of the pancreas with overall 5-year survivals between 30% and 40%. MCNs are part of the spectrum of mucin-secreting tumors of the pancreas that includes the intraductal papillary mucin neoplasms (IPMN). These lesions, although similar in regard to cellular origin and mucin production, have been formally made distinct clinicopathologic entities by the WHO and Armed Forces Institute of Pathology (AFIP) in 1996. MCNs account for up to 5% of all exocrine pancreatic tumors and 10% of cystic pancreatic neoplasms. The pathogenesis of these lesions remains uncertain at this time. Nonetheless, the striking female preponderance has raised the question of hormonal dependence or whether, like the solid-pseudopapillary tumor, these lesions represent developmental anomalies due to close association of the dorsal pancreatic anlage and genital ridge during embryogenesis (genital ridge hypothesis). Some key epidemiologic features help distinguish these lesions from other cystic neoplasms, and in particular, IPMNs. These lesions are nearly exclusively found in women (9:1 female:male ratio). The mean age at diagnosis is 49 years with a range from 20 to 82 years. Although patients may have abdominal symptoms on the basis of mass effect and obstruction or a palpable mass (60% in some series), a significant number will be identified incidentally. Pancreatitis is rare, as the lesion does not communicate with the main pancreatic duct, except for the <20% of cases with documented fistulization. On imaging studies, the lesions are usually solitary macrocystic mutilocular lesions (occasionally unilocular) in the body and tail regions of the pancreas. Less than 10% of lesions are located in the head of the pancreas. These lesions can be quite large, up to 35 cm as reported in the literature. Peripheral calcifications may be evident. Septal thickening and mural nodules may be seen and may indeed harbor malignancy. Dilation of the main pancreatic duct is unusual and should raise suspicion for an IPMN. On ERCP, the papillary orifice should be normal in appearance without mucin extrusion. The main pancreatic duct may be displaced, and in unusual cases, fistulization to the pancreatic duct may be noted. The pancreatic duct may become obstructed in the setting of invasive malignancy. Endoscopic ultrasound demonstrates a macrocystic lesion with variable findings of septal thickening and mural nodules, both concerning for malignant degeneration (Figure 12-5). FNA may be diagnostic with the typical finding of highly viscous fluid consistent with mucin hypersecretion. Fluid may be sent for cytology looking for mucin and mucin-producing epithelial cells. Cyst fluid amylase should be low given the absence of ductal communication, and tumor markers CEA and Ca 72-4 are typically elevated, the degree to which roughly correlates with the grade of dysplasia. As in the case of IPMNs, fluid CEA >300 ng/ mL is highly sensitive and specific for a mucinous neoplasm. The diagnosis of MCN is usually made on the basis of a combination of epidemiology (middle-aged woman), clinical history (mostly asymptomatic or with mild pain), radiologic/EUS findings (unilocular or multicompartmental lesion of the pancreas body and tail without pancreatic duct dilation), and with cytology/tumor markers (mucin-containing cyst fluid with elevated fluid CEA and low amylase). Surgical pathology demonstrates multicompartmental, mucin containing cystic lesions lined
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Figure 12-5. Endoscopic ultrasound demonstrates a macrocystic lesion with variable findings of septal thickening and mural nodules, both concerning for malignant degeneration.
by flat epithelium with varying degrees of atypia. Mucin may be demonstrated with alcian blue, mucicarmine, or PAS stains. A characteristic feature of mucinous cystic neoplasms is the finding of an ovarian-type stroma supporting the cystic mass. This stroma may demonstrate focal hyalinization. There are reports of estrogen and progesterone receptor staining in both the stromal and epithelial elements. In addition, the epithelium will stain positively for cytokeratins and in up to 40%, neuroendocrine markers may be positive. As with IPMNs, cysts are classified pathologically on the basis of the grade of cellular atypia. Four categories have been established, including adenoma, borderline/low malignant potential, carcinoma in situ, and invasive cancer. Mucinous cystic neoplasms have a significant propensity for malignant degeneration. Location in the pancreatic head, multilocularity, and solid mural nodules are associated with a high risk of invasive malignancy. Malignant MCNs may demonstrate features of typical ductal adenocarcinoma (reflecting the cell of origin of this tumor), an undifferentiated adenocarcinoma often with osteoclast-like giant cells, and sarcomatous degeneration of the supporting stroma. In contrast to IPMNs, lymph node involvement (group I and group II nodes) is far greater in frequency, approaching 60% of cases of invasive cancer. Recurrence and tumor-related death are associated with the presence of invasion and the completeness of excision. Therefore, surgery should be aimed at complete resection of the lesion and nodal dissection. Overall 5-year survival rate for cysts with carcinoma is 50%, again demonstrating a more favorable prognosis compared to typical ductal adenocarcinoma. However, with transmural invasion, survival is approximately 30%. Therefore, most authors recommend assuming that all MCNs are either premalignant or malignant at diagnosis and should be resected in entirety in suitable candidates.
INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM The IPMN is an increasingly recognized cystic neoplasm of the pancreas characterized by intraductal proliferation of mucin-producing cells, arranged in papillary fashion. There may be involvement of the main pancreatic duct, side branch ducts, or
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a combination of involvement. This lesion is most commonly seen in elderly men, and is most often located in the head of the pancreas. The varied clinical presentations, ranging from being detected as incidental lesion on cross-sectional imaging to relapsing AP and obstructive jaundice, makes this an important lesion in one’s consideration of a broad differential diagnosis of abdominal symptomatology. One may find a wide variety of lesions including ductal dilation, cyst formation with septations, and possibly solid mass lesions in the case of neoplastic degeneration. Given the significant propensity for malignant degeneration, it is critically important to accurately diagnose this cystic neoplasm. There has been an evolving role for magnetic resonance cholangiopancreatography to classify lesions according to ductal anatomy and provide information regarding the nature of the lesion (solid features concerning for malignancy). EUS-guided FNA provides valuable information on morphologic features and provides cyst fluid and tissue for cytology and biomarker testing, which is helpful in diagnosis and possibly, prognosis. The medical literature has seen a dramatic surge in the number of reports pertaining to IPMNs since the original description by Ohashi and Maruyama in 1982. These Japanese investigators provided the seminal clinicopathologic narrative of four patients in whom they observed malignant pancreatic duct neoplasms characterized by markedly dilated main pancreatic duct in association with hypersecretion of mucin extruding through a dilated pancreatic duct orifice at the major papilla. Of perhaps greater importance, they also noted a more favorable overall prognosis compared to patients with more typical ductal adenocarcinomas of the pancreas. Over 20 different names have been used to describe this lesion in the literature, including most notably, mucinous ductal ectasia, mucin-hypersecreting tumor, and duct-ectatic type pancreatic ductal carcinoma. In addition, for many years, the relationship between IPMNs and MCNs (including mucinous cystadenomas and mucinous cystadenocarcinomas) remained unclear. As set forth by both the WHO and the AFIP in 1996, MCNs and IMPNs are distinct entities along the spectrum of mucinous neoplasms of the pancreas. They differ in epidemiology and morphologic characteristics (location in the pancreas and communication with pancreatic duct). However, they are both associated with mucin overproduction and a propensity for malignant degeneration. The true epidemiology of IMPNs remains uncertain. The perceived increased incidence may in fact be due to a greater awareness of the disease rather than a change in disease occurrence. In one surgical series, up to 20% of resections for pancreatic malignancy were for IPMNs. IPMNs comprise up to 8% of all exocrine tumors of the pancreas, and from 5% to 36% of all cystic lesions of the pancreas. Causative factors remain poorly defined. There are some preliminary reports indicating that alcohol, tobacco, and dietary nitrosamines may promote the development of IPMNs. Some series have described an association with extrapancreatic neoplasia (up to 30% patients), raising the question of an underlying germ line process. Molecular studies of the cells lining the cyst have provided some clues in regard to the pathogenesis and natural history. These clearly have suggested a step-wise progression over a long period of time in most patients, with correlation between histopathologic stage and frequency of specific gene mutations.
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Figure 12-6. Considered the gold standard study, ERCP may demonstrate a patulous papillary orifice with mucin extrusion in up to 50% of patients, ductal dilation in 100%, and ductal filling defects due to mucin.
In most clinical series, a male predominance exists. The mean age of diagnosis is 68, with patients diagnosed from 60 to 70 years of age. There have been case reports of IPMNs being discovered in individuals as young as 30. In general, patients with side branch variety IPMNs are younger than those with main pancreatic duct involvement. Although the entire pancreas may be involved, most lesions emanate from the head (up to 80%). Clinically, the most common presenting symptoms appear to be abdominal pain, weight loss, anorexia, and diarrhea. These occur as a result of relapsing AP or CP in obstruction of the pancreatic duct by mucin or a malignant stricture (up to 80%). Rarely, patients may present concurrently with a new diagnosis of diabetes mellitus. Large lesions in the head of the pancreas or those with solid components may result in obstructive jaundice (10%). Due to the expansion of imaging availabilities, IPMNs are also being discovered incidentally. Elevations in serum tumor markers (CEA or CA 19-9) are noted in <20% of patients. The diagnosis of IPMNs requires a combination of clinical, radiologic, endoscopic, and cytopathologic data. A variety of imaging modalities may demonstrate characteristic findings. Most symptomatic patients will undergo screening with transabdominal US and/or CT. In addition to characterizing the size and location of the cystic lesion, CT may also provide information on associated ductal dilation, solid components, regional adenopathy, and the status of the biliary tract. Features such as the presence of main pancreatic duct dilation >10 mm, side branch dilation >15 mm, a solid mass, and diffuse pancreatic involvement all raise concern for a malignant IPMN. Considered the gold standard study, ERCP may demonstrate a patulous papillary orifice with mucin extrusion in up to 50% of patients, ductal dilation in 100%, and ductal filling defects due to mucin (Figure 12-6). In fact, filling of the pancreatic duct may be challenging due to impedance from the intraductal mucin, which may then require use of an occlusion balloon. Pancreatic juice can be sampled for cytology in addition to performing brushings of the duct. The sensitivity and specificity of these
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techniques is approximately 40% and 100%, respectively. Special techniques, including acquiring cytology following secretin stimulation, appear to enhance sensitivity. There is growing interest in using pancreatic juice mutational analysis (K-ras) and measurements of telomerase activity (present in up to 90% of malignant IPMNs) to further enhance the detection rate of malignant IPMNs. ERCP also provides a conduit for per oral pancreatoscopy and intraductal ultrasound (IDUS) with high frequency (15 to 20 MHz) probes. Per oral pancreatoscopy may show typical papillary protrusions (“fish-eggs”) and IDUS may reveal focal wall thickening and nodularity. Although some investigators have demonstrated usefulness of these techniques both in diagnosis and in preoperative staging, they are not widely available and may not be technically feasible in all cases. MRI/MRCP is increasingly seen as comparable, and perhaps superior, to ERCP in the diagnosis and staging of IPMNs. Studies have demonstrated a diagnostic accuracy of 80% to 100% and enhanced detection rate for mural nodules compared to ERCP. In addition to mural nodules, main pancreatic duct >15 mm and combined side branch and main duct involvement are features on MRI/MRCP concerning for malignancy. Although MRI/MRCP does not provide the ability for cytology acquisition as does ERCP, the ability to assess the entire ductal anatomy without accompanying procedural risk makes this an essential imaging modality for evaluating patients with IPMNs. EUS has become an essential diagnostic modality for evaluating suspected IPMNs with a sensitivity and specificity of 86% and 99% using ERCP as the gold standard. On morphologic grounds, these lesions may appear as focal or diffuse dilations of the pancreatic duct or side branches. Cysts with internal septations and mural nodules may be identified. Accompanying solid mass lesions may also be seen and are an ominous finding. EUS-guided FNA provides fluid and tissue for cytopathology (yield only about 30%) and for measurement of biomarkers (amylase and CEA). Elevated amylase and CEA are consistent in IPMNs. A cyst fluid CEA >300 ng/mL supports the diagnosis of a mucinous neoplasm such as IPMN. Values in excess of 1000 ng/ml are highly suggestive of malignant degeneration. Recent data have examined the potential of 18-FDG PET in determining benign versus malignant cystic neoplasms, including patients with an IPMN. Sensitivity and specificity for 18-FDG PET was 94%. The authors concluded that 18-FDG PET should be routinely used in combination with CT in the preoperative evaluation of patients with cystic lesions of the pancreas. The main differential diagnosis that is considered when evaluating patients with suspected IPMNs includes chronic pancreatitis, ductal adenocarcinoma of the pancreas, and a mucinous cystic neoplasm (cystadenoma or cystadenocarcinoma). Changes often seen in CP may also be features when imaging the pancreas of patients with IPMNs. One recent study of EUS features noted several findings more common in IPMN as compared to CP, including dilation of PD (89% versus 42%), cysts (45% versus 11%) and pancreas atrophy (32% versus 3%). These authors concluded that two or more parenchymal abnormalities typical of chronic pancreatitis make IPMN less likely, including hyperechoic foci and stranding, calcifications, and lobularity of the gland. Patients with ductal adenocarcinoma tend to have far greater systemic symptoms and weight loss, and on imaging have more invasive features than IPMNs. In contrast to MCNs, IPMNs are more frequently seen in the pancreatic head versus in the body and tail of the pancreas, have a male rather than female predominance, and communicate with the pancreatic duct.
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On gross pathology, IPMNs exhibit cystic dilation of the main pancreatic duct alone or in combination with side branch changes. In approximately 25% of cases, only side branch duct involvement may be seen. A minority of IPMNs are multifocal, with intervening segments of normal pancreas. In a variable number of cases, one may see solid mass lesions, often arising from cystic mural nodules. Microscopically, the mucinous epithelium is characterized by papillary projections emanating from the pancreatic duct. The cells may exhibit a gastroenteric, pancreatobiliary, or oncocytic differentiation. The significance of these varying histologic categories in regard to natural history and prognosis remains uncertain. As in the case of mucinous cystic neoplasms, IPMNs are classified according to degree of epithelial cellular atypia. The four categories include adenoma, borderline tumor, carcinoma in situ, and invasive carcinoma. As the lesion progresses, there is a loss of mucin production and nuclear polarity. Carcinoma in situ is seen in up to 60% of IPMNs, with the highest prevalence in those lesions with combined main duct and side branch involvement, and the lowest with side branch disease only. Invasive carcinoma is seen in up to 35% of cases and regional (group I) lymph nodes may be found in 20% to 30%. Our understanding of the natural history of IPMNs continues to evolve. At this time, it is believed that the majority of lesions are slow growing; some taking decades to progress. The estimated 5-year survival for all patients is 60%, which compares favorably to typical ductal adenocarcinoma of the pancreas. Although the majority of lesions are benign, the rate of malignant degeneration and factors associated with this progression remain uncertain. Studies to date have demonstrated a more favorable course for side branch IPMNs compared to mixed or main duct variants (5-year survival of 90% versus 47%). In agreement with this, several imaging surveillance studies have confirmed minimal progression in most side branch IPMNs followed by MRI/MRCP over several years. In addition, multivariate analysis has established that abnormal liver tests, concurrent alcohol use, and p53 overexpression are associated with worse outcomes, whereas gross mucus identified at endoscopy was associated with a more favorable outcome. In contrast to colorectal and gastric malignancies, high frequency microsatellite instability is not associated with a good prognosis. As noted, radiologic, endosonographic, cytologic, and biochemical markers may be used to classify the risk of invasive malignancy in any given lesion. However, these markers are neither sensitive nor specific enough to base confident clinical decisions on in all cases. These limitations in our understanding have led some investigators to advocate surgical resection in all suitable patients. Because of the potentially diffuse nature of the disease process, careful preoperative imaging evaluation is essential to help guide the nature and extent of resection. Nonetheless, most surgical resections are guided by intraoperative evaluation of surgical margins by frozen section or intraoperative pancreatoscopy in combination with an assessment of the potential for operative morbidity and mortality associated with wider resection in any individual patient. A study of 113 patients with IPMNs (40 invasive and 73 noninvasive) demonstrated a 62% and 67% recurrence rate for invasive carcinoma after partial resection and total pancreatectomy, respectively (91% recurrences within 3 years). Noninvasive carcinomas rarely recur (8% after partial) and 0% recur after total pancreatectomy (median follow-up 32 to 37 months). Overall, the 5-year survival rate in this study was 84.5% for noninvasive malignancies and 36% for invasive carcinomas.
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Noninvasive, expectant management is reasonable in patients at high risk for surgical morbidity and mortality. Additionally, patients with focal side branch variant IPMN, <2.5 cm in size may be carefully watched with serial imaging studies (such as MRCP), as the risk of malignant progression is low. If there is growth of the lesion or evidence of main pancreatic duct involvement over time, surgical therapy would be indicated. New treatment options, including cyst lavage with alcohol to ablate the epithelium, are under study in patients who may not be suitable surgical candidates.
Uncommon Cystic Neoplasms of the Pancreas There is a growing list of pancreatic neoplasms that may demonstrate significant cystic components. Many of these are typically solid neoplasms that infrequently undergo cystic degeneration. Although rare, these lesions should remain on the differential diagnosis of a newly identified cystic mass in the pancreas.
CYSTIC NEUROENDOCRINE TUMORS There are now over 20 reported cases of cystic degeneration of pancreatic neuroendocrine tumors. The reported cases demonstrate no gender, age (range 19 to 85 years), or anatomic location predilection. Despite positive immunohistochemical staining, only 30% to 40% of lesions are considered hormonally functional, the majority of which have been gastrinomas. There are reports of locally invasive or metastatic lesions, with a suggestion that this may be occurring at a less than expected frequency compared to purely solid neuroendocrine tumors. Surgical treatment is recommended in all cases.
ACINAR CELL CYSTIC NEOPLASM The acinar cell neoplasm is a rare solid neoplasm of the pancreas, which has been reported to have a cystic variant. Although unproven, the acinar cell cystadenocarcinomas may represent malignant degeneration of the recently described acinar cell cystadenomas. Acinar cell cystadenocarcinomas are generally large, encapsulated, multilocular cystic masses ranging from 5 to 35 cm in size. They may be located throughout the pancreas. The cysts are filled with nonmucinous liquid. Lining cells may be cylindrical or cuboidal and demonstrate typical acinar differentiation. In the few reports published, it appears that these lesions are aggressive with a significant propensity for peritoneal and hepatic dissemination.
OTHER LESIONS Cystic ductal adenocarcinomas account for up to 10% of all cystic tumors of the pancreas in some series. This may be more common in the adenosquamous histologic subtype. Mechanisms include:
1. Tumor necrosis, usually in large, poorly differentiated tumors. 2. Retention cyst or pseudocyst formation due to ductal obstruction. 3. The development of large, ectatic duct structures seen in some well-differentiated tumors.
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Additional rare pancreatic neoplasms that may exhibit cystic degeneration include lymphoma, leimyosarcoma, Schwannoma, and malignant fibrous histiocytoma. Metastatic deposits in the pancreas, including renal cell carcinoma and melanoma, have been noted to be cystic in nature. Approximately eight reported cases of cystic pancreatic paragangliomas have been described. Nonfunctional paragangliomas of the pancreas usually do not produce any symptoms and are found either incidentally or when they become large enough to be palpable. Most lesions were located in the head of the pancreas. Dermoid cysts of the pancreas, also called cystic teratomas, are rare neoplasms of germ cell origin. Only 12 cases have been described in the world literature. Symptoms are due to tumor compression of neighboring tissues. Vascular tumors of the pancreas are cystic benign tumors accounting for 0.1% of all pancreatic tumors. There are case reports of lymphangioma, hemangioma, hemolymphangioma, hemangiopericytoma, hemangioblastoma, and hemangiosarcoma. Lymphangioma is the most frequent of these pancreatic tumors and approximately 34 cases have been reported. Most lesions are found in women (70%) with a mean age of 47 years. Diagnosis is usually made on the basis of histologic evaluation with identification of endothelial cells lining the internal surface of the cystic spaces with a characteristic immunohistochemical staining pattern positive for factor VIII-R antigen and CD31.
Conclusions The growth of cross-sectional abdominal imaging has resulted in a dramatic increase in our awareness of cystic lesions of the pancreas. Wider availability and expertise with EUS has provided clinicians with the ability to evaluate these lesions with greater frequency and accuracy. Pseudocysts, still considered the most frequent cystic lesion of the pancreas, remain a challenging complication of both AP and CP. The advent of endoscopic diagnosis and drainage of pseudocysts has provided a safe and effective option for evaluation and treatment. Although our understanding of cystic neoplasms of the pancreas has also evolved over the past two decades, many issues remain unsettled. The pathogenesis, biologic behavior, and natural history for many cystic neoplasms of the pancreas are poorly defined. In appropriate candidates, surgical resection remains the standard of care in symptomatic disease, unclassified lesions, or in lesions in which the biologic behavior cannot be determined on the basis of cyst fluid markers, cytology, or radiologic characteristics. EUS has revolutionized our ability to evaluate these lesions and will continue to expand in this role. In the future, evaluation of these lesions will incorporate molecular techniques to further classify the diagnosis and natural history. EUS also has the capability of providing a therapeutic option. Trials evaluating the role of ethanol or radiofrequency ablation of cystic neoplasms are currently underway.
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45. Sahani D, Prasad S, Saini S, et al. Cystic pancreatic neoplasms evaluation by CT and magnetic resonance cholangiopancreatography. Gastrointest Endosc Clin N Am. 2002;12:657-672. 46. Sarr MG, Murr M, Smyrk TC, et al. Primary cystic neoplasms of the pancreas. Neoplastic disorders of emerging importance-current state-of-the-art and unanswered questions. J Gastrointest Surg. 2003;7(3):417-428. 47. Sarr MG, Carpenter HA, Prabhakar LP, et al. Clinical and pathologic correlation of 84 mucinous cystic neoplasms of the pancreas: can one reliably differentiate benign from malignant (or premalignant) neoplasms? Ann Surg. 2000;231:205-212. 48. Casadei R, Minni F, Selva S, et al. Cystic lymphangioma of the pancreas: anatomoclinical, diagnostic and therapeutic considerations regarding three personal observations and review of the literature. Hepatogastroenterology. 2003;50:1681-1686. 49. Stamm B, Burger H, Hollinger A. Acinar cell cystadenocarcinoma of the pancreas. Cancer. 1987;60:2542-2547. 50. Strobel O, Z’graggen K, Schmitz-Winnenthal FH, et al. Risk of malignancy in serous cystic neoplasms of the pancreas. Digestion. 2003; 68:24-33. 51. Sugiyama M, Abe N, Tokuhara M, et al. Magnetic resonance cholangiopancreatography for postoperative follow-up of intraductal papillary-mucinous tumors of the pancreas. Am J Surg. 2003;185(3):251-255. 52. Telford JJ, Carr-Locke DL. The role of ERCP and pancreatoscopy in cystic and intraductal tumors. Gastrointest Endosc Clin N Am. 2002;12:747-75. 53. Warshaw AL. Mucinous cystic tumors and mucinous ductal ectasia of the pancreas. Gastrointest Endosc. 1991;37:199-201. 54. Warshaw AL. Compton CC. Lewandrowski K. Cardenosa G. Mueller PR. Cystic tumors of the pancreas. New clinical, radiologic, and pathologic observations in 67 patients. Ann Surg. 1990;212:432-443. 55. Warshaw AL, Rattner DW. Timing of surgical drainage for pancreatic pseudocyst. Clinical and chemical criteria. Ann Surg. 1985;202:720-724. 56. Wiersema MJ. Endosonography-guided cystoduodenostomy with a therapeutic ultrasound endoscope. Gastrointest Endosc. 1996;44:614-617. 57. Yamaguchi K, Tanak M. In: Atlas of Cystic Neoplasms of the Pancreas. Fukuoka, Japan: Kyushu University Press; 2002. 58. Zamboni G, Terris B, Scarpa A. et al. Acinar cell cystadenoma of the pancreas: a new entity? Am J Surg Pathol. 2002;26:698-704. 59. Zamboni G, Scarpa A, Bogina G. et al. Mucinous cystic tumors of the pancreas: clinicopathological features, prognosis, and relationship to other mucinous cystic tumors. Am J Surg Pathol. 1999;23:410-422.
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Surgical Approaches to Pancreatic Cancer Giorgos C. Karakousis, MD; Francis R. Spitz, MD
Introduction Carcinoma of the pancreas is the eighth most common cancer in the United States. However, it is the fifth leading cause of cancer deaths. Because of the aggressive nature of this cancer, the incidence and mortality rates are virtually identical. Because this carcinoma is often diagnosed late in its disease process, the majority of patients are not resectable at the time of diagnosis. Although the etiology of pancreatic carcinoma is not clearly delineated, certain risk factors have been identified, including age, chronic pancreatitis (CP), and cigarette smoking. This chapter addresses surgical issues related to the preoperative, operative, and postoperative management of patients with carcinoma of the head of the pancreas. Emphasis will be placed on preoperative staging and assessment of resectability, operative management, and the palliative surgical procedures for this disease. Because of the relatively low incidence, aggressive nature, high mortality, and complex surgical management of this cancer, this disease is best managed in high volume centers with the collaboration of experienced surgeons, gastroenterologists, medical oncologists, and radiation oncologists.
Preoperative Evaluation and Staging Crucial to the management of pancreatic adenocarcinoma is the adequate and effective preoperative evaluation of the patient. Because the majority of presenting patients are unresectable, identification of potentially resectable patients is fundamental to avoiding unnecessary laparotomy and morbidity for these patients. The definition of unresectable disease for pancreatic carcinoma includes one or more of the following:
1. Encasement by the mass of the celiac axis vessels or superior mesenteric artery
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2. Occlusion of the superior mesenteric or portal vein by tumor 3. Presence of distant metastatic disease. The diagnosis of pancreatic adenocarcinoma is often delayed because of the vague symptoms with which it can present. For lesions of the head of the pancreas, which constitute the majority, patients often present with symptoms of obstructive jaundice. A history of weight loss may also often be elicited and should alert the clinician to a potential malignant etiology for jaundice. Abdominal and back pain symptoms are frequently absent and when present, may reflect more advanced disease. Rarely, patients may manifest symptoms of exocrine (malabsorption) or endocrine (diabetes) insufficiency of the gland. Physical exam may demonstrate jaundice but does not usually reveal a palpable abdominal mass, although in instances of more advanced disease, palpable lymphadenopathy in Virchow’s (supraclavicular) node, Sister Mary Joseph’s (periumbilical) node, or ascites (with carcinomatosis) may be evident. Occasionally, pancreatic cancer may be associated with migratory thrombophlebitis. Pancreatic adenocarcinoma is most commonly initially diagnosed on a standard computed tomography (CT) scan of the abdomen and pelvis. Once the diagnosis is suspected, additional evaluation is warranted prior to taking the patient for potentially curative resection. Assessment of resectability involves evaluating for distant metastatic disease and local extent of the tumor. For distant metastatic disease, assessment is performed with chest x-ray, physical examination, review of systems, and laboratory evaluation along with the cross-sectional imaging evaluating the peritoneum and liver. In addition to these routine studies, a head CT may be indicated if neurological symptoms or changes in mental status or mood are present, and a bone scan may be warranted for otherwise unexplained symptoms of bone pain. Evaluation of the local extent of the tumor is best performed with quality cross-sectional imaging of the pancreas and endoscopic ultrasound (EUS). This cross-sectional imaging can be either in the form of thinsectioned CT scanning through the pancreas with dynamic intravenous contrast or dynamic magnetic resonance imaging (MRI) evaluation with MR cholangiogram (MRCP) and MRA/MRV. With quality preoperative cross-sectional imaging studies, surgical resectability rates of 70% and higher have been reported. Careful evaluation of arterial involvement is crucial to the assessment of resectability. Specifically, celiac axis or superior mesenteric arterial encasement or involvement may demonstrate unresectable disease. This is best evaluated on quality cross-sectional imaging (CT or MRI), and/or EUS with evaluation of the perivascular planes. Arteriogram may be helpful in defining the arterial anatomy and identifying aberrant vasculature, although it is not as sensitive in identifying actual vessel involvement as it assesses the lumen and not the adventitia of the vessels. Close evaluation of the superior mesenteric vein and portal system is also required preoperatively as many tumors of the head of the pancreas and uncinate process are in close proximity to the portal vein confluence. Assessment preoperatively should look for abutment of the portal vein along with potential encasement of the portal vein and loss of patency of the superior mesenteric portal vein confluence. A careful preoperative evaluation for local and distant extent of tumor allows for preliminary staging of the patient. The most recent stage groupings of pancreatic cancer by the American Joint Committee on Cancer (2002) are displayed in Table 13-1. The identification of patients who can be palliated nonoperatively and are not surgical candidates reduces the number of unnecessary laparotomies and their ensuing
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Table 13-1
AJCC TNM CLASSIFICATION AND STAGE GROUPINGS OF PANCREATIC ADENOCARCINOMA Primary Tumor (T) Tx T0 Tis T1 T2
Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor less than 2 cm in greatest dimension and limited to the pancreas Tumor greater than 2 cm in greatest dimension and limited to the pancreas T3 Tumor extending beyond the pancreas but not involving the celiac axis or the superior mesenteric artery T4 Tumor involving the celiac axis or the superior mesenteric artery
Regional Lymph Nodes (N) Nx Regional lymph nodes cannot be assessed N0 Absence of regional lymph node metastasis N1 Presence of regional lymph node metastasis
Metastases (M) Mx Distant metastasis cannot be assessed M0 Absence of distant metastasis M1 Presence of distant metastasis
Stage Groupings 0 IA IB II IIB
III IV
Tis, N0, M0 T1, N0, M0 T2, N0, M0 T3, N0, M0 T1, N1, M0 T2, N1, M0 T3, N1, M0 T4, any N, M0 Any T or N, M1
Adapted from American Joint Committee on Cancer: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer- Verlag; 2002: 157-164 .
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morbidity. As stated, EUS has become a useful tool in the assessment of respectability for pancreatic cancers. Specifically, ultrasound evaluation of the vascular structures is a sensitive means of identifying vascular involvement. Additionally, EUS-guided fine needle aspiration (FNA) appears to be a relatively well-tolerated procedure for making the diagnosis of adenocarcinoma of the pancreas in select patient populations. Endoscopic retrograde cholangiopancreaticography (ERCP) is a useful tool in evaluating biliary and pancreatic ductal anatomy in patients who either require diagnosis or palliation. While the role of routine preoperative biliary stenting of patients who undergo pancreaticoduodenectomy is controversial, it is clear that patients who do undergo ERCP should have stenting of the biliary system to prevent the sequelae of cholangitis. FNA biopsy for the diagnosis of pancreatic cancer should not be routinely applied to this patient population. This procedure is helpful in patients who are clearly unresectable and require a diagnosis prior to receiving nonsurgical treatment or in patients who will be enlisted in a study protocol and require confirmed pathologic diagnosis for enrollment. For patients who are clearly resectable and have a defined mass suspicious for carcinoma, we do not routinely recommend this procedure, as it would not alter management. Additionally, at the time of exploration, we do not routinely perform an FNA or intraoperative core needle biopsies of the mass. These tests have a limited sensitivity and increase the potential for seeding tumor and local recurrence. The role of laparoscopy in patients with adenocarcinoma of the pancreas has been a subject of debate. Opponents of using this method point to the high resectability rates and the low yield of laparoscopy in patients who have had extensive preoperative assessment, including EUS, thin-cut CT, or MRI. Additional arguments against laparoscopy include:
1. If done at the time of surgery it adds time to an already long procedure. 2. It is sometimes difficult to thoroughly assess the abdomen via laparoscopy, particularly in patients with previous abdominal surgery. 3. If done on a separate procedure, it requires a separate anesthesia and operative admission. The potential benefit of laparoscopy is the identification of disease not appreciated by preoperative imaging techniques that would preclude resection and allow the patient to avoid the morbidity of laparotomy. This most commonly will be small volume liver metastases or peritoneal lesions. In reported series of patients who had undergone standard CT scan evaluation, rates as high as 36% of unresectable disease were identified that could potentially alter management. Based on this, these authors have recommended laparoscopy with ultrasound evaluation. With the advent of more sophisticated cross-sectional imaging, however, the benefit of diagnostic laparoscopy is less clear and somewhat more controversial. Many groups currently apply a selective approach to laparoscopy, employing laparoscopy in patients with marginally resectable tumors who may be at higher risk for metastatic or peritoneal disease. Surgical resection remains the standard method of potentially definitive cure for localized pancreatic carcinoma, and pancreaticoduodenectomy, a modification of the procedure first described by Whipple in 1935, remains the standard surgical procedure for patients with carcinoma of the head of the pancreas. A further modification of this
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procedure is a pylorus preserving pancreaticoduodenectomy in which the antrum and pylorus of the stomach are preserved. This procedure is routinely applied by many surgeons, as there is a limited oncologic value to resection of the antrum. There is a belief (although this has not been demonstrated in prospective randomized trials) that the preservation of the antrum may lead to better overall long-term function.
Surgical Resection If laparoscopy is being performed, laparoscopic evaluation of the peritoneum, peritoneal surfaces, bowel, mesentery, liver, and stomach should be done prior to exploration. If laparoscopy is not being performed, an initial right subcostal incision is made to evaluate the liver for small volume metastases and the peritoneum and bowel for potential peritoneal metastases. If there is no evidence of metastases, extension to a bilateral subcostal incision provides the exposure of choice.
RESECTION OF THE WHIPPLE SPECIMEN Once the evaluation of the abdominal cavity for metastatic disease has been performed, mobilization and identification of the mesenteric vein inferior to the pancreas is performed (Figures 13-1 and 13-2). This can be performed by mobilization of the right colon with extension medially dissecting into the lesser sac and following the middle colic vein down to the mesenteric vein just below the pancreas. Alternatively, this can be identified by a kocherization of the third portion of the duodenum centrally until one approaches the mesenteric vessels. Once the mesenteric vessel is identified and dissected below the pancreatic lesion and the lesser sac has been opened and mobilized exposing the pancreas, a generous kocherization of the entire duodenum is performed. Time spent at this maneuver reduces the amount of work later in the procedure. We typically kocherize medially to the level of the aorta. Once the duodenum has been mobilized, portal dissection is performed. Proper identification of the vascular anatomy is crucial. Aberrant vessels that should be identified include a replaced or accessory right hepatic artery, which will lie lateral and posterior to the portal structures. In the gastrohepatic ligament, a replaced left or accessory left hepatic artery may be identified. Aberrant anatomy may be identified on preoperative if not initially identified on arteriogram or cross-sectional imaging. Careful attention should be made to avoid vascular injury to hepatic vessels, as an inadvertent injury to these vessels is associated with high morbidity and mortality. The hepatic artery is identified, dissected, and followed to the take-off of the gastroduodenal artery. The gastroduodenal artery should be mobilized and encircled. Identification of the common and proper hepatic artery with good visualization of their anatomy to avoid injury should be made prior to ligating the gastroduodenal artery. There is often a group of lymph nodes in this area, which is best dissected and removed to better expose this area. It should be noted that extensive lymphadenectomy has not been found to significantly improve survival outcomes, although it is associated with an increased morbidity. Once the gastroduodenal artery is identified, divided, tied, and suture ligated, dissection of the biliary system is performed. If a cholecystectomy has not been performed in the past, the gallbladder is mobilized along with the common bile duct and common hepatic duct. The common hepatic duct is transected just cephalad to the insertion of the cystic duct. Once this is done, identification and mobilization of the portal vein posteriorly is performed. Dissection should be carried down to the level of the
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Figure 13-1. A schematic
of the pancreas showing its anatomic relationship with major adjacent abdominal organs including spleen, stomach, duodenum, gallbladder, liver and colon.
Figure 13-2. Anatomy
following removal of the Whipple specimen. The head of the pancreas, duodenum, gallbladder, and antrum of the stomach have been removed en bloc with associated lymph nodes.
pancreas. Following this, the antrum of the stomach is transected if the pylorus is not preserved. The stomach is then reflected lateral to the portal vein, better exposing the area and the pancreas. The jejunum is then divided distal to the ligament of Treitz. The jejunal and distal duodenal vessels are divided and tied and the bowel is maneuvered beneath the mesenteric vessels and to the right of the portal vein. Upon completion of this maneuver, exposure of the portal vein above and the superior mesenteric vein below allows for dissection of the pancreas off these vessels. This should be done under direct visualization to avoid any potential damage by finger dissection. A portal injury at this time can be difficult to manage and therefore any adherence of the tumor to the vein is best assessed through careful dissection. The pancreas is then divided anterior to the vessels. We favor direct division with a knife, which limits the ischemia associated with the dissection. Pancreatic vessels are then oversewn or cauterized based on the extent of their bleeding. Sharp transection of the pancreas also allows for a clean cut and visualization of the pancreatic duct. The speci-
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Figure 13-3. Anatomy following reconstruction of the Whipple procedure. A pancreaticojejunostomy, choledochojejunostomy, and gastrojejunostomy have been performed.
men is then dissected free of the portal vein and then posteriorly, the uncinate process is dissected along the superior mesenteric artery. Careful dissection along this margin is crucial to obtaining negative margins for head of pancreas and uncinate tumors. The specimen is then sent for pathologic evaluation and we routinely evaluate the bile duct and pancreatic margins by frozen section.
RECONSTRUCTION AFTER REMOVAL OF THE WHIPPLE SPECIMEN After resection of the Whipple specimen, reconstruction is accomplished first by performing a pancreaticojejunal anastomosis (Figure 13-3). The pancreatic remnant should be mobilized from the retroperitoneum and splenic vein. Care should be taken to not devascularize the remnant and any questionable tissue should be debrided prior to anastomosis. A retrocolic jejunal limb is brought up and a side of jejunum to end pancreas anastomosis is preferred. Our standard anastomosis is a two-layer with a duct mucosa pancreaticojejunostomy performed over a stent. A posterior layer of 3-0 seromuscular sutures along with an anastomosis of 4-0 or 5-0 absorbable monofilament sutures is preferred. The biliary anastomosis is performed with interrupted 4-0 absorbable monofilament sutures. This is performed via an end of bile duct to side of jejunal anastomosis. For patients who do not have biliary dilatation, a stent should be considered to maintain the patency of the anastomosis. The gastrojejunostomy is performed in an antecolic fashion. A gastrostomy tube and jejunostomy tube can be placed at this time prior to closure. We routinely place jejunostomy tubes although we do not routinely place gastrostomy tubes. For tumors that involve the portal vein, venous resection should be considered. Venous resection can be safely performed with a similar outcome in selected patients who have tumors that can be resected en bloc with the portal vein and negative margins. Tumors encasing the arterial structures or with thrombosis of the portal vein should not be considered for resection because the outcome is poor for these patients, who will likely receive a margin positive resection. When performing a portal vein resection, care should be taken to extensively dissect out the portal vein, splenic vein, and superior mesenteric vein prior to the resection. Most commonly, the involved portion of the vein is just cephalad to the superior mesenteric-splenic vein confluence.
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Preservation of the splenic vein is preferred to avoid the potential development of gastric varices. The conduit of choice for replacement or repair of the portal vein is the internal jugular vein. Alternatively, there are times when extensive mobilization of the portal vein and the mesenteric vein will allow for a primary closure.
Postoperative Management and Care Due to improvements in anesthetic management, surgical techniques, and ICU care, the mortality of pancreaticoduodenectomy has fallen from rates as high as 20% to rates as low as in the <2% to 4% range (morbidity rates though continue to remain as high as 30% and upwards). Studies evaluating operative volume of surgeons and institutions have clearly demonstrated a trend where high volume centers and high volume surgeons demonstrate better outcomes and lower morbidity and mortality than low volume centers or surgeons. Therefore, this type of procedure is ideally performed in a high volume center. An important part of the perioperative management includes evaluation and early treatment of intra-abdominal abscess or pancreaticojejunostomy leak. Liberal use of CT scan of the abdomen and CT-guided drainage of any fluid collections should be utilized in any patients who develop elevated white blood cell counts or fevers following the early postoperative period. With early identification and management, the morbidity and potential mortality of these complications is significantly reduced. The judicious use of blood transfusions is critical in the perioperative period, as the use of blood transfusions in the perioperative period has been associated with poorer patient outcomes, presumably through an immunosuppressive mechanism. Despite the improvements in surgical care, perioperative management and adjuvant chemotherapy, radiation therapy, or chemoradiation, long-term patient survival still remains poor, with the 5-year survival rate for carcinoma of the head of the pancreas being in the 20% range with a median survival of approximately 2 years. These results further emphasize the importance of proper patient selection for surgery and management of these patients in high-volume centers to reduce the morbidity and mortality of the surgery itself. Clearly, advances in early diagnosis and/or in adjuvant or neoadjuvant therapy are required to improve results further.
Palliative Surgical Procedures With quality preoperative radiologic diagnostic studies, and histologic diagnosis obtainable by EUS-FNA, many patients with unresectable disease can be identified and avoid laparotomy and surgical procedures. However, surgical intervention may be indicated in these unresectable patients with gastric outlet obstruction or biliary obstruction who may not be amenable to or who have failed endoscopic or percutaneous drainage. The three challenges in managing patients with unresectable pancreatic cancer relate to the treatment of their acute and chronic pain, treatment of their biliary obstruction, and treatment of gastric outlet obstruction.
Biliary Obstruction Nonoperative decompression of the biliary system can be accomplished endoscopically or percutaneously in experienced hands with a success rate of greater than 90%. Studies evaluating endoscopic decompression versus surgical bypass have
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resulted in identical survival times and relief of jaundice. With use of expandable metal stents, long-term palliation of biliary obstruction can be obtained without the need for multiple procedures. In patients with a confirmed histologic diagnosis of carcinoma who are deemed unresectable without evidence of gastric outlet obstruction, biliary decompression through endoscopic or percutaneous routes is preferred. Surgical palliation may be required for patients in whom nonoperative methods of decompression have failed or in patients who are undergoing laparotomy for either gastric outlet obstruction or were identified to be unresectable at laparotomy. A choledochojejunostomy constructed with a Roux limb or an uncut Roux limb is the preferred surgical decompression procedure for most surgeons. A cholecystojejunostomy can be performed in situations where a choledochojejunostomy would require too extensive a dissection or because the tumor location would be technically difficult. Although this procedure requires less dissection and operative time, the long-term durability of this decompression is less favorable.
Gastric Outlet Obstruction Gastric outlet obstruction secondary to duodenal obstruction from a locally advanced pancreatic cancer is rare, but may occur either at initial presentation or later in the natural course of the disease. The gastrojejunostomy is the optimal palliation for patients with unresectable disease and gastric outlet obstruction. The role of gastrojejunostomy in patients undergoing other surgical procedures for unresectable cancer including choledochojejunostomy is less clear. Although traditionally rates of 15% to 20% of ultimate gastric outlet obstruction have been quoted for patients who did not undergo potentially curative resection, more recent series have reported lower rates. Additionally, gastric outlet obstruction is often a symptom that occurs close to the time of death and therefore surgical procedures are often not required for treatment. Considering the above data, we do not routinely perform prophylactic gastrojejunostomies, but consider gastrojejunostomies for patients who have evidence of gastric outlet obstruction or clinical, anatomic, or endoscopic evidence of external compression of the duodenum at the time of surgery.
Bibliography Barreiro CJ, Lillemoe KD, Koniaris LG, et al. Diagnostic laparoscopy for periampullary and pancreatic cancer: what is the true benefit? J Gastrointest Surg. 2002;6:75-81. Conlon KC, Dougherty E, Klimstra DS, Coit DG, Turnbull AD, Brennan MF. The value of minimal access surgery in the staging of patients with potentially resectable peripancreatic malignancy. Ann Surg. 1996;223:135–141. Crist DW, Sitzmann J, Cameron JL. Improved hospital morbidity, mortality, and survival after the Whipple procedure. Ann Surg. 1987;206:358. Dalton RR, Sarr MG, van Heerden JA. Carcinoma of the body and tail of pancreas: is curative resection justified? Surgery. 1992;111:489. Evans BD, Abruzzese JL, Willett CG. Cancer of the pancreas. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia: Lippincott; 2000. Fortner JG. Regional pancreatectomy for cancer of the pancreas, ampulla and other related sites. Ann Surg. 1984;199:418.
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Foo ML, Gunderson LL, Nagorney DM, et al. Patterns of failure in grossly resected pancreatic ductal adenocarcinoma treated with adjuvant irradiation +5 fluorouracil. Int J Radiat Oncol Biol Phys. 1993;26:483. Fuhrman GM, Charnsangavej C, Abbruzzese JL, et al. Thin-section contrast-enhanced computed tomography accurately predicts the resectability of malignant neoplasms. Am J Surg. 1994;167:104. Fuhrman GM, Leach SD, Staley CA, et al. Rationale for en bloc vein resection in the treatment of pancreatic adenocarcinoma adherent to the superior mesenteric-portal venous confluence. Ann Surg. 1996;223:154. Gastrointestinal Tumor Study Group. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer. 1987;59:2006. Geer RJ, Brennan MF. Prognostic indicators for survival after resection of pancreatic adenocarcinoma. Am J Surg. 1993;165:68. Itani KM, Coleman RE, Akwari OE, et al. Pylorus-preserving pancreaticoduodenectomy: a clinical and physiologic appraisal. Ann Surg. 1986;20:655. Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet. 2004;27;363:1049-1057. Lieberman MD, Kilburn H, Lindsey M, et al. Relation of preoperative deaths to hospital volume among patients undergoing pancreatic resection for malignancy. Ann Surg. 1995;222:638. Merchant NB, Conlon KC. Laparoscopic evaluation in pancreatic cancer. Semin Surg Oncol. 1998;15:155–165. Norton J, Chang AE, Bollinger RR, et al (eds.) Essential Practice of Surgery. New York: Springer-Verlag; 2003, 199-217. Rumstadt B, Schwab M, Schuster K, et al. The role of laparoscopy in preoperative staging of pancreatic carcinoma. J Gastrointest Surg. 1997;1:245. Shepherd HA, Royle G, Ross APR. Endoscopic biliary endoprosthesis in the palliation of malignant obstruction of the distal common bile duct: a randomized trial. Br J Surg. 1988;75:1166. Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol. 1997;15:928. Stojadinovic A, Brooks A, Hoos A, Jaques DP, Conlon KC, Brennan MF. An evidencebased approach to the surgical management of resectable pancreatic adenocarcinoma. J Am Coll Surg. 2003;196:954-964. Warshaw AL, Compton CC, Lewandrowski K, et al. Cystic tumors of the pancreas. Ann Surg. 1990;212:432. Yeo CJ, Cameron JL, Lillemoe KE, et al. Pancreaticoduodenectomy for cancer of the head of the pancreas; 201 patients. Ann Surg. 1995:221:721. Yeo CJ, Abrams RA, Grochow LB, et al. Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. Ann Surg. 1997;225:621. Yeo CJ, Cameron JL, Lillemoe K, et al. Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, Part 2: Randomized controlled trial evaluating survival, morbidity and mortality. Ann Surg. 2002;236:355–368.
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Biliary Tract Surgery Rachel Rapaport Kelz, MD, MSCE; Jon B. Morris, MD
Introduction Dramatic improvements in preoperative and intraoperative imaging, endoscopic and laparoscopic techniques, and anesthetic procedures have led to marked advances in the field of hepatobiliary surgery. In this chapter, we will attempt to describe common operations used to treat biliary disease, including the preoperative evaluation, basic technical aspects of the procedure, and postoperative care, that are vital to the modern management of patients undergoing biliary tract surgery.
Preoperative Evaluation The majority of patients with biliary disorders present with right upper quadrant pain and/or jaundice. Aside from conducting a thorough history and physical exam, basic laboratory studies should be checked, including a complete blood count (CBC), serum electrolytes, and liver function tests with a coagulation profile. A right upper quadrant (RUQ) ultrasound should then be performed to evaluate the gallbladder, the biliary ducts, and identify any mass lesions. An algorithmic approach to the complete evaluation of RUQ pain can be viewed in Figure 14-1. The preoperative evaluation of gallbladder and biliary tract lesions is paramount to providing optimal care to the patients. The decision to undergo further imaging is often based on the results of the ultrasound exam and the clinical expertise of the center of care. In patients who have gallbladder disease, further imaging is warranted if there is a clinical suspicion for common bile duct (CBD) stones. The American College of Surgeons has outlined a plan for the use of preoperative cholangiography in patients who are at high risk for choledocholithiasis, ie, those patients who present with clinical jaundice or cholangitis, visible choledocholithiasis, or dilated CBD and who are at moderate risk or those patients who present with hyperbilirubinemia, elevated alkaline phosphatase levels, pancreatitis, or multiple gallstones. The physician chooses between
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Figure 14-1. Evaluation of right upper quadrant pain presumed to be biliary in origin.
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endoscopic retrograde cholagiopancreatography (ERCP), magnetic resonance cholangiopancreatography (MRCP), and intraoperative cholangiogram with or without common duct exploration based on the likelihood that a therapeutic intervention is required, the feasibility of obtaining either study, and the patient factors that might prohibit the use of one study or the other. The local skills within each center vary substantially, and accordingly, practice patterns must be influenced by regional expertise to provide effective and safe care. When jaundice is associated with either mass lesions or dilated ducts without obvious gallstones, further imaging is generally obtained before operative intervention. The work-up is designed to alleviate the obstructive jaundice and to define the pathologic anatomy as securely as possible to plan the optimal therapeutic intervention. Common studies include but are not limited to cat scan (CT), magnetic resonance imaging (MRI), ERCP, MRCP, and endoscopic ultrasound (EUS.) Of course, the options also include proceeding to surgery with a planned operative cholangiogram and the possibility of a common duct exploration. Patients who present with biliary obstruction and signs of infection are usually treated with antibiotics and decompression prior to surgical intervention. Decompression is usually performed either endoscopically or percutaneously, allowing for biopsies or brushings to be taken at the time of intervention. Only in rare circumstances do these modalities fail, in which case surgical decompression may be required. Prior to performing biliary surgery for obstructive jaundice, it is especially important to optimize medical comorbidities, normalize the renal dysfunction that is often associated with dehydration, and improve nutritional status with the use of enteral/ parenteral nutrition for 4 to 6 weeks. Nutritional supplements should include vitamin K prior to surgery, as these patients will often be coagulopathic from the deficits in clotting factors associated with obstructive jaundice.
Common Procedures CHOLECYSTECTOMY Indications (see Table 14-1)
LAPAROSCOPIC CHOLECYSTECTOMY Laparoscopic cholecystectomy was first performed in France in 1985 and in the United States in 1988. It has become the standard of care for symptomatic gallstone disease. It is one of the most commonly performed general surgical procedures, with approximately 560,000 cases performed per year. In 1990, more than 5 billion dollars was spent on the diagnosis and treatment of gallstone disease. Since the incorporation of the minimally invasive laparoscopic cholecystectomy into routine general surgical practice, some surgeons have expanded the criteria for performing cholecystectomy to include patients with asymptomatic gallstones. Most studies, however, suggest that prophylactic cholecystectomy in women of childbearing age, in diabetes, and in patients with spinal cord disease, is rarely indicated due to the potential complications associated with the procedure. The role for prophylactic cholecystectomy in transplant patients, however, continues to evolve. The operation usually requires general
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Table 14-1
CHOLECYSTECTOMY Absolute Indications Symptomatic gallstones Biliary cholic Obstructive jaundice Acute cholecystitis Gallstone pancreatitis Ascending cholangiitis
Relative Indications Classic symptoms without stones and negative GI work-up without stones Biliary dyskinesia Porcelain Gallbladder Asymptomatic Gallstones Patients under 60 years of age Chilean women Large stones Post heart/lung transplant patients
anesthesia and is subject to the same risks and complications as open cholecystectomy. The timing of cholecystectomy for acute cholecystitis has changed dramatically over the past decade. The current recommendation to avoid recurrence is to perform early cholecystectomy (within 72 hours of presentation) on patients with complicated gallstone disease rather than interval cholecystectomy.
Advantages Patients have a reduction in pain after the operation, and a short stay or outpatient procedure with an accelerated convalescence is usually the norm.
Disadvantages There is a higher incidence of bile duct injury with laparoscopic cholecystectomy (0.4% to 0.6%) than with open cholecystectomy (0.2% to 0.3%). Laparoscopy requires abdominal insufflation with CO2 . This exposes patients to the additional risks of CO2 embolism, hypercarbia, and decreased venous return.
Technical Aspects The patient is taken to the operating room and placed in the supine position, after which general anesthesia with endotracheal intubation is obtained. All patients undergoing biliary tract surgery should receive a dose of prophylactic preoperative
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Figure 14-2. Exposure of the triangle of calot (common hepatic duct, cystic duct, and liver edge).
antibiotics. An umbilical trocar is inserted for the laparoscope and three upper abdomen trocars are then inserted under direct vision. The omental/visceral adhesions are then dissected carefully off the gallbladder and the gallbladder is grasped and retracted in a cephalad and lateral fashion. The cystic duct and cystic artery are unequivocally identified and dissected free from surrounding structures (Figure 14-2). An intraoperative laparoscopic ultrasound can be obtained to rule out choledocholithiasis at this point or an intraoperative, fluoroscopically guided cholangiogram can be obtained by partially dividing the cystic duct and introducing a cholangiocatheter through one of the trocars. Certain centers recommend routinely performing intraoperative cholangiograms to minimize common duct injuries. Cholangiography is not always performed if the suspicion for common duct stones is low or has been treated preoperatively. The cystic artery and duct are then individually ligated and divided between laparoscopically applied clips. The gallbladder is then removed in a retrograde manner. Any laparoscopic cholecystectomy in which the right upper quadrant or the triangle of Calot cannot be visualized, there is hemorrhage, the time of procedure is excessive, or there is a bile duct injury or injury to any other organ should be converted to an open procedure. Conversion to open from laparoscopic is not and should not be considered a complication. This is still an acceptable way to conduct cholecystectomy in the 21st century.
Complications Complications of laparoscopic cholecystectomy include but are not limited to: veress needle injury (vascular or other organs), trocar injury, bleeding from the abdominal wall, omental or mesenteric adhesions, a cystic artery branch of the liver bed, and importantly, postoperative fluid collection or bile leak. If recognized at the time of surgery, all of these problems should be corrected immediately without leaving the operating room. Bile leaks occur in approximately 2% of patients undergoing cholecystectomy. They often present with nonspecific symptoms of nausea, vomiting, distension, bloating, persistent pain and fever, or jaundice. Any of these signs should prompt a thorough evaluation including history and physical exam, laboratory studies and imaging including an ultrasound or CT scan to identify any collections (Figure 14-3). Collections should be drained and if they are bilomas then an HIDA scan or
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Figure 14-3. Evaluation of postoperative laparoscopic cholecystectomy.
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ERCP should be performed to evaluate for an ongoing leak. If the HIDA is positive or the patient presents initially with jaundice or bile leaking through a wound, then an ERCP should be performed along with sphincterotomy and stent placement so long as the injury is not a complete transection. If bile duct injury with complete obstruction is identified, treatment is with percutaneous transhepatic decompression followed by surgical correction usually with a Roux-en-Y choledochojejunostomy. It is extremely important to note that if an injury is identified intraoperatively and the surgical staff does not have the expertise to repair the injury, an appropriate plan would be to place drains widely, close the patient, and transfer to a tertiary care center for definitive management.
COMMON BILE DUCT EXPLORATION/CHOLEDOCHOSCOPY Indications Common duct explorations are usually performed for known stone disease when ERCP has failed or is unavailable due to anatomic limitations or a lack of local expertise. If possible, the etiology of any bile duct obstruction should be known to the surgeon prior to exploration.
Technical Aspects The common bile duct (bluish-green in color), hepatic artery, and duodenum are identified. In a reoperative situation, it is often helpful to have a transhepatic stent placed that can often be palpated at the time of exploration to help guide identification of the duct in a very scarred porta hepatis. The duct is usually opened longitudinally to avoid injuring the blood supply. Gentle manipulation will often allow small stones to be extracted. The duct is then flushed proximally and distally. A cholangiogram is obtained to identify any stones that could not be palpated. Stone forceps, Dormia baskets, and Fogerty balloon catheters can be used to retrieve further debris and stones. A small catheter or sound (3 French) is then passed through the ampulla to confirm patency. If impacted stones are at the level of the ampulla, they can be removed via transduodenal sphincterotoplasty at the time of surgery or postoperatively via ERCP. The choledochotomy is closed over a T-tube with interrupted absorbable sutures (Figure 14-4). The T-tube is then brought out through the skin and left to gravity drainage until return of bowel function. A T-tube cholangiogram is obtained on postoperative day 5 or 6. If clear, the tube is capped and removed 2 to 4 weeks later, depending on the patient's comorbid conditions and the durability of the repair. If more proximal stones remain, they can be removed via fluoroscoscopic guidance via the T-tube tract to help with the manipulation in the postoperative setting. On a rare occasion, if sphincterotomy has already been performed and multiple stones remain lodged in the ampulla, a choledochoduodenostomy or choledochojejunostomy can be performed as outlined below.
TRANSDUODENAL SPHINCTEROPLASTY Indications Transduodenal sphincteroplasty is rarely performed. Its main indication is the removal of impacted stones when both ERCP and common duct exploration have
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Figure 14-4. Common duct exploration.
failed, the presence of multiple intrahepatic strictures in a nondilated duct and to treat post-ERCP bleeding unresponsive to medical therapy. It can also be helpful in unusual circumstances to clarify the etiology of an ampullary obstruction.
Technical Aspects The duodenum and pancreas are mobilized extensively (Kocher maneuver) to allow access to the second portion of the duodenum. A longitudinal incision at least 3 cm in length is made on the antimesenteric side of the duodenum. A catheter is placed into the ampulla from below, or if the common duct has already been opened, a sound can be placed from above to help identify the ampulla. A sphincterotomy is performed at 11 o’clock. The sphincteroplasty is performed using sutures placed in an interrupted fashion around the new orifice between the duodenum and the bile duct. The pancreatic duct must be identified and preserved. Choledochoscopy can be performed to ensure the removal of all stones. Biopsies of suspicious areas should be performed. The duodenum is closed in the orientation in which it was opened using interrupted sutures.
Complications Complications include but are not limited to: leak, pancreatitis from extensive manipulation of the ampulla, or impingement upon the pancreatic duct from the sphincteroplasty sutures.
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BILIARY DIVERSION Choledochoduodenostomy Indications
As mentioned above, this procedure is often used in the setting of persistent biliary obstructions from stone disease when sphincterotomy has failed. It can also be used when obstruction exists from benign strictures secondary to chronic pancreatitis or other benign conditions. In malignant disease, it should only be used when life expectancy is short and stenting is unsuccessful in the setting where future duodenal obstruction is not a concern. A common duct diameter of at least 1 cm is desirable. Technical Aspects
The duodenum is identified and mobilized to allow approximation with the proximal common bile duct in a tension-free manner. The common bile duct is exposed and transected and direct anastomosis is made in an end-to-end fashion to the antimesenteric duodenum. Interrupted #3-0 absorbable sutures are used circumferentially as a single layer an end-to-side choledochoduodenostomy. If a tension-free anastomosis cannot be achieved, a choledochojejunostomy should be performed as outlined below. Complications
Complications include but are not limited to: leak, stricture formation if the duct is small or secondary to extension of malignancy, and “sump syndrome”, ie, cholangiitis from food in the bile duct.
Choledochojejunostomy Indications
This operation is still commonly performed for biliary drainage after common duct resection, repair of ductal injuries, and for relief of obstruction from benign and malignant biliary strictures. Its role for decompression in noncurable malignant diseases of the biliary tree and pancreas, however, is waning due to the popularity and success of endoscopic and percutaneous stents. Technical Aspects
The bile duct is exposed for an appropriate length with minimal dissection if a sideto-side anastomosis is to be performed and a longitudinal incision is made anteriorly high above the malignancy. For an end-to side anastomosis, the duct is resected back to healthy viable tissue and sharply divided. The anastomosis is done with interrupted sutures (Figure 14-5) of the finest suture possible. The Roux limb must reach the duct in a tension-free manner and must have a sufficient blood supply to ensure the proper healing of the Roux stump and the anastomosis. Complications
Complications include but are not limited to: leak, stricture formation if the duct is small, or recurrent jaundice secondary to extension of malignancy.
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Figure
14-5. Roux-en-Y hepaticojejunostomy end-toside.
Repair of Proximal Duct Injuries Indications
Bile duct injury identified intraoperatively or persistent biliary leak following trauma to the biliary tree either due to iatrogenic causes or other physical trauma that does not respond to or is not amenable to conservative management with stents and drains. Preoperative cholangiography utilizing MRCP/ERC and PTC, as appropriate, is ideal. Technical Aspects
Great caution is used when exploring the right upper quadrant in patients with previous biliary leaks. The anatomy is often obscured by a dense inflammatory response. It is often easiest to start by identifying the left hepatic duct and then carrying the dissection to the right to uncover the confluence of the right and left ducts. It is helpful to divide the liver in the gallbladder fossa (“liver split technique”) and open the umbilical fissure to improve exposure of the confluence of the ducts for proximal injuries. Tissues must be carefully dissected and identified. All devitalized tissue must be debrided. The confluence is opened with a 1-cm incision. A Roux-en-Y limb is brought up to the hilum. On occasion, intrahepatic ducts must be sewn together to enlarge the aperture for the anastomosis. After the entire posterior layer is in place, the jejunum is snugged down to the duct and the posterior row is tied in place. Then the anterior sutures are placed sequentially from left to right into the jejunum and tied in place. Typically, a Roux-en-Y choledochojejunostomy can be performed. However, when the ducts have completely retracted into the liver parenchyma, an hepaticojejunostomy or Kasai procedure must be performed similar to that described for the treatment of biliary atresia. In this setting, it is helpful to prepare the bowel in a modified fashion to reinforce the suture line. A 50- to 70-cm Roux limb in a retrocolic position is customarily employed. The antimesenteric jejunal end is opened with two applications of the GIA60 staple instrument. This allows the mucosa, muscle, and serosa to be
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put firmly together and provides an increased purchase for the sutures that are used for the repair. The repair is then constructed between the jejunal limb and the entire hepatic fossa down to the level of the posterior capsule. This completely places a limb of jejunum around the edge of the hepatic fossa as a Kasai procedure. The two ducts are usually stented through the jejunum. However, if stents were placed transhepatically preoperatively, then these stents are used. If transjejunal stents are used then, the jejunum is often sutured to the anterior right rectus muscle on the right side of the midline incision to allow easy access to the ducts through the area. Closed suction drains are placed on both the right and left sides of the anastomosis. Complications
Complications include but are not limited to: leak, cholangiitis, and late strictures. Note: A more comprehensive description of bile duct injuries can be found in Chapter 4.
Resection of Middle-Third and Proximal Bile Duct Tumors Indications
Therapy for bile duct tumors is determined by resectability and location within the bile duct. Tumors are categorized by their location grossly within the bile duct and then proximal tumors are divided by their Bismuth Classification (Figure 14-6A,B.) Most tumors are adenocarcinomas. These tumors respond poorly to chemotherapy and radiation, making surgery the best chance for cure. Accordingly, because the type of procedure to be performed varies by the location of the tumor within the duct, an extensive preoperative work-up is required. Carcinomatosis, vascular encasement, and distal metastasis preclude resection for cure. Preoperative work-up for these tumors usually includes CT scan/MRI, ERCP/MRCP, and/or PTC, along with an EUS to define the anatomy and extent of the tumor and its relationship to the vessels. Tumors in the distal one-third of the duct are treated by the Whipple procedure and will be discussed elsewhere in this book. Proximal tumors are treated with bile duct resection that may require concomitant en bloc liver resection. Technical Aspects
Preoperative decompression of the salvageable liver segments will often be performed to minimize postoperative hepatic dysfunction. Additionally, some groups favor preoperative portal vein embolization of the liver to be resected to stimulate preoperative liver regeneration when the proposed liver remnant is thought to be marginal. The abdomen is first inspected, often laparoscopically, for carcinomatosis and liver metastasis. Any suspicious lesions aside from the primary tumor are biopsied. If biopsies are positive, stents are left in place or a bypass is performed. The primary tumor is not biopsied intraoperatively for fear of tumor dissemination. The gallbladder is removed from the liver bed without dividing the blood supply or cystic duct. The common hepatic artery and portal vein are identified just above the pancreas and encircled with vessel loops. The hepatic artery and portal vein are skeletonized, leaving all adjacent tissue with the bile duct as part of the specimen. When the tumor is deemed resectable it is divided distally and the distal end is retracted to facilitate the proximal dissection. For middle-third and proximal type I tumors, the hepatic ducts are divided right above the bifurcation, the cystic artery is ligated and divided, and a Roux-en-Y cholangiojejunostomy is usually performed. For type II, IIIa, and
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Figure 14-6A. Gross description of bile duct tumor location within the biliary tree.
Figure 14-6B. Class-
ification of hilar cholangiocarcinoma.
IV tumors, the American College of Surgeons recommends a right trisegmentectomy and for type IIIb tumors, a formal left hepatic lobectomy. The caudate lobe should be included with liver resections for type III and IV tumors. Intraoperative ultrasound can be very helpful with determining the true resectability of tumors that extend beyond the hepatic duct bifurcation. When a liver resection needs to be included in the specimen, the hepatic artery and portal vein are dissected away from the spared liver and the branches feeding the involved liver are ligated and divided. The hepatic parenchyma is then marked and divided. Often, a Roux-en-Y intrahepatic cholangiojejunostomy is then fashioned in a mucosal to mucosal fashion. Some prefer leaving transhepatic stents that can also be used for brachytherapy following resection. Closed suction drains are left in the resection bed and the abdomen is closed.
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Complications
Complications include but are not limited to bile leak, bleeding, and infection. Cholangiitis is more likely if the Roux limb is too short and there is frequent contamination of the biliary tree with food. Coagulation factors need to be replaced if the INR is elevated and bleeding occurs. Most infectious collections can be drained percutaneously.
Postoperative Care Coagulation profiles should be checked and microvascular bleeding with an INR >1.5-2.0 should be treated with fresh frozen plasma and concentrated coagulation factors. Phosphate levels should be followed in any case in which a liver resection is performed and repleted, especially for the first postoperative week, as they will often fall dangerously low secondary to hepatic regeneration. When stents or T-tubes are placed intraoperatively, they are usually left to gravity drainage for 5 days or until return of bowel function. Prior to capping these tubes, they are usually studied in interventional radiology. If a satisfactory image is obtained, then they are capped and removed approximately 4 weeks later. The time for removal must be decided on an individual basis by the surgeon, taking into consideration the clinical condition of the patient, the location of the injury, and the cholangiographic photos. If drains are left in place, they are removed once stents have been capped and the output remains nonbilious. Abdominal pain, fevers, or worsening liver function tests (after an initial peak in transaminases) should warrant a fever work-up with cultures and abdominal imaging to rule out biloma or abscess.
Conclusion One must keep in mind that the biliary surgery should be a multidisciplinary endeavor with gastroenterologists, interventional radiologists, and surgeons working collaboratively as a team to benefit the patient.
Bibliography Baker RJ, Fischer JE, eds. Mastery of Surgery. 4th ed. Philadelphia: Lippincott, Williams & Wilkins; 2001. Cameron JL. Current Surgical Therapy. 7th ed. St. Louis, Mo: Mosby; 2001. Fried GM, Feldman LS, Klassen DR. Laparoscopic cholecystectomy. In: ACS Surgery: Principles and Practice. Retrieved from http://www.acsurgery.com Gallstones and Laparoscopic Cholecystectomy, NIH Consensus Statement Online 1992 Sep 14-16 [cited 2004, March 30];10(3):1-20 McClelland RN, ed. Selected Readings in General Surgery. Vol 27. Dallas, Tex: The University of Texas Southwestern Campus at Dallas; 2001.
Suggested Reading Courcoulas AP, et al. Laparoscopic cholecystectomy in the transplant population. Surg Endosc. 1996;10516-10519. Donohoe JH, et al. Laparoscopic Cholecystectomy: Operative Technique. Mayo Clin Proc. 1992; 67:441-448.
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Groen PC, et al. Biliary tract cancers. New Eng J Med. 1999;341:1368-1378. Jarnagin WR, et al. Operative repair if bile duct injuries involving the hepatic duct confluence. Arch Surg. 1999;134:769-775. Lorimer JW, et al. Intraoperative cholangiography is not essential to avoid duct injuries during laparoscopic cholecystectomy. Am J Surg. 1995;169:344-347. Martin IG, et al. Fundus-first laparoscopic cholecystectomy. Surg Endosc. 1995;9:203206. Rosenthal RJ, et al. Options and strategies for the management of choledocholithiasis. World J Surgery. 1998;22:1125-1132. Rossi RL, et al. Biliary reconstruction. Surg Clin N Amer. 1994;74:825-841. Schwesinger WH, et al. Changing indications for laparoscopic cholecystectomy: stones without symptoms and symptoms without stones. Laparoscopic Surgery. 1996;76:493504. Shea JA, Berlin JA, et al. Indications for and outcomes of cholecystectomy: a comparison of the pre and postlaparoscopic eras. Ann Surg. 1998;227:334-350. Siperstein A, et al. Comparison of laparoscopic ultrasonography and fluorocholangiography in 300 patients undergoing laparoscopic cholecystectomy. Surg Endosc. 1999;13:113-117. Woods MS, et al. Biliary tract complications of laparoscopic cholecystectomy are detected more frequently with routine intraoperative cholangiography. Surg Endosc. 1995;9:1076-1080.
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Imaging of the Pancreatobiliary System Using Endoscopic Ultrasound Nuzhat A. Ahmad, MD
Introduction Endoscopic ultrasound (EUS) is an imaging technique that combines endoscopy and ultrasonography. An ultrasound transducer is mounted on the tip of the endoscope, allowing accurate imaging of lesions located within and adjacent to the gastrointestinal wall. EUS is used routinely in the evaluation of numerous gastrointestinal disorders, including the diagnosis and staging of gastrointestinal tumors. During the past 10 years, its applications have become more established, mainly because of improvements in the technology of endoscopes (eg, video chips rather than fiberoptics) and ultrasound transducers. The applications of EUS have also expanded to include EUS-guided fine-needle aspiration (EUS-FNA) of lesions located within and outside the gastrointestinal wall, as well as therapeutic applications such as celiac axis neurolysis and pancreatic pseudocyst drainage. This chapter will focus on EUS imaging of the pancreatobiliary system. The role of EUS in pancreatic cancer staging and cystic lesions of the pancreas is discussed elsewhere in this book.
Instruments Echoendoscopes, which use sound waves for imaging tissue consistency and interfaces between tissue planes, are of three types: radial endoscopes, linear array endoscopes, and small caliber ultrasound probes. There is a water-filled balloon surrounding the tip of the echoendoscope, which provides an acoustical interface with the wall of the gastrointestinal tract, thus overcoming the difficulty inherent in imaging through an air-filled lumen. The frequencies of echoendoscopes, which are higher than those used in transabdominal ultrasound, permit better delineation of the gastrointestinal wall layer pattern. However, these higher frequencies also have lower
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penetration. Color Doppler can also be used with certain echoendoscopes to establish the presence of flow, which is indicative of a vascular structure. The echoendoscopes have oblique optics, which limit the endoscopic field of view.
ECHOENDOSCOPES There are two basic types of echoendoscopes available to perform EUS: radial scanner and linear array echoendoscopes. The radial echoendoscope produces a 360 degree image perpendicular to the shaft of the endoscope, similar to computed tomography (CT), allowing complete visualization of the gastrointestinal tract and its adjacent structures. It has the option of scanning at 12 or 7.5 MHz. The higher-frequency scanning (12 MHz) allows for better visualization of details at close range. The lower the frequency, the better the penetration of ultrasound waves; thus, at 7.5 MHz, the scanning range increases over 12 MHz. The linear array echoendoscope provides a 100 degree field of view for the Pentax/ Hitachi system (FG-36UA) and 180 degree field of view for the new Olympus/ Acoustic imaging echoendoscope (GF-UC30P). Images are obtained along a plane parallel to the endoscope axis. The Pentax FNA scope has 5.0 and 7.5 MHz frequencies, whereas the Olympus FNA instrument has only a 7.5 MHz frequency. The linear array echoendoscopes also have a channel that allows the passage of a needle for fine aspiration or injection under ultrasound guidance in real time. Doppler ultrasound capability in these echoendoscopes enables visualization of vascular structures, thus guiding the path of the aspiration needle to prevent vascular structures from being injured.
INTRADUCTAL PROBES The technical evolution of EUS has led to the development of small caliber, flexible intraductal ultrasound (IDUS) miniprobes, which can be passed through the channel of a standard endoscope or duodenoscope, directly into the bile or pancreatic ducts, thus providing cross-sectional imaging from within the biliary or pancreatic ducts. This visualization can be accomplished either during the course of an endoscopic retrograde cholangiopancreatography (ERCP), or percutaneously under fluoroscopic guidance. Some probes also permit passage over a guidewire. By virtue of their high frequencies, ranging from 12 MHz to 30 MHz, these systems provide very detailed images of the gastrointestinal wall layers. Their main limitation is lack of depth of penetration of the ultrasound beam given their high frequencies. There are currently three commercially available systems to perform IDUS: electronic cylindrical phased array, which use thin catheters, have no rotating parts and produce a 360 degree image; a combined probe, which allows both radial and linear scanning; and a mechanical radial sector scan system, which also provides a 360 degree image. The mechanical probes are more commonly used because these provide better images than electronic probes. One of the impediments to widespread use of probes is their cost and fragility.
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Figure
15-1. Endosonographic appearance of choledocholithiasis. The 9.6-mm bile duct stone is visualized as a hyperechoic focus with acoustic shadowing.
Endosonography of the Biliary System CHOLEDOCHOLITHIASIS The clinical and biochemical manifestations of choledocholithiasis range from asymptomatic to jaundice, cholangitis, and gallstone-induced pancreatitis. When the clinical features strongly suggest the presence of bile duct stones, management is fairly straightforward; therapeutic ERCP with or without cholecystectomy will, in most cases, constitute the entire management. Unfortunately, the clinical picture is often equivocal or uncertain. Although stones are unlikely to be present in the bile duct when the clinical index of suspicion is low, their presence can never be completely ruled out based on clinical and biochemical parameters. The gold standard test is ERCP, which compared to other tests such as ultrasonography has the advantage of permitting intervention if a common bile duct stone is present. However, ERCP is invasive and carries a significant risk of complications such as pancreatitis. Thus, an accurate and noninvasive method for bile duct imaging would be highly desirable. Currently available modalities, other than ERCP, for diagnosing choledocholithiasis include transabdominal ultrasonography (TUS), CT, magnetic resonance cholangiopancreatography (MRCP), and EUS. Given its low cost and lack of complications, TUS is usually the first modality of choice to image the common bile duct (CBD). The sensitivity of ultrasound for the detection of dilated bile ducts from biliary obstruction, ranges in various studies from 55% to 91%. However, the CBD passes posterior to the duodenal bulb, making visualization by TUS technically suboptimal secondary to intervening bowel gas. This anatomy is well suited for EUS because the transducer is placed into the duodenal bulb, thus making it feasible to obtain extremely high-resolution common bile duct images as the duct courses nearby. The bile duct is visualized as a three-layer structure. Alternatively, it may also appear as a single layer structure. CBD stones are visualized as hyperechoic foci with strong acoustic shadowing (Figure 15-1). Comparisons of EUS, ERCP, and MRCP for the diagnosis of choledocholithiasis demonstrate similar accuracy rates, ranging from 85% to 95%. Studies comparing EUS with ERCP have found no significant differences between the two tests, with
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respect to sensitivity, specificity, and positive and negative predictive values, for detection of choledocholithiasis. The negative predictive value of EUS for choledocholithiasis has been demonstrated to be as high as 97%. Therefore, when EUS is negative for choledocholithiasis, ERCP or intraoperative cholangiography can be avoided. Despite its overall accuracy, imaging by EUS may be compromised by air in the bile duct (as might occur after endoscopic sphincterotomy), surgical clips, calcification in the pancreas, and the presence of a duodenal diverticulum. In patients with symptomatic cholelithiasis who are at low risk of choledocholithiasis as predicted by clinical history, biochemical tests, and US imaging, the risk of harboring CBD stones is 2% to 3%. These patients can be treated with laparascopic cholecystecetomy without any preoperative imaging of the CBD. Patients who have a high risk for harboring CBD stones—as predicted by episodes of acute cholangitis, acute pancreatitis, abnormal liver enzymes, and/or a dilated CBD (>10 mm) on imaging—will have a 50% to 80% risk of choledocholithiasis. Based on the available expertise, these patients may undergo an ERCP for diagnosis and treatment of choledocholithiasis. The decision is usually taken in a multidisciplinary fashion, with the involvement of surgeons and gastroenterologists. For patients with intermediate risk of CBD stones—a history of acute cholangitis or biliary pancreatitis, unexplained anomalies in liver blood tests, and/or moderate dilatation of the CBD (between 8 and 10 mm in diameter)—stones are identified in 20% to 50% of cases. For these patients, a strategy to include EUS in the preoperative evaluation, followed by an ERCP if stones are found, is suggested. In patients with acute gallstone pancreatitis, three recently published studies have suggested that EUS should replace ERCP as the first procedure in patients with mild and moderate acute pancreatitis, thus avoiding unnecessary ERCPs and diminishing ERCP-induced morbidity. Another study further emphasized this point by demonstrating that the rate of morbidity and mortality could be reduced by systematically using EUS in cases of acute gallstone pancreatitis, followed by ERCP with sphincterotomy only when EUS demonstrated CBD stones. IDUS has been shown to be a useful adjunct to ERCP in the diagnosis and management of choledocholithiasis. IDUS can detect small stones and can differentiate these from air bubbles. In comparative studies, the sensitivity of IDUS for detection of choledocholithiasis was 96.8% versus 81% for ERCP, and 45% for transabdominal ultrasound. In another recent series of patients with suspected choledocholithiasis undergoing ERCP, it was found that IDUS findings changed management in 37% of patients. In practice, IDUS can be used to increase the diagnostic accuracy in patients with normal cholangiograms and a high suspicion of choledocholithiasis.
BILE DUCT STRICTURES When a biliary stricture is encountered, two issues need to be addressed. First, differentiation between malignant and benign bile duct disease needs to be determined. Second, when a bile duct lesion is found to be malignant, accurate diagnosis of locoregional tumor extension is imperative for determining suitable treatment. Unless the clinical history is strongly suggestive, differentiation between benign and malignant strictures can be difficult. This problem may be resolved by EUS and/or IDUS, which can identify and characterize biliary tumors. Endosonographically, the common bile duct can be seen to consist of three layers (mucosa, muscle layer, and
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serosa). Endosonographically, a cholangiocarcinoma will appear as an irregular mass, with a variable mostly hypoechoic appearance, either surrounding or infiltrating the duct. Distal CBD lesions are usually easily imaged by EUS, which can visualize the local extent of the primary tumor as well as the status of regional lymph nodes. Proximal tumors may be difficult to detect because of the limited penetration of echoendoscope transducers. For the detection of small cholangiocarcinomas, EUS is as sensitive as ERCP and superior to US, CT, and angiography. Endosonographic staging of cholangiocarcinomas is based on TNM staging. The overall accuracy of EUS for T- and N-staging of cholangiocarcinomas ranges from 72% to 81%, and 61% to 81%, respectively. The overall accuracy of EUS for staging of proximal cholangiocarcinomas was 86% for T-staging and 64% for N-staging. In contrast to EUS, IDUS is often better able to evaluate the proximal biliary system and surrounding structures. IDUS, however, has limited depth of penetration, which hinders evaluation of distant structures and lymph nodes. For patients without obstructive jaundice, the ultrasound probes can be inserted into the bile duct through the biopsy channel of a duodenoscope. For patients with bile duct stenosis, dilation may be required prior to passage of the ultrasound probe. With IDUS, the common bile duct will be visualized as either two or three layers. IDUS can help distinguish benign from malignant strictures based on bile duct anatomy and unique sonographic imaging characteristics. IDUS criteria that suggest malignancy include a hypoechoic mass with inhomogenous, echo-poor areas invading surrounding tissue, and disruption of the normal bile duct structure. Using these criteria, the sensitivity, specificity, and accuracy of IDUS were 91%, 80%, and 89%, respectively, for the diagnosis of malignant bile duct strictures. IDUS has been compared to both EUS and ERCP with tissue sampling for determining the nature of bile duct strictures. IDUS was significantly more accurate than EUS (89% versus 76%), as well as ERCP with tissue sampling (90% versus 67%) for a final diagnosis in patients with indeterminate strictures. In contrast, IDUS did not compare favorably with percutaneous cholangioscopy and cholangioscopic-directed biopsy. The sensitivity, specificity, and accuracy of IDUS for diagnosing cholangiocarcinoma were only 89%, 50%, and 76%, respectively, as compared to a sensitivity, specificity, and accuracy of 93%, 100%, and 95% for percutaneous cholangioscopy. For staging of cholangiocarcinoma, IDUS can be particularly useful, as it can identify longitudinal tumor extent, as well as extension of the tumor into surrounding tissues including the pancreas. When compared with surgical findings, IDUS is more accurate than EUS for local tumor staging (77% versus 54%). This benefit is more defined for proximal bile duct tumors extending to the bifurcation. IDUS has also been found to be more accurate than cholangiography for determination of longitudinal spread of tumor towards the liver (84% versus 47%) and toward the duodenum (96% versus 43%). Definition of extent of longitudinal spread is invaluable in planning operative resection. It has been suggested that IDUS should be performed prior to or within a few days of biliary stent placement, because reactive changes in the bile duct secondary to stent placement may mimic malignant changes, leading to overestimation of tumor extent.
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Figure
15-2. Endosonographic appearance of a normal pancreas. SV = splenic vein, PD = pancreatic duct, PP = pancreatic parenchyma.
Endosonography of the Pancreas EUS provides a safe and relatively noninvasive method of obtaining detailed structural information on the pancreatic parenchyma, ducts, and related structures. The close proximity of the pancreas to the gastric and duodenal lumen permits EUS to obtain high resolution imaging without interference by overlying or intervening bowel gas. Endosonographically, the normal pancreatic parenchyma is homogenous, finely granular with smooth margins and a slightly hyperechoic appearance. The main pancreatic duct is seen as a thin anechoic linear structure coursing through the parenchyma (Figure 15-2). There is also usually a clearly detectable difference in the echo density of the ventral and dorsal pancreas. There can, however, be a variation in the appearance of the pancreas, especially in older patients, in whom the “classic” normal appearance may be less frequent. Given this potential wide variability in the endosonographic appearance of the pancreas, distinguishing normal from abnormal can be a challenge. Because EUS can provide information about both the pancreatic parenchyma and the ducts, it may detect abnormalities not demonstrated by other tests such as ERCP, transabdominal ultrasound, and CT scan.
CHRONIC PANCREATITIS The EUS diagnosis of chronic pancreatitis (CP) relies on several criteria, which include ductal and parenchymal abnormalities1,2 . Parenchymal abnormalities include inhomogenity, atrophy, hyperechoic foci and/or strands, lobularity, and reduced echogenicity. Ductal criteria include ductal dilation, hyperechoic duct margins, irregular duct margins, stones, and side branch ectasia (Figure 15-3). It is generally agreed upon that in the absence of any criteria, CP is unlikely, whereas CP is likely if five criteria are seen, even when other tests to assess the pancreas such as ERCP and standard tests of pancreatic function are normal. The clinical significance of fewer (1 to 4) features found on EUS is unclear, particularly when other diagnostic tests such as ERCP and function testing are normal. There are only limited data on the long-term natural history of “mild” CP diagnosed by EUS. In addition, all criteria may not be equally important. For example, the presence of intraductal calcifications alone is highly suggestive of CP even in the absence of other criteria. There may also be age-related
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Figure 15-3. Endosonographic dem-
onstration of a pancreatic duct stone in a patient with chronic pancreatitis. The stone is seen as a hyperechoic focus within the pancreatic duct.
changes in the pancreas, such as a dilated pancreatic duct, which may affect the diagnostic threshold for diagnosis of chronic pancreatitis. Endosonographic findings have been compared with other methods of determining chronic pancreatitis including other forms of imaging, histology, and pancreatic function testing. In a study comparing EUS with histology, the total number of endosonographic criteria were predictive of histologic chronic pancreatitis. The sensitivity and specificity using a threshold diagnosis of three criteria was 87% and 64%; for four criteria, 78% and 73%; for five criteria, 60% and 83%; and for six criteria, 43% and 91%, respectively. The studies concluded that a minimum of four or more criteria was optimal for the diagnosis of chronic pancreatitis. Several studies have compared endosonography to ERCP in patients with suspected chronic pancreatitis. Some of these studies have used a standardized grading system (the Cambridge Classification) for both EUS and ERCP, thus making them directly comparable. Each study evaluated the pancreas for the presence of 9 to 11 described criteria and then considered EUS to be abnormal if the total number of criteria exceeded a certain threshold number (eg, 3, 4, or 5). Excellent agreement was demonstrated between EUS and ERCP in the diagnosis of chronic pancreatitis when the threshold of 3 criteria was considered. In cases where they disagreed, the majority were abnormal by EUS and normal by ERCP. The total number of EUS criteria were also found to be independent predictors of chronic pancreatitis. When EUS was compared to functional testing of the pancreas, in which pancreatic juice was analyzed following stimulation with secretin, agreement between the two tests was found in 75% of cases. In those cases, where there was disagreement, the EUS was abnormal with a normal functional test. It is unclear if EUS is more sensitive to mild changes of CP or if EUS was “overdiagnosing” early CP. An inflammatory mass associated with CP may mimic the radiologic features of pancreatic cancer. As a result, there may be cases where unnecessary resection is performed in those with CP. Currently, no test has proven to be consistently accurate in making this distinction. EUS is most reliable and helpful when the examination is either clearly normal or abnormal. When EUS is completely normal, other imaging and functional testing for chronic pancreatitis will likely be normal and therefore are unwarranted, unless the clinical suspicion for pancreatitis is very high. Similarly, if the EUS exam is thoroughly abnormal, then there is a strong possibility that the patient has pancreatitis
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Figure 15-4. Gastrinoma not seen on
CT, TUS, and MRI, visualized endosonographically as a hypoechoic, homogenous, solid lesion in the head of the pancreas.
and further testing for diagnosis may be unwarranted. It must be stressed, however, that EUS should be used in the context of a thorough clinical evaluation. In patients in whom the pancreas is not clearly normal or abnormal, the clinical significance of EUS findings is unclear. It is this group of patients in whom EUS can potentially be of further use if and when definitions and terminology used for the endosonographic diagnosis of CP are improved.
PANCREATIC ENDOCRINE TUMORS Pancreatic neuroendocrine tumors often prove difficult to localize by conventional imaging modalities because of their small size. In contrast to other pancreatic neoplasms, patients with suspected neuroendocrine neoplasms are referred when there is documentation of unregulated hormone production but conventional imaging studies are normal. Endosonographically, these appear as discrete, homogenous and hypoechoic lesions, which may be located within the pancreas or adjacent to the gland (Figure 15-4). After biochemical diagnosis, EUS is an excellent localization tool with overall sensitivity, specificity, and accuracy of up to 93%, 95%, and 93%, respectively. In one report of patients with negative ultrasonography and CT scans, EUS detected endocrine tumors in the pancreas with high sensitivity (82%) and specificity (95%). EUS also compares favorably with somatostatin receptor scintigraphy (SRS) for pancreatic gastrinoma localization. However, both of these tests may miss gastrinomas in the duodenal wall. EUS is clearly superior to SRS for the localization of insulinomas. In addition, because insulinomas are nearly always located in the pancreas and less prone to metastasis, EUS may be used as the only preoperative localizing modality. In contrast, in patients with gastrinomas and glucagonomas, because of the more frequent incidence of metastasis and extrapancreatic location, EUS is typically used in conjunction with other studies. It must be emphasized that EUS is not a screening test for endocrine tumors. It should be used in patients who already have a biochemical diagnosis of a hypersecreting tumor. EUS has also been shown to be cost-effective in management algorithms for pancreatic neuroendocrine tumors, largely due to a decrease in the number of diagnostic angiograms and venous sampling procedures.
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Figure 15-5.
Endosonographic demonstration of microlithiasis not detected by prior TUS or CT.
PANCREATIC DUCT STRICTURES IDUS has been used for differentiating between benign and malignant pancreatic duct strictures. In one study, IDUS correctly identified 92% pancreatic duct strictures as benign. In one study where findings were correlated with histopathologic findings, IDUS was compared with EUS, CT, and ERCP in diagnosis of pancreatic duct strictures. The sensitivity of EUS, CT, ERCP, and IDUS in diagnosing malignant strictures was 92.9%, 64.3%, 85.7%, and 100%, respectively. Specificity of EUS, CT, ERCP, and IDUS was 58.3%, 66.7%, 66.7%, and 91.7%, respectively. These findings need to be confirmed in further studies.
Endosonography of the Gallbladder The gallbladder wall typically appears as a three-layer structure: the first layer represents the mucosa, the second layer represents the muscular layer, and the third layer represents the serosal layer.
MICROLITHIASIS/SLUDGE Biliary microlithiasis is considered an important cause of idiopathic acute pancreatitis. Conventional transabdominal US is routinely used in the detection of cholelithiasis but it may not be able to detect small stones. It has been suggested that EUS may have a role in the evaluation of patients with idiopathic pancreatitis by detection of microlithiasis (Figure 15-5). In a prospective study of 89 patients with acute pancreatitis, the use of EUS in detecting occult cholelithiasis was studied. Eighteen patients (20%) were classified as having idiopathic pancreatitis after evaluation by US, CT, and ERCP. Endoscopic ultrasonography performed in these 18 patients revealed 1 to 9 mm gallstones in 14 patients and choledocholithiasis in three patients. Thus, cholelithiasis can be detected by EUS in a large number of patients classified as having idiopathic pancreatitis by conventional radiologic examinations. With identification of a biliary cause of acute pancreatitis, treatment can be initiated early, thereby reduc-
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ing the risk of recurrent pancreatitis with its associated morbidity and mortality. The accuracy of EUS in combination with stimulated biliary drainage (SBD) for diagnosis of cholecystitis and microlithiasis has also been studied. It was found that the sensitivity for combined EUS/SBD was 92.4% with a 100% positive predictive value for microlithiasis. Further, the study also demonstrated that the majority of patients with positive EUS/SBD who underwent cholecystectomy had resolution of their biliary pain over an average 10.5 month follow-up period.
GALLBLADDER POLYPS The widespread use of transabdominal US in patients with suspected gallstones has increased the detection rate of gallbladder polyps. Gallbladder polyps are identified as immobile, echo structures protruding into the gallbladder lumen without acoustic shadowing (Figure 15-6). Endoscopic ultrasonography may be used as an adjunct to abdominal US for further characterization of gallbladder polyps. It has been shown that a polypoid lesion without echogenic spots, microcysts, or artifacts on endosonography, can be considered a neoplasm. Overall, EUS has been found to be superior to TUS in differentiating the nature of these gallbladder lesions (97% compared to 71%). Choi et al3, in a study of 132 patients with gallbladder polyps, presented a new method to predict neoplastic gallbladder polyps using a scoring system based on five EUS variables. Size was the most significant predictor for the risk of neoplastic polyps. Polyps less than or equal to 5 mm in diameter were non-neoplastic. The risk of neoplasia increased when the polyps exceeded 15 mm in diameter. At a cutoff EUS score of 6, the sensitivity and specificity for the risk of neoplastic polyps was 84.6%. The authors concluded that a score based on five EUS variables identifies patients at risk of neoplasia when polyps are between 5 to 15 mm in diameter3.
GALLBLADDER CANCER STAGING Defining the extent of gallbladder cancer is important in planning the type of therapeutic intervention needed. EUS can delineate the detailed layer structure of the gallbladder as well as absence or presence of regional lymph nodes. Thus, EUS can assist in the staging of gallbladder carcinoma, and in conjunction with other imaging modalities can determine tumor resectability and direct management. The accuracy of EUS in staging of gallbladder carcinoma according to the TNM classification, has been demonstrated to be 87.5%, 66.7%, 71.4%, and 71.4% for T1, T2, T3, and T4 carcinomas, respectively. Overall accuracy for tumor invasion was 76.9% and for regional lymph nodes was 89.7%. EUS is not an adequate technique for diagnosing distant metastasis. Thus, EUS as an adjunct to other diagnostic modalities, is a valuable tool in planning management of patients with gallbladder carcinoma.
Endosonography in Ampullary Carcinoma EUS is also used for staging of tumors of the ampulla. These tumors have a better prognosis compared to pancreatic cancer, and in some cases may even be amenable to local resection. Ampullary neoplasms are usually diagnosed by biopsies performed during an ERCP or a simple upper endoscopy. Endosonographically, tumors of the ampulla of Vater can be seen as an isoechoic or hypoechoic localized thickening of the duodenal wall (Figure 15-7). EUS has demonstrated superiority over CT in detecting
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Figure 15-6. Endosonographic appearance of gallbladder polyp.
Figure 15-7. Ampullary polyp.
periampullary tumors less than 2 to 3 cm in diameter. EUS is capable of imaging the distal biliary and pancreatic ducts, permitting assessment of the extent of tumor invasion into the ducts. The reported accuracy rates of EUS for staging of ampullary tumors range from 71% to 89% for T-staging, and 54% to 95% for N-staging, respectively. Misstaging of ampullary tumors can occur because of oblique scanning or a previous sphincterotomy. The presence of an endobiliary stent has also been shown to be associated with understaging of the lesion. Intraductal ultrasonography, which can clearly demonstrate the duodenal papillary region, with the sphincter of Oddi visualized as a single muscle layer, is preferable to EUS for evaluation of small ampullary lesions. Itoh et al evaluated the usefulness of IDUS in diagnosing tumor extension of cancer of the papilla of Vater and compared preoperative diagnosis with that of histopathology. They demonstrated the overall
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Figure 15-8. Example of EUSguided FNA of a pancreatic mass.
accuracy of EUS to be 87.5% for determining tumor extent and 100% for tumors limited to the sphincter of Oddi muscle layer. However, as expected the sensitivity of nodal staging was lower at 66.7%. Currently, EUS has a definite role in staging of ampullary neoplasms. It is the most accurate modality available to assess the T-stage of ampullary tumors. EUS is not as accurate for N- or M-staging. The differentiation between early carcinoma, adenoma, and inflammatory swelling of the papilla is often not possible by EUS. However, even when histopathology demonstrates a villous adenoma, EUS of an infiltrative growth may raise the suspicion for a focal malignancy.
Endoscopic Ultrasound-Guided Fine-Needle Aspiration EUS has evolved from a diagnostic imaging modality to one that can also be used for tissue acquisition and therapeutic procedures. These advances are largely due to the development of linear scanning instruments, which scan in the long axis of the endoscope and permit fine-needle aspiration by allowing real-time visualization of the needle as it is advanced into the tissue of interest (Figure 15-8). Several needles are available for performing EUS-FNA (Wilson-Cook, Winston Salem, NC; GIP Mediglobe, Tempe, AZ; Olympus Corporation, Melville, NY), ranging in size from 19 to 22 gauge with a depth of penetration of up to 10 cm. All needles have a central stylet beveled to match the needle tip, thereby enhancing the sharpness of the device. A Trucut biopsy needle device with a 15 gauge needle providing a 10 mm tissue core has also been introduced. EUS-FNA has an advantage over CT or ultrasound guided biopsy because of its ability to sample lesions that are too small to be identified by other methods, or that are intimately associated with blood vessels, precluding safe access by other methods. In addition, EUS-FNA minimizes the risk of needle track seeding by biopsy through a segment of gastrointestinal wall that may ultimately be included in the resection specimen. The results of EUS-FNA of pancreatic masses are excellent, with sensitivity of 85 to 90% and specificity of virtually 100%. For FNA of suspected cholangiocarcinoma, the sensitivity, specificity, positive predictive value, negative predictive value,
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and accuracy have been demonstrated to be 86%, 100%, 100%, 57%, and 88%, respectively. EUS-FNA can alter patient management by preventing surgery for tissue diagnosis in inoperable disease and avoiding surgery in benign disease. EUS-FNA is a generally safe procedure with a complication rate of <1%. Complications include bleeding, perforation, and infections, particularly when targeting cystic lesions of the pancreas. Pneumoperitoneum has also been reported when endoscopy closely followed EUS-FNA, suggesting that intestinal insufflation should be minimized or avoided for a short period (eg, 2 days) after EUS-FNA. A small risk of pancreatitis (usually mild) has been observed following biopsy of pancreatic lesions (1 of 121 patients in one report and 2 of 100 in another).
Endosonography-Guided Celiac Plexus Neurolysis Pain related to pancreatic cancer and chronic pancreatitis is predominantly transmitted through the celiac plexus. Celiac plexus neurolysis (CPN) is a chemical splanchnicectomy of the celiac plexus, which ablates the afferent nerve fibers that transmit pain from intra-abdominal viscera. CPN can be performed percutaneously, surgically, or under endosonographic guidance. Of all the CPN techniques short of surgical intervention, endosonographic guidance offers the most direct access to the celiac plexus, which is located at the origin of the celiac artery and easily identified at endosonography. CPN is most commonly used to palliate pain from pancreatic cancer but has also been used for relieving pain in CP. Patients with inoperable pancreatic cancer and abdominal pain requiring narcotic analgesics are potential candidates for CPN. The timing of the injection may be a predictor of response. In one study, CPN was more effective when the block was performed early after pain onset rather than late in its course. This difference was postulated to be related to involvement of other visceral and somatic nerves in terminal stages. Thus, CPN performed soon after the onset of pain from pancreatic cancer may increase the rate of response. Selection of patients with pain related to CP for CPN is less clear. Patients with pain refractory to high doses of narcotics may be appropriate candidates.
TECHNIQUE The procedure is carried out under conscious sedation, on an outpatient basis. EUS-CPN is performed using a linear array echoendoscope. The celiac artery is a landmark structure readily visualized on EUS. The ganglion is not visualized as a discrete structure on endosonography, but is identified by its relative position to the celiac artery. The right celiac ganglion is most commonly located 6 mm inferior to the celiac artery origin and the left ganglion is most commonly located 9 mm inferior to the celiac artery origin. An aspiration needle is used to perform the neurolysis. By using real-time US, the needle, which is primed with normal saline, is advanced to the level of the celiac trunk, immediately adjacent and anterior to the lateral aspect of the aorta. A small volume of saline solution is injected to clear the needle; aspiration for 10 seconds is performed. If no blood is obtained, 10 mL of 0.25% bupivacaine is injected first, followed by 20 mL of dehydrated absolute alcohol. For plexus blocks in CP, 20 mL of 0.25% bupivacaine is injected followed by 80 mg of triamcinolone.
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An echo dense cloud is typically identified with alcohol injection but not with steroid injection. The injections can also be equally distributed on both sides of the celiac trunk. There is no comparison study of the two techniques, but researchers who have used both have reported similar results. It is important to understand both methods of injection because the anatomy may dictate which method is used. The average time for the CPN portion of the exam is 15 minutes. Prior to discharge, the patient should have his or her blood pressure assessed for orthostasis. Wiersema’s initial study of EUS-CPN in patients with pancreatic cancer demonstrated a significant reduction in pain that persisted for at least 12 weeks. In another study of EUS-guided celiac plexus neurolysis for pancreatic cancer, 58 patients with painful and inoperable pancreatic cancer were evaluated at eight observation points before and after EUS-CPN for up to 6 months. Pain scores were lower (P = 0.0001) 2 weeks after EUS celiac plexus neurolysis, an effect that was sustained for 24 weeks when adjusted for morphine use and adjuvant therapy. Overall, 45 of the 58 patients (78%) experienced a decline in pain scores after EUS celiac plexus neurolysis 4. These results are similar to those achieved by the surgical and transcutaneous approach. The role of EUS-CPN is not yet well-established in patients with CP, though evidence suggests that it may be an effective tool in these patient’s management. A report of 90 patients with CP in whom triamcinolone was injected demonstrated a significant improvement in pain scores in 55% of patients at 8 weeks follow-up. This dropped off to sustained relief in only 10% of patients by 24 weeks. A cost comparison performed within this study demonstrated a $200 savings for EUS-CPN compared to CT-guided CPN. A randomized controlled trial of EUS-CPN versus CT-guided CPN in patients with CP demonstrated this method to be more effective than CT-guided CPN. A significant improvement in pain scores with reduction in pain medication usage occurred in 50% of patients having the EUS-guided block as compared to only 25% with CT-guided CPN. Persistent benefit was experienced by 40% of patients at 8 weeks and by 30% at 24 weeks. EUS-guided celiac block was the preferred technique among patients who experienced both techniques. Mild complications of EUS CPN include transient diarrhea (4% to 15%), transient orthostasis (1%), and transient increase in pain (9%). The diarrhea and hypotension occur due to a relative unopposed visceral parasympathetic activity, as a result of sympathetic blockade. In addition, cephalic spread of the neurolytic agent may result in involvement of the cardiac nerves, and plexus major complications (2.5%) have included retroperitoneal bleeding and peripancreatic abscess.
Complications Endoscopic ultrasonography, in general, has a major complication rate of approximately 0.05%. The more common complications include esophageal perforation (postdilation, 0-24%), pharyngeal and duodenal perforation, and bleeding. The risks associated with conscious sedation for diagnostic EUS are not significantly more than for esophagogastroduodenoscopy (EGD), though EUS is a more time consuming procedure and usually requires more medications compared to a standard EGD. Using a national endoscopic database, the rate of complications from EUS was 2% compared with 0.7% for EGD and 5.2% for ERCP. IDUS has proven to be safe for both pancreatic and biliary duct imaging. The only complication with IDUS reported in the literature is mild pancreatitis occurring
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in 2% to 5% of patients undergoing pancreatic IDUS. No complications have been reported with biliary IDUS.
Conclusions EUS has undoubtedly reached maturity, with widespread acknowledgement of its value and future potential as a therapeutic tool. EUS has been used for imaging with clinical impact in various diseases of the pancreatobiliary system. The unique capability of EUS to not only obtain high resolution images of small lesions, but to also access those areas for tissue acquisition as well as potential therapy, with a minimally invasive technique, will be unmatched in the future.
References 1. Lees WR. Endoscopic ultrasonography of chronic pancreatitis and pancreatic pseudocysts. Scand J Gastroenterol. 1986;123:123-129. 2. Lees WR, Vallon AG, Denyer ME, Vahl SP, Cotton PB. Prospective study of ultrasonography in chronic pancreatic disease. BMJ. 1979;1:162-164. 3. Choi WB, Lee SK, Kim MH, et al. A new strategy to predict the neoplastic polyps of the gallbladder based on a scoring system using EUS. Gastrointest Endosc. 2000; 52:372-379. 4. Gunaratnam NT, Sarma AV, Norton ID, Wiersema MJ. A prospective study of EUSguided celiac plexus neurolysis for pancreatic cancer pain. Gastrointest Endosc. 2001; 54:316-324.
Suggested Reading Levy MJ, Wiersema MJ. EUS-guided celiac plexus neurolysis and celiac plexus block. Gastrointest Endosc. 2003;57:923-930. Rosch T. Endoscopic ultrasonography: imaging and beyond. Gut. 2003;52:1220-1226. Chak A, Catanzaro A. Innovative methods of biliary tract diagnosis:intraductal ultrasound and tissue acquisition. Gastrointest Endosc Clin N Am. 2003;13:609-622. Palazzo L, O’Toole D. EUS in common bile duct stones. Gastrointest Endosc. 2002;56: S49-S57. Sahai AV. EUS and chronic pancreatitis. Gastrointest Endosc. 2002;564:S76-S81.
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Magnetic Resonance Imaging/Magnetic Resonance Cholangiopancreatography of the Pancreatobiliary System Wendy C. Hsu, MD; Evan S. Siegelman, MD
Introduction Magnetic resonance imaging with magnetic resonance cholangiopancreatography (MRI/MRCP) is a noninvasive imaging modality that has been shown to be highly accurate for evaluation of anatomy and disorders of the pancreatobiliary system. Recent technical advances not only have improved overall image quality, but also have made functional evaluation possible. In some clinical circumstances, MRI/MRCP can replace endoscopic retrograde cholangiopancreatography (ERCP) as the study of choice for diagnostic evaluation of the pancreatobiliary tract. This chapter will review the rationale, technique, and role of MRI/MRCP for the evaluation of pancreatic and biliary disorders.
Rationale for MRI/MRCP MRI is a powerful imaging tool with a high safety profile. MRI/MRCP has been advocated as a comprehensive diagnostic imaging modality of the pancreas and biliary system. In patients who present with right upper quadrant pain typical for cholecystitis or biliary colic, sonography or nuclear cholescintigraphy should be considered as the initial imaging study. Subsequently, MRI/MRCP, computed tomography (CT), ERCP, nuclear imaging, percutaneous transhepatic cholangiography (PTC) or intraoperative cholangiography (IOC) may be performed for further assess-
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ment or treatment. However, MRI/MRCP is currently the single imaging modality that can reliably provide information on the pancreatobiliary ducts, surrounding tissues, vasculature, and function in one session. Relative strengths and limitations of MRI/MRCP compared to other imaging modalities are presented in Table 16-1. MRI is noninvasive, does not use ionizing radiation, and utilizes a safe intravenous contrast agent (Gadolinium chelate), which is not nephrotoxic and has a low rate of allergic reactions. MRCP is less operator dependent than modalities such as ERCP, sonography, PTC, or IOC. ERCP is associated with a 1% to 14% rate of postprocedure complications such as pancreatitis and less commonly hemorrhage or perforation, with higher complication rates in patients who require papillotomy for cannulation1. Menon et al 2 found MRI/MRCP to be well tolerated and preferred by patients over ERCP, with patients reporting less pain and discomfort. MRI/MRCP has excellent soft tissue contrast, with especially high sensitivity for detection of fat, fluid, hemorrhage, and contrast enhancement. Images can be directly obtained in any specified plane, optimizing views. MRI/MRCP is limited by decreased sensitivity for the presence of calcification and gas, which are more accurately detected and characterized by CT. Spatial resolution of MRI/MRCP has improved with new techniques, but remains slightly lower than that of ERCP and helical CT. Having a cardiac pacemaker is currently considered an absolute contraindication to MRI. Other contraindications include certain types of intracranial aneurysm clips. Relative contraindications include claustrophobia and pregnancy. Although MRI during pregnancy appears safe, no long-term data exist and MRI is not generally advised in the first trimester. If a patient is critically ill, intubated, or otherwise cannot perform adequate breath holding, CT is recommended over MRI as it can be performed in less time and produces less motion artifacts in patients who cannot breath hold.
Pancreatobiliary MRI/MRCP Technique At our institution, when an abdominal MRI is requested for evaluation of the pancreatobiliary system, the upper abdomen from the diaphragm to the iliac crest is imaged. The specific sequences obtained vary by institution. In general, both T1weighted and T2-weighted sequences are obtained in various planes, in addition to MRCP (heavily T2-weighted) sequences. Gadolinium intravenous contrast material is then administered and dynamic imaging is performed with a T1-weighted fat-suppressed sequence in the arterial, venous, and delayed phases. Water is of low signal intensity on T1-weighted images and is sometimes used as a negative contrast to provide additional contrast between pancreas and duodenum on enhanced imaging. Glucagon may also be administered by intravenous or intramuscular injection to reduce artifacts from bowel motion. At some institutions, MRCP has been performed in isolation without use of conventional MRI sequences or dynamic contrast-enhanced imaging. However, we believe that performing a complete abdominal MRI examination in addition to MRCP is often necessary for complete patient evaluation. MRCP is performed using heavily T2-weighted sequences that selectively result in high signal from static or slow-moving fluid (Table 16-2) such as bile and pancreatic juice in the pancreatobiliary tract. Images are acquired or projected to resemble images obtained at ERCP (Figure 16-1). In the past decade, ultrafast imaging techniques have been used, which can acquire an image in less than a second. These ultrafast techniques
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Table 16-1
STRENGTHS AND LIMITATIONS OF MRI COMPARED TO OTHER PANCREATOBILIARY IMAGING MODALITIES Strengths
Limitations
MRI/MRCP
Comprehensive approach (ducts, surrounding tissue, vasculature, potentially function). No ionizing radiation. Noninvasive. No sedation required. Non-nephrotoxic contrast agent: gadolinium. Excellent soft tissue contrast and sensitivity to contrast enhancement. Direct multiplanar sections. Shows ducts proximal to obstruction. Higher patient satisfaction over ERCP. Lower cost than ERCP.
Less sensitive for calcification and gas. Less sensitive for ampullary/periampullary lesions than ERCP. Lower spatial resolution than ERCP, CT. Longer scan times than CT. Artifacts. Less availability than CT, US.
ERCP
Capability for biopsy, manometry, sonography, and therapeutic intervention. High spatial resolution of ducts, including side branches. Direct visualization of ampulla.
Highly operator dependent. Failure rate 3%-10%. Invasive, with sedation required. 1-15% complication rate Higher cost and less availability. Does not evaluate parenchyma surrounding ducts.
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Table 16-1, continued
Strengths
Limitations
CT
High spatial resolution. Speed. High sensitivity for calcification and gas. Well-tolerated, requiring less patient cooperation. Reformatting in multiple planes.
Exposure to ionizing radiation. Insensitive for evaluating ducts. Less soft tissue contrast than MRI. Allergic reactions and nephrotoxicity associ ated with iodinated contrast.
Transabdominal sonography
No ionizing radiation. Real-time imaging. Portability and availability. Lower cost.
Highly operator dependent. Bowel gas obscures anatomy. Lower spatial and contrast resolution. Limited active field of view.
Nuclear imaging (Cholescintigraphy, PET)
Functional.
Poor spatial resolution. Exposure to ionizing radiation.
PTC/IOC
High spatial resolution. Capability for therapeutic interventions.
Highly operator dependent. Invasive. Requires sedation.
MRI/MRCP = Magnetic resonance imaging/magnetic resonance cholangiopancreatography ERCP = Endoscopic retrograde cholangiopancreatography CT = Computed tomography PET = Positron emission tomography PTC = Percutaneous transhepatic cholangiography IOC = Intraoperative cholangiography
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Table 16-2
TISSUE CHARACTERISTICS ON MRI T1 Signal Intensity
T2 Signal Intensity
Bright Fat Blood (methemoglobin) Proteinaceous material Melanin Gadolinium contrast (and other paramagnetic substances) Slow flow within vessels (Calcium rarely, in the micromolecular form)
Bright Fluid that is static or slow moving is very bright, especially on heavily T2-weighted MRCP sequences (e.g. cysts, fluid collections, pancreatobiliary ducts).
Intermediate Nonspecific
Intermediate Nonspecific
Dark Calcium Old blood (hemosiderin) Gas Fibrous tissue Iron, metals Barium
Dark Calcium Old blood (hemosiderin) Gas Fibrous tissue Iron, metals Barium Brisk flow within vessels
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Figure
16-1. Normal MRCP in a man without biliary symptoms. Coronal slab projection MRCP shows normal right and left intrahepatic ducts (arrows), cystic duct, common bile duct, gallbladder, and pancreatic duct. As this is a projection image, any fluid filled bowel segment that is present within the same volume may be superimposed on the ductal structures of interest. In this example a portion of distal stomach is superimposed on a central segment of the common bile duct. There is non visualization of the most distal common bile duct in keeping with normal sphincter tone.
and use of specialized torso surface coils have decreased artifacts from abdominal gas, respiratory motion, surgical clips, and biliary stents while increasing signal-to-noise ratio and spatial resolution. These techniques have not only improved image quality but also made it possible to perform kinematic (dynamic) MRCP imaging, in which changes in the pancreatobiliary tract can be observed on sequential images. Two complementary techniques are performed as part of MRCP. One technique acquires one or more thick (30 to 80 mm) slabs in the coronal and/or coronal oblique planes. The other technique obtains multiple thin (2 to 5 mm) sections in the axial and/or coronal planes. A maximal intensity projection (MIP) can then be constructed from the thin-slice tomographic source images. On these heavily T2-weighted sequences, fluid within the peritoneal cavity, bowel, cysts, and other fluid containing structures will also be depicted as high signal intensity and in some cases may create artifact that may obscure the pancreatobiliary system. Various techniques have been investigated to further improve the performance of MRI/MRCP. Kinematic (dynamic) imaging can be performed with or without the intravenous administration of secretin, which stimulates secretion of enzymatic fluid into the pancreatic duct. This technique improves delineation of the pancreatic ducts. A succession of MRCP images is obtained in kinematic imaging to assess pancreatic exocrine reserve and help detect functional ampullary obstruction or obstruction of the accessory duct in patients with symptomatic pancreatic divisum. Some MRI contrast agents have delayed biliary excretion. Some investigators have taken advantage of this phenomenon to obtain functional contrast enhanced MRCP. Mangafodipir-trisodium is the one currently available FDA-approved con-
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trast agent that has biliary excretion. Kinematic imaging performed with this agent may better depict the intrahepatic ducts as well as suggest the presence of functional biliary obstruction in delayed and decreased biliary excretion 3. One limitation of Mangafodipir-trisodium enhancing MRI is that dynamic enhanced imaging cannot be performed. It is anticipated that gadolinium chelates that also have biliary excretion (which can be injected dynamically to provide dynamic enhanced imaging of the pancreas and biliary tract) will be FDA approved in the near future.
Evaluation of the Biliary Tract NORMAL VARIANTS Several variants of the biliary tree have been described and are associated with an increased risk of bile duct injury during open and/or laparoscopic surgery. These variants may be related to the cystic duct and include low or medial insertion of the cystic duct, cystic duct insertion into right hepatic duct, parallel course of the cystic and common hepatic ducts, and a short cystic duct. Other variants are related to aberrant intrahepatic ducts inserting into the common bile duct, common hepatic duct, cystic duct, or gallbladder. Variant or anomalous biliary anatomy is present at intraoperative cholangiography in over 42% of patients, and variant cystic duct insertion or course is present at ERCP in approximately 38% of patients4,5. Injury to the biliary tract may result in post-procedural strictures or peritonitis from a bile leak. MRCP has been used to identify biliary ductal anatomy to assist in surgical planning. MRCP was found to have sensitivity of 86% and specificity of 100% for variants of the cystic duct and sensitivity of 71% and sensitivity of 100% for variants of the right hepatic duct6. The extrahepatic ducts including the common bile duct, common hepatic duct, and cystic ducts are often well depicted on MRCP. The smaller peripheral intrahepatic ducts are not consistently revealed unless they are pathologically dilated due to obstruction. The depiction of intrahepatic ducts can be improved with a contrast agent that is excreted into the biliary tract. Intravenous Mangafodipir-trisodium is such an agent and has been investigated for use in mapping the ductal anatomy, specifically in potential liver donors, for surgical planning 7.
UNSUCCESSFUL ERCP MRI/MRCP is valuable in the evaluation of the biliary tract after failed or incomplete ERCP. Failed or incomplete ERCP occur in up to 10% to 20% of procedures. In patients after biliary-enteric anastamosis, ERCP may not be technically possible. In other cases, failed cannulation of the papilla can result from factors structural abnormalities such as periampullary diverticula, duodenal stenosis, and operator inexperience. MRI/MRCP is often able to provide a noninvasive evaluation of the pancreatic and bile ducts in these patients8.
EVALUATION OF POSTSURGICAL/POSTTRAUMATIC COMPLICATIONS MRCP is the study of choice in patients who have undergone biliary-enteric anastamosis as ERCP may be technically difficult or impossible to accomplish in these cases. MRCP can depict the biliary-enteric anastamosis in patients who have under-
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gone Billroth and bypass procedures. Donor-recipient biliary anastomoses in liver transplant patients can also be evaluated. MRCP can reveal complications including strictures and choledocholithiasis in these patients with a high degree of accuracy. In patients after biliary surgery or trauma, CT and sonography may show a nonspecific fluid collection but cannot establish the content of the fluid. Cholescintigraphy may identify bile leak as a source of the fluid collection and ERCP may then be performed to localize and treat the site of bile leak. However, some bile leaks may not be identified on ERCP, as the retrograde injection of contrast may not opacify leaks arising from disconnected (often aberrant) biliary segments or leaks adjacent to a lowpressure outlet such as a surgical drain. MRI/MRCP can assist in the diagnosis and localization of postoperative or post-traumatic biliary leaks and fistulae9.
CONGENITAL CYSTIC AND DEVELOPMENTAL ANOMALIES MRI/MRCP has been used to evaluate congenital cystic disease of the biliary tract. MRCP has been shown to be accurate in the evaluation of choledochal cysts and complications such as development of gallstones10. Patients with choledochal cysts have an increased risk of pancreatitis and cholangiocarcinoma, which can be detected on MRI/MRCP. MRCP can depict the cystic areas of intrahepatic ductal dilation associated with Caroli disease, as well as the focal dilation responsible for the “cobra head” appearance of a choledochocele, representing the expanded portion of the distal common duct prolapsing into the duodenum.
BILIARY OBSTRUCTION A meta-analysis by Romagnuolo et al11 in 2003 reviewed 498 abstracts published from January 1987 to March 2003 and selected 67 studies (4711 patients) to assess the performance of MRCP in the evaluation of biliary obstruction. In the studies examined, findings on MRCP were compared to a gold standard that included intraoperative cholangiography, ERCP, intravenous cholangiography, surgical exploration, or a combination of these procedures. MRCP was found to be highly accurate for diagnosis of obstruction, with a sensitivity of 97% and specificity of 98%. MRCP identified the level of obstruction with a sensitivity of 98% and specificity of 98%. Accurate determination of the levels of obstruction not only aids in the differential diagnosis, but also in choice of therapeutic intervention. Patients with distal bile duct obstruction are better evaluated and treated via a retrograde endoscopic approach while those with proximal obstruction may be better treated by PTC. With biliary obstruction, the increased ductal caliber increases the conspicuity of 3rd and 4th order peripheral ducts on MRCP, which are not well depicted when normal in caliber. The biliary ducts both proximal and distal to an obstruction are well demonstrated on MRCP, whereas retrograde contrast injection at ERCP may not opacify ducts proximal to a high-grade obstruction, or do so at the risk of inducing sepsis with high-pressure injection. The use of T1 and less heavily-weighted T2 sequences provides information about surrounding tissues and assists in determining the nature of the obstruction. The ductal caliber seen on MRCP may more closely approximate the true caliber, which may be overestimated at ERCP due to effects of contrast injection. Although MRCP is highly accurate for detecting and localizing biliary obstruction, it has variable accuracy ranging from 30% to 98% for differentiation between
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benign and malignant causes of obstruction. The meta-analysis by Romagnuolo et al determined the MRCP sensitivity and specificity of malignancy to be 88% and 95% respectively11. Some studies have only evaluated MRCP sequences in isolation, but the addition of T1, T2, and contrast enhanced sequences can increase the sensitivity, specificity, and accuracy by 20%12 . The lower spatial resolution of MRCP compared to ERCP may at times limit assessment of contour irregularity of a stricture. MRCP is suboptimal for evaluation of the ampullary and periampullary portions of the duct, but this limitation may be mitigated by the use of kinematic imaging with or without secretin.
BILIARY STONE DISEASE MRCP has a reported range of sensitivity of 86% to 100%, specificity of 93% to 100%, positive predictive value of 92% to 100%, and negative predictive value of 95% to 100% for the detection of choledocholithiasis. Romagnuolo et al in their meta-analysis estimated the sensitivity to be 92% and specificity 97% for the detection of choledocholithiasis11. The sensitivities and accuracies of unenhanced CT and transabdominal ultrasound are not considered adequate for detection of choledocholithiasis. Soto et al13 found MRCP and oral-contrast (iopodic acid) enhanced CT cholangiography to be much more sensitive than unenhanced CT for detection of bile duct calculi, with sensitivities of 96%, 92%, and 65%, respectively. Calculi in the biliary tract appear as low signal intensity foci surrounded by high signal intensity bile on MRCP. In some patients, focal concentric thickening of the bile duct wall may be present at the level of obstruction and is a clue to an underlying stone, although this is not specific. Pitfalls of MRCP may result in false positive or false negative diagnosis of common duct calculi14. Entities that may mimic a calculus include other intraluminal filling defects such as pneumobilia, sludge, blood clot, or tumor. Features indicating pneumobilia include presence of air-fluid level and location in the nondependent portion of the duct. Artifacts from adjacent metallic clips, indentation from a crossing right hepatic or gastroduodenal artery, or the cystic duct insertion site may occasionally mimic a ductal filling defect on certain projections. Attention to the thin section and cross sectional images is important to correctly interpret these appearances. False positive results may also occur when transient contraction of the sphincteric muscle surrounds the distal common bile duct. Using current techniques, MRCP can depict common bile duct calculi as small as 2 mm in diameter (Figure 16-2). However, in general, MRCP may be less sensitive than ERCP and EUS for calculi measuring = 3 mm in diameter. The thin section MRCP source images have higher spatial resolution and must be carefully evaluated for optimal detection of small calculi. On thick slab MRCP or maximal intensity projections, the presence of surrounding high signal intensity bile may obscure some calculi. When calculi are located in the ampulla or sphincteric portion of the distal common bile duct, they may be missed on MRCP. MRCP may be used to screen preoperative patients for choledocholithiasis. The presence of choledocholithiasis complicates cholecystectomy and is associated with higher surgical morbidity. Those found to have biliary duct calculi require therapeutic endoscopic stone extraction. Patients who have a negative MRCP prior to cholecystectomy could be spared unnecessary ERCP and its potential complications. The algorithm for MRI/MRCP evaluation of choledocholithiasis prior to
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Figure 16-2A. MRCP illustration of cho-
ledocholithiasis. A. Thin section sagittal and B. axial heavily T2-weighted images show the presence of multiple low signal intensity stones within the common bile duct.
Figure 16-2B.
cholecystectomy is still evolving, and may be based on the level of clinical risk for choledocholithiasis. Most preoperative patients who are determined to be at high risk for choledocholithiasis based on clinical and laboratory data do not have stones. Some advocate screening MRCP for patients in both high risk and moderate risk categories15. Other authors recommend that high risk patients proceed directly to ERCP for diagnostic evaluation and stone extraction. In this scenario, MRCP would be reserved for those patients with only moderate to low risk of choledocholithiasis16. The data for MRCP applied to intrahepatic biliary stone disease is limited. In general, MRCP is less sensitive for detection of abnormalities in the smaller-caliber peripheral ducts than it is for abnormalities in the larger central ducts. However, in the setting of obstruction, intrahepatic ducts enlarge, and MRCP may be superior to ERCP for detection of obstructing intrahepatic stones17.
MRI/MRCP of the Pancreaticobiliary System Figure
337 16 -2C.
Coronal slab projection MRCP ideally shows the dilated intrahepatic and extrahepatic ducts. The common bile duct stones are less well depicted compared to A and B because adjacent high signal intensity bile is partially obscuring stone visualization.
Transabdominal sonography remains the study of choice for evaluation of cholecystolithiasis. However, MRI is highly sensitive and accurate in the diagnosis of gallstones and may outperform sonography and CT. Gallstones are best seen on T2 weighted and MRCP images as foci of signal void within the gallbladder (Figure 16-3).
AMPULLARY AND PERIAMPULLARY ABNORMALITIES MRCP is believed to be less accurate than ERCP and EUS for evaluating abnormalities involving the ampullary and periampullary segments of the common duct. Artifacts from duodenal motion, gas, or fluid may obscure these regions. In addition, normal physiologic contraction of the sphincteric muscle may mimic stone, stricture, or malignancy in the ampulla and distal common duct. However, kinematic MRCP (also referred to as dynamic MRCP imaging) is a promising technique that has been shown to improve the performance of MRCP in the evaluation of the distal common bile duct and ampullary segments. In kinematic imaging, serial MRCP images are obtained to assess contractility and morphologic changes in the sphincteric portion of the duct over time. The absence of sphincteric relaxation on kinematic MRCP has been correlated with the presence of ampullary/periampullary obstruction18. This technique has the potential to detect obstruction due to both structural abnormalities such as tumor, stricture, congenital abnormalities, or stone as well as functional abnormalities such as sphincter of Oddi dysfunction. Findings on kinematic MRCP may determine the necessity for biliary intervention in biliary ductal dilation.
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Figure
16-3. MRI demonstration of gallstones. An axial heavily T2-weighted image shows multiple 1-3 mm low signal intensity calculi within the gallbladder lumen. There is no gallbladder wall thickening or pericholecystic fluid to suggest acute cholecystitis.
BILIARY STRICTURES MRCP can depict biliary findings associated with primary sclerosing cholangitis (PSC) including the multiple tandem focal strictures and bead-like dilations that predominantly involve the intrahepatic biliary tract (Figure 16-4)19. In a study of 150 consecutive patients referred for signs and symptoms of cholestasis, out of whom, 146 (97%) patients successfully underwent MRCP, the sensitivity and specificity of MRCP was 88% and 99%, respectively, for diagnosing primary sclerosing cholangitis20. MRI also provides information about coexisting cirrhosis and/or portal hypertension and can demonstrate ducts proximal to an obstruction not evaluated by ERCP. Nevertheless, ERCP remains the gold standard for diagnosis of PSC, as it is more sensitive for early strictures that have yet to cause obstructive biliary dilation. Advantages of ERCP are related to contrast injection under pressure and higher spatial resolution that can reveal subtle ductal contour changes. Thus, while MRCP is accurate for diagnosing more advanced disease, it cannot reliably exclude early PSC. ERCP is recommended to evaluate early disease as well as perform therapeutic intervention. MRI/MRCP is complementary to ERCP in the diagnosis and management of patients with PSC. MRI/MRCP is noninvasive and well-suited for follow-up of PSC once the diagnosis is established. Disease progression and development of cholangiocarcinoma can be assessed. The use of MRCP would decrease the need for ERCP, as only a minority of patients with PSC develop dominant strictures that require interventional treatment. Pitfalls that may simulate strictures include arterial pulsation, crossing vessels, sphincteric muscle contraction, stents, intraluminal filling defects, and surgical clips. Again, careful evaluation of different projections and thin section images are crucial to avoiding misinterpretation. MRCP may also overestimate the length of a high-grade stricture near or distal to the hilum, as the extrahepatic duct downstream may be collapsed.
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Figure 16-4. MRCP illustration of primary sclerosing cholangitis in a man with ulcerative colitis. Coronal slab projection MRCP reveals diffuse irregular dilation of the intrahepatic ducts and a long stricture of the common bile duct.
CHOLANGIOCARCINOMA Cholangiocarcinoma (CCA) in or outside the setting of PSC can be difficult to diagnose with available tests or imaging modalities, as findings may be nonspecific and subtle. The peripheral type of CCA typically presents at an advanced stage as a large mass seen best on imaging sequences with gadolinium. There is heterogeneous enhancement on delayed images consistent with the fibrotic nature of this tumor. The hilar (Klatskin’s) and extrahepatic types of CCA present earlier with obstructive signs and symptoms. These types circumferentially infiltrate the duct walls, and may be depicted as an obstructing stricture with irregular contours and abrupt termination, referred to as the “shoulder sign” that is suggestive of malignancy. Occasionally, a papillary growth projecting into the lumen may be revealed as a filling defect. MRI/ MRCP has been advocated as the current optimal initial evaluation for suspected cholangiocarcinoma, providing information on local extent, hepatic metastases, and vascular involvement 21. Bile duct walls greater than 5 mm with enhancement post gadolinium on nonMRCP sequences is suggestive of CCA, but is not a sensitive indicator of malignancy. Wall thickening and enhancement can be seen in various infectious and inflammatory disorders of the biliary tract, including ascending cholangitis and PSC. It is difficult to differentiate benign and malignant disease, but performance of MRCP as discussed previously can be improved by the use of T1- and T2-weighted and gadolinium enhanced sequences to detect features such masses, abscesses, or cirrhosis that may help distinguish among the different entities. It is recommended that MRI/MRCP evaluation of CCA be performed prior to intervention, as inflammation related to stent placement can result in wall thickening and enhancement and lead to overestimation of the extent of disease.
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Evaluation of the Pancreas and Pancreatic Duct The pancreatic duct is smaller in caliber than the common bile duct and is more difficult to evaluate in its entirety with MRI/MRCP unless it is dilated. Kinematic MRCP with secretin has been shown to improve depiction of the pancreatic duct and its abnormalities. Imaging sequences that are most effective for evaluating the pancreatic parenchyma often emphasize contrast differences between the high signal intensity on T1-weighted images of the normal pancreatic tissue and the relatively lower signal intensity of many pathologic processes. The pancreas demonstrates the highest signal intensity on T1-weighted imaging of all the parenchymal abdominal organs due to its high protein content. MRI is also highly sensitive, more sensitive than CT, for detection of presence of contrast enhancement. Patterns of enhancement seen after gadolinium administration help differentiate various pathologic conditions.
DEVELOPMENTAL ANOMALIES Pancreas divisum is found in approximately 7% of the population on ERCP, with rates ranging from 4% to 14% on autopsy series. In this anomaly, the dorsal pancreas fails to fuse with the ventral pancreas such that the larger dorsal duct empties via the smaller minor papilla. In some patients, this may result in obstruction at the minor papilla related to poor drainage. Some believe that detection of pancreas divisum has important clinical implications, as it may be associated with recurrent pancreatitis related to functional obstruction, while others believe the finding is coincidental. The dorsal duct anatomy in pancreas divisum is demonstrated on MRCP with a high degree of accuracy 22 . The diagnosis of divisum on ERCP is based on opacification of an abbreviated ventral duct at injection of contrast via the major papilla without demonstration of the dorsal duct. However, in some cases this ductal termination may be mistakenly interpreted on ERCP as a complete obstruction due to other causes. MRCP reveals the dorsal duct in continuity emptying into the duodenum via the minor papilla without a connection between the dorsal and ventral ducts. The development of a “Santorinicele” (focal dilation of the segment of the duct at the minor papilla) after secretin administration in patients with pancreas divisum suggests functional obstruction at the minor papilla serving the dorsal duct. Secretin-MRCP revealing a Santorinicele identifies patients who may potentially benefit from endoscopic papillotomy or sphincterotomy 23. An annular pancreas is demonstrated when pancreatic tissue partially or completely surrounds the duodenum. This is best seen on the T1 weighted sequences in which bright pancreatic tissue surrounds the duodenum. A T1-negative oral contrast agent such as water may also be helpful to distend the duodenum and to contrast with the high signal intensity of pancreatic tissue. On MRCP, an abnormal encircling duct may be identified.
PANCREATITIS MRI/MRCP has been used to evaluate chronic and acute pancreatitis and assist in therapeutic planning (Table 16-3). Enhanced CT is the current imaging modality of choice for the evaluation of complications of acute pancreatitis because of its excellent sensitivity for peripancreatic inflammation, fluid collections, and necrosis. Patients with acute pancreatitis are often very ill and may be unable to cooperate with pro-
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Table 16-3
UTILITY OF MRI/MRCP IN PANCREATITIS Comments Acute Pancreatitis
Identify etiologies Assess complications
Determine prognosis
Chronic Pancreatitis Assist in diagnosis/ exclusion Detect ductal abnormalities
Evaluate function
For practical purposes, contrast enhanced CT remains the modality of choice. However, MRI/ MRCP may be helpful in cooperative patients if CT is contraindicated or under the following circumstances. Choledocholithiasis, pancreatic cancer, divisum, sphincter of Oddi dysfunction. Characterize hemorrhagic or proteinaceous fluid collections that may benefit from lytic therapies. Detect parenchymal necrosis. Less sensitive than CT for detection of gas in fluid collections. MRI/MRCP severity score may correlate better with morbidity than the CT score.
Improve detection with secretin. Reliably exclude presence of pancreatic disease in general with secretin (NPV 98%). Less sensitive than CT for calcifications. Show communication of pseudocysts with pancreatic duct. Sensitivity improved with secretin. Determine need for and influence choice of therapeutic intervention. Assess exocrine reserve with secretin.
longed exam times of multiple breath-hold sequences. Thus, they may be better suited to CT than MRI. However, MRI/MRCP is highly accurate for assessing and staging acute pancreatitis and can be considered an alternative when contrast enhanced CT is contraindicated or equivocal such as in patients with renal failure or contrast allergy. Lecesne et al 24 prospectively evaluated 30 patients who underwent both MRI/MRCP and contrast enhanced CT and found good correlation (Spearman rank test score r = 0.71 to 0.82) for findings of inflammation, necrosis, and severity index between the two modalities. In addition, a linear progressive correlation was noted between the severity index determined by MRI/MRCP and patient morbidity (defined as sepsis, pseudocyst, or need for surgery). In contrast, the severity score as determined by CT did not correlate linearly with morbidity. The authors suggest that MRI/MRCP was
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superior in this respect because it was more reliable than CT in differentiating peripancreatic inflammation from a small hemorrhagic fluid collection. Because of higher sensitivity of MRI to contrast enhancement, MRI may be able to detect pancreatic necrosis at an earlier stage. MRI is sensitive to the presence of hemorrhage or protein within fluid collections and can suggest the need for of lytic therapy at the time of drainage. MRI can clearly differentiate the presence of focal fat versus necrosis, both of which appear low in density on CT. Contrast enhanced MRI sequences also detect the presence of splenic venous thrombosis or arterial pseudoaneurysm. In patients with chronic pancreatitis, ERCP is performed to evaluate the status of the pancreatic duct and determine the need for intervention. However, contrast injection at ERCP fails to fully opacify the pancreatic ducts in up to 30% of patients and results in an incomplete examination. A retrospective study in patients with pancreatitis found MRCP had very good sensitivity of 91% for depicting the pancreatobiliary ducts and an accuracy of 92% for detecting changes in ductal caliber and irregularity when compared with ERCP25. In general, segments that were only slightly narrowed or slightly dilated at ERCP were not as consistently characterized by MRCP. MRCP can also detect intraductal filling defects such as calculi or debris. The recent ultrafast techniques combined with administration of secretin have been used to perform kinematic MRCP and improve detection of side branches and depiction of the main pancreatic duct, particularly in the tail 26. Changes in these segments have been associated with early chronic pancreatitis. The benefits of secretin were most pronounced in patients who were clinically suspected to have pancreatic disease but were not found to have pancreatic ductal abnormalities with CT and/or US. In this scenario, side branches were revealed in 63%, increased from 4%, of ductal segments (head, body, or tail) evaluated. In cases in which patients were already known to have ductal dilation from severe chronic pancreatitis, depiction of side branches improved from 71% to 100% of segments evaluated. A prospective study evaluating 95 patients with known or suspected pancreatic disease demonstrated that overall sensitivity for detection of chronic pancreatitis increased from 77% to 89% after secretin. The negative predictive value of MRCP for any pancreatic abnormality increased from 84% to 98% after secretin administration 27. Standards of references in that study included ERCP, intraoperative findings, and/or clinical follow-up. Secretin-MRCP may improve detection of intraductal filling defects as well as provide assessment of exocrine function by evaluating duodenal filling. Secretin-MRCP appears reliable for the diagnostic evaluation of chronic pancreatitis, particularly for diagnosing cases associated with subtle ductal abnormalities. The pancreas may appear atrophic and diffusely hypointense on both T1- and T2-weighted images and hypoenhanced after gadolinium administration. MRI/MRCP is less sensitive than CT for presence of calcifications in chronic pancreatitis and for the presence of gas in peripancreatic fluid collections.
PANCREATIC DUCTAL ADENOCARCINOMA A wide range of imaging modalities has been applied to detect and stage pancreatic adenocarcinoma including CT, percutaneous sonography, endoscopic sonography, MRI/MRCP, ERCP, and PET with variable success28. In a prospective study by Adamek et al 29, MRI/MRCP was determined to be more accurate for detection of pancreatic adenocarcinoma than ERCP; MRI/MRCP had a sensitivity of 84% and specificity of 97% compared to ERCP, which was 70% sensitive and 94% specific.
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Table 16-4
INDICATIONS FOR MRI/MRCP FOR EVALUATION OF PANCREATIC ADENOCARCINOMA Indication
Scenario
1. Detection
Equivocal findings on CT/US. Enlarged pancreatic head on CT/US without visible mass. Suspicion for small, non-contour-deforming tumor.
2. Staging to determine resectability
Definitive characterization of hepatic lesions which are indeterminate on CT. Potentially more accurate assessment of vascular invasion.
Studies have also shown that MRI is superior to nonhelical and single detector CT for the detection and staging of pancreatic malignancy 30, but in clinical practice, patients are often routinely referred for helical CT. The basis for better performance of MRI over CT has been attributed to excellent soft tissue contrast and sensitivity to contrast enhancement that renders small tumors more conspicuous. MRI/MRCP including gadolinium enhancement accurately evaluates vascular involvement, regional invasion, and distant metastases, factors determining resectability. The current indications for MRI/MRCP for the investigation of pancreatic ductal adenocarcinoma are shown in Table 16-4. The accuracy of newer multidetector helical CT (MDCT) scanning compared to MRI/MRCP has yet to be determined. One recent study suggests that the excellent spatial resolution of MDCT improves the detection of small (<2 cm) pancreatic tumors31. Differentiating carcinoma from chronic pancreatitis based on imaging criteria remains problematic. The “double duct sign” at MRCP, as it is at ERCP, is highly suggestive of a pancreatic adenocarcinoma indicating mass effect in the head of the pancreas obstructing both the pancreatic and common bile ducts (Figure 16-5). However, this finding is nonspecific and can also be seen with scarring from chronic pancreatitis, leading to false positive diagnoses. On conventional MRI sequences, presence of a focal mass that is lower in signal intensity on T1-weighted imaging in the normally higher signal intensity pancreatic parenchyma supports the diagnosis of adenocarcinoma. However, fibrotic changes in the pancreatic parenchyma related to chronic pancreatitis may also appear well circumscribed and low in signal intensity. Enhancement characteristics can also be similar, with delayed enhancement relative to the surrounding parenchyma reflecting the hypovascularity and fibrotic nature of both disease processes32 . The presence of normal pancreatic tissue surrounding the mass favors malignancy. However, a non-border deforming pancreatic head mass in a patient with chronic pancreatitis may be difficult to characterize. It may represent either an adenocarcinoma that has resulted in secondary post obstructive chronic pancreatitis or benign scar without malignancy due to prior pancreatitis.
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Figure 16-5. MRCP
illustration of the “double-duct” sign in a man with pancreatic cancer. Coronal slab projection MRCP reveals dilated pancreatic and common bile ducts to the level of the pancreatic head. While this single image provides information concerning the level and likely etiology of the obstruction, it provides no information of whether a responsible tumor is resectable. Other sequences (not shown) were necessary to show unresectable disease.
ISLET CELL NEOPLASMS (NEUROENDOCRINE TUMORS) Contrast enhanced MRI/MRCP appears to be sensitive for detection of pancreatic islet cell tumors, although studies are often limited by small patient populations and different proportions of the various subtypes of tumors. Islet cell tumors are well demonstrated on multiple imaging sequences on MRI/MRCP33. Compared to CT, MRI demonstrates better soft tissue contrast and increased sensitivity for intravenous contrast enhancement that potentially makes smaller tumors more apparent. The three most common types are insulinomas, gastrinomas, and nonfunctioning tumors. Most insulinomas are benign, whereas the majority of gastrinomas and nonfunctioning tumors are malignant. Functional islet cell tumors are generally small (<2 cm) at the time of diagnosis. Functioning islet cell tumors typically show high signal intensity on T2-weighted images and appear lower in signal intensity than surrounding pancreas on T1-weighted images. They are hypervascular and demonstrate avid enhancement on arterial phase images, although exceptions occur when the tumor demonstrates scirrhous features. Nonfunctioning tumors are often advanced at presentation with a diameter greater than 5 cm and carry a poorer prognosis. These are also hypervascular with enhancement characteristics similar to the functioning tumors. However, nonfunctioning tumors frequently demonstrate heterogeneous signal intensity with prominent areas of necrosis and cystic degeneration (Figure 166). Symptoms are related to mass effect on the pancreatic duct and adjacent organs. Hypervascular liver metastases may be identified. In contrast to pancreatic ductal adenocarcinoma, islet cell tumors less often result in pancreatic ductal obstruction, vascular encasement, vascular thrombosis, or peritoneal metastases.
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Figure 16-6A. MRI of metastatic islet cell tumor of the pancreas. Two T2-weighted
images of the abdomen obtained through the level of the A. pancreatic body and B. pancreatic head show multiple liver metastases. On T2-weighted images, metastatic disease is often isointense to spleen. A solid and cystic mass of the pancreatic head represents the patient’s primary islet cell tumor.
Figure 16-6B. Pancreatic head.
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CYSTIC PANCREATIC NEOPLASMS The pseudocyst accounts for approximately 90% of all cystic pancreatic lesions. The remaining 10% represent cystic neoplasms. It may be difficult to differentiate pseudocysts from cystic neoplasms, but clinical history of prior pancreatitis is helpful. The appearances of the various cystic neoplasms can be nonspecific, but in some cases imaging with MRI/MRCP may be able to strongly suggest a specific diagnosis. Cystic structures are well depicted on MRI/MRCP, better than on CT, with fluid demonstrating very high signal intensity on T2- and heavily T2-weighted sequences. As a result, there is excellent contrast between the fluid and the solid components of pancreatic cystic lesions. This allows more confident assessment of the number and size of cysts as well as definition of cyst margins34. Accurate assessment of these features is important for differentiation between serous and mucinous cystic neoplasms, which has subsequent implications for patient management. Serous cystadenomas are managed conservatively while mucinous cystic neoplasms are considered potentially malignant and thus are usually candidates for surgical resection. Serous cystadenomas are benign and typically demonstrate multiple clustered microcysts less than 2 cm in diameter each (Figure 16-7). Larger tumors may have a characteristic fibrous central scar exhibiting delayed enhancement. Mucinous cystic neoplasms are typically composed of uni- or multilocular macrocysts greater than 2 cm diameter. Invasion of surrounding structures and presence of liver metastases indicate malignancy, but otherwise, imaging features are not specific for malignant transformation of mucinous tumors. Less common primary cystic lesions of the pancreas include intraductal papillary mucinous tumor (IPMT) and solid and papillary epithelial neoplasm (SPEN). The gold standard for diagnosis of a main branch IPMT has been ERCP, which identifies the presence of intraductal mucin with direct inspection. However, some authors suggest that MRI/MRCP is not only complementary, but also superior to ERCP for evaluation of IPMT35. Copious amounts of mucin may impede retrograde contrast injection, resulting in incomplete examination at ERCP, whereas the mucin itself allows excellent depiction of the pancreatic ducts on MRI/MRCP. Features that are suggestive of malignancy of IPMT on MRCP include maximum main duct diameter of 15 mm, diffuse dilation of the main pancreatic duct, and mural nodules within the duct 36. Regarding SPEN, the appearance of a large, well-encapsulated, hemorrhagic mass in a young woman is virtually pathognomonic. The presence of hemorrhagic degeneration in these tumors is well characterized by MRI.
PANCREATIC TRANSPLANT Pancreatic transplants are being performed with increasing frequency, typically in conjunction with renal transplants in patients with type I diabetes. Magnetic resonance imaging with angiography is ideally suited for the evaluation of pancreatic transplants. When evaluation for pancreatic transplant complications is required, gadolinium enhanced MRI with angiographic detail may be performed without risk of toxicity to the transplant kidney. Transplant dysfunction has been associated with decreased parenchymal enhancement 37. Transplant arterial and venous complications such as thrombosis and stenosis are well depicted on MRI angiography.
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Figure 16-7A. MRI find-
ings of a benign serous cystadenoma of the pancreas. A. Coronal heavily T2-weighted and B. contrast enhanced fat suppressed T1-weighted images show a well-circumscribed cystic mass of the pancreatic head with enhancing internal septae. This is the typical appearance of a “microcystic” serous cystadenoma. There are greater than 6 cysts separated by enhancing thin septa, none of the cysts are >2 cm, and there are no solid enhancing components. This patient had no signs or symptoms related to the pancreas and thus was not treated with surgery.
Figure 16-7B.
Conclusions MRI/MRCP has been successfully used for diagnostic evaluation of a wide variety of pancreatobiliary disorders (Table 16-5). In some circumstances, it has become the study of choice, replacing ERCP and other imaging modalities because of its safety
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Table 16-5
INDICATIONS FOR PANCREATICOBILIARY MRI/MRCP General Indications for MRI/MRCP Indication Contraindication to contrast enhanced CT Minimizing exposure to ionizing radiation
Comments Renal failure Allergy to iodinated contrast Pregnancy Pediatric population Repeated follow-up imaging
Biliary Indications for MRI/MRCP Indication Demonstration of variant anatomy
Unsuccessful ERCP Status post biliary-enteric anastamosis Presence of biliary obstruction
Choledocholithiasis Primary sclerosing cholangitis
Comments Depiction of aberrant intra- or extrahepatic ducts prior to biliary surgery or as part of evaluation of potential liver donor. Manganese-containing contrast agent that is administered IV and excreted into biliary tract may be helpful for intrahepatic ducts. Evaluation and follow-up of congenital cystic anomalies. Study of choice. Study of choice. Highly sensitive for detection and localization of obstruction. Less sensitive for determining whether cause is malignant or benign, but may be equal to or better than other modalities. Highly sensitive and specific. Detects stones 2 mm or greater. May be study of choice for follow-up to assess disease progression and development of malignancy. Detects cirrhosis, portal hypertension. Cannot exclude subtle early PSC.
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Table 16-5, continued
Biliary Indications for MRI/MRCP Indication Cholangiocarcinoma
Comments Study of choice for evaluation and staging of CCA. Perform before intervention, as post-procedure inflammation may mimic disease involvement.
Pancreatic Indications for MRI/MRCP Indication Demonstration of developmental anomalies Pancreatitis Pancreatic adenocarcinoma
Islet cell tumor
Cystic pancreatic neoplasm Hemochromatosis
Pancreatic transplant
Comments Pancreas divisum/dominant dorsal duct. Annular pancreas. Applications in acute and chronic disease (see Table 16-3). Detection and staging (see Table 16-4). Hypovascular, with delayed enhancement. May be difficult to distinguish from scarring from chronic pancreatitis. Sensitive even for small (<2 cm) tumors. Hypervascular, with early enhancement. Hypervascular liver metastases. Excellent for depicting features of fluid-containing structures. Iron deposition results in very low in signal intensity on T2-weighted sequences. Pancreatic involvement denotes late stage of disease. Detects pancreatic dysfunction and vascular complications. Non-nephrotoxic to the associated renal transplant.
and accuracy. In other scenarios, MRI/MRCP has proven reliable as a complementary or alternative imaging modality, providing additional information that determines need for treatment and directs choice of therapies. MRI/MRCP shows promise as a comprehensive “all-in-one” initial approach for assessment of the pancreatobiliary system. New technology including faster techniques for image acquisition and higher magnetic field strengths are already becoming clinically available and will further improve the performance of MRI/MRCP.
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References 1. Barthet M, et al. Complications of endoscopic sphincterotomy: results from a single tertiary referral center. Endoscopy. 2002;34(12):991-7. 2. Menon K, et al. Patient satisfaction after MRCP and ERCP. Am J Gastroenterol. 2001;96(9):2646-50. 3. Lee VS, et al. Volumetric mangafodipir trisodium-enhanced cholangiography to define intrahepatic biliary anatomy. AJR Am J Roentgenol. 2001;176(4):906-8. 4. Puente SG, Bannura GC. Radiological anatomy of the biliary tract: variations and congenital abnormalities. World J Surg. 1983;7(2):271-6. 5. Shaw MJ, Dorsher PJ, Vennes JA. Cystic duct anatomy: an endoscopic perspective. Am J Gastroenterol. 1993;88(12):2102-6. 6. Taourel P, et al. Anatomic variants of the biliary tree: diagnosis with MR cholangiopancreatography. Radiology. 1996;199(2):521-7. 7. Kapoor V, et al. Intrahepatic biliary anatomy of living adult liver donors: correlation of mangafodipir trisodium-enhanced MR cholangiography and intraoperative cholangiography. AJR Am J Roentgenol. 2002;179(5):1281-6. 8. Soto JA, et al. MR cholangiopancreatography after unsuccessful or incomplete ERCP. Radiology. 1996;199(1):91-8. 9. Vitellas KM, et al. Using contrast-enhanced MR cholangiography with IV mangafodipir trisodium (Teslascan) to evaluate bile duct leaks after cholecystectomy: a prospective study of 11 patients. AJR Am J Roentgenol. 2002;179(2):409-16. 10. Irie H, et al. Value of MR cholangiopancreatography in evaluating choledochal cysts. AJR Am J Roentgenol. 1998;171(5):1381-5. 11. Romagnuolo J, et al. Magnetic resonance cholangiopancreatography: a meta-analysis of test performance in suspected biliary disease. Ann Intern Med. 2003;139(7):54757. 12. Kim MJ, et al. Biliary dilatation: differentiation of benign from malignant causes— value of adding conventional MR imaging to MR cholangiopancreatography. Radiology. 2000;214(1):173-81. 13. Soto JA, et al. Diagnosing bile duct stones: comparison of unenhanced helical CT, oral contrast-enhanced CT cholangiography, and MR cholangiography. AJR Am J Roentgenol. 2000;175(4):1127-34. 14. Irie H, et al. Pitfalls in MR cholangiopancreatographic interpretation. Radiographics. 2001;21(1):23-37. 15. Kim JH, et al. MR cholangiography in symptomatic gallstones: diagnostic accuracy according to clinical risk group. Radiology. 2002;224(2):410-6. 16. Calvo MM, et al. Role of magnetic resonance cholangiopancreatography in patients with suspected choledocholithiasis. Mayo Clin Proc. 2002;77(5):422-8. 17. Kim TK, et al. Diagnosis of intrahepatic stones: superiority of MR cholangiopancreatography over endoscopic retrograde cholangiopancreatography. AJR Am J Roentgenol. 2002;179(2):429-34. 18. Kim JH, et al. Differential diagnosis of periampullary carcinomas at MR imaging. Radiographics. 2002;22(6):1335-52. 19. Fulcher AS, et al. Primary sclerosing cholangitis: evaluation with MR cholangiography: a case-control study. Radiology. 2000;215(1):71-80.
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20. Textor HJ, et al. Three-dimensional magnetic resonance cholangiopancreatography with respiratory triggering in the diagnosis of primary sclerosing cholangitis: comparison with endoscopic retrograde cholangiography. Endoscopy. 2002;34(12):984-90. 21. Khan SA, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut. 2002;51 (Suppl 6):VI1-9. 22. Bret PM, et al. Pancreas divisum: evaluation with MR cholangiopancreatography. Radiology. 1996;199(1):99-103. 23. Manfredi R, et al. Pancreas divisum and “santorinicele”: diagnosis with dynamic MR cholangiopancreatography with secretin stimulation. Radiology. 2000;217(2):403408. 24. Lecesne R, et al. Acute pancreatitis: interobserver agreement and correlation of CT and MR cholangiopancreatography with outcome. Radiology. 1999;211(3):727-35. 25. Sica GT, et al. Comparison of endoscopic retrograde cholangiopancreatography with MR cholangiopancreatography in patients with pancreatitis. Radiology. 1999;210(3):605-10. 26. Manfredi R, et al. Severe chronic pancreatitis versus suspected pancreatic disease: dynamic MR cholangiopancreatography after secretin stimulation. Radiology. 2000;214(3):849-55. 27. Hellerhoff KJ, et al. Dynamic MR pancreatography after secretin administration: image quality and diagnostic accuracy. AJR Am J Roentgenol. 2002;179(1):121-9. 28. Tamm EP, et al. Diagnosis, staging, and surveillance of pancreatic cancer. AJR Am J Roentgenol. 2003;180(5):1311-23. 29. Adamek HE, et al. Pancreatic cancer detection with magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography: a prospective controlled study. Lancet. 2000;356(9225):190-3. 30. Ichikawa T, et al. Pancreatic ductal adenocarcinoma: Preoperative assessment with helical CT versus dynamic MR imaging. Radiology. 1997;202(3):655-662. 31. Bronstein YL, et al. Detection of small pancreatic tumors with multiphasic helical CT. AJR Am J Roentgenol. 2004;182(3):619-23. 32. Johnson PT, Outwater EK. Pancreatic carcinoma versus chronic pancreatitis: dynamic MR imaging. Radiology. 1999;212(1):213-8. 33. Semelka RC, et al. Islet cell tumors: comparison of dynamic contrast-enhanced CT and MR imaging with dynamic gadolinium enhancement and fat suppression. Radiology. 1993;186(3):799-802. 34. Minami M, et al. Cystic neoplasms of the pancreas: comparison of MR imaging with CT. Radiology. 1989;171(1):53-6. 35. Koito K, et al. Mucin-producing pancreatic tumors: comparison of MR cholangiopancreatography with endoscopic retrograde cholangiopancreatography. Radiology. 1998;208(1):231-7. 36. Irie H, et al. MR cholangiopancreatographic differentiation of benign and malignant intraductal mucin-producing tumors of the pancreas. AJR Am J Roentgenol. 2000;174(5):1403-8. 37. Krebs TL, et al. Acute pancreatic transplant rejection: evaluation with dynamic contrast-enhanced MR imaging compared with histopathologic analysis. Radiology. 1999;210(2):437-42.
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Pancreaticobiliary Diseases: The Role of the Interventional Radiologist Richard Shlansky-Goldberg, MD; Aalpen Patel, MD
Introduction The role of interventional radiology in the treatment of pancreaticobiliary diseases has expanded over time as techniques and imaging methods have improved. Most of the interventional percutaneous procedures are complementary to endoscopic techniques to provide the ultimate care for patients.
History The technique of percutaneous puncture of the biliary tree was first reported in the 1920s1. In the early 1960s, the technique of percutaneous cholangiography became more routinely practiced along with the ability to decompress the biliary system with drainage catheters2 . In addition, the use of skinny needle technique that developed in the early 1970s demonstrated that cholangiography could be performed safely for the study of the biliary tract 2 . Transhepatic cholangiography is typically performed during the course of biliary decompression. With the advent of cross sectional imaging and endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography without drainage is performed much less often. More often cholangiography is performed through indwelling percutaneous drainage catheters or through an indwelling T-tube to gain detailed intraluminal information about the biliary system. There are still several reasons to perform cholangiography particularly in the jaundiced patient. It provides a precise definition of the site and cause of the obstruction. It also gives a surgical road map to plan possible resection and provides drainage with a catheter or stent. In addition, it can diagnose biliary obstruction in diseases that may not have dilation on cross-sectional imaging such as in sclerosing cholangitis.
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Percutaneous Biliary Drainage Transhepatic cholangiography is typically performed using a skinny thin walled needle such as a 21 or 22 gauge Chiba. Patient preparation requires the evaluation of coagulation parameters and prophylactic antibiotics. Serum creatinine should also be evaluated. Although contrast is not intentionally injected into the vascular system during the needle passes, contrast may be injected into the hepatic or portal vein. Depending on the degree of difficulty, a patient may receive a moderate amount of intravascular contrast. If the patient is not already on antibiotics, and even if the patient is afebrile and has a normal white count, intravenous antibiotics are administered prophylactically. Our current prophylactic regimen is to use Unasyn or Levaquin if the patient is penicillin allergic. If the patient is allergic to both, vancomycin and gentamicin is an alternative. Our guidelines for biliary drainage include an international normalized ratio of less than 1.5 and a platelet count of greater than 50,000. If the patient is clinically infected, several hours of antibiotics may be prudent as biliary penetration is decreased in an obstructed system. Review of any cross sectional or ERCP imaging is critical prior to the procedure to plan the approach. The puncture is generally made through the mid-axillary line at the ninth or tenth intercostal space. When possible, we try a subcostal approach to prevent a transpleural route. Ultrasound and fluoroscopic guidance may assist in this. In those cases where hilar obstruction is suspected or there is ascites, a left sided subxiphoid approach may be necessary. Minute quantities of contrast are injected during slow withdrawal of the needle under fluoroscopic guidance. Due to the wide safety margin with the use of a skinny needle, multiple passes with varying angles can be performed to locate an intrahepatic biliary duct. Once initial ductal filling is confirmed, contrast is further injected to evaluate a site of obstruction. If decompression is to be provided, either the same access site is chosen, if not too central within the hilum, or another more peripheral duct is punctured. Central access is not recommended (especially important for biliary drainage) as it is associated with higher bleeding complications due to risk of injury to the hepatic artery. There are several potential pitfalls in diagnosing the level of obstruction when initially performing a percutaneous transhepatic cholangiogram. The initial images may give a false impression of a high obstruction. This is caused by an elevated biliary pressure and poor mixing of contrast with bile. In addition, the common bile duct is higher in a supine patient than the intrahepatic ducts so that hydrostatic pressure must be overcome to provide good opacification. Improved opacification can be obtained with tilting the patient 45 degrees upright and left lateral or left posterior oblique to fill the left ducts that are more anterior than the right ducts. Indications for transhepatic cholangiography include defining the level of obstruction in patients with dilated biliary ducts, to evaluate for presence of suspected stones, determine etiology of cholangitis, evaluate bile duct inflammatory disorders, and to demonstrate leak from injury 3. The indications for biliary drainage include decompressing an obstructed biliary system, dilating biliary strictures, removing stones and diverting or stenting bile duct defect causing obstruction or a bile leak 3. Once access is gained into the biliary tree, the obstructing lesion can be crossed if the patient is not cholangitic. This allows placement of an internal-external catheter that may be capped to provide internal drainage of bile, negating the need of a bag and preventing dehydration, and loss of bile salts and electrolytes. If the patient is febrile or has an
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elevated white count, external drainage may be used for several days until the infection is treated. Some lesions may not be able to be crossed at the initial drainage due to complexity of the obstruction and the degree of dilation. Allowing for several days of decompression can improve the success rate of crossing a lesion. Other ways to improve the success rate of crossing an obstruction includes using a combined percutaneous transhepatic route with ERCP guidance during a rendezvous procedure. In addition direct puncture of the common bile duct can be performed to allow for both antegrade and retrograde interrogation of the obstruction4. The success rate of percutaneous transhepatic cholangiography for dilated and nondilated ducts is 95% and 65%, respectively 3. The procedural success for catheterizing the biliary tree after cholangiography for dilated and nondilated ducts is 95% and 70%, respectively. The success of internal drainage or crossing into the duodenum after successfully catheterizing the duct is 90%. Complications of transhepatic cholangiography when performed with a 21 gauge or smaller needle are low3. Major complications include sepsis, cholangitis, bile leak, hemorrhage, or pneumothorax with a rate of 2%. Major complication rates of biliary drainage include: sepsis, 2.5%; hemorrhage, 2.5%; localized inflammatory or infectious complication, 1.2%; pleural complications, 0.5%; and death, 1.7%. Cholangiography obtained through indwelling catheters is typically performed with ionic or non-ionic contrast. A scout radiograph is useful prior to the drainage to see calcifications from stones that may be obscured by instilled contrast. An early film is usually obtained demonstrating ease of flow of contrast into the duodenum. Contrast should be gently injected through a syringe and films should be obtained in the anterior-posterior, right and left oblique. Care should be taken not to over distend the biliary system. This is particularly important in patients who are obstructed or have cholangitis as over injection may result in bacteremia with potential septicemia. Filling under gravity may be indicated in immunosuppressed patients, particularly those having recently undergone liver transplantation, in order to limit the potential to raise the intraductal biliary pressure. Gravity infusion helps to decrease bacteremia and risk of extravasation from a recent anastomosis in these patients. If a percutaneously placed internal-external drain is in place, the optimal cholangiogram is obtained by removing the tube over a wire and injecting contrast through a short sheath placed over the wire in a peripheral duct. This also has the advantage of being able to obtain information about the flow of bile through a prior obstruction.
Biliary Injury The majority of bile duct injuries are iatrogenic and are usually associated with cholecystectomy. In a study by Kovalcik et al, the complication rate for open cholecystectomy with or without common duct exploration was 14.3% with a mortality of 0.52%5. Injuries may be referred to as acute injuries requiring urgent intervention whereas other injuries are more insidious, usually resulting in stricture. In a study by Ghahremani et al the most frequent injury was rupture of an intrahepatic duct from a Fogarty balloon used to blindly sweep the intrahepatic bile ducts 6. Other injuries seen in their study include perforation, laceration, or dissection of the duct. Cystic duct leaks were also seen resulting in a biloma. Patients also developed obstructive
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jaundice due to stricture of the common bile duct. Some injuries were caused by cystic duct ligation too close to the common duct. Many of these injuries may heal without intervention. However, major injuries to the bile duct causing obstruction or leakage will require cholangiography and drainage of the biliary tract. With the advent of laparoscopic cholecystectomy additional complications are being seen. Although the overall complication rate is lower than that for a standard cholecystectomy, the complication rate for biliary tract injuries is higher and depends on the experience of the surgeon. Trerotola et al. described major and minor injuries7. Major complications were described as common hepatic or bile duct stricture, obstruction, or transection. These injuries are seen more often if no intraoperative cholangiogram is performed and usually require surgical intervention. Minor injuries resulted from a cystic duct or choledochojejunostomy leak. Other injuries to the duct have been attributed to excessive use of the cautery device. The coordinated radiologic and surgical approach to the management of these patients has been described by vanSonnenberg et al 8. More recently a classification system has been proposed to describe these injuries9. One anatomical variant of the biliary tree that is prone to injury is an aberrant right hepatic duct. This variation can be seen at operative cholangiography 4.6% to 5.5% of the time and at autopsy up to 18% of the time10. This duct can be ligated or transected inadvertently during surgery. The aberrant duct drains a variable amount of the right lobe of the liver, usually the dorsocaudal lobe. If the aberrant duct drains only a small fraction of the right lobe, a ligated duct may go unnoticed. Christensen et al reported a small series of patients who had prolonged symptoms from bile duct injury with chronic pain or episodes of recurrent cholangitis ranging from 2 weeks to 126 months after laparoscopic cholecystectomy10. Ultrasound and CT were helpful in demonstrating the obstructed ducts in a segment of the right lobe, whereas ERCP was nondiagnostic in these cases. Ultrasound was helpful in localizing the isolated ducts so that percutaneous drainage could be performed. Injuries that result in biliary leak can be the most difficult to treat due to complete biliary decompression. Without obstruction and ductal dilatation transhepatic drainage may be unsuccessful due to the inability to opacify the system. ERCP may be helpful in diagnosing the leak, however, if the injury is a full transection of the duct, the proximal portion of the biliary tree will not be opacified. We usually attempt drainage as a way to control the leak and aid during reconstructive surgery in identifying the transected portions of the biliary tree. If the patient presents with perihepatic fluid, CT or ultrasound guided drainage of this fluid collection is helpful in controlling the leak. This is particularly important in patients suspected of being infected. If these perihepatic collections are well controlled and the patient is stable, time may be allowed for the collection to resolve and demonstrate the fistula to the leak.
Benign Strictures and Stone Disease Localized benign strictures are typically caused by chronic inflammation due to stone disease or iatrogenic injury after surgery, whereas multifocal strictures are caused by diffuse processes such as sclerosing cholangitis or chemotherapy toxicity. Percutaneous treatment after transhepatic biliary drainage has several advantages over endoscopic techniques. Cholangioplasty can be performed through the percutaneous tract and stones may be extracted or pushed into the duodenum. As an aid to cholangiography, with tract dilatation, cholangioscopy can be performed. In addi-
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tion after tract dilatation, the stricture can be stented with a large diameter capped catheter to obtain the greatest patency. In addition, the area can be stented for a long duration requiring only minimal sedation for further evaluation and tube change. This is particularly important in strictures due to sclerosing cholangitis where repeat intervention is needed and that the stricture may be very proximal making endoscopic therapy difficult11. Following catheter stenting, the patient may undergo a clinical trial with the tube positioned and capped above the area of narrowing so that if symptoms reoccur, the tube may be uncapped to provide relief of the obstruction. In patients who have undergone a surgical reconstruction with a choledochojejunostomy, percutaneous intervention may be performed when endoscopic techniques are not possible due to the inability to reach the surgical anastomosis. The success rate of percutaneous intervention is at least 50% to 60% long-term with an extremely low morbidity and mortality making the technique more desirable than surgery. We have a benign stricture protocol that involves placing a large bore catheter (16-18 French) across the stricture after cholangioplasty12,13. After the initial drainage, the maximum size hydrophilic flexible catheter, usually 14 French, is placed. Following this, cholangioplasty to 6 to 10 mm is performed on the stricture and the catheter is up-sized to a silastic catheter, either 16 or 18 French. We keep the catheter in place for a minimum of 6 months with tube changes after 3 months to ensure catheter patency. Following stenting for 6 months, the patient undergoes an over the wire cholangiogram. If the cholangiogram demonstrates patency and adequate flow of contrast, the catheter is changed for a modified short catheter so that its tip will remain above the stricture and be capped for the patient to undergo a clinical trial for 2 weeks. If the patient remains asymptomatic after the trial and the liver function test remains normal and the final cholangiogram is widely patent, the tube is removed. If there are equivocal findings, the patient may undergo a biliary Whitaker test or cholangioscopy to access patency. If the patient fails the clinical trial, the patient can undergo repeat cholangioplasty with a larger stent for another 6 months or may be referred for surgical revision. Due to their limited patency, there is virtually no role for metal stents in benign disease except in very rare situations.
Malignancy Metal stents seemed the ideal solution for malignant biliary strictures due to their ability to be delivered through small 9 to 10 French tracts and expanded to sizes of 8 mm and higher. Prior to the introduction of metal stents, the primary reasons for biliary re-interventions for plastic biliary endoprostheses were due to stent migration and occlusion. Occlusions were typically from sludge build-up in the relatively small internal luminal diameters of the 9 to 14 French plastic stents. This occurs because of bacterial growth and deposition of a matrix containing glycoprotein along with deconjugation of bilirubin with deposition of calcium bilirubinate within the stent. With the advent of metal stents, with their larger luminal diameters, it was hoped that the need for re-intervention would be reduced or eliminated. However, metal stents once thought to be the panacea for biliary obstructions, still have significant limitations with the greatest problem being limited patency rate. Stent occlusion happens due to several reasons. The surface of the stent is open to allow for the drainage of side branch radicals, allowing tumor ingrowth or benign mucosal hyperplasia to occlude or narrow
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the stent. Stents such as the Wallstent (Boston Scientific) can shorten upwards of 40% with time and withdraw from the area of tumor or stricture. In addition, sludge can deposit on the stent wires leading to obstruction and tumor can outgrow the boundaries of the stent, which is a problem particularly in hilar lesions. Early results for the treatment of malignant obstructions with both the Gianturco stent and Wallstent were not much better than results from the plastic stents. A multicenter European trial reported approximately a 50% recurrence rate with the Gianturco stent14. Early reports of the Wallstent had a high late complication rate with Gillams et al reporting 42% of their malignant strictures reoccurred15. Adam et al detailed a late complication rate of only 7% with the Gianturco stents16. Another report by Lameris et al revealed late complications of jaundice and cholangitis to be related to the location of the stent. Hilar lesions had a higher complication rate of 17% and common duct lesions had a rate of 2.4%17. The patency rate is affected more by the location of the tumor than by the type of malignancy18. Covered stents may have higher patency rates; however, the available evidence remains. (These reports and many others confirm that although the placement of metal stents are easier with smaller tracts than the conventional plastic stents, reintervention will often be required, especially in slow-growing malignancies such as cholangiocarcinoma. This statement is especially true if the stents are placed in benign disease. The use of covered biliary stents may prolong patency, but the results from early trials remain limited19.) Reintervention in patients with metal stents can be extremely difficult, especially if the patient is septic and hypotensive. In addition, because the metal stent cannot be removed like plastic stents, access to the biliary tree can be difficult. The access to the biliary tree must be gained in such a way that allows for initial decompression and later recanalization of the indwelling stent. If the new puncture is too low within the duct, it is likely that the indwelling obstructed stent will block adequate access into the common duct. Because most metal stents are readily seen on fluoroscopy, a cholangiogram can first be obtained by aiming for the stent. Once opacification is obtained, then a second puncture can be performed to enter a duct suitable for recanalizing the stent. Care must be taken in entering the stent to avoid entering the stent from the side rather from the proximal opening. In addition, once the stent is engaged, one needs to remain in the center of the stent rather than going under the wire mesh between the stent and the duct wall. This is particularly difficult in the Gianturco Z-stent as the opening to the stent is large and easily crossed as opposed to the Wallstent that has smaller side openings. A 1 J or 3 J wire, such as a Rosen, works well. Confirmation of the wires central location within the stent can be obtained with multiple oblique views. Another helpful technique is to use a small occlusion balloon or 5-mm angioplasty balloon, pushing it through the stent as a test to ensure the central location of the stent. Once confirmation of the central path of wire is ascertained, recanalization can be performed. If the stent has shortened above the stricture or tumor has overgrown the stent, a new stent should be deployed. If debris, sludge, tumor, or epithelial overgrowth has taken place, the stent should be “dredged” with a latex occlusion balloon and angioplastied to the full diameter of the stent. If this method fails to open the stent adequately, then another stent placed within the first stent should be deployed. If a biloma or abscess has formed due to the obstruction, it should be drained using conventional percutaneous techniques prior to removing the external biliary drain.
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Other novel percutaneous techniques for biliary decompression have also been investigated for use in malignant obstructions. We have used a single articulated catheter to obviate the need for multiple catheters in patients with complex biliary strictures or strictures associated with small or immature tracts20. Two- and threearm articulated drains (8-14 French) made from segments of biliary catheters. In patients where internal stenting may be difficult or undesirable, articulated catheters allow satisfactory external and internal drainage of complex benign and malignant strictures through a single tract, avoiding the need for multiple transhepatic catheters. Another novel technique involves alternative ways to decompress the biliary tree when catheter manipulation through the common bile duct cannot be performed. Soulez et al described percutaneous puncture from the left lobe of the liver to the stomach in 35 patients with biliary obstruction creating a hepaticogastrostomy 21,22 . The technical success was achieved in all patients with a mean patency of 234 days. This technique provided an alternative route to drain patients internally when attempts to cross into the duodenum from the common bile duct fail. Permanent external drainage is always problematic because of the need to carry a bag of draining bile in addition to the loss of fluids and electrolytes.
Liver Transplantation The biliary complication rate in orthotopic liver transplantation is approximately 10% to 37% 23-26. Complications are due to stricture or leak usually at the biliary anastomosis. Currently at our institution, biliary reconstruction is performed with a choledocho-choledochostomy with a T-tube placed through the anastomosis for approximately 3 to 4 months. A choledochojejunostomy is typically performed in biliary revisions or retransplantation. The advantages of the choledochocholedochostomy is that the T-tube optimally stents the tract and allows for easy cholangiography to evaluate elevations in liver function tests and bilirubin that may represent rejection, ischemia, or biliary obstruction. Most noninvasive diagnoses of transplant biliary complications are performed with CT, ultrasound, or nuclear medicine. Elevated liver functions tests are helpful, however, cholangiography is essential along with liver biopsy to evaluate the status of the transplant. Early after transplant, T-tube cholangiography is performed for abnormal liver function tests. After the T-tube is removed, conventional percutaneous cholangiography is needed. One of the newer modalities used to image the biliary tree is MR cholangiography. Biliary leak in a transplant patient can be devastating because the patient is immunocompromised. Most frequently leaks develop at the T-tube choledochostomy early after surgery. Because the majority of the blood supply to the common duct arises from branches of the gastroduodenal artery that are transected during surgery, the duct is susceptible to ischemia and disruption of the anastomosis. The donor or recipient cystic duct remnant can also leak. Other areas of the biliary tree can extravasate, leading to biloma formation but this is usually related to hepatic artery thrombosis and biliary necrosis and is usually located in the donor biliary segment. Kaplan et al. drained bilomas in 16 patients with thrombosis of the hepatic artery. Ten of these patients subsequently required retransplantation within 4 months of drainage27. The leaks that develop from the T-tube tract are usually managed conservatively with ERCP or biliary drainage but anastomotic leaks usually require endoscopic or percutaneous cholangioplasty or surgical repair. Rare findings that mimic
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biliary leak on CT or ultrasound are mucoceles of the cystic duct remnant requiring cholangiography or ERCP to make the diagnosis. Leakage of bile can also occur immediately after the T-tube has been removed. Because patients with liver transplants are on immunosuppressive medical therapy including corticosteroids, there is delayed healing of the T-tube tract with little to no granulation tissue. Due to this reason and the need for cholangiography, the tube remains in place for 3 to 4 months. Even after this amount of time a tract may not form. At our institution, a study of 40 liver transplant patients demonstrated that eight patients had major complications of their T-tube involving biliary leak or dislodgment from an immature tract. Six patients were managed by re-catheterization of the tract while the other two required transhepatic drainage. Biliary obstruction in transplant patients can at times be difficult to diagnose. The most common cause of biliary obstruction in the transplant patient is biliary stricture with approximately 50% at the anastomosis23. These strictures are most likely due to scar formation with narrowing of the duct. Different degrees of narrowing can be seen around an indwelling T-tube that may or may not lead to obstruction once the tube is removed. The size of the extrahepatic bile ducts may increase slightly with time and does not usually signify obstruction. Campbell et al demonstrated in serial cholangiograms of 40 liver transplant patients a slight increase in size of both the donor common hepatic duct and native common bile duct 28. In a few of the patients this dilatation was related to migration of the T-tube into native common bile duct. Nonanastomotic strictures are usually seen in the donor common hepatic duct, bifurcation and intrahepatic ducts and may be due to ischemia, therefore these patients should have their hepatic artery evaluated. Less often these strictures can be caused by previously indwelling catheters. Another cause of obstruction is biliary sludge related to sloughed ductal epithelium caused by ischemia, infection, or rejection. Other causes of obstruction are recurrent sclerosing cholangitis, kinking of the common bile duct, duodenal diverticulum, or stones. Clinical evidence of obstruction in patients with a diffusely dilated biliary tree without a definite stricture can be seen in some patients. In a study by Miller et al, more prominent diffuse dilatation of the biliary tree was seen in patients with elevated enzymes consistent with obstruction without cholangiographic evidence of a stricture29. The mean caliber of the common duct dilated from 7.5 mm to 14.8 mm and the hepatic duct dilated from 5.9 mm to 12.8 mm. Diffuse dilatation with clinical evidence of obstruction was thought to be related to dysfunction of the sphincter of Oddi with denervation of the ampulla. Most of these patients improved with surgical revision of the choledochocholedochostomy to a choledochojejunostomy. Management of patients with biliary stricture is usually percutaneous dilatation performed through a transhepatic tract as the T-tube tract may not be well formed, increasing the risk of bile leak and infection. Both anastomotic and nonanastomotic strictures can be dilated. Ward et al reported in a series of 152 patients, 16 nonanastomotic strictures, 11 of which had infections such as CMV, rejection, or occluded hepatic arteries that did not respond to dilatation as well as those patients who had no underlying abnormality 30. Zajko et al reported an 81% patency rate at 6 months and a 70% rate at 6 years for a series of 72 strictures of which 56 were anastomotic31. Gomes suggests that these strictures should be dilated and followed closely with early repeat dilatation, if needed, so that a long-term catheter is not left in place because of the increased risk of infection 26. Obstructing lesions other than strictures such as
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sludge and stones can be removed either through a T-tube tract or transhepatic tract as is typically performed in nontransplant patients.
Pancreatic Diseases Percutaneous therapy for the sequelae of nonvascular complications of pancreatitis is performed for pancreatic pseudocyst and fistula. Acute pancreatitis can present on CT with a range of findings from minimal edema of the pancreatic parenchyma to extensive phlegmonous changes due to necrotizing hemorrhagic pancreatitis. Small fluid collections can develop within the body of the pancreas and dissect through tissue planes to almost any location within the body. These collections may go on to develop a dense fibrous capsule filled with pancreatic secretions and tissue debris within 6 weeks. Simple pseudocysts have varying amounts of pancreatic enzymes depending on the condition of the pancreatic duct. They are usually not infected; however, they may become infected further complicating a patient’s clinical course. Larger cysts, if left untreated, may go on to rupture or become an abscess. With severe hemorrhagic pancreatitis, tissue necrosis may develop with phlegmonous changes of the pancreas and surrounding tissues. Pseudocysts less than 5 to 6 cm are generally not drained and will resolve without intervention. Larger pseudocysts are typically drained for several reasons including fever, sepsis, pain, and biliary and gastric obstruction. Their management remains somewhat controversial due to reports of percutaneous drainage failures. Criado et al reviewed their 10-year experience of 42 patients with pseudocysts and concluded that percutaneous drainage is safe and valuable for the acute management of patients but believed that because there was a lack of resolution in many cases and a high recurrence rate, percutaneous drainage should not be considered as a definitive form of therapy 32 . The success of percutaneous drainage for simple pseudocyst has been reported to be better than that for pancreatic abscess, 33% to 100% versus 32% to 79%, respectively 33. More aggressive therapy is needed when there is a large amount of pancreatic necrosis due to the large amount of solid material that is in the abscess cavity that tends to occlude percutaneous catheters. Large size catheters such as 24 French with mechanical debridement devices and multiple treatments are often needed to remove the large amount of necrotic tissue. Other authors have reported high success rates for percutaneous drainage and advocate it for several reasons. The usual surgical procedure is to perform a cystoenterostomy that requires a period of 6 weeks for cyst wall maturation. During this period, there is an increased risk of cyst-related complications. In addition, these patients are generally sick, which makes them a poor surgical risk. Most studies comparing surgical with percutaneous therapy demonstrate significantly less morbidity and mortality for percutaneous drainage. Adams et al compared surgical internal drainage of 42 patients with percutaneous therapy in 52 patients, demonstrating a 16.7% complication rate for surgical drainage versus a 7.7% complication for percutaneous therapy 34. These findings were not statistically significant; however, the surgical group had a 7.1% death rate, while the percutaneous group had no deaths, although there was a drain tract infection rate of 48.1%. VanSonnenberg et al reviewed the outcome of 101 patients treated percutaneously with infected and noninfected pseudocysts and demonstrated a success rate of 86% and 94.1%, respectively35. The mean duration of drainage was 19.6 days. Six patients underwent surgical drainage for persistent drain-
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age. Various access routes were used such as transperitoneal, retroperitoneal, transhepatic transgastric, transduodenal, and even an inadvertent transplenic route. Several authors advocate the transgastric route for drainage to establish a tract to the stomach. This creates the equivalent to a surgical cystogastrostomy that allows for internal drainage of the obstructed pancreatic duct. External drainage is maintained until the output decreases to a minimal amount. The external portion of the drain is then cut and the amputated catheter is pushed in to the stomach. Das et al advocate using two catheters along the same tract with one internal pigtail catheter between the cyst and stomach and another external drain in the cyst to optimize drainage36,37. Mueller et al described the transhepatic route for those cases of lesser sac collections that were not reachable by the transgastric route38. Typical tube management involves monitoring patients with pancreatic tubes to determine the end point for therapy. We typically use continuous drainage when outputs are greater than 100 mL per day and gravity drainage when less. We will remove the catheter when there is less than 10 to 20 mL/day output and there is no ductal communication. In addition, a CT scan will be obtained to ensure that there is no loculated fluid. Multiloculated pseudocysts or complicated abscesses may require multiple large catheters such as 20 to 24 French sump drains. In a study by Steiner et al of nonsimple cyst drainages, only 8 of 25 patients could be treated by a percutaneous route only 39. The remainder of patients required some combination of surgical and percutaneous therapy. More recent investigators have suggested with the use of large catheters with debridement, the outcomes of percutaneous intervention are improved. Echenique et al reported their results using aggressive percutaneous techniques for debriding infected pancreatic necrosis in 20 patients 40. The average number of interventions was 17 with a range of 7 to 32 debridements ranging from 30 to 120 minutes in duration that ultimately negated the need for surgery. These aggressive techniques will hopefully improve the success rate for percutaneous interventions in these difficult patients. Another complication of pancreatitis is fistula formation to other organs (internal) or to skin (external). The fistulas can produce massive amounts of fluid, as the pancreas makes over one liter of fluid per day. Patients can develop communication to the peritoneum developing ascites and pleural space developing hydrothorax. Fistula communication had been reported to other areas such as the biliary tree, duodenum, and colon to name a few. If the fistula is due to duct disruption rather than obstruction, it is more likely to heal with conservative management. If the fistula develops with an obstructed pancreatic duct, closure is unlikely without aggressive therapy. The measurement of amylase and the amount of fluid output has value in determining the likelihood of closure and is related to the degree of ductal obstruction. The surgical therapy is typically Roux-en-Y pancreaticojejunostomy for proximal duct obstructions or distal pancreatectomy for body or tail obstructions. Percutaneous catheter drainage will usually successfully treat pancreatic fistulae especially when combined with Octreotide to suppress pancreatic secretions. Fotoohi et al demonstrated that persistent fistulae in 27 of 60 patients with pancreatitis eventually resolved with catheter drainage in 97%. Fistulae were more likely in patients with severe pancreatitis. Recent investigations have reported percutaneous recanalization of an obstructed duct using plastic stents, Mathieson et al have reported the successful use of Gianturco Z stent to treat ductal obstruction41. We had stented two pancreatic ducts to treat external cutaneous fistulas42 . One patient had a long-standing cutane-
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ous fistula from his distal duct. He developed a communication to a loop of jejunum. The tract was dilated and stented with an articulated drain for approximately 3 months. The stent was then removed and external drainage ceased. The other patient had a cutaneous fistula from his mid duct. A stenosis was demonstrated adjacent to the fistula. The stenosis was dilated and stented with an articulated plastic stent for approximately 4 months; however, after removal of the stent, the fistula returned. A Palmaz stent was successfully placed across the stenosis healing the fistula. Cope et al reported the successful long-term outcome of three additional patients with pancreatic strictures that were percutaneously managed with transductal catheters. Cyanoacrylate tissue adhesive had also been used to embolize the pancreatic duct fistula43.
Conclusion The role of interventional radiology in the treatment in biliary and pancreatic disease is diverse. Percutaneous access allows for a variety of interventions that are complementary to endoscopic techniques. They provide for not only first line therapies but also alternatives when endoscopic techniques fail. The combination of these two approaches provides optimal care of patients with biliary and pancreatic disease.
References 1. Mueller P. Biliary interventions: a historical perspective. Semin Intervent Radiol. 1996;13:197-200. 2. Glenn F, Evans J, Mujahed Z, Thorbjarnarson B. Percutaneous transhepatic cholangiography. Ann Surg. 1962;156:451-462. 3. Burke DR, Lewis CA, Cardella JF, et al. Quality improvement guidelines for percutaneous transhepatic cholangiography and biliary drainage. J Vasc Interv Radiol. 2003;14:S243-246. 4. Shlansky-Goldberg RD, Ginsberg GG, Cope C. Percutaneous puncture of the common bile duct as a rendezvous procedure to cross a difficult biliary obstruction. J Vasc Interv Radiol. 1995;6:943-946. 5. Kovalcik PJ, Burrell MJ, Old WL Jr. Cholecystectomy concomitant with other intraabdominal operations. Assessment of risk. Arch Surg. 1983;118:1059-1062. 6. Ghahremani GG, Crampton AR, Bernstein JR, Caprini JA. Iatrogenic biliary tract complications: radiologic features and clinical significance. Radiographics. 1991;11:441-456. 7. Trerotola SO, Savader SJ, Lund GB, et al. Biliary tract complications following laparoscopic cholecystectomy: imaging and intervention. Radiology. 1992;184:195200. 8. vanSonnenberg E, D’Agostino HB, Easter DW, et al. Complications of laparoscopic cholecystectomy: coordinated radiologic and surgical management in 21 patients. Radiology. 1993;188:399-404. 9. Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of biliary injury during laparoscopic cholecystectomy. J Am Coll Surg. 1995;180:101-125. 10. Christensen RA, vanSonnenberg E, Nemcek AA Jr, D’Agostino HB. Inadvertent ligation of the aberrant right hepatic duct at cholecystectomy: radiologic diagnosis and therapy. Radiology. 1992;183:549-553. 11. MacCarty RL, LaRusso NF, Wiesner RH, Ludwig J. Primary sclerosing cholangitis: findings on cholangiography and pancreatography. Radiology. 1983;149:39-44.
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31. Zajko AB, Sheng R, Zetti GM, Madariaga JR, Bron KM. Transhepatic balloon dilation of biliary strictures in liver transplant patients: a 10-year experience. J Vasc Interv Radiol. 1995;6:79-83. 32. Criado E, De Stefano AA, Weiner TM, Jaques PF. Long term results of percutaneous catheter drainage of pancreatic pseudocysts. Surg Gynecol Obstet. 1992;175:293-298. 33. Balthazar EJ, Freeny PC, vanSonnenberg E. Imaging and intervention in acute pancreatitis. Radiology. 1994;193:297-306. 34. Adams DB, Anderson MC. Percutaneous catheter drainage compared with internal drainage in the management of pancreatic pseudocyst. Ann Surg. 1992;215:571-578. 35. vanSonnenberg E, Wittich GR, Casola G, et al. Percutaneous drainage of infected and noninfected pancreatic pseudocysts: experience in 101 cases. Radiology. 1989; 170:757-761. 36. Das KM, Kochhar R. Pancreatic pseudocysts: treated with dual drainage. Clin Radiol. 1992;45:92-93. 37. Das K, Kochhar R, Kaushik SP, et al. Double pigtail cystogastric stent in the management of pancreatic pseudocyst. J Clin Ultrasound. 1992;20:11-17. 38. Mueller PR, Ferrucci JT, Jr., Simeone JF, et al. Lesser sac abscesses and fluid collections: drainage by transhepatic approach. Radiology. 1985;155:615-618. 39. Steiner E, Mueller PR, Hahn PF, et al. Complicated pancreatic abscesses: problems in interventional management. Radiology. 1988;167:443-446. 40. Echenique AM, Sleeman D, Yrizarry J, et al. Percutaneous catheter-directed debridement of infected pancreatic necrosis: results in 20 patients. J Vasc Interv Radiol. 1998; 9:565-571. 41. Mathieson JR, Cooperberg PL, Murray DJ, Dashefsky S, Christensen R, Schmidt N. Pancreatic duct obstruction treated with percutaneous antegrade insertion of a metal stent: report of two cases. Radiology. 1992;185:465-467. 42. Shlansky-Goldberg RD, Soulen MC, Rosato EF, Cope C. Percutaneous management of external pancreatic fistulas: the use of articulated and metal stents. J Vasc Interv Radiol. 1995;6:191-196. 43. Findeiss LK, Brandabur J, Traverso LW, Robinson DH. Percutaneous embolization of the pancreatic duct with cyanoacrylate tissue adhesive in disconnected duct syndrome. J Vasc Interv Radiol. 2003;14:107-111.
Index
aberrant pancreas, 5–6 abscess, pancreatic, 260 acalculous cholecystitis, acute, 30, 37–38 accessory gallbladder, 18–19 accessory pancreas, 5–6 acinar cell cystadenoma, of pancreas, 268–269 acinar cell cystic neoplasms, of pancreas, 282 acinar cystic transformation, of pancreas, 268–269 acute pancreatitis, 147–177 in choledocholithiasis, 51 chronic pancreatitis after, 185 complications of, 170–172 diagnosis of, 148–155 differential diagnosis of, 154–155 drug-induced, 150–152 etiology of, 155–159 MRI/MRCP in, 340–342 pseudocyst in, 259–260 radiology in, 159–161 severity of, 162–167 spectrum of, 147 treatment of, 161–170 antibiotics for, 168–169 nutritional, 169–170 percutaneous, 361 Acute Physiologic and Chronic Health Evaluation (APACHE) score, for acute pancreatitis, 166
adenocarcinoma ampullary, 96–98, 320–322 bile duct epithelium. See cholangiocarcinoma cystic ductal, 282 pancreatic. See pancreatic cancer adenoma, ampullary, 96–98 Agarwal and Pitchumoni criteria, for acute pancreatitis, 164 age factors, in gallstone formation, 25–26 agenesis of gallbladder, 17 of pancreas, 6–7 AIDS, cholangiopathy in, 139–140 Alagille syndrome, bile duct paucity in, 11–12 alcohol, pancreatitis due to, 185–186 acute, 157–158 chronic, 197 ampulla of Vater, dysplasia of, 96–98, 320–322, 337 amylase conditions affecting, 153–155 in pancreatitis, 149–152 analgesia, for chronic pancreatitis, 197 angiography, in pancreatic cancer, 244– 245 annular pancreas, 4–5, 340 antibiotics for acute pancreatitis, 168–169 for cholangitis, 128
368
Index
Ascaris lumbricoides, cholangitis due to, 130–131 ascites in chronic pancreatitis, 203 in pancreatic duct leakage, 235 Atlanta classification, of peripancreatic fluid collections, 260 Atlanta criteria, for acute pancreatitis, 163 atresia, biliary, 12–13 autoimmune chronic pancreatitis, 186– 187 autosomal dominant polycystic kidney disease biliary cysts in, 10–11 pancreatic cysts in, 267 autosomal recessive polycystic kidney disease, biliary cysts in, 9–10 Balthazar score, for acute pancreatitis, 165 Bank criteria, for acute pancreatitis, 164 bile ducts aberrant, injury of, 356 accessory, 16–17 atresia of, 12–13 brown stones in, 29 cancer of. See also cholangiocarcinoma drainage for, 357–359 resection of, 307–309 choledochal cyst of, 13–15, 334 common. See common bile duct congenital anomalies of extrahepatic, 12–17 intrahepatic, 7–12 cystic disorders of, 8–11 development of, 2–4 duplication of, 16–17 extrahepatic. See extrahepatic bile ducts injuries of, 60–90 diagnosis of, 72–75 etiology of, 69–72 repair of, 306–307 treatment of, 76–84, 355–356 intrahepatic. See intrahepatic bile ducts leakage from after cancer surgery, 306–307 in endoscopic procedures, 76–79 in liver transplantation, 71–73, 359–360 obstruction of in biliary cancer, 357–358 MRI/MRCP in, 334–335
in pancreatic cancer, 294–295 in pancreatitis, 202 paucity of, 11–12 polycystic conditions of, 9–11 positional alterations of, 16–17 stenosis of, 16–17 stones in, MRI/MRCP in, 335–337 strictures of, 71, 73, 75, 79–83 in cancer, 357–358 endoscopic ultrasound in, 314–315 interventional radiology in, 356– 357, 360–361 in liver transplantation, 360–361 MRI/MRCP in, 338 tumors of, resection of, 307–309 ultrasound probes for, 312 biliary cirrhosis, in choledocholithiasis, 51 biliary colic acalculous, 38, 124–125 calculous, 30–31, 50 biliary sludge, 28–29, 49, 319–320 biliary sphincter, dilation of, for choledocholithiasis, 57–58 biliary tract. See also bile ducts development of, 2–4 diversion of, 305–309 drainage of, percutaneous, 354–355 normal variants of, 333 surgery on. See also specific procedures postoperative evaluation of, 333–334 preoperative evaluation for, 297–299 biliovascular fistulas, 72–73, 83 bilirubin, in biliary sludge, 28, 49 biopsy endoscopic ultrasound-guided, 322–323 of pancreas in cancer, 245–247, 290 in pancreatic serous cystic neoplasms, 245–247 black gallstones, 29, 48 bronchobiliary fistula, 35 brown gallstones, 29, 48 CA 19-9 tumor marker in pancreatic cancer, 240 in pancreatic duct strictures, 221–222 calcification, of gallbladder, 40 calculous cholecystitis, acute, 30, 121–124 caliculi, gallbladder. See gallstones Cambridge classification, of chronic pancreatitis, 180–181
Index cancer ampullary, 96–98, 320–322 of bile ducts. See also cholangiocarcinoma drainage for, 357–359 resection of, 307–309 gallbladder, 31, 39–40, 320 pancreatic. See pancreatic cancer Caroli’s syndrome and Caroli’s disease, biliary cysts in, 10 celiac plexus blockade for chronic pancreatitis, 199–200 endoscopic ultrasound-guided, 323–324 for pancreatic cancer, 250 cestodes, cholangitis due to, 135–138 chemotherapy, for cholangiocarcinoma, 114–115 cholangiocarcinoma, 103–120 classification of, 103–105 clinical presentation of, 107 diagnosis of, 107–110 endoscopic ultrasound in, 315 MRI/MRCP in, 339 pathology of, 103–105 risk factors for, 104, 106–107 staging of, 111–112 treatment of, 112–117 cholangiography in cholangiocarcinoma, 109 choledocholithiasis discovered during, 62 intraoperative, in choledocholithiasis, 55 percutaneous transhepatic, 354–355 for biliary strictures, 79, 81–82 for choledocholithiasis, 54, 62 cholangiohepatitis, Oriental, 138 cholangiopancreatography. See endoscopic retrograde cholangiopancreatography; magnetic resonance cholangiopancreatography cholangiopathy, AIDS-related, 139–140 cholangioplasty, endoscopic, 356–357 cholangioscopy, in cholangiocarcinoma, 110 cholangitis bacterial, 125–129 in choledocholithiasis, 50–51 MRI/MRCP in, 338 parasitic, 129–138 recurrent pyogenic, 138–139 viral, 140 cholecystectomy. See also laparoscopic cholecystectomy bile duct injury in, 355–356
369
indications for, 300 open for cancer, 40 for choledocholithiasis, 63 sphincter of Oddi dysfunction after, 91 cholecystic fistulas, 35 cholecystitis acute acalculous, 30, 37–38, 124–125 acute calculous, 30, 32–34, 121–124 emphysematous, 36–37 cholecystojejunostomy, for pancreatic cancer, 248–249 cholecystotomy, percutaneous, for cholecystitis, 125 choledochal cyst, 13–15, 334 choledochoduodenostomy, 305 choledochojejunostomy, 305 choledocholithiasis, 47–68 biliary sludge and, 49 cholangiocarcinoma in, 106 clinical manifestations of, 50–51 diagnosis of, 52–55 endoscopic ultrasound in, 313–314 epidemiology of, 47 Mirizzi’s syndrome in, 63–64 MRI/MRCP in, 335–336 pathogenesis of, 47–48 primary, 49 risk factors for, 50 risk stratification in, 52–53 secondary, 49 treatment of, 55–63 choledochoscopy, 303 cholelithiasis, gallbladder. See gallstones cholescintigraphy, in cholecystitis, 32 cholesterol gallstones, 24–28, 47–48 chronic pancreatitis, 179–215 autoimmune, 186–187 classification of, 179–182 clinical presentation of, 189–191 complications of, 201–203 diagnosis of, 192–196, 204–205 duct stones in, 225–226 endoscopic ultrasound in, 316–318 epidemiology of, 179 etiology of, 185–189 hereditary, 188 idiopathic, 188 minimal change, 182 MRI/MRCP in, 340–342 obstructive, 186
370
Index
pathology of, 182 pathophysiology of, 182–185 prognosis for, 203–204 treatment of, 196–201 cirrhosis, biliary, in choledocholithiasis, 51 Clonorchis sinensis, cholangitis due to, 131–133 colic, biliary, 30–31, 38, 50 colon, biliary fistulas with, 35 common bile duct abnormalities of, MRI/MRCP in, 337 exploration of, 303 gallstones in. See choledocholithiasis computed tomography in acute pancreatitis, 160–161, 167 in cholangiocarcinoma, 108 in cholangitis, 127 in choledocholithiasis, 52 in chronic pancreatitis, 192 in pancreatic cancer, 240–241, 244, 288 in pancreatic pseudocyst, 261 in serous cystic neoplasms, 274 congenital anomalies of biliary tract, 7–17, 334 of gallbladder, 17–20 of pancreas, 2, 4–7 cysts, 266–268 MRI/MRCP in, 340 cyst(s) biliary, 8–11 choledochal, 13–15, 334 pancreatic. See pancreas, cystic lesions of; pancreas, pseudocysts of cystadenocarcinoma, of pancreas mucinous, 276 serous, 273–275 cystadenoma, of pancreas acinar cell, 268–269 mucinous, 276 serous, 273–275, 347 cystic ductal adenocarcinoma, of pancreas, 282 cystic fibrosis, chronic pancreatitis in, 188 cystogastrostomy, for pancreatic pseudocyst, 362 diabetes mellitus, in chronic pancreatitis, 191 dilation, of pancreatic duct stricture, 224 dissolution therapy, for choledocholithiasis, 63 diverticulum, of gallbladder, 18–19
“double duct sign,” in pancreatic cancer, 343 drainage. See also percutaneous drainage of biliary tract, 354–355, 359 nasobiliary, for bile leaks, 76 of pancreatic pseudocysts, 234, 263– 264, 361–362 drugs gallstones due to, 27 pancreatitis due to, 150–152 duodenum biliary fistulas with, 35 obstruction of, in pancreatic cancer, 249–250 duplication of bile ducts, 16–17 of gallbladder, 18–19 duplication cysts, of pancreas, 266 dysplasia, of pancreas, 6–7 echinococcosis cholangitis in, 135–138 pancreatic cysts in, 268 echoendoscopes, 312 ectopic gallbladder, 18–19 ectopic pancreas, 5–6 electrohydraulic lithotripsy, for choledocholithiasis, 60–61 embryology, of pancreas, 1–2 emphysematous cholecystitis, 36–37 endometrial cysts, of pancreas, 266 endoscopic procedures for bile duct strictures, 356–357 for bile leaks, 76–79 for pancreatic duct strictures, 222–225 for pancreatic pseudocysts, 232–234, 264 for pancreatic stones, 228–229 endoscopic retrograde cholangiopancreatography (ERCP) in acute pancreatitis, 167–168 in biliary strictures, 79, 81 in choledocholithiasis, 54, 313–314 in chronic pancreatitis, 192–193 in intraductal papillary mucinous neoplasm, 279–280 in pancreatic cancer, 242 in pancreatic duct stones, 226–227 in pancreatic duct strictures, 210–220 pancreatitis after, 159 in sphincter of Oddi dysfunction, 95–97 unsuccessful, MRI/MRCP in, 333
Index endoscopic ultrasound, 311–325 in ampullary carcinoma, 320–322 in bile duct strictures, 314–315 in biliary sludge, 319–320 in celiac plexus neurolysis, 323–324 in cholangiocarcinoma, 110 in choledocholithiasis, 55, 313–314 in cholelithiasis, 319–320 in chronic pancreatitis, 194–195, 316–318 complications of, 324–325 in fine-needle aspiration, 322–323 in gallbladder cancer, 320 in gallbladder polyps, 320 instruments for, 311–312 in intraductal papillary mucinous pancreatic neoplasms, 280 in pancreatic cancer, 242–247, 288 in pancreatic duct stones, 227 in pancreatic duct strictures, 221, 319 in pancreatic neuroendocrine tumors, 251–252, 318 in pancreatitis, acute, 161 in serous cystic pancreatic neoplasms, 274 enteral nutrition, for acute pancreatitis, 169–170 enteric duplication cysts, of pancreas, 266 ERCP. See endoscopic retrograde cholangiopancreatography (ERCP) EUS. See endoscopic ultrasound exercise, gallstone formation and, 27 extracorporeal shock wave lithotripsy for choledocholithiasis, 59–61 for gallstone dissolution, 32, 60 for pancreatic stones, 229–230 extrahepatic bile ducts cholangiocarcinoma of, 103–120 congenital anomalies of, 12–17 development of, 3–4 normal variants of, 333 Fasciola hepatica, cholangitis due to, 134 fibrosis, of pancreas, 184 fine-needle aspiration endoscopic ultrasound-guided, 322–323 in pancreatic cancer, 245–247, 290 in pancreatic serous cystic neoplasms, 274 fistulas biliary-enteric, 35 biliovascular, 72–73, 83 pancreatic, in pancreatitis, 203, 362–363 flukes, liver, cholangitis due to, 131–134
371
gallbladder agenesis of, 17 anatomy of, 21 calcification of, 40 cancer of, 31, 39–40, 320 congenital anomalies of, 17–20 development of, 3–4 diverticulum of, 18–19 ectopic, 18–19 fistulas of, 24 heterotopic tissue in, 19–20 hypomotility of, cholesterol stone formation in, 24–25 hypoplasia of, 18–19 inflammation of. See cholecystitis interposed, 18–19 mobile, 18–19 multiple, 18–19 physiology of, 21 polyps of, 38–39, 320 porcelain, 40 septation of, 18–19 sludge in, 28–29 stones in. See gallstones structural variations of, 18–19 gallstones biliary pain due to, 38, 50 black, 29, 48 brown, 29, 48 cholecystitis due to, 30, 32–34, 37– 38, 121–124 cholesterol, 24–28, 47–48 dissolution therapy for, 63 extraction of, for choledocholithiasis, 58 formation of cholesterol, 24–28, 47–48 pigment, 29, 48 ileus due to, 36 intrahepatic, 49, 64 medical treatment of, 31–32, 63 Mirizzi’s syndrome in, 34–35 MRI/MRCP in, 335–337 pancreatitis due to, 51, 183 pathophysiology of, 21–23 pigment, 29, 48 risks for, 22–23 types of, 21–22 gastric outlet obstruction in pancreatic cancer, 295 in pancreatitis, 202 gastrinoma, 250–252, 344
372
Index
gender factors, in gallstone formation, 25–26 genetic factors in chronic pancreatitis, 187–188 in pancreatic cancer, 240 Gianturco stent, for biliary obstruction, 358 Gilbert’s syndrome, gallstone formation in, 28 Glasgow criteria, for acute pancreatitis, 162, 164 hemangioma, of pancreas, 283 hematocrit, in acute pancreatitis, 166–167 hepaticogastrostomy, for biliary drainage, 359 hepatobiliary iminodiacetic acid scan in cholecystitis, 32 in choledocholithiasis, 53 hepatolithiasis, 49, 64 hereditary pancreatitis, 188 heterotopic pancreas, 5–6 heterotopic tissue, in gallbladder, 19–20 human immunodeficiency virus infection, cholangiopathy in, 139–140 hydatid cysts, of pancreas, 268 hypercalcemia, chronic pancreatitis in, 189 hypertriglyceridemia, pancreatitis in, 158–159 hypoplasia of gallbladder, 18–19 of pancreas, 6–7 ileus, gallstone, 36 Imrie’s (Glasgow) criteria, for acute pancreatitis, 162, 164 infections, of biliary system. See cholangitis; cholecystitis injury, bile duct. See bile ducts, injuries of insulinoma, 250–252, 344 interposed gallbladder, 18–19 interventional radiology, 353–365. See also specific procedures for biliary injury, 355–356 for cancer, 357–359 history of, 353 for liver transplantation complications, 359–361 for pancreatic disease, 361–363 for percutaneous biliary drainage, 354–355 for stone disease, 356–357 for strictures, 356–357
intraductal papillary mucinous neoplasm, 277–282, 346 intrahepatic bile ducts cholangiocarcinoma of, 103–120 congenital anomalies of, 7–12 cystic disorders of, 8–11 development of, 3 paucity of, 11–12 polycystic conditions of, 9–11 solitary cysts of, 8–9 stones in, MRI/MRCP in, 336 intrahepatic gallstones, 49, 64 islet amyloid polypeptide, in pancreatic cancer, 240 islet cell tumors, 250–252, 318, 344–345 jaundice in choledocholithiasis, 50 in pancreatic cancer, 247 kidney failure of, chronic pancreatitis in, 189 polycystic disease of biliary cysts in, 9–11 pancreatic cysts in, 267 laparoscopic cholecystectomy, 299–303 advantages of, 300 bile duct injury in, 69–70, 83, 356 for cholecystitis, 33–34, 38, 124 for choledocholithiasis, 63 complications of, 69–70, 83, 301– 303, 356 disadvantages of, 300 for polyps, 39 prophylactic, 299 technical aspects of, 300–301 laparoscopic examination, in pancreatic cancer, 290 laser lithotripsy, for choledocholithiasis, 61 leaks, from bile ducts after cancer surgery, 306–307 in endoscopic procedures, 76–79 in liver transplantation, 71–73, 359–360 linear array echoendoscope, 312 lithiasis common bile duct. See choledocholithiasis gallbladder. See gallstones lithotripsy, extracorporeal shock wave for gallstone dissolution, 32, 60 for pancreatic stones, 229–230
Index liver fibrosis of, biliary cysts in, 9–10 resection of for bile duct tumors, 307–309 for cholangiocarcinoma, 112–114 stones in, 49, 64 transplantation of bile duct complications in, 70–72, 83–84, 359–361 for cholangiocarcinoma, 114 tumors of, excision of, bile duct injury in, 72 liver flukes, cholangitis due to, 131–134 liver function tests, in pancreatitis, 155, 157 lymphangioma, of pancreas, 283 lymphoepithelial cysts, of pancreas, 265 magnetic resonance cholangiopancreatography in acute pancreatitis, 161 in cholangitis, 127 in choledocholithiasis, 53, 313–314 in intraductal papillary mucinous neoplasm, 280 magnetic resonance imaging with. See magnetic resonance imaging/ magnetic resonance cholangiopancreatography in pancreatic cancer, 241 in pancreatic duct stones, 226 magnetic resonance imaging in acute pancreatitis, 161 in cholangiocarcinoma, 108 in chronic pancreatitis, 193–194 in intraductal papillary mucinous neoplasm, 280 in pancreatic cancer, 241, 244, 288 in serous cystic neoplasms, 274 magnetic resonance imaging/magnetic resonance cholangiopancreatography, 327–351 of biliary tract in ampullary abnormalities, 337 in cholangiocarcinoma, 339 in congenital anomalies, 334 in gallstones, 335–337 in normal variations, 333 in obstruction, 334–335 postoperative, 333 in strictures, 338 after unsuccessful ERCP, 333
373
of pancreas and pancreatic duct in adenocarcinoma, 342–343 in congenital anomalies, 340 in cystic neoplasms, 346–347 in neuroendocrine tumors, 344–345 in pancreatitis, 340–342 in transplantation, 346 rationale for, 327–330 technique for, 328, 332–333 tissue characteristics in, 331 maldigestion, in chronic pancreatitis, 191 malignancy. See cancer; specific diseases Marseilles classification, of pancreatitis, 179–180 Marshall multiple organ dysfunction score, for acute pancreatitis, 165 mechanical lithotripsy, for choledocholithiasis, 59–60 medications gallstones due to, 27 pancreatitis due to, 150–152 metastasis from cholangiocarcinoma, 111–112 from pancreatic neuroendocrine tumors, 252 methyl-tert-butyl ether, for choledocholithiasis, 63 microlithiasis, biliary, endoscopic ultrasound in, 319–320 Milwaukee classification, of sphincter of Oddi dysfunction, 92 minimal change chronic pancreatitis, 182 Mirizzi’s syndrome in choledocholithiasis, 63–64 in gallstone disease, 34–35 mobile gallbladder, 18–19 MRCP. See magnetic resonance cholangiopancreatography MRI. See magnetic resonance imaging mucinous cystic neoplasms, of pancreas, 276–277 nasobiliary drain, for bile leaks, 76 necrosis, in pancreatitis, 168–169, 184 neoplasms. See cancer; specific tumors nerve blockade, for chronic pancreatitis, 197 neuroendocrine tumors, of pancreas, 250–252, 318, 344–345 nucleating factors, in gallstone formation, 25 nutrition, for acute pancreatitis, 169–170
374
Index
obesity, gallstone formation in, 27 obstruction of bile ducts in biliary cancer, 357–358 MRI/MRCP in, 334–335 in pancreatic cancer, 294–295 in pancreatitis, 202 of duodenum, in pancreatic cancer, 249–250 of gastric outlet in pancreatic cancer, 295 in pancreatitis, 202 of pancreatic duct chronic pancreatitis in, 186 retention cysts in, 267 Opisthorchis, cholangitis due to, 133 Oriental cholangiohepatitis, 138 oxidative stress hypothesis, for chronic pancreatitis, 182–183 pain biliary acalculous, 30–31, 38 in choledocholithiasis, 50 in pancreatic cancer, 250 in pancreatitis acute, 148–149 chronic, 189–191 right upper quadrant, differential diagnosis of, 297–298 palliative treatment for cholangiocarcinoma, 115–117 for pancreatic cancer, 249, 294–295 pancreacticojejunostomy, for chronic pancreatitis, 200–201 pancreas abscess of, 260 adenocarcinoma of. See pancreatic cancer agenesis of, 6–7 annular, 4–5, 340 biopsy of in cancer, 245–247, 290 in pancreatic serous cystic neoplasms, 245–247 cancer of. See pancreatic cancer congenital anomalies of, 2, 4–7 cystic lesions of, 257–286. See also pancreas, pseudocysts of acinar cell neoplastic, 282 acinar cystic transformation, 268–269 congenital, 267–268
ductal adenocarcinoma, 282 endometrial, 266 enteric duplication, 266 hydatid, 268 incidental, 269 intraductal papillary mucinous neoplastic, 277–282, 346 lymphoepithelial, 265 mucinous neoplastic, 276–277 neoplastic, 269–282, 346 neuroendocrine, 282 retention, 266–267 serous neoplastic, 273–275, 347 solid-pseudopapillary, 271–273, 346 types of, 258–259 uncommon, 282–283 development of, 1 dysplasia of, 6–7 fibrosis of, 184 fistulas of, in pancreatitis, 203, 362–363 function of, 1–2 gastrinoma of, 250–252, 344 heterotopic, 5–6 hypoplasia of, 6–7 insulinoma of, 250–252, 344 neuroendocrine tumors of, 250–252, 318, 344–345 pseudoaneurysm of, in pseudocyst, 261 pseudocysts of, 257–264 classification of, 260 clinical features of, 260–261 definition of, 257, 259 diagnosis of, 261–262 epidemiology of, 259 etiology of, 259–260 in leakage, 230–235 MRI/MRCP in, 346 natural history of, 262–263 in pancreatitis, 170–171, 201–202 pathogenesis of, 259–260 treatment of, 263–264, 361–362 transplantation of, 346 vascular tumors of, 283 pancreas divisum, 4, 340 pancreatic cancer, 202–203, 239–256 clinical presentation of, 239–240 cystic, 269–273, 276–282 diagnosis of, 240–247, 288 duct strictures in, 217–225 epidemiology of, 239
Index MRI/MRCP in, 342–343 staging of, 240–247, 287–291 surgical treatment of, 287–296 in duodenal obstruction, 295 in gastric outlet obstruction, 295 palliative, 249, 294–295 postoperative management in, 294 preoperative evaluation and staging for, 287–291 resection in, 291–294 survival rate in, 294 treatment of, 247–250 unresectable, 287–288 pancreatic duct congenital anomalies of, 340 decompression of, in pancreatitis, 199 leaks from, 230–235 obstruction of, retention cysts in, 267 stones of, 225–230 strictures of, 217–225, 319 ultrasound probes for, 312 pancreatic enzyme supplements, for chronic pancreatitis, 197–199 pancreatic function tests, in chronic pancreatitis, 195–196 pancreatic rest, 5–6 pancreaticoduodenectomy for cholangiocarcinoma, 113 for pancreatic cancer, 290–294 pancreatitis acute. See acute pancreatitis chronic. See chronic pancreatitis hereditary, 188 in pancreatic duct stricture, 218–219 tropical, 186 parapapillary fistula, 35 parasitic cholangitis, 129–138 Ascaris lumbricoides, 130–131 Echinococcus, 135–138 liver fluke, 131–134 percutaneous drainage of biliary tract, 354–355, 359 of pancreatic pseudocysts, 234, 361–362 for pancreatitis, 361 percutaneous transhepatic cholangiography bile leaks in, 73 for biliary strictures, 79, 81–82 for choledocholithiasis, 54, 62 pigment gallstones, 29, 48 pleural effusion, in pancreatic duct leakage, 235
375
polycystic conditions, of biliary tract, 9–12 polycystic kidney disease biliary cysts in, 9–11 pancreatic cysts in, 267 polyps, gallbladder, 38–39, 320 porcelain gallbladder, 40 positron emission tomography, in cholangiocarcinoma, 110 primary duct hypothesis, of chronic pancreatitis, 184 primary sclerosing cholangitis cholangiocarcinoma in, 104 MRI/MRCP in, 338 probes, for endoscopic ultrasound, 312 pseudoaneurysm of pancreas, in pseudocyst, 261 of splenic artery, in chronic pancreatitis, 203 pseudocysts, pancreatic. See pancreas, pseudocysts of pseudopapillary neoplasm, solid, 271– 273, 346 Puestow procedure, for chronic pancreatitis, 200–201 racial factors, in gallstone formation, 25–26 radial echoendoscope, 312 radiation therapy, for cholangiocarcinoma, 114 radiography in chronic pancreatitis, 192 in pancreatic duct stones, 226 Ranson criteria, for acute pancreatitis, 162–163 recurrent pyogenic cholangitis, 138 retention cysts, of pancreas, 266–267 roundworms, cholangitis due to, 130–131 Santorinicele, 340 secretin test, in pancreatitis, 342 sentinel acute pancreatitis event hypothesis, 185 septate gallbladder, 18–19 serine protease inhibitor, Kazal type 1, in pancreatitis, 188 serous cystic neoplasms, of pancreas, 273–275, 347 sex differences. See gender factors skin, biliary fistulas with, 35 sludge, biliary, 28–29, 49, 319–320 small intestine, biliary fistulas with, 35
376
Index
solid-pseudopapillary neoplasm, 271– 273, 346 solitary cysts, of biliary tract, 8–9 sphincter of Oddi dysfunction, 91–96 biliary, 92 classification of, 92 diagnosis of, 91–94 differential diagnosis of, 94–95 pancreatic, 93 treatment of, 95–96 sphincteroplasty, transduodenal, 303–304 sphincterotomy for choledocholithiasis, 55–57 for pancreatic duct strictures, 222–224 for pancreatic stones, 228–229 splenic artery, pseudoaneurysm of, in chronic pancreatitis, 203 splenic vein, thrombosis of, in chronic pancreatitis, 203 steatorrhea, in chronic pancreatitis, 191 stenosis, of bile ducts, 16–17 stents for bile leaks, 76, 78 for biliary obstruction, 357–358 for biliary strictures, 82–83, 357 for cholangiocarcinoma, 115–117 for cholangitis, 128 for choledocholithiasis, 61–62 for pancreatic cancer, 248, 249 for pancreatic duct stricture, 224 stones common bile duct. See choledocholithiasis gallbladder. See gallstones pancreatic, 225–230 strictures of bile ducts. See bile ducts, strictures of of pancreatic duct, 217–225, 319 tapeworms, cholangitis due to, 135–138 thoracobiliary fistula, 35 thrombosis, splenic vein, in chronic pancreatitis, 203 TNM classification, of pancreatic cancer, 289 toxic-metabolic theory, of chronic pancreatitis, 183 transduodenal sphincteroplasty, 303–304 transhepatic cholangiography, 354–355 transjugular intrahepatic portosystemic shunt, bile duct injury in, 72
transmural drainage, of pancreatic pseudocysts, 264 transpapillary drainage, of pancreatic pseudocysts, 234, 264 transplantation liver bile duct complications in, 70–72, 83–84, 359–361 for cholangiocarcinoma, 114 pancreatic, 346 trauma, bile duct injury in, 72 tropical pancreatitis, 186 tumor(s). See cancer; specific tumors tumor markers for cholangiocarcinoma, 107–108 for pancreatic cancer, 240 for pancreatic serous cystic neoplasms, 275 ultrasonography. See also endoscopic ultrasound in cholangiocarcinoma, 108, 110, 315 in cholangitis, 127 in choledocholithiasis, 52, 55 in chronic pancreatitis, 192, 194–195 in intraductal papillary mucinous neoplasm, 280 in pancreatic cancer, 242, 244–247 in pancreatic duct stones, 226–227 in pancreatic duct strictures, 221 in pancreatic neuroendocrine tumors, 251–252, 318 in pancreatic pseudocyst, 261, 264 in pancreatitis, acute, 159–161 in serous cystic neoplasms, 274 ursodeoxycholic acid, for gallstone dissolution, 31–32, 63 vascular tumor, of pancreas, 283 Von Hippel-Lindau disease, pancreatic cysts in, 267–268 Wallstent stent, for biliary obstruction, 358 weight loss in chronic pancreatitis, 191 rapid, gallstone formation in, 27 Whipple procedure for pancreatic cancer, 290–294 for pancreatic duct stricture, 225
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The Clinician’s Guide to Gastrointestinal Oncology
The Clinician’s Guide to Inflammatory Bowel Disease
Dr. Michael Kochman, with contributions from other recognized experts of diverse gastrointestinal backgrounds, uses a multidisciplinary approach in presenting the necessary information to optimally manage patients. A balanced approach allows the reader to quickly synthesize an individualized care plan based upon the recommendations of highly skilled professionals.
The Clinician’s Guide to Liver Disease
Michael Kochman, MD 440 pp., Soft Cover, 2005, ISBN 1-55642682-8, Order# 76828, $59.95
The Clinician’s Guide to Acid/Peptic Disorders and Motility Disorders of the Gastrointestinal Tract
Henry Parkman, MD and Robert S. Fisher, MD 336 pp., Soft Cover, 2006, ISBN 1-55642716-6, Order# 77166, $59.95 This comprehensive and easy to reference text provides clinicians with the necessary information to evaluate, treat, and manage patients with acid/peptic and motility disorders. Written with a readerfriendly format and including images, tables, and algorithms, this is the ideal reference for gastroenterologists, surgeons, oncologists, and internists looking to keep pace with the latest treatment options available today.
Gary R. Lichtenstein, MD 336 pp., Soft Cover, 2003, ISBN 1-55642554-6, Order# 75546, $46.95
K. Rajender Reddy, MD and Thomas Faust, MD 376 pp., Soft Cover, 2006, ISBN 1-55642675-5, Order# 76755, $59.95
Handbook of Digestive Diseases
Anil Minocha, MD, FACP, FACG 448 pp., Soft Cover, 2004, ISBN 1-55642665-8, Order# 76658, $35.95
Johns Hopkins Manual for Gastrointestinal Endoscopy Nursing Jeanette Ogilvie, RN, BSN; Lynn Norwitz, BS; and Anthony Kalloo, MD 192 pp., Spiral Bound, 2002, ISBN 155642-576-7, Order# 75767, $36.95
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