CHAPTER 9 Gall bladder and extrahepatic bile ducts
Chapter contents
Introduction
Gall bladder cancer is the fifth most common cancer involving the gastrointestinal tract, but it is the most common malignant tumour of the biliary tract worldwide. The percentage of patients diagnosed as having gall bladder cancer after simple cholecystectomy for presumed gall bladder stone disease is 0.5–1.5%. This tumour is traditionally regarded as a highly lethal disease with an overall 5-year survival of less than 5%. The marked improvement in the outcome of patients with gall bladder cancer in the last decade is because of the aggressive radical surgical approach that has been adopted, and due to improvements in surgical techniques and perioperative care.1
Carcinoma of the hepatobiliary ducts is associated with cholelithiasis and chronic cholecystitis, hepatitis B and C, cirrhosis and alcohol, primary sclerosing cholangitis (PSC), which carries an increased risk of 10–20%, and biliary papillomatosis.2,3 It develops through a multistep histopathological sequence. Historically, premalignant or non-invasive neoplastic lesions of bile ducts have been called biliary dysplasia or atypical biliary epithelium. In 2005, a conceptual framework and diagnostic criteria for biliary intraepithelial neoplasia (BilIN) were proposed using the livers of patients with hepatolithiasis. In 2007, consensus was reached for the terminology of BilIN and a three-grade classification system (BilIN-1, BilIN-2 and BilIN-3) based on the degree of atypia was proposed.4
Cholangiocarcinomas (CC) are broadly classified into intrahepatic tumours, (extrahepatic) hilar tumours and (extrahepatic) distal bile duct tumours. There has been recent progress in identifying potential risk factors for the tumour, and in the use of emerging technologies for diagnosis and palliative treatment. Diagnosis may be improved by new approaches to enhance the diagnostic yield and utility of biliary cytology. The role of new imaging approaches such as positron emission tomography scanning, endoscopic ultrasound and optical coherence tomography for diagnosis are being examined and defined. Long-term results for transplantation protocols for curative intent in non-resectable localised disease have been described. Photodynamic therapy looks extremely promising for adjunct therapy of intrahepatic mass lesions.5
Intrahepatic cholangiocarcinoma (ICC), also known as cholangiocellular carcinoma or peripheral bile duct carcinoma, is an intrahepatic malignant tumour that consists of cells resembling the biliary epithelium (see Ch. 8, p. 308). The proportion of ICC among primary hepatic malignancies is approximately 10% worldwide. Some ICCs arising from the large biliary duct are likely to exhibit an aggressive course even in cases of small tumour size.6 ICC is reportedly a late complication of primary sclerosing cholangitis. Most of the preceding pathological conditions are forms of chronic cholangitis, and longstanding inflammation, chronic injury, and regenerative hyperplasia of the biliary epithelium. Biliary epithelial dysplasia is encountered in the intrahepatic bile ducts both near and remote from ICC foci in the liver and near and remote from the chronically inflamed biliary tree.7
Carcinoma of the extrahepatic bile ducts constitutes one-third of biliary tract cancers.8 In contrast to gall bladder cancer, gallstones are present in only 20% of cases.8 There is, however, an association between carcinoma and sclerosing cholangitis or chronic suppurative cholangitis, biliary parasites such as liver flukes, ulcerative colitis and choledochal cysts.8 A proportion of carcinomas may arise in pre-existing benign papillary neoplastic lesions, which may be localised or multifocal; papillary tumours have a better prognosis.8
A range of other neoplastic and tumour-like processes occurs in the region (Box 9.1).8,9
Endoscopic techniques
Malignancies of the bile duct are often suspected in patients with abnormal serum hepatic enzyme levels and obstruction of the biliary system. Although cross-sectional imaging can provide evidence for biliary obstruction and a malignancy arising from the bile duct, a definitive diagnosis is often obtained through the use of endoscopic procedures.10 Endoscopic retrograde cholangiopancreatography (ERCP), the most commonly performed procedure for cholangiocarcinoma, can provide a diagnosis through brush cytology of the bile duct. Duct brushing cytology is an important tool in evaluation of the extrahepatic biliary tract and large pancreatic ducts. The emergence of neoadjuvant therapies underscores the importance of accurate preoperative diagnosis by noninvasive means.11
Procedures for collecting cytological material from the biliary tree are the following:
Relief from biliary obstruction can be provided with temporary plastic stenting or permanent metal stenting. Photodynamic therapy guided by ERCP may provide improved palliation from biliary obstruction in the future. Endoscopic ultrasonography (EUS) complements the role of ERCP and may provide a tissue diagnosis through EUS-FNA and staging through ultrasound imaging. High-resolution ultrasound images can provide detailed information regarding the relationship between a mass and the bile duct wall. Despite these advances in endoscopic techniques and imaging of the bile duct, a tissue diagnosis often remains elusive in many patients.
Complications and contraindications
The overall complication rate of ERCP in non-selected patients in one series was 12.6%, consisting of post-ERCP pancreatitis (5.1%), bleeding (3.7%), cholangitis (1.9%), cardiopulmonary complications (0.9%), and perforation (0.5%); procedure-related mortality was 0.1%.14 The postprocedural complications of EUS-FNA, include abdominal pain, nausea, vomiting and gastrointestinal bleeding. They are considered to be rare but require further evaluation with prospective studies.13,15–18
Normal cytology
Bile duct brushings
Normal bile duct or pancreatic ductal epithelium has the following features in bile duct brushings: (Figs 9.1–9.4).
Benign conditions
Inflammatory and reactive processes
Inflammatory changes and organisms have been demonstrated in bile by gall bladder FNA preoperatively in cholecystitis. Intraoperative FNA has been used to diagnose abscess and xanthogranulomatous cholecystitis by finding a mixed inflammatory cell component in company with large numbers of foamy histiocytes and surrounding capillary blood vessels.19 Chronic pancreatitis is discussed later in Chapter 10.
Changes due to primary sclerosing cholangitis (PSC), stent placement and postoperative effect are similar in all types of cytological samples and include a range of regenerative and degenerative alterations in bile duct epithelium, with cells reminiscent of squamous metaplasia, nuclear enlargement, nuclear size variation, prominent nucleoli and cellular disorganisation (Fig. 9.5A–C).
Parasitic infestation
Cytological findings: parasitic infestation
In the samples of bile submitted for cytological examination, ova of liver flukes (e.g. Clonorchis sinensis and Opisthorchis viverrini) may be identified against a background of granular necrotic debris, neutrophils and eosinophils.20 Fasciola hepatica infestation may also be identified. Criteria for recognition of Clonorchis ova include small size, laminated walls, opercula with prominent shoulders and spinous processes (Fig. 9.6). Whole worms, or parts thereof, may also be seen.21 Biliary infestation with Clonorchis is also associated with epithelial hyperplasia, goblet cell metaplasia, squamous metaplasia and adenomatous hyperplasia.21 The high mucin content of the bile is associated with bacterial superinfection, stone formation and, later, cholangiocarcinoma may supervene. All these conditions may coexist.
Dysplasia
Premalignant changes in bile ductal or gall bladder epithelium, dysplasia and carcinoma in situ are now recognised in the gall bladder and extrahepatic bile ducts. These lesions are considered to be the precursors of the corresponding invasive carcinomas.9 Layfield et al. have shown that premalignant lesions, that is dysplasia and carcinoma in situ, can be diagnosed on bile duct brushings. Dysplasia has been graded as high and low. Since biopsy of small mucosal lesions may be technically difficult, brushings are often the only way to diagnose premalignant lesions.22
