FOXL2 Mutation Analysis of Ovarian Sex Cord-Stromal Tumors: Genotype-Phenotype Correlation With Diagnostic Considerations

Int J Gynecol Pathol. 2018 Jul;37(4):305-315. doi: 10.1097/PGP.0000000000000426.


Correlation of FOXL2 mutation status with morphologic features and reticulin staining patterns was performed in a comprehensive single-institutional cohort of ovarian sex cord-stromal tumors. Fifty-one cases were included, 35 of which were morphologically diagnosed as adult granulosa cell tumor, 4 as Sertoli-Leydig cell tumor, 11 as fibroma/fibrothecoma and 1 as a thecoma. Of the adult granulosa cell tumors, 31 (88.6%) harbored FOXL2 mutation. Abundant pale cytoplasm was seen in 51.6% (16/31) of FOXL2 mutated tumors, compared with 6.7% (1/15) among FOXL2 wild type tumors (P=0.003). Nearly half of FOXL2 negative tumors showed individual pericellular reticulin staining pattern, while none of the FOXL2 positive cases demonstrated this feature (P=0.0001). Nested reticulin pattern was observed in 67.7% of FOXL2 positive tumors, compared with 20% of FOXL2 negative cases (P=0.004). Indeterminate reticulin staining pattern was seen in nearly one third of cases in both groups. Nested reticulin pattern was 87.5% specific and 67.7% sensitive for FOXL2 mutation, while individual reticulin pattern was 100% specific for absence of FOXL2 mutation. No statistical significance was observed between the 2 groups in tumor size, mitotic activity, nuclear atypia, and nuclear grooves. Follow-up was available for 44 patients ranging from 0.3 to 259 months (mean: 67.5 mo). Two patients developed recurrence, both of them harbored FOXL2 mutation. In conclusion, the pathology diagnosis of sex cord-stromal tumors continues to be difficult, and reticulin staining remains a valuable tool as an initial step in the diagnostic work-up. Individual pericellular reticulin pattern essentially rules out adult granulosa cell tumor, while cases with indeterminate or nested patterns can be subjected to FOXL2 mutation testing to aid the diagnosis.

MeSH terms

  • Adult
  • Cohort Studies
  • Female
  • Fibroma / diagnosis
  • Fibroma / genetics
  • Fibroma / pathology
  • Follow-Up Studies
  • Forkhead Box Protein L2 / genetics*
  • Genetic Association Studies
  • Granulosa Cell Tumor / diagnosis
  • Granulosa Cell Tumor / genetics
  • Granulosa Cell Tumor / pathology
  • Humans
  • Mutation
  • Neoplasm Recurrence, Local
  • Ovarian Neoplasms / diagnosis*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology
  • Retrospective Studies
  • Sertoli-Leydig Cell Tumor / diagnosis
  • Sertoli-Leydig Cell Tumor / genetics
  • Sertoli-Leydig Cell Tumor / pathology
  • Sex Cord-Gonadal Stromal Tumors / diagnosis*
  • Sex Cord-Gonadal Stromal Tumors / genetics
  • Sex Cord-Gonadal Stromal Tumors / pathology
  • Thecoma / diagnosis
  • Thecoma / genetics
  • Thecoma / pathology


  • FOXL2 protein, human
  • Forkhead Box Protein L2