CTNNB1-Driven Tumors of the Testis and Ovary: A Unifying Concept

Several gonadal neoplasms harbor recurrent CTNNB1 mutations, including sex cord-stromal tumors, such as Sertoli cell tumors (not otherwise specified), gonadal signet ring stromal tumors, and ovarian and testicular microcystic stromal tumors (MCSTs), in addition to gonadal solid pseudopapillary neoplasms (SPNs). Despite being classified as separate entities, they have notable morphologic and immunophenotypic similarities. Of note, gonadal SPNs have been regarded as the counterparts of pancreatic SPNs, but their relationship remains poorly understood. We analyzed 32 gonadal CTNNB1-driven tumors, including testicular Sertoli cell tumors, NOS (n = 8), MCSTs (n = 2), and signet ring stromal tumors (n = 6), and ovarian MCSTs (n = 11), a signet ring stromal tumor (n = 1), and SPNs (n = 4), together with 9 pancreatic SPNs. Histologic features were reviewed, and immunohistochemistry for SF-1, SOX9, WT1, β-catenin, inhibin, and calretinin was performed. CTNNB1 mutation status was assessed by next-generation sequencing in selected cases. DNA methylation profiling was performed successfully in 25 (61%) tumors. All gonadal tumors showed overlapping morphologic features, comprising variable combinations of tubular, solid, signet ring, and microcystic patterns, although the abundance of individual patterns varied between entities. Pancreatic SPNs showed similar cytologic features to gonadal tumors and commonly exhibited solid and pseudopapillary architecture with frequent cystic structures but lacked true tubular differentiation. Immunohistochemically, SF-1 expression was present in 27 of 31 (87%) tested gonadal tumors, whereas all pancreatic SPNs were negative (4 of 4). Diffuse nuclear β-catenin expression was identified in all evaluable gonadal and pancreatic tumors (35 of 35; 100%). SOX9 and WT1 were expressed in 19 of 21 (90%) and 24 of 25 (96%) gonadal tumors, respectively. In contrast, pancreatic SPNs were negative for SF-1 and WT1 in all evaluable cases (4 of 4 each), with only a single case showing focal SOX9 positivity. Inhibin and calretinin expression was largely absent in gonadal tumors, with only rare focal or weak positivity (3 cases) and a single ovarian MCST showing diffuse calretinin expression. Methylation analysis demonstrated closely related epigenetic profiles among gonadal CTNNB1-driven tumors, regardless of their histologic classification, whereas pancreatic SPNs formed a separate cluster. These findings indicate that several CTNNB1-driven tumors of the gonads currently classified as different entities share morphologic, immunophenotypic, and epigenetic features, supporting the concept that they represent variations within the same spectrum. Despite some morphologic overlap, these gonadal tumors are different from pancreatic SPN based on DNA methylation signatures.