Feature Summary of iCCA in Keywords:
Small duct iCCA: Mass forming. mucin-poor. CRP positive. BAP1, IDH1/2 mutation, and FGFR2 fusion.
Large duct iCCA: geographic infiltrative. mucin-producing columnar epithelium. S100P-positive. Mutations in K -ras and SMAD4.
Cholangioblastic cholangiocarcinoma: Women. young age. neuroendocrine-like cytology. inhinbin-positive. and NIPBL-NACC1 gene fusion.
Cholangiocarcinoma (CC A) is a hepatobiliary malignancy with features of biliary epithelial differentiation. Anatomically, CCA occurs proximal to the second-degree bile ducts and is referred to as intrahepatic Cholangiocarcinoma (, iCCA) ). iCCA can further be classified into two major types, small-duct iCCA, and large-duct iCCA. A unique variant of iCCA, i. e. cholangioblastic cholangiocarcinoma is recently recognized. The key diagnostic features of these three iCCAs are summarized below.
1. Small-duct iCCA: Small-duct iCCA is the most common form of iCCA. It is usually present in peripheral hepatic parenchyma and is characterized by a mass-forming gross appearance. It is frequently associated with chronic parenchymal liver diseases such as chronic viral hepatitis.
Histologically, small-duct iCCA is characteristically a mucus-poor ductule-like solid tumor composed of cuboidal or low columnar cells in variable growth patterns such as solid trabecular, anastomosing, and tubulopapillary patterns. Immunohistochemically, small-duct iCCA are positive for C -reactive protein (, CRP), IMP3, N-Cam, and N-cadherin, but negative for S100P. Immunohistochemical CRP positivity, together with the radiological finding of peripheral mass may serve as a diagnostic hallmark for small-duct iCCA. Characteristic molecular features include frequent BAP1, IDH1/2 hotspot mutations and FGFR2 fusion.
2. Large-duct iCCA: Large ductal iCCA is an infiltrative duct-forming adenocarcinoma composed of columnar to cuboidal mucin-producing epithelium in ductal or tubular pattern in a fibrotic stroma, similar to perihilar cholangiocarcinoma. It is associated with chronic cholangiopathies (e.g. primary sclerosing cholangitis). S100P is a good marker for large-duct iCCA. Large ductal iCCA is also positive for Muc5AC, Muc6, but negative for CRP.
In contrast to small duct iCCA, large duct iCCA is commonly associated with mutations in K -ras and SMAD4 and the amplification of MDM2. Large duct type iCCA shows more invasive growth and poorer prognosis than small duct type iCCA.
3. Cholangioblastic cholangiocarcinoma (cCCA): Cholangioblastic cholangiocarcinoma is a unique histological variant of iCCA predominantly seen in women and 66% of cases are below the age of 40. The tumor consists of ductular-like epithelia with bimorphic cytology in various growth patterns. A basophilic small cell population mimics neuroendocrine cells. A positive immunohistochemical stain for inhibin is characteristic. It is only patchy positive for chromogranin or synaptophysin, but negative for INSM1.
Cholangioblastic cholangiocarcinoma harbors a unique NIPBL-NACC1 gene fusion. It does not contain gene mutations commonly present in other variants of intrahepatic cholangiocarcinoma.
Regardless of the subtypes, iCCA also exhibits different histological differentiation such as adenosquamous, mucinous, clear cell, and lymphoepithelioma-like carcinoma. The lymphoepithelioma-like iCCA may be EVB-associated and respond to a specific therapy.
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Key References
Zen, Yoh. “Intrahepatic cholangiocarcinoma: typical features, uncommon variants, and controversial related entities.” Human pathology vol. 132 (2023): 197-207. doi:10.1016/j.humpath.2022.06.001 https://pubmed.ncbi.nlm.nih.gov/35697170/
Chung, Taek, and Young Nyun Park. “Up-to-Date Pathologic Classification and Molecular Characteristics of Intrahepatic Cholangiocarcinoma.” Frontiers in medicine vol. 9 857140. 31 Mar. 2022, doi:10.3389/fmed.2022.857140 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9008308/
Kendall, Timothy et al. “Anatomical, histomorphological and molecular classification of cholangiocarcinoma.” Liver international : official journal of the International Association for the Study of the Liver vol. 39 Suppl 1 (2019): 7-18. doi:10.1111/liv.14093 https://onlinelibrary.wiley.com/doi/10.1111/liv.14093
Vij, Mukul et al. “Pathological, molecular, and clinical characteristics of cholangiocarcinoma: A comprehensive review.” World journal of gastrointestinal oncology vol. 14,3 (2022): 607-627. doi:10.4251/wjgo.v14.i3.607 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8919011/
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