Pathology
Histological Classifications
There are separate histological classifications of intrahepatic and extrahepatic CC. The WHO classifications are given in Table 3.
Macroscopic Features of Intrahepatic CC. Intrahepatic CCs are whiter and firmer than HCCs as they contain more desmoplastic stroma. They occur more commonly in non-cirrhotic livers than HCCs and are divided into four macroscopic types (Table 4). The intraductal type carries the best prognosis and the periductal type carries the worst.
Histological Grade
Over 90% of CCs are adenocarcinomas and are classified (1–4) according to the percentage of tumour composed of glandular tissue. Some types of adenocarcinoma are not graded (eg, carcinoma in situ, clear cell adenocarcinoma and papillary adenocarcinoma). Signet ring cell carcinoma is graded as 3 and small cell carcinoma as 4. Although histological grade correlates with postoperative outcome, stage is more important.
Molecular Diagnosis
CC is often associated with inactivation of tumour suppressor genes, for example, p53, Smad-4, bcl-2 and p16. Mutations in oncogenes have also been described including K-ras, p53, c-erbB-2 and c-neu. Chromosomal aneuploidy has been reported in over 80% of PSC-associated CC. Although mutations can lead to detectable phenotypic changes, molecular profiling in biliary cytology does not currently have an established diagnostic or prognostic role.
Combined Hepatocellular–Cholangiocarcinomas
This entity should be distinguished from 'collision' tumours in which separate CCs and HCCs are present in the same liver. Combined hepatocellular–CCs are uncommon primary liver tumours accounting for 1–15% of all CCs. These are divided into classical and stem cell types. The latter is divided into the typical subtype in which there are nests of mature-appearing hepatocytes with peripheral clusters of small cells with the immunohistochemical profile of stem/progenitor cells; the intermediate cell subtype with tumour cells intermediate between hepatocytes and cholangiocytes; and the cholangiocellular type with tumour cells growing in an anastomosing pattern. In one series, 28% of HCCs contained cells expressing biliary/progenitor cell markers cytokeratin (CK) 7 and/or CK19. 'Non-classical' intrahepatic CCs are usually smaller and often arise in chronic liver disease, mostly HCV infection, and/or with significant fibrosis.
Distinction From Other Tumours
Distinguishing intrahepatic CC from metastatic adenocarcinoma and other primary liver tumours can be difficult. Accurate differentiation, particularly from foregut metastases (lung, oesophagus, stomach, pancreas), often cannot be made histologically. Other modalities, especially imaging, are essential. Immunohistochemistry panels including CK7, CK19, CK20, CDX-2, TTF-1, oestrogen/progesterone receptors and PSA, depending on clinical context, can be helpful. CCs are usually CK7 positive and CK20 negative. In distinguishing HCC from CC, lack of mucin production and expression of HepPar-1, CD10 and glypican-3 by HCC are useful.