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Histology of liver cancer

The liver consists of hepatocytes, interstitial connective tissue, blood vessels, sinusoidal cells (endothelial and Kupffer cells), and biliary ductal epithelium.  Liver cancer can originate from all these different cell types. The most common is liver cell carcinoma, (hepatocellular carcinoma) originating from hepatocytes, and cholangiocarcinoma originating from biliary duct epithelium.

Precursor lesions

Similar to many other cancer types, there are precursor lesions in the liver possible to diagnose and prevent from further developing into manifest cancer.

  • Dysplastic nodules (adenomatous hyperplasia)
  • Hepatocellular adenoma
  • Biliary intraepithelial neoplasia

In countries with high incidence of hepatocellular carcinoma (HCC) there is a high prevalence of chronic hepatitis B or C virus infection. Despite treatment of patients with hepatitis,  some of them will develop cirrhosis that increases the risk of hepatocellular carcinoma. Chronic hepatitis B or C virus infections predispose to cirrhosis and HCC. Some patients with cirrhosis develop dysplastic nodules demonstrating atypical cellular morphology in regenerating hepatocytes. Radiological techniques can detect liver nodules, and needle biopsy might further determine the nature; whether they represent precursor lesions or manifest HCC.

Hepatocellular adenomas (HCA) are often difficult to separate from HCC, especially when using needle biopsy. Important differential diagnostic clues are cell morphology, number of mitotic figures and the presence of liver trabecula thicker than 2-3 cell layers. Adenomas are seen almost exclusively in non-cirrhotic livers. When multiple adenomas (>10) are seen, the condition is designated as adenomatosis. It is a paradox that HCA can be difficult to separate from HCC, although HCA seldom develop into HCC.

Besides HCC, intrahepatic cholangiocarcinoma is the most frequent primary malignant liver tumor. These are tumors that originate from intrahepatic biliary ducts. Precursor lesions are designated as biliary intraepithelial neoplasia (BIL-IN) grade I, II and III. These lesions can be seen in biliary ducts close to the hilum. Grade I represents epithelium with slight deviation from normal biliary epithelium, while grade III represent cellular changes corresponding to carcinoma in situ. Patients with sclerosing primary cholangitis, ‘inflammatory bowel disease’ (IBD), especially ulcerative colitis, and patients with either hepatholithiasis and dilatation of biliary ducts (Caroli syndrome) or hamartomas, predispose for BIL-IN and cholangiocarcinoma. Brush cytology from biliary ducts can be used to detect precursor lesions, and enables follow-up and consideration of relevant interventions.


  • Hepatocellular carcinoma (HCC)
  • Intrahepatic cholangiocarcinoma (IHCC)

HCC is the most frequent primary cancer in the liver followed by intrahepatic choloangiocarcinoma. HCC are classified according to the similarity to normal hepatocytes and ordinary liver trabecles. Immunohistochemical markers that determine the histogenetic origin are "hepato" or polyclonal CEA. Using the immunohistochemical markers and microscopic evaluation enable determination of whether metastasis or primary tumor in 95-100% of cases.

The same applies to cholangicarcinomas, where the use of cytokeratin CK7 and CK20 can separate intestinal cancer metastasis (CK 20 positive) from pancreaticobiliary cancer (CK 7 positive). The epithelium in pancreatic and intra- and extrahepatic biliary ducts are almost identical concerning morphology and immunohistochemical markers.

A type of HCC is important to recognize, the fibrolamellar type. This type is seen mainly in younger females, and have better prognosis compared to ordinary HCC. Histologically the fibrolamellar types are characterized by large eosinophilic tumor cells and a lamellar connective tissue.

Other cancer types

  • Mixed hepatocellular carcinoma and cholangiocarcinoma
  • Cystadenocarcinoma in intrahepatic biliary ducts
  • Hepatoblastoma (children)
  • Undifferentiated carcinoma
  • Epitheloid hemangioendothelioma
  • Angiosarcoma
  • Embryonal sarcoma (children)
  • Rhabdomyosarcoma

These are rare tumors that can be difficult to diagnose and separate from metastasis, especially in needle biopsies.

Benign tumors

Benign tumors are hemangiomas, focal nodular hyperplasia, hamartomas (von Meyenburg complex) cysts and angiomyolipomas. The three first mentioned are frequently seen, and are often suspected to be metastases in imaging techniques.


Majority of liver specimens are needle biopsies to determine whether the lesion represents primary malignant tumor or metastasis. These small specimens are always adequately fixed in formalin. The larger liver operation specimens, such as resections of metastasis and primary tumors, must be adequately handled in order to be properly fixed. Thus, enough formalin (10 parts more formalin than specimen volume) should be used after cutting slices (not completely through the specimen) and there must be put some soft substance in between the slices.

Pathology reports

A liver removed due to a primary liver tumor should be examined and reported with the following information:

  • Tumor localization (segment)
  • Tumor size (millimeter)
  • Histological type (WHO)
  • Grading (1–3 (4))
  • Penetration of liver capsule
  • Resection borders in hilum close/extrahepatic biliary duct
  • Tumor infiltration in blood vessels
  • Lymph node metastasis
  • Extrahepatic spread (diaphragm/vena cava/metastases to other organs)
  • ”Milan” criteria:
    • Low risk for tumor progression: 1 tumor ≤ 5cm or 1–3 tumors < 3 cm
    • High risk for tumor progression: > 3 tumors > 3 cm or 1 tumor > 5 cm

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