Abstract Background: Ovarian sex cord-stromal tumors (SCSTs) represent about 7% of ovarian tumors. Since the exact diagnosis of these rare malignancies is difficult to establish and could modify the appropriate therapeutic strategy, the GINECO group (Group of National Investigators for Ovarian Cancer Studies) developed the National Rare Ovarian tumor Observatory in 2002 which proposes a systematic pathological second opinion for all cases of rare ovarian tumor diagnosed in France. We investigated whether a systematic second opinion in one of the expert centers (Lyon, France), using evaluation of FOXL2 mutation and FOXL2 level of expression for all samples of suspected SCSTs cases, could improve diagnosis and classification of sex cord-stromal tumors. Methods: Immunostaining for FOXL2 and new molecular markers is being developed in this pathology. The aim of this study was to evaluate the benefit of a systematic second opinion and the use of a new algorithm that rationalizes the use of these new tools, to allow more accurate diagnosis and classification of SCSTs. Data were collected in a recent database dedicated to rare ovarian cancer “Observatory for rare malignant tumors of the ovary”. Seventy-two patients from the database were included. All tumor samples were referred to referent center for morphological and IHC review. Search for FOXL2C134W mutation and immunostaining of FOXL2 were performed. Results: FOXL2 mutation was present in 44 out of 47 adult granulosa cell tumors (A-GCTs) (94%), in 2 out of 8 thecomas (25%) and in 1 out of 10 sertoli leydig tumors (10%). These results confirm FOXL2 mutation as a specific marker for A-GCTs. Immuno-expression of FOXL2 was present in 44 out of 45 SCSTs (97.8%). After a second opinion, using morphological and classical immunohistochemistry markers only, 15% of the initial diagnoses were modified. With the use of our algorithm, initial diagnosis was changed in 22%. Conclusion: New tools like the search of a FOXL2 mutation are fundamental to obtain an optimal diagnosis and classification of these tumors. The use of an algorithm could be generalized to homogenize practice and rationalize the use of these markers. We hope this algorithm can also adjust and standardize the therapeutic strategy. Citation Format: Thibaut Goulvent, Denis Maillet, Ruth Rimokh, Philippe Cassier, Marie-Cecile Vacher-Lavenu, Pierre Meeus, Patricia Pautier, Pierre Duvillard, Jerome Alexandre, Eric Pujade-Laurraine, Mojgan Devouassoux-Shisheboran, Isabelle Treilleux, Isabelle Ray-coquard. Impact of a second opinion for sex cord stromal tumors through expression and molecular analysis of FOXL2: a study of the GINECO group and TMRO network. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3480. doi:10.1158/1538-7445.AM2013-3480