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

Authors

Kvetoslava Michalova, Andres M Acosta, Petr Martinek, Marian Grendar, Esther Oliva, Kyle Devins, Anais Malpica, J Kenneth Schoolmeester, Amy A Swanson, Deyin Xing, Jersy Lasota, Ankur Sangoi, Pavel Dundr, Jiri Soukup, Thomas M Ulbright, Michal Michal

Published in

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. Pages 101052. Aug 04, 2026. Epub Aug 04, 2026.

Abstract

Several gonadal neoplasms harbor recurrent CTNNB1 mutations, including sex cord-stromal tumors, such as Sertoli cell tumor, NOS and gonadal signet ring stromal tumor, ovarian and testicular microcystic stromal tumor (MCST), in addition to gonadal solid pseudopapillary neoplasms (SPN). 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 SPN, but their relationship remains poorly understood. We analyzed 28 gonadal sex cord-stromal tumors, including testicular Sertoli cell tumors NOS (n=8), MCSTs (n=2), and signet ring stromal tumor (n=6), ovarian MCSTs (n=11), signet ring stromal tumor (n=1), together with ovarian SPNs (n=4) and pancreatic SPNs (n=9). Histologic features were reviewed, and immunohistochemistry for SF-1, SOX9, WT1, β-catenin, inhibin, and calretinin was performed. CTNNB1 mutation status was assessed by NGS in selected cases. DNA methylation profiling was performed successfully in 25 tumors (61%). 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 27/31 (87%) tested gonadal tumors whereas all pancreatic SPNs were negative (4/4). Diffuse nuclear β-catenin expression was identified in all evaluable gonadal and pancreatic tumors (35/35, 100%). SOX9 and WT1 were expressed in 19/21 (90%) and 24/25 (96%) of gonadal tumors, respectively. In contrast, pancreatic SPNs were negative for SF-1 and WT1 in all evaluable cases (4/4 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.

PMID:
42551832
Bibliographic data and abstract were imported from PubMed on 05 Aug 2026.

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