Liver and intrahepatic bile ducts - tumor - Cholangiocarcinoma (intrahepatic / peripheral)

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Liver and intrahepatic bile ducts - tumor

Other malignancies

Cholangiocarcinoma (intrahepatic / peripheral)

Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 9 January 2013, last major update February 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
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● Adenocarcinoma arising from intrahepatic bile duct epithelial cells
● Also called bile duct carcinoma

Clinical features
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● 10% of primary liver cancers
● Diagnosis of exclusion - must rule out metastatic adenocarcinoma
● High prevalence in southeast and eastern Asia, including Korea
● 10-20% are associated with chronic bile stasis or cholangitis due to anabolic steroids, autosomal dominant polycystic disease, choledochal cysts, congenitally dilated hepatic ducts (Caroli’s disease), congenital hepatic fibrosis, intrahepatic lithiasis (5-10%), liver flukes Clonorchis sinensis or Opisthorchis viverrini, primary sclerosing cholangitis, Thorotrast
● Rarely associated with neoplastic transformation of von Meyenburg complexes (Am J Surg Pathol 2000;24:1131)
● Not associated with cirrhosis
● Usually age 60+ years; no gender preference; but mean age 40 years in those with primary sclerosing cholangitis or chronic inflammatory bowel disease
● 50-75% metastasize to regional lymph nodes, adrenals, brain, lungs, vertebrae or elsewhere at autopsy
● 50% metastasize to perihilar, peripancreatic or para-aortic nodes
● Death usually within 6 months; 5 year survival in resectable cases is 30%
● Poor prognostic factors: lymphatic or intrahepatic metastases (Am J Surg Pathol 1999;23:892)
● Klatskin tumor: hilar tumor arising at confluence of left and right hepatic ducts; clinically detected early due to obstruction
● Laboratory: normal AFP, occasional hypercalcemia

Classification
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● Liver Cancer Study Group of Japan: mass-forming, periductal infiltrating, intraductal growth types (Radiographics 2009;29:683)

Morphologic classification

Case reports
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● 55 year old woman with synchronous, small cholangiocarcinoma and small hepatocellular carcinoma arising in two different dysplastic nodules, in an explant cirrhotic liver (Mod Pathol 2002;15:1096)
● 61 year old woman with history of Caroli’s disease with extensive pulmonary vascular spread in the form of carcinomatous arteriopathy (Arch Pathol Lab Med 2002;126:717)

Gross description
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● Solitary, 7-10 cm, multinodular or diffuse small nodules < 1 cm
● Gray-white and firm; often hepatomegaly and satellite nodules
● No peripheral hyperemic zone seen in metastatic disease; rarely cirrhosis
● Rarely bile stained, although may see bile in periphery; may invade portal vein

Gross images
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Various images

Mass forming cholangiocarcinomas

Periductal infiltrating cholangiocarcinoma

Klatskin tumor

Micro description
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● Moderate to well-differentiated adenocarcinoma with glandular and tubular structures, mucin production and dense desmoplasia
● Epithelial cells are anaplastic, cuboidal to columnar with eosinophilic cytoplasm and round central nuclei, tumor cells are heterogeneous even within the same gland but resemble bile duct cells, not hepatocytes
● Tumor spreads along hepatic plates, duct walls, via nerves (perineural invasion in 81%), but not sinusoidal
● Stroma may be circumferential around glands; associated with neutrophils
● Variable vascular invasion; no bile production
● Patterns: adenosquamous, clear cell, colloid, lymphoepithelioma-like, mucoepidermoid, osteoclast giant cell, rhabdoid, sarcomatous, signet ring
● Bile ductular carcinoma: composed of small glands resembling reactive bile ductules, NCAM+ (Histopathology 2007;51:390)
● Cholangiolocellular carcinoma: cholangiocarcinoma, hepatocellular carcinoma and background cirrhosis; must differentiate from hepatocellular carcinoma with CK19+, CK7+ (Histopathology 2006;49:138)

Micro images
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Various images

Mass forming cholangiocarcinomas

Cholangiocarcinoma Arising in Caroli’s disease Associated with multiple von Meyenburg complexes

Comparison: hepatocellular carcinoma versus cholangiocarcinoma (left to right): H&E, MOC31, pCEA

Various images

Cytology description
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● Abundant, finely granular cytoplasm

Positive stains
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● Mucin (almost always), CEA (cytoplasmic and luminal, not canalicular), CAM 5.2, AE1-AE3, keratin 903 (74%), CK7 (90-96%) and CK19 (84%); reduced CK903 (Mod Pathol 2002;15:1181)
● Also CK20 (30-70%, more often positive in non-peripheral tumors, Am J Surg Pathol 2000;24:870), EMA, amylase, PTH-related peptide, p53 (10-94%), PCNA, MOC31 and BerEP4
● Also MUC1, MUC4, CD151, p27, COX2, fascin, tenascin, metallothionine
● MMP7 may be a favorable prognostic factor (Hum Pathol 2008;39:710)

Negative stains
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● AFP, HepPar1

Molecular description
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● Kras mutations
● Downregulation of β-catenin, aberrant expression and activation of ErbB, HGF, IL6

Differential diagnosis
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● Benign bile duct proliferations: smaller, no atypia and incidental
● Epithelioid hemangioendothelioma: vascular markers+, mucin-
● Extrahepatic biliary tree
● Hepatocellular carcinoma with ductular differentiation
● Metastatic adenocarcinoma: most likely from breast, colon (CK7- / CK20+ [strong]), gallbladder, pancreas; exclude based on clinical and radiographic findings

Intraductal cholangiocarcinoma

Gross description
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● Pink-white papillary excrescences within dilated ducts

Gross images
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Various images

Micro description
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● Papillary and flattened epithelium
● Non-invasive by definition, although may have capacity to invade through duct wall
● Resemble villous adenomas with fibrovascular cores lined by columnar, mucinous epithelium and flat epithelium
● “Carcinoma” implies high grade dysplastic features

Micro images
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Various images

Differential diagnosis
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Intraductal lesions without high grade dysplasia:
● Adenomatosis
● Biliary papillomatosis
● Intraductal adenoma

Lymphoepithelioma-like cholangiocarcinoma

General
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● Rare, < 10 cases reported (Am J Surg Pathol 2001;25:516, Mod Pathol 2001;14:527)
● Asian men and women ages 41-67 years, usually EBV related
● May have better prognosis than ordinary cholangiocarcinoma

Gross description
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● 3-12 cm, yellow-white and firm; may have tumor satellites; no cirrhosis

Micro description
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● Syncytial pattern of undifferentiated epithelial cells and glands in lymphocyte-plasma cell rich stroma (note: presence of glands differentiates this from lymphoepithelioma-like carcinoma)
● May have granulomatous reaction

Micro images
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Focal granulomatous reaction CK19 EBER

Neoplastic glands with dense lymphoplasmacytic infiltrates

Positive stains
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● CK7, CK19, AE1-AE3 and EBER-1 (in situ hybridization)

Negative stains
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● CK20, CEA

Differential diagnosis
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● Metastatic lymphoepithelioma-like carcinoma from other sites

End of Liver and intrahepatic bile ducts - tumor > Other malignancies > Cholangiocarcinoma (intrahepatic / peripheral)

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