What question did this study set out to answer?

This review aims to summarize molecular alterations in non-epithelial ovarian cancers to refine diagnosis and treatment.

March 12, 2026Open Access

42P Low-risk gestational trophoblastic neoplasia with primary resistance to methotrexate should be treated with multi-agent chemotherapy rather than single agent actinomycin D

Puntos clave

This review aims to summarize molecular alterations in non-epithelial ovarian cancers to refine diagnosis and treatment.
Conducted an umbrella review of systematic and narrative reviews from multiple databases.
Analyzed data on mutation prevalence and immunohistochemical profiles across NEOC subtypes.
Registered the study in PROSPERO to ensure methodological transparency.
Identified subtype-specific molecular markers, such as FOXL2 mutations in adult granulosa cell tumors.
Noted that tumor recurrences are more frequent with specific mutations like TERT and GATA4.
Found diagnostic markers for yolk sac tumors and SCCOHT, including AFP and SMARCA4 mutations.

Resumen

Background: Non-epithelial ovarian cancers (NEOCs) account for 8-10% of ovarian neoplasms and include malignant ovarian germ cell tumors (MOGCTs), sex cordstromal tumors (SCSTs), and small cell carcinomas, primarily hypercalcemic type (SCCOHT).Their rarity and histologic diversity lead to diagnostic challenges and limited therapeutic options.We aimed to synthesize available evidence on molecular alterations in NEOCs to refine diagnostic criteria, improve prognostic stratification, and identify actionable targets for precision therapy. Methods:We performed an umbrella review of systematic and high-quality narrative reviews indexed in MEDLINE, Scopus, Web of Science, and ProQuest up to February 1st, 2025.We extracted and analyzed data regarding mutation prevalence, immunohistochemical (IHC) profiles and clinical correlations across NEOC subtypes, reported percentages reflect prevalence in the overall population of the included sources.The study is registered in PROSPERO (ID:1077663).Results: Analysis of 83 reviews identified subtype-specific molecular markers.In adult granulosa cell tumors (AGCTs), the FOXL2 c.402C>G mutation (98%) is central to diagnosis, while overexpression of VEGF (95%), WT1(62%), EGFR (74%), and GNAS (30%) have been identified as relevant markers detected by IHC.Tumor recurrences are more frequent with TERT promoter mutations (39%) and overexpression of GATA4 (40%) and SMAD3 (28%).Juvenile GCTs are characterized by inhibin overexpression (47%) and mutations in AKT1 (71%) and DICER1 (25%).In Sertoli-Leydig cell tumors, DICER1 mutations (57%) are associated with adverse prognosis.Dysgerminomas typically harbor KIT mutations (39%), which confer worse prognosis, and show overexpression of c-KIT (79%), SALL4 (55%), OCT3/4 (70%), NANOG (34%), and PLAP (47%).Yolk sac tumors consistently express of AFP (69%), SALL4 (94%), and GPC3 (79%) as diagnostic markers.SCCOHT is genetically defined by SMARCA4 mutations (84%), and combined loss of SMARCA4 and SMARCA2 expression on IHC is associated with poorer prognosis (93%).Conclusions: NEOCs harbor distinct molecular alterations enabling precision therapies.Basket-trial frameworks are needed to exploit these vulnerabilities.

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