FOXL2 Mutation Status in Sex Cord-stromal Tumors Cannot be Predicted by Morphology

Abstract

Granulosa-cell tumors (GCTs) are the most common type of malignant ovarian sex cord-stromal tumor (SCST). The histopathologic diagnosis of these tumors can be challenging. A recurrent somatic mutation of the forkhead box L2 (FOXL2) gene has been identified in adult GCT. In this retrospective single-center study of 44 SCST, a morphologic review together with analysis of FOXL2 C134W was evaluated in relation to tumor morphology. In addition, TERT promoter mutation testing was performed. Twelve of 36 cases got an altered diagnosis based on morphology alone. The overarching architectural growth pattern in 32/44 (72.7%) tumors was diffuse/solid with several tumors showing markedly heterogeneous architecture. In correlation to FOXL2 C134W mutation status, cytoplasmic color, and nuclear shape, differed between the FOXL2 C134W positive and FOXL2 C134 W negative groups, but these differences were not significant when comparing them separately. Nineteen of 44 cases underwent TERT promoter sequencing with a positive result in 3 cases; 2 adult GCTs and 1 cellular fibroma. Three patients developed a recurrence of which 2 were FOXL2 C134W positive adult GCTs and the third was an unclassified SCST. In conclusion, the morphologic and immunohistochemical diagnosis of different SCSTs is challenging and one cannot reliably identify FOXL2 mutation-positive tumors solely by morphologic features. Therefore, broad use of molecular analysis of the FOXL2 C134W mutation is suggested for SCSTs, and further studies are needed to evaluate the clinical outcome of these tumors as well as the diagnostic and prognostic implications of TERT promoter mutations.