Sertoli cell tumor is a type of testicular sex cord-stromal tumor (TSCST) typically driven by gain-of-function CTNNB1 variants. Recently, molecular studies have identified TSCSTs (including Sertoli cell tumors) with loss-of-function APC variants, raising the possibility that germline APC alterations may predispose to TSCSTs. In this study, we evaluated 4 TSCSTs from 4 individual patients, including 3 APC-mutant neoplasms identified in prior studies (1 in a patient with familial adenomatous polyposis [FAP] and 2 in patients with unknown syndromic status) and 1 tumor of unknown mutational status diagnosed in a patient with known FAP. Three neoplasms were typical Sertoli cell tumors, and 1 was a malignant unclassified TSCT. All neoplasms exhibited diffuse nuclear beta-catenin expression. Non-neoplastic tissue could be obtained for DNA sequencing in the 3 Sertoli cell tumors. Comparative assessment of non-neoplastic and lesional tissue in these cases suggested that germline APC variants with subsequent inactivation of the gene (loss of heterozygosity) were the likely oncogenic driver of these Sertoli cell tumors. In the malignant unclassified TSCSTs, APC inactivation was also interpreted as the most likely driver event, and the germline origin of the variant was inferred using a recently published method. The results of this study suggest that pathogenic germline APC alterations (eg, FAP and variants thereof) may predispose to TSCSTs.
The American journal of surgical pathology. 2023 Oct 09 [Epub ahead of print]
Stephanie Siegmund, Costantino Ricci, Chia-Sui Kao, Ankur R Sangoi, Sambit Mohanty, Christopher D M Fletcher, Maurizio Colecchia, Andres M Acosta
Department of Pathology of Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Department of Medical and Surgical Sciences (DIMEC), Maggiore Hospital-AUSL Bologna, University of Bologna, Bologna., Department of Pathology, Stanford University, Stanford, CA., Department of Pathology, CORE Diagnostics and Advanced Medical Research Institute, Gurgaon, Haryana, India., Department of Pathology, Vita-Salute San Raffaele University, Milan, Lombardy, Italy.