Pathology of intrahepatic cholangiocarcinoma

Abstract

Intrahepatic cholangiocarcinoma (iCC) is a primary carcinoma of the liver with increasing significance and major pathogenic, clinical and therapeutic challenges. Classically, it arises from malignant transformation of cholangiocytes bordering small portal bile duct (BD) to second-order segmental large BDs. It has three major macroscopic growth pattern [mass-forming (MF), periductal infiltrative (PI), and intraductal growth (IG)] and histologically is a desmoplastic stroma-rich adenocarcinoma with cholangiocyte differentiation. Recent data pointed out noteworthy degree of heterogeneity in regards of their epidemiology and risk factors, pathological and molecular features, pathogenesis, clinical behaviors and treatment. Notably, several histological variants are described and can coexist within the same tumor. Several different cells of origin have also been depicted in a fraction of iCCs, amongst which malignant transformation of ductules, of hepatic stem/progenitor cells, of periductal glands or through oncogenic reprogramming of adult hepatocytes. A degree of pathological overlap with hepatocellular carcinoma (HCC) may be observed in a portion of iCC. A series of precursor lesions are today characterized and emphasize the existence of a multistep carcinogenesis process. Overall, these new data have brought up in proposal of new histological or molecular classifications, which could soon replace current anatomic-based classification and could have major impact on establishment of prognosis and on development of novel target treatment approaches.

Keywords: Intrahepatic cholangiocarcinoma (iCC); cells of origin; immunohistochemistry; macroscopic features; microscopic variants.

Figure 1

Macroscopic patterns of intrahepatic cholangiocarcinoma (iCC). (A) Mass-forming type consisting of a single solid and lobulated mass with no connection macroscopically discernible with a bile duct. It is characterized by irregular but well-defined and not encapsulated borders; (B) periductal infiltrating type characterized by growth along a bile duct, without mass formation; (C) mixed pattern associating mass-forming type and periductal infiltrating type.

Figure 2

Traditional intrahepatic cholangiocarcinoma (iCC). (A) Hematoxylin and eosin stain. ICCs typically elicit prominent fibrodesmoplastic stromal reaction (original magnification, ×10); (B) hematoxylin and eosin stain. Moderately differentiated iCC characterized by infiltrative irregular glands lined by columnar-shaped and moderately pleomorphic cells with eosinophilic cytoplasm (original magnification, ×40); (C) hematoxylin and eosin stain. Poorly differentiated iCC displaying a solid growth pattern, without identifiable glandular lumens and composed of more highly atypical cells (original magnification, ×40).

Figure 3

Rare histological variants of intrahepatic cholangiocarcinoma (iCC). (A) Hematoxylin and eosin stain. Adenosquamous variant of iCC showing two components: a squamous component (blue arrow) and a glandular and trabecular component (yellow arrow) (original magnification, ×20); (B) hematoxylin and eosin stain. Dyskeratotis is seen within groups of tumoral cells in the squamous component (original magnification, ×40); (C) hematoxylin and eosin stain. Mucinous variant of traditional iCC containing large tumoral glands lined by a mucinous neoplastic epithelium with luminal mucin accumulation (original magnification, ×10); (D) hematoxylin and eosin stain. Clear cell type of iCC characterized by cells showing an abundant clear cytoplasm (original magnification, ×20); (E) hematoxylin and eosin stain. Sarcomatoid variant of iCC showing large sheets of spindled cells intermingled with few glandular structures (original magnification, ×10); (F) pan-cytokeratin stain. The spindled cells are keratin positive, confirming their carcinomatous nature (original magnification, ×20).

Figure 4

Unconventional intrahepatic cholangiocarcinoma (iCC). (A) Hematoxylin and eosin stain. Intraductal papillary neoplasm of the bile duct (IPNB) consisting of papillary proliferation in the lumen of a dilated large bile duct. Papillae are characterized by a delicate fibrovascular axis and are lined by atypical columnar cells (original magnification, ×20); (B) hematoxylin and eosin stain. ICC with predominant ductal plate malformation corresponding to a vaguely nodular carcinomatous area composed of irregularly dilated neoplastic glands (original magnification, ×10); (C) hematoxylin and eosin stain. The dilated lumens of these tumoral glands are lined by a single layer of cuboidal epithelial cells (original magnification, ×40).

Figure 5

Cholangiolocellular carcinoma (CLC). (A) Gross specimen of a 38 years old patient who was transplanted for a CLC developed in a cirrhotic liver due to chronic hepatitis B virus infection. Grossly, this lesion corresponds to a mass-forming type with central yellowish necrotic area and several satellite nodules; (B) hematoxylin and eosin stain. CLC consists of well differentiated ductular glands lined with mild atypical cells and growing in a tubular, cord-like and anastomosing pattern (original magnification, ×40); (C) albumin mRNA in situ hybridization (ISH). Most of the tumor cells demonstrate a cytoplasmic hybridization signal (original magnification, ×40).

Figure 6

Precursor lesions of intrahepatic cholangiocarcinoma (iCC). (A) Hematoxylin and eosin stain. High grade biliary intraepithelial neoplasia (BillN) characterized by atypical epithelial cells with multilayering of nuclei (original magnification, ×40); (B) hematoxylin and eosin stain. Intraductal papillary neoplasm of the bile duct (IPNB) of a large bile duct which was discernible at macroscopic level (original magnification, ×2).

Figure 7

Conventional combined hepatocellular-cholangiocarcinoma. (A) Gross specimen showing a unique whitish lesion, relatively well demarcated, similar to a classical cholangiocarcinoma; (B) hematoxylin and eosin stain. Whole section demonstrating a tumor composed of two distinct components: a cholangiocarcinoma component (blue arrow) and a hepatocellular carcinoma component (yellow arrow); (C) hematoxylin and eosin stain. Intermediate area with a gradual transition between the two components: hepatocellular carcinoma component in the upper left corner and cholangiocarcinoma component in the lower right corner, separated by pseudoacinar formations lined not by hepatocytes, but by cuboidal, cholangiocyte-like cells (original magnification, ×20).

Figure 8

Scirrhous hepatocellular carcinoma. (A) Hematoxylin and eosin stain. The carcinoma shows a hepatoid morphology with polygonal tumor cells containing moderate eosinophilic cytoplasm, invading an abundant fibrous stroma, without any glandular differentiation or mucin production (original magnification, ×40); (B) HepPar1 stain. Tumor cells are characterized by a lower expression of HepPar1 in a portion of cells, in comparison with a classical hepatocellular carcinoma (original magnification, ×40); (C) albumin mRNA in situ hybridization (ISH). All of the tumor cells demonstrate an intense cytoplasmic hybridization signal (original magnification, ×40); (D) cytokeratin 7 stain. Tumor cells show a higher expression of cytokeratin 7 in comparison with a classical hepatocellular carcinoma (original magnification, ×40).

Figure 9

Bile duct adenoma. (A) Hematoxylin and eosin stain. Benign tumor represented by small tubular structures lined by a single layer of non-atypical cubocylindrical cells admixed with variable inflammation and fibrosis (original magnification, ×40); (B) cytokeratin 7 stain. All tubular structures are well demarcated with the cytokeratin 7 stain (original magnification, ×20).