Pathological, molecular, and clinical characteristics of cholangiocarcinoma: A comprehensive review

Abstract

Cholangiocarcinomas are a heterogeneous group of highly aggressive cancers that may arise anywhere within the biliary tree. There is a wide geographical variation with regards to its incidence, and risk-factor associations which may include liver fluke infection, primary sclerosing cholangitis, and hepatolithiasis amongst others. These tumours are classified into intrahepatic, perihilar and distal based on their anatomical location. Morphologically, intrahepatic cholangiocarcinomas are further sub-classified into small and large duct variants. Perihilar and distal cholangiocarcinomas are usually mucin-producing tubular adenocarcinomas. Cholangiocarcinomas develop through a multistep carcinogenesis and are preceded by dysplastic and in situ lesions. While clinical characteristics and management of these tumours have been extensively elucidated in literature, their ultra-structure and tumour biology remain relatively unknown. This review focuses on the current knowledge of pathological characteristics, molecular alterations of cholangiocarcinoma, and its precursor lesions (including biliary intraepithelial neoplasia, intraductal papillary neoplasms of the bile duct, intraductal tubulopapillary neoplasms and mucinous cystic neoplasm).

High-grade dysplasia of the cystic duct margin: how should this be managed?

“…The radiological findings of our patient were consistent with that of cystic duct lesions, described as distension of the gallbladder in the absence of cholelithiasis 9. However, aside from active cholecystitis, she was not known to have any of the commonly reported risk factors of biliary cancers: PSC, fluke infections, cirrhosis or exposure to specific toxins 7. There may be benefit in testing patients with premalignant lesions for these specific risks so the monitoring can be tailored to be more aggressive if required.…”

“…Premalignant lesion such as HGD of the cystic duct is a precursor of cystic duct carcinoma; however, due to its rarity, it is often grouped together with cholangiocarcinoma (CCA), gallbladder cancer or cancers of the biliary tree 6. HGD is a late-stage component of the epithelial cancer progression from normal cells to hyperplasia or metaplasia, dysplasia (low and high grade) and eventually carcinoma 7 8. With changing nomenclature over the years, HGD has also been referred to as ‘atypical biliary epithelia’, ‘carcinoma in situ’, ‘biliary intraepithelial neoplasia 3’ (BilIN-3) or ‘high grade BilIN’ 7 8.…”

“…HGD is a late-stage component of the epithelial cancer progression from normal cells to hyperplasia or metaplasia, dysplasia (low and high grade) and eventually carcinoma 7 8. With changing nomenclature over the years, HGD has also been referred to as ‘atypical biliary epithelia’, ‘carcinoma in situ’, ‘biliary intraepithelial neoplasia 3’ (BilIN-3) or ‘high grade BilIN’ 7 8. Literature on HGD in the cystic duct found incidentally after cholecystectomy is scarce, though what little data is available would suggest an incidence of 0.1–0.8%, with outliers in endemic regions reaching 12% 2–4 8…”

Pathologies of Precursor Lesions of Biliary Tract Carcinoma

“…The mean age at the time of detection was 45 years for low-grade BilIN, and 60 years for high-grade BilIN, and 71 years for GBC [ 90 ]. High-grade BilINs show sequential molecular and genetic alterations related to cell kinetics [ 91 ]. p21, p53, and cyclin D1 expression along with down-regulated DCP4 and p16 expression are observed in the histological progression of BilIN [ 63 , 92 , 93 ].…”

National guidelines for the diagnosis and treatment of hilar cholangiocarcinoma

“…Gene sequencing to assess molecular alterations is now emerging to differentiate between benign and malignant strictures[ 38 ]. Singhi et al [ 39 ] evaluated a 28-gene next-generation sequencing panel using biliary specimens from endoscopic retrograde cholangiopancreatography (ERCP).…”