Alvand, Saba

Abstract Introduction/Objective Ovarian endometrioid carcinomas can display varied morphologic and immunophenotypic features, complicating diagnosis and grading. We analyzed adnexal tumors with absent or limited PAX8 expression to distinguish endometrioid carcinoma from histologic mimics such as sex cord-stromal and carcinoid tumors. Methods/Case Report We retrospectively reviewed ovarian tumors with epithelioid morphology and absent or limited PAX8 expression. Detailed histologic evaluation and immunophenotyping were performed. Features including sex cord-like morphology, background endometriosis, associated borderline components, and squamous morular or mucinous differentiation were assessed. PAX8, CK7 and β-catenin, sex cord and neuroendocrine markers were evaluated. Results Sixteen cases were identified (age 33–76, median 69). Sex cord-like morphology was present in all. Endometriosis or adenofibroma (n = 5), squamous/mucinous differentiation (n = 5), and hyalinized/corded patterns (n = 5) were observed. Most cases (13/16) lacked PAX8 expression; 14 showed aberrant nuclear β-catenin. Sex cord markers were negative. CK7 was negative or focal in 7 cases; 3 showed neuroendocrine marker expression. Conclusion Some ovarian endometrioid carcinomas lack PAX8 and mimic sex cord or neuroendocrine tumors, imposing diagnostic challenges. Aberrant β-catenin and characteristic morphology aid diagnosis. Ancillary testing, including immunohistochemistry and CTNNB1 mutation analysis, is essential to avoid misclassification and guide appropriate management.

Abstract Introduction/Objective Mutations in KIT and PDGFRA drive the majority of gastrointestinal stromal tumors (GIST) and inform targeted therapy selection. While single-driver mutations are typical, a subset of cases harbors multiple KIT mutations, complicating clinical interpretation. This study investigated the frequency, distribution, and inferred hierarchy of primary and secondary KIT mutations using DNA-based sequencing in a large GIST cohort. Methods/Case Report We retrospectively reviewed 579 GIST cases that underwent DNA-based next-generation sequencing using a custom panel targeting all coding exons of KIT and PDGFRA. Tumor-rich formalin-fixed paraffin-embedded (FFPE) tissue was required. In double-mutant cases, the mutation with higher variant allele frequency (VAF) was presumed to be primary. Results Mutations in KIT or PDGFRA were detected in 482/579 cases (83.2%). Among KIT-mutant cases, 28 had two mutations and one had three. Secondary mutations frequently occurred in exons 13, 14, and 17 and were significantly more common in non-gastric tumors (p < 0.0001). Primary mutations most often involved exon 11. Conclusion VAF analysis enabled classification of mutation hierarchy in cases with multiple KIT mutations. The distinct anatomical and exon-specific distribution of primary vs. secondary mutations highlights their potential therapeutic implications and warrants further study.