FGFR1 Mutations Are Rare Alternate Oncogenic Drivers in FOXL2 -Wildtype Adult Granulosa Cell Tumors of the Ovary.

Adult granulosa cell tumors (aGCTs) of the ovary are uniquely characterized by an almost ubiquitous somatic mutation in the FOXL2 gene (p.C134W). We report the first series of 7 aGCTs harboring pathogenic FGFR1 kinase domain mutations, providing a novel alternative oncogenic mechanism in these rare FOXL2 -wildtype tumors. Archival sex cord-stromal tumors that underwent targeted DNA sequencing (MSK-IMPACT, Oncopanel, and Foundation Medicine assays) were reviewed. Histopathologic and immunophenotypic features were reviewed by expert pathologists. Seven cases were identified with FGFR1 hotspot mutations (codons N546, N577, K656, and K687), 6 of which lacked the pathognomonic FOXL2 p.C134W variant. All tumors demonstrated the classic histology of aGCT (microfollicular growth, Call-Exner bodies, "coffee bean" nuclei) with 5/5 showing robust inhibin-α positivity by immunohistochemistry. No distinct morphologic or immunophenotypic differences were found compared with conventional FOXL2 -mutant aGCTs. Clinically, most patients presented at early stage (IA) and underwent surgical management. Four patients experienced recurrent disease involving peritoneal or omental sites, but overall clinical behavior was comparable to typical aGCTs. These findings establish FGFR1 alterations as an alternative oncogenic driver in a subset of FOXL2 -wildtype aGCTs. From a diagnostic standpoint, the absence of FOXL2 p.C134W mutation does not exclude the diagnosis of aGCT when the morphology and immunoprofile are characteristic.