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Hepatocellular adenoma usually arises in the absence of significant fibrosis. Herein, we report seven patients with serum amyloid A-positive hepatocellular neoplasm, which shares features with inflammatory hepatocellular adenoma arising in alcoholic cirrhosis. Seven patients (two women and five men, age range 41-67 years) with hypervascular hepatocellular nodules associated with alcoholic cirrhosis were retrieved from our pathological files (1997-2011). The hepatocellular nodules were multiple (>3) in all patients and 17 nodules were histologically examined. We surveyed the immunoreactivity for serum amyloid A, glutamine synthetase, and glypican-3 in the hepatocellular nodules and control lesions, including 5 focal nodular hyperplasia, 18 dysplastic nodules, and 54 hepatocellular carcinomas in various background diseases. In all, 15 of 17 nodules showed strong and distinct immunoreactivity for serum amyloid A, sharing features with inflammatory hepatocellular adenoma. The serum amyloid A-positive hepatocellular neoplasms showed increased cellular density, inflammatory infiltrate, sinusoidal dilatation, and ductular reaction to various degrees. Although about a half of dysplastic nodules and hepatocellular carcinomas showed focal immunoreactivity for serum amyloid A, the extent of serum amyloid A expression was significantly higher in serum amyloid A-positive hepatocellular neoplasms, than in control nodules. The serum amyloid A-positive hepatocellular neoplasms did not show the overexpression of glutamine synthetase or immunoreactivity for glypican-3. In contrast, most hepatocellular carcinomas showed the overexpression of glutamine synthetase and immunoreactivity for glypican-3, irrespective of background diseases. In conclusion, this study highlights a characteristic group of hepatocellular neoplasms arising in alcoholic cirrhosis, which share features with inflammatory hepatocellular adenomas. These serum amyloid A-positive hepatocellular neoplasms may be a new type of inflammatory hepatocellular tumors in alcoholic patients.

We studied the tumor cell expression patterns of E-cadherin and matrix metalloproteinase-1, -2, -7, and -9 in a tissue microarray composed of 20 normal livers, 10 hepatocellular adenomas, 43 hepatocellular carcinomas with cirrhosis and 33 hepatocellular carcinomas without cirrhosis. Hepatocellular adenoma was characterized by the complete absence of matrix metalloproteinase-7 expression; hepatocellular carcinoma with cirrhosis was characterized by a significantly low expression of E-cadherin; and hepatocellular carcinoma without cirrhosis was characterized by low matrix metalloproteinase-9 expression. The staining intensity score of E-cadherin=3, matrix a metalloproteinase-7<1, and matrix metalloproteinase-9>or=2 can be used as the diagnostic criteria for hepatocellular adenoma and for distinguishing hepatocellular adenoma from normal, hepatocellular carcinoma with cirrhosis, and hepatocellular carcinoma without cirrhosis. E-cadherin<2 and matrix metalloproteinase-9<2 can be used for distinguishing both hepatocellular carcinoma with cirrhosis and hepatocellular carcinoma without cirrhosis from normal. Although statistically not significant, hepatocellular carcinoma without cirrhosis showed a higher E-cadherin expression and a lower matrix metalloproteinase-9 expression than hepatocellular carcinoma with cirrhosis, which could be partially responsible for the less aggressive behavior found in hepatocellular carcinoma without cirrhosis when compared with hepatocellular carcinoma with cirrhosis. These results, if confirmed in a further study of small biopsy specimens and of histologically ambiguous cases, could lead to the application of these markers in the diagnosis and differential diagnosis of hepatocellular neoplasms in our surgical pathology practice.

Glypican-3 is a heparin sulfate proteoglycan normally expressed in fetal liver and placenta, but not in normal adult liver. Preliminary studies have shown that glypican-3 can be useful for the diagnosis of hepatocellular carcinoma. We performed immunohistochemistry for glypican-3 on 80 resection cases of hepatocellular lesions to examine the utility of glypican-3 immunohistochemistry in hepatocellular carcinoma at two ends of the differentiation spectrum. Staining was compared to Hep Par 1 in poorly differentiated cases. Glypican-3 was expressed in 46 (79%) hepatocellular carcinomas (56, 83 and 89% of well, moderately and poorly differentiated respectively) and seven (64%) fibrolamellar carcinomas. Of the 16 well differentiated cases, 10 closely resembled adenoma and were diagnosed due to focal abnormalities and/or loss of reticulin. Glypican-3 expression was seen in 50% in this group. Hepatocellular carcinomas arising in cirrhotic liver were more likely to be glypican-3 positive (91 vs 57%, P=0.004). All hepatic adenomas and macroregenerative nodules were negative, and three (43%) high grade dysplastic nodules were positive. Focal staining was seen in regenerative nodules in four (11%) cirrhosis cases. Glypican-3 was significantly more sensitive than Hep Par 1 for diagnosis of poorly differentiated hepatocellular carcinomas (89 vs 63%, P=0.02). The difference was more significant when only cases with diffuse positive staining were considered (83 vs 21%, P<0.001). In conclusion, glypican-3 has high sensitivity for the diagnosis of hepatocellular carcinoma, but is less sensitive in the extremely well differentiated hepatocellular carcinoma and fibrolamellar variant of hepatocellular carcinoma. Caution should be exercised in using glypican-3 in biopsy specimens as cirrhotic nodules can show strong expression. Glypican-3 can be especially useful in the identification of poorly differentiated hepatocellular carcinoma as it has higher sensitivity compared to Hep Par 1.

Hepatic adenomas are benign neoplasms of the liver that occur in several well-defined clinical settings, but principally that of excess hormone exposure. They have a small but poorly characterized risk of malignant degeneration. The clinical presentation and pathological findings were reviewed for all hepatic adenomas resected between January 1, 2003 and July 1, 2006. Immunohistochemistry for p53, beta-catenin and alpha-fetoprotein (AFP) were performed on those cases with malignant transformation and exon 3 of beta-catenin was amplified and sequenced. A total of 17 hepatic adenomas were resected and 3 showed malignant transformation. All three cases were in women with an age range of 23-33 years. The clinical presentations were vague abdominal pain. Histologically, the malignant transformation occurred within otherwise typical hepatic adenomas. Two of three cases showed patchy atypia throughout the hepatic adenoma. The hepatocellular carcinoma arose as distinct nodules directly within the adenomas, effectively ruling out synchronous lesions. The hepatocellular carcinomas were unifocal in two cases and multifocal in one case with the greatest dimensions of the hepatocellular carcinoma being 2.5, 2.2, and 1 cm. Immunostains for AFP and beta-catenin were negative in both the hepatic adenomas and areas of hepatocellular carcinoma. p53 immunostaining was positive within the areas of malignant transformation in one case. No mutations or deletions were seen in exon 3 of the beta-catenin gene for either the adenomas or the carcinoma. In conclusion, two of the cases that developed hepatocellular carcinomas showed cytological atypia in the background adenoma. The hepatocellular carcinomas arose as distinct nodules within the adenomas. No common molecular pathway of hepatocellular carcinogenesis was observed by examining AFP, beta-catenin, and p53 immunostains and no beta-catenin mutations or deletions were found.

Hepatic adenomas are strongly linked to excess hormonal exposure, but little else is known about their pathogenesis. The Wnt signaling pathway, which is activated in both hepatocellular carcinomas and hepatoblastomas, has not been studied in hepatic adenomas. Fifteen hepatic adenomas were studied by immunohistochemistry for estrogen, progesterone, and androgen receptors (ER, PR, AR, respectively) and correlated with the results of immunostaining for beta-catenin. Direct sequencing was performed to look for mutations in key genes involved in the Wnt signaling pathway: Exon 3 of beta-catenin encompassing the glycogen synthase kinase 3beta (GSK-3beta) phosphorylation region and the mutational cluster region of the adenomatosis polyposis coli protein (APC). Analysis for loss of heterozygosity (LOH) at chromosome 5q was also performed. Immunostaining for both ER and PR was present in 11/15 (73%) adenomas, and staining with one hormone receptor was positively associated with staining for the other receptor. AR positivity was present in 3/15 cases. Nuclear accumulation of beta-catenin was present in 7/15 (46%) of adenomas, indicating activation of the Wnt signaling pathway. However, no beta-catenin mutations, no APC mutations in the mutational cluster region, and no 5q LOH were detected. Two APC polymorphisms of unknown significance were seen. No clear association between beta-catenin nuclear accumulation and hormone receptor positivity was discerned. Activation of the Wnt signaling pathway appears to be important in a subset of hepatic adenomas but does not result from common beta-catenin or APC mutations and does not appear to be directly linked to hormonal receptor status.