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

Author: Omid Savari, M.D.
Senior Author: Joseph F. Tomashefski, Jr., M.D.
Editorial Board Member Review: Raul S. Gonzalez, M.D.
Editor-in-Chief Review: Debra Zynger, M.D.

Revised: 4 October 2018, last major update September 2018

Copyright: (c) 2002-2018, PathologyOutlines.com, Inc.

PubMed Search: Cholangiocarcinoma [title] liver "intrahepatic bile duct"

Related Topics: Intraductal cholangiocarcinoma, lymphoepithelioma-like cholangiocarcinoma

Cite this page: Savari, O. Cholangiocarcinoma (intrahepatic / peripheral). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/livertumorcholangiocarcinoma.html. Accessed November 12th, 2018.
Definition / general
  • Intrahepatic cholangiocarcinoma is an epithelial malignancy arising from the intrahepatic biliary tree
  • Recently divided into small duct type and large duct type, which have morphologic and molecular (but not prognostic) differences (Am J Surg Pathol 2018;42:1334, Surg Pathol Clin 2018;11:403)
Essential features
  • Unencapsulated, white-tan and firm intrahepatic mass
  • Glandular malignancy with various degrees of atypia and differentiation, infiltrating a dense fibrous stroma
  • Exclusion of metastatic adenocarcinoma by thorough review of the patient's clinical history and application of an appropriate immunohistochemistry panel
Terminology
  • Also known as peripheral cholangiocarcinoma and intrahepatic bile duct carcinoma
ICD-10 coding
Epidemiology
  • Incidence in the Western world is approximately 1 - 2 per 100,000 (J Cancer Res Clin Oncol 2011;137:1071)
  • Comprises 15% of primary liver malignancies worldwide
  • Second most common malignancy arising from the liver
  • Accounts for 3% of all cases of gastrointestinal cancer
  • Comprises about 10% of all cholangiocarcinomas
  • More common in East Asia, due to endemic liver fluke infection
  • More common in older patients (over 75% of patients are older than 65 at initial diagnosis) (Gastroenterology 2009;136:1134)
  • Slightly more common in males than females (Hepatology 2011;54:173)
Pathophysiology
  • Chronic inflammation of the intrahepatic bile ducts is a known risk factor in cholangiocarcinogenesis
  • Proinflammatory cytokines activate inducible nitric oxide synthase resulting in oxidative DNA damage, inhibition of DNA repair enzymes and expression of cyclooxygenase 2 (COX2)
  • Bile acids and oxysterols activate epidermal growth factor receptor (EGFR) and enhance COX2 expression (Gastroenterology 2002;122:985)
  • COX2 dysregulates cholangiocarcinoma growth and promotes apoptosis resistance and positively regulates pro-oncogenic signaling pathways such as hepatocyte growth factor (HGF), IL6 and EGFR (Semin Liver Dis 2010;30:186)
  • TP53 and SMAD4 mutations are more frequent in liver fluke associated cholangiocarcinoma
  • BAP1 and IDH1 / 2 mutations are more frequent in non liver fluke associated cholangiocarcinoma (Medicine (Baltimore) 2016;95:e2491)
Etiology
Diagrams / tables

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Morphologic classification

Clinical features
  • Asymptomatic in early stages (19 - 40% incidentally identified) (J Am Coll Surg 2001;193:384)
  • Nonspecific symptoms in late stages, such as abdominal pain, malaise, night sweats and cachexia
Laboratory
  • ↑ serum alkaline phosphatase
  • ↑ total bilirubin
  • ↑ aspartate aminotransferase
  • ↑ serum CEA
  • ↑ serum CA19-9
  • Normal to slightly ↑ serum AFP
Radiology description
  • Usually single, large, homogeneous mass with irregular margins on CT scan
  • Intratumoral calcification is common
Radiology images

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CT scan

Ultrasound

MRI

Prognostic factors
  • Tumor stage, microvascular invasion and lymph node metastasis are the most important prognostic factors (Oncol Rep 2013;29:1259)
Case reports
Treatment
  • Surgical resection of the tumor is the potential curative therapy
  • Resistant to the traditional chemotherapy but recent studies show increased survival rate with EGFR inhibitor erlotinib and gemcitabine / cisplatin combination therapy (Lancet Oncol 2012;13:181)
Gross description
  • Usually large, nonencapsulated, well demarcated, firm (due to desmoplastic reaction), white-tan to gray and nodular intrahepatic mass
  • More frequent in the right lobe of the liver
  • Satellite nodules are present in 30%
  • Calcification is common
  • Noncirrhotic background liver in most cases
  • Grossly classified into 3 types in some articles (World J Hepatol 2010;2:419):
    1. Mass forming: hepatic parenchymal solid mass
    2. Periductal infiltrating: infiltrates along the portal tracts, causing bile duct strictures
    3. Intraductal growth: papillary or polypoid growth inside a dilated bile duct
Gross images

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Mass forming cholangiocarcinomas

Periductal infiltrating cholangiocarcinoma

Microscopic (histologic) description
  • Intrahepatic cholangiocarcinoma consists of infiltrating well formed or cribriform glands in an abundant fibrous stroma
  • Malignant glands are lined by cells with varying degrees of atypia and pleomorphism
  • Usually well differentiated adenocarcinoma with mild atypia, intracytoplasmic lumina and intraluminal cellular debris; however, focal atypia with marked pleomorphism can also be present
  • Commonly infiltrates between hepatic parenchymal cords at the periphery of the tumor
  • Multicentricity and perineural invasion are common
  • Histologic variants include mucinous, signet ring cell, clear cell, lymphoepithelioma-like, thyroid follicular-like, adenosquamous and sarcomatoid
Microscopic (histologic) images

Images hosted on PathOut server:

Contributed by Omid Savari, M.D.

With necrosis

With sclerotic stroma

High magnification

Infiltrating hepatic parenchyma

Poorly differentiated



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Various images

Cytology description
  • Isolated, clusters and sheets of cuboidal or columnar cells with various degrees of nuclear enlargement and pleomorphism
  • Wide range of glandular differentiation on cell block
  • > 10 proliferating ductules on FNA is helpful to differentiate cholangiocarcinoma from metastatic adenocarcinomas (Diagn Cytopathol 2000;22:359)
Positive stains
Molecular / cytogenetics description
Differential diagnosis
Board review question #1
What are the mutations associated with liver fluke associated cholangiocarcinoma?

  1. BAP1 and IDH1 / 2
  2. BRAF and MET
  3. mTOR and MET
  4. TP53 and SMAD4
Board review answer #1
D. TP53 and SMAD4 mutations are more frequent in liver fluke associated cholangiocarcinoma.
Board review question #2
Which of the following regarding intrahepatic cholangiocarcinoma risk factors is false?

  1. Multiple bile duct hamartomas are not a risk factor
  2. Cirrhosis is an independent risk factor
  3. Hepatolithiasis is associated with a 6 to 50 fold increased risk of intrahepatic cholangiocarcinoma
  4. Non liver fluke associated cholangiocarcinoma is associated with BAP1 and IDH1 / 2 gene mutations
Board review answer #2
A. Multiple bile duct hamartomas (von Meyenburg complexes) are a risk factor for intrahepatic cholangiocarcinoma.