Hepatocellular carcinoma arising in adenoma: similar immunohistochemical and cytogenetic features in adenoma and hepatocellular carcinoma portions of the tumor

Abstract

Well-differentiated hepatocellular carcinoma in non-cirrhotic liver can show morphological features similar to hepatocellular adenoma. In rare instances, hepatocellular carcinoma can arise in the setting of hepatocellular adenoma. This study compares the immunohistochemical and cytogenetic features of the hepatocellular adenoma-like and hepatocellular carcinoma portions of these tumors. Immunohistochemistry for β-catenin, glutamine synthetase, serum amyloid A protein, glypican-3, and heat-shock protein 70 was done in 11 cases of hepatocellular carcinoma arising in hepatocellular adenoma in non-cirrhotic liver. Tumors with nuclear β-catenin and/or diffuse glutamine synthetase were considered β-catenin activated. Fluorescence in situ hybridization (FISH) was done in nine cases for gains of chromosomes 1, 8 and MYC. There were seven men (33–75 years) and four women (29–65 years). Focal atypical morphological features were seen in hepatocellular adenoma-like areas in 7 (64%) cases. Hepatocellular adenoma-like areas showed features of inflammatory hepatocellular adenoma in 7 (64%) cases; 4 of these were also serum amyloid A-positive in the hepatocellular carcinoma portion. β-catenin activation, heat-shock protein 70 positivity, and chromosomal gains on FISH were seen in the hepatocellular adenoma portion in 55%, 40%, and 56% of cases, and 73%, 60%, and 78% of cases in the hepatocellular carcinoma portion, respectively. In conclusion, the hepatocellular adenoma-like portion of most cases of hepatocellular carcinoma arising in hepatocellular adenoma shows features typically seen in hepatocellular carcinoma such as focal morphological abnormalities, β-catenin activation, heat-shock protein 70 expression, and chromosomal gains. Hepatocellular adenoma-like areas in these tumors, especially in men and older women, may represent an extremely well-differentiated variant of hepatocellular carcinoma, whereas the morphologically recognizable hepatocellular carcinoma portion represents a relatively higher grade component of the tumor.

Correlation of exon 3 β-catenin mutations with glutamine synthetase staining patterns in hepatocellular adenoma and hepatocellular carcinoma

“…Activation of β-catenin is a high-risk feature in hepatocellular adenomas, and these tumors are frequently associated with hepatocellular carcinoma (4, 28). Our previous studies have shown that careful morphologic review of these tumors can enable the diagnosis of hepatocellular carcinoma in most cases (24, 25, 28).…”

“…Our previous studies have shown that careful morphologic review of these tumors can enable the diagnosis of hepatocellular carcinoma in most cases (24, 25, 28). It has been recommended that tumors with β-catenin activation should be classified as atypical hepatocellular neoplasms or hepatocellular neoplasms with uncertain malignant potential (29, 30).…”

Combined use of heat-shock protein 70 and glutamine synthetase is useful in the distinction of typical hepatocellular adenoma from atypical hepatocellular neoplasms and well-differentiated hepatocellular carcinoma

“…In some instances, tumors resembling hepatocellular adenoma that occur in men, older women or have focal atypical features may represent extremely well-differentiated variants of hepatocellular carcinoma. 2,19,22 The utility of HSP70, GS, and glypican-3 has been explored for distinction of dysplastic nodule and hepatocellular carcinoma. 20,28,29 There is limited data about the utility of these markers in the distinction of hepatocellular adenoma and hepatocellular carcinoma.…”

“…These results as well as earlier studies indicate that the diagnosis of hepatocellular adenoma with β-catenin activation should be made with caution even though it is a recognized WHO subtype 31 as most of these tumors exhibit atypical morphologic features and focal reticulin loss and a diagnosis of hepatocellular carcinoma may be possible after careful evaluation. 22,34 Concurrent or subsequent hepatocellular carcinoma has been reported in up to 40% of hepatocellular adenoma with β-catenin activation, 18 and most of these cases exhibit cytogenetic changes similar to hepatocellular carcinoma, 19 further emphasizing that most of the β-catenin activated hepatocellular neoplasms are likely to be hepatocellular carcinoma. Hence diffuse GS staining can help in the diagnosis of hepatocellular carcinoma and in recognizing the potential high-risk outcome in atypical hepatocellular neoplasms that lack diagnostic features of hepatocellular carcinoma.…”

“…18,19 It has been suggested that most hepatocellular adenomas with diffuse GS staining may represent extremely well-differentiated variant of hepatocellular carcinoma. 19,22 …”