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.

Background Our study examines impact of HPV status and patient-specific characteristics on recurrence-free survival (RFS) and overall survival (OS) for SCC and ECA. Methods This multi-continental retrospective study analyzed clinicopathologic data of 634 patients with microscopically confirmed cervical cancer (CC; only SCC and ECA) across Asia, Europe, and North America. HPV status was determined using PCR or HPV in situ hybridization (ISH) for both HR-HPV (SCC and ECA) and LR-HPV (SCC), using same platform. Descriptive analysis and Cox regression models were produced. Results Out of total 634 patients, 533 (84.1%) were HPVA and 101 (15.9%) were HPVI. 65% had SCC morphology (88.1%: HPVA; 11.9%: HPVI) and 35% had ECA differentiation (76.6%: HPVA; 23.4%: HPVI). Compared to ECA, patients with SCC were older (median age: 51 vs. 45 years old; p < 0.001), had higher HPVA status (88.1% vs. 76.6%; p < 0.001), and a higher rate of lymph-vascular invasion (LVI; 64.8% vs. 56.8%; p = 0.004). However, patients with ECA had a higher rate of metastases to pelvic organs (13.5% vs. 2.4%; p < 0.001). In univariable analysis, HPV status, tumor type, higher FIGO stage, older age, LVI positive, lymph node metastasis (LNM), and adjuvant treatment were all associated with impaired RFS and OS (all p ≤ 0.007). In multivariable analysis, LVI, HPV status, institution, and tumor type remained significant for RFS, while age at diagnosis, FIGO stage, LVI, and tumor type remained significant for OS. Conclusion Tumor type and HPV status play significant role in determining survival outcomes in CC.