Anatomical, histomorphological and molecular classification of cholangiocarcinoma

Abstract

Cholangiocarcinoma constitutes a heterogeneous group of malignancies that can emerge at any point of the biliary tree. Cholangiocarcinoma is classified into intrahepatic, perihilar and distal based on its anatomical location. Histologically, conventional perihilar/distal cholangiocarcinomas are mucin‐producing adenocarcinomas or papillary tumours; intrahepatic cholangiocarcinomas are more heterogeneous and can be sub‐classified according to the level or size of the displayed bile duct. Cholangiocarcinoma develops through multistep carcinogenesis and is preceded by dysplastic and in situ lesions. Definition and clinical significance of precursor lesions, including biliary intraepithelial neoplasia, intraductal papillary neoplasms of the bile duct, intraductal tubulopapillary neoplasms and mucinous cystic neoplasm, are discussed in this review. A main challenge in diagnosing cholangiocarcinoma is the fact that tumour tissue for histological examination is difficult to obtain. Thus, a major clinical obstacle is the establishment of the correct diagnosis at a tumour stage that is amenable to surgery which still represents the only curable therapeutic option. Current standards, methodology and criteria for diagnosis are discussed. Cholangiocarcinoma represents a heterogeneous tumour with regard to molecular alterations. In intrahepatic subtype, mainly two distinctive morpho‐molecular groups can currently be discriminated. Large‐duct type intrahepatic cholangiocarcinoma shows a high mutation frequency of oncogenes and tumour suppressor genes, such as KRAS and TP53 while Isocitrate Dehydrogenase 1/2 mutations and Fibroblast Growth Factor Receptor 2‐fusions are typically seen in small‐duct type tumours. It is most important to ensure the separation of the given anatomical subtypes and to search for distinct subgroups within the subtypes on a molecular and morphological basis.

Distinct clinical and prognostic implication of IDH1/2 mutation and other most frequent mutations in large duct and small duct subtypes of intrahepatic cholangiocarcinoma

“…In the present study, we identified 27 (20.8%) and 103 (79.2%) cases as large duct and small duct type ICCs respectively, according to accepted classification criteria [10,14], but the proportion of large duct type in ICCs was lower than previously reported [10,15]. There are two possible explanations.…”

“…HE staining was performed routinely on a set of TMAs. According to histological features, we subclassified ICCs into two types: large duct and small duct [11,14,15].…”

“…In fact, the distinction between ICC and perihilar cholangiocarcinoma at second-order biliary branches is someway artificial and seems to take in consideration of surgical implications rather than molecular, histological and anatomical aspects [10]. As proposed by several investigators [10][11][12][13][14][15], ICCs are much heterogeneous and can be histologically classified into two subtypes according to the size of displayed bile duct: large duct type and small duct type (also known as bile duct type and cholangiolar type). Moreover, this category individuates ICC subgroups with different clinical and molecular features [12,13].…”

“…Moreover, this category individuates ICC subgroups with different clinical and molecular features [12,13]. For example, large duct type ICC representatively lacks IDH1/2 mutation and FGFR2-fusion, characteristics exclusively seen in small duct ICC [14]. Whereas, KRAS mutation was detected in 23% of large duct type and 1% of small duct type ICC respectively (P = 0.00003) [15].…”

A novel mouse model of cholangiocarcinoma uncovers a role for a SOX17-Tensin 4 pathway in tumor progression

“…17 Histopathological studies classified biliary intraepithelial neoplasia (BilIN), intraductal tubulopapillary neoplasms and intraductal papillary neoplasms of bile ducts (IPNB) as non-invasive precursor lesions. [18][19][20] Whereas BilINs develop in large bile ducts and present as flat or micropapillary dysplasia of the bile duct epithelium, IPNBs are macroscopic lesions of the large ducts characterized by exophytic papillary structures with fibrovascular core and prominent intraductal growth. 21,22 Biliary micro-hamartomas, also called von Meyenburg complexes, are irregular ductal structures surrounded by dense stroma.…”