Hepatocellular Neoplasms Arising in Association With Androgen Use

Correlation between androgen use and hepatocellular neoplasia is well established. However, there are no detailed studies of the histopathology and immunohistochemical/molecular profile of these tumors. We studied 9 patients with androgen-associated hepatocellular neoplasms. In addition to histology, immunostains for liver fatty acid-binding protein, β-catenin, glutamine synthetase, C-reactive protein, and serum amyloid A were utilized for tumor subtyping. Molecular testing using Solid Tumor Targeted Cancer Panel was performed on 3 cases. The neoplasms were predominantly seen in male individuals (7/9). Two patients (22%) had multifocal lesions. All lesions had architectural and 4/9 had cytologic atypia. Cholestasis was present in 6/9 cases. Reticulin was focally disrupted in 5/9 cases. Given the clinical setting, all lesions were classified as well-differentiated hepatocellular neoplasms of uncertain malignant potential. In cases with follow-up (6/9 cases, 67%), there were no recurrences or metastases. On the basis of the immunoprofile, 7 (78%) cases were β-catenin activated (including 1 hepatic adenoma with concurrent hepatocyte nuclear factor 1α inactivation) and 2 (22%) had inflammatory phenotype. Somatic mutations in CTNNB1 were detected in all 3 tested cases (all β-catenin activated by immunostain), all involving exon-3. Our data indicate that androgen-associated hepatocellular neoplasms most often develop in male individuals and always show some degree of atypia and/or focal reticulin disruption. Most are β-catenin activated, often harboring CTNNB1 exon-3 mutations, and a minority is inflammatory type. Although β-catenin and inflammatory pathways likely play a role in pathogenesis, the heterogenous molecular profile suggests there are other (yet to be characterized) primary oncogenic mechanisms in this unique tumor type.