Recent Advances in Pathology of Intrahepatic Cholangiocarcinoma

Abstract

Intrahepatic cholangiocarcinoma (ICCA) is a malignant epithelial neoplasm characterized by biliary differentiation within the liver. ICCA is molecularly heterogeneous and exhibits a broad spectrum of histopathological features. It is a highly aggressive carcinoma with high mortality and poor survival rates. ICCAs are classified into two main subtypes: the small-duct type and large-duct types. These two tumor types have different cell origins and clinicopathological features. ICCAs are characterized by numerous molecular alterations, including mutations in KRAS, TP53, IDH1/2, ARID1A, BAP1, BRAF, SAMD4, and EGFR, and FGFR2 fusion. Two main molecular subtypes-inflammation and proliferation-have been proposed. Recent advances in high-throughput assays using next-generation sequencing have improved our understanding of ICCA pathogenesis and molecular genetics. The diagnosis of ICCA poses a significant challenge for pathologists because of its varied morphologies and phenotypes. Accurate diagnosis of ICCA is essential for effective patient management and prognostic determination. This article provides an updated overview of ICCA pathology, focusing particularly on molecular features, histological subtypes, and diagnostic approaches.

Keywords: classification; diagnosis; intrahepatic cholangiocarcinoma; molecular genetics; pathology.

Figure 1

Intrahepatic cholangiocarcinoma, small-duct type. (a) A well-defined, lobulated, yellow-gray mass is present. (b) The tumor cells are arranged in a glandular pattern in fibrous stroma (hematoxylin-eosin stain, ×100).

Figure 2

Intrahepatic cholangiocarcinoma, large-duct type. (a) A gray-white, periductal-infiltrating tumor. (b) The infiltrating dilated tumor glands along the large bile duct wall. Desmoplastic stroma and perineural invasion are present (hematoxylin–eosin stain, ×40).

Figure 3

Intrahepatic cholangiocarcinoma, cholangiolocarcinoma subtype. (a) A well-defined, gray-yellow, solid tumor. (b) Tumor cells arranged in a small glandular and cord-like pattern in hyaline fibrous stroma (hematoxylin–eosin stain, ×100).

Figure 4

Intrahepatic cholangiocarcinoma with a ductal plate malformation pattern. (a) A gray-white nodular tumor with irregular border. (b) The tumor showing a ductal plate malformation pattern with irregularly dilated lumens (hematoxylin–eosin stain, ×40).

Figure 5

Intrahepatic cholangiocarcinoma, adenosquamous carcinoma subtype. (a) A well-defined, white-pink, solid tumor. (b) Adenocarcinoma components with tubule formation intermixed with squamous cell carcinoma components with keratinization (hematoxylin–eosin stain, ×100).

Figure 6

Pathological diagnostic approach of intrahepatic cholangiocarcinoma based on clinical and radiologic findings, histologic features (tumor cells morphology, growth pattern), and immunohistochemistry. ICCA, intrahepatic cholangiocarcinoma; CLLCA, cholangiolocarcinoma; ICDPM, intrahepatic cholangiocarcinoma with ductal plate malformation pattern; ASCA, adenosquamous carcinoma; SCC, squamous cell carcinoma; MCCA, mucinous carcinoma; SRCCA, signet-ring cell carcinoma; CCCA, clear cell carcinoma; MECA, mucoepidermoid carcinoma; LELCA, lymphoepithelioma-like carcinoma; SACCA, sarcomatous cholangiocarcinoma; TCCA, transitional cell carcinoma; CBCCA, cholangioblastic cholangiocarcinoma; EBCCA, enteroblastic cholangiocarcinoma; MPCA, micropapillary carcinoma; ACCA, acinar cell carcinoma. ^(a) CLLCA and ^(b) ICDPM are considered small-duct type of conventional ICCA.