Table of Contents
Definition / general | Clinical features | Klatskin (hilar) tumors | Diagnosis | Laboratory | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Molecular / cytogenetics description | Differential diagnosisCite this page: Gulwani H. Carcinoma of extrahepatic bile ducts. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/gallbladdercarcinomaextrahepatic.html. Accessed November 29th, 2023.
Definition / general
- Rare (1 per 100,000 in U.S.); 90 - 95% of extrahepatic bile duct malignancies are adenocarcinomas (bile duct carcinoma, cholangiocarcinoma)
- Present in 0.5% of autopsies
- 2 - 3 times less common than gallbladder carcinoma
Clinical features
- More common in Native Americans, Mexicans, Israelis, Japanese
- Present with painless, progressive jaundice; 1/3 have gallstones (10% in bile ducts themselves), 20% had prior biliary tract surgery
- Usually age 60+; rare before age 40 unless have risk factors below
- Small at diagnosis because even small tumors cause obstruction and jaundice
Risk factors:
- Clonorchis sinensis and Opisthorchis viverrini infestations, primary sclerosing cholangitis, chronic ulcerative colitis, choledochal cysts, Caroli disease, congenital hepatic fibrosis
- Also cystic fibrosis, familial polyposis coli, chronic typhoid carriers, biliary giardiasis, Thorotrast exposure, pancreaticobiliary maljunction (PBM) with bile duct dilatation (J Hepatobiliary Pancreat Surg 2008;15:15)
Spread and metastases:
- Local extension to ampulla of Vater, colon, duodenum, gallbladder, liver, omentum, pancreas, stomach
- Tumors from right or left hepatic duct usually extend proximally into liver or distally to common hepatic duct
- Tumors from cystic duct extend to gallbladder or common bile duct
- Tumors from distal common bile duct extend to pancreas, duodenum, stomach, colon, omentum
- Metastases to regional lymph nodes, liver, lungs, peritoneum
Klatskin (hilar) tumors
- 70% of tumors
- Arise at confluence of right and left hepatic ducts at liver hilus
- Slow growing with infrequent distant metastases, have marked sclerosing characteristics
- Poorer prognosis since difficult to resect
- 28 - 89% have positive margins
Diagnosis
- Tissue diagnosis is optimal because clinical diagnosis is often incorrect
- Also brushings, bile drainage cytology
Laboratory
- Elevated alkaline phosphatase but normal serum bilirubin suggests location above hepatic duct bifurcation or incomplete common bile obstruction
Prognostic factors
- Presence of intraepithelial spread is not an indicator of a poor prognosis but carcinoma in situ at the bile duct stump can cause recurrence (Mod Pathol 2008;21:807)
- Mean survival 6 - 18 months, 2 years if resectable
- 5 year survival is only 5% but is 60% for T1 tumors (which are rare)
Favorable:
- Low stage, papillary histology, lack of metallothionein expression (Hum Pathol 2009;40:1706), distal tumors, CDX2 and MUC2 (Am J Clin Pathol 2005;124:361)
Unfavorable:
- High grade or high stage tumors, positive surgical margins, hilar tumors, decreased expression of focal adhesion kinase (Hum Pathol 2010;41:859), IMP3 expression (Hum Pathol 2009;40:1377), nuclear KIT expression (Mod Pathol 2007;20:562)
- Presence of tumor necrosis in the nodal tumors, severe nuclear atypia of the tumor cells in lymph vessels (Hum Pathol 2005;36:655)
Case reports
- 42 year old Japanese woman with obstructive jaundice (Acta Med Okayama 2010;64:63)
Treatment
- Klatskin tumors require resection of hepatic duct bifurcation
- Distal tumors may require Whipple procedure
Gross description
- Either firm, gray nodules within bile duct wall or diffusely infiltrative (2%)
- Often extends into adjacent structures
- Limits of tumor often difficult to detect due to desmoplasia
- Tumors may be papillary, multifocal and friable
Microscopic (histologic) description
- Nodular or diffusely infiltrative tumors with marked desmoplastic response
- Sclerosing, nodular, polypoid papillary or mixed types
- Resembles gallbladder carcinoma
- Most are well or moderately differentiated with conspicuous glands but have extensive perineural invasion
- Even well differentiated tumors may have poorly differentiated foci deep within wall
- Mucin always present within tumor cells and glandular lumina
- Tumor cells cuboidal or columnar, with vesicular nuclei and prominent nucleoli
- Usually angiolymphatic invasion, necrosis and chronic inflammatory infiltrate
- Often adjacent intestinal and pylori metaplasia
- Dysplasia usually present
- Variants include adenosquamous, clear cell, colloid, mucoepidermoid, small cell, squamous cell, undifferentiated (pleomorphic, sarcomatoid, giant cell) carcinomas
- Pyloric gland phenotype involves younger patients, usually well differentiated tumors with characteristic stellar pattern, extensive perineural invasion, MUC6+ and MUC5AC+ (Hum Pathol 2012;43:2292)
- Diagnostically difficult cases are extremely well differentiated but still have thickened duct wall with prominent desmoplastic response and perineural invasion
Microscopic (histologic) images
Positive stains
- Mucin, CEA, CK7 (Am J Surg Pathol 2000;24:870, Arch Pathol Lab Med 2000;124:1196), P-cadherin and CD24 (Hum Pathol 2010;41:1558), EGFR (Hum Pathol 2010;41:485)
Negative stains
Molecular / cytogenetics description
- Promoter hypermethylation is important mechanism in inactivation of p16 gene (Arch Pathol Lab Med 2006;130:33)
- Telomere shortening has been observed in dysplastic epithelium and invasive adenocarcinomas of biliary tract (Mod Pathol 2006;19:772)
Differential diagnosis
- Intraductal spread of hepatocellular carcinoma, cholangiocarcinoma, metastatic carcinoma
- Metastatic carcinoma:
- Breast, colon, ovary, kidney
- Spread from adjacent tumors of ampulla, colon, duodenum, gallbladder, liver, pancreas, stomach
- Sclerosing cholangitis:
- No perineural invasion, no random glandular infiltration