Multifocal Hepatic Neoplasia in 3 Children With APC Gene Mutation

• Published in: The American journal of surgical pathology Vol. 37; no. 7; pp. 1058 - 1066
• Main Authors: Gupta, Anita, Sheridan, Rachel M, Towbin, Alexander, Geller, James I, Tiao, Gregory, Bove, Kevin E
• Format: Journal Article
• Language: English
• Published: United States Lippincott Williams & Wilkins, Inc 01-07-2013
• Subjects: Adenoma - genetics; Adenoma - metabolism; Adenoma - pathology; Adenoma - surgery; beta Catenin - metabolism; Biomarkers, Tumor - metabolism; Female; Genes, APC; Germ-Line Mutation; Glutamate-Ammonia Ligase - metabolism; Glypicans - metabolism; Hepatoblastoma - genetics; Hepatoblastoma - metabolism; Hepatoblastoma - pathology; Hepatoblastoma - surgery; Humans; Infant; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver Neoplasms - surgery; Liver Transplantation; Male; Neoplasms, Multiple Primary
• ISSN: 0147-5185; 1532-0979
• DOI: 10.1097/PAS.0b013e31828aeb18

Hepatoblastoma (HB), the most common hepatic neoplasm in children is associated with germline mutations in adenomatous polyposis coli tumor-suppressor gene that cause familial adenomatous polyposis syndrome. Individuals with familial adenomatous polyposis have a 750 to 7500× the risk of developing HB. We report 3 children with APC gene mutation, who underwent resection or liver transplant for HB. In addition to HB, all 3 patients had multiple independent adenoma-like nodules lacking qualities of intrahepatic metastases. Twenty-five nodules were subjected to immunohistochemical analysis using a panel of antibodies including glypican-3 (GPC3), β-catenin, cytokeratin AE1/AE3, CD34, Ki-67, glutamine synthetase (GS), and fatty acid binding protein. The nodules were round, ranged in size from 0.2 to 1.5 cm, and paler than the background liver. All lacked the chemotherapy effect. The nodules were circumscribed but nonencapsulated and composed of well-differentiated hepatocytes with occasional minor atypical features and absent or rare portal tracts. One lesion displayed a “nodule-within-nodule” pattern. The nodules demonstrated diffuse GS overexpression. Nine (36%) nodules were focally reactive for GPC3, and 1 (4%) displayed focal nuclear β-catenin expression. The associated HB showed diffuse expression of GS, GPC3, and β-catenin nuclear staining. We interpret these nodules as neoplastic with most being adenomas (GPC3 negative) that show features of independent origin and represent early stages of carcinogenesis, implying potential to progress to HB or hepatocellular carcinoma. To our knowledge, this is the first report of multifocal neoplasms in patients with HB and APC gene mutation.