FOXL2 Mutation Status in Granulosa Theca Cell Tumors of the Ovary

Abstract

Ovarian sex-cord stromal tumors that have between 10% and 50% granulosa cells in a prominent fibrothecomatous background have been referred to as granulosa theca cell tumors or mixed granulosa theca cell tumors. The classification and prognosis of these tumors is not clear. Most adult granulosa cell tumors of the ovary harbor a mutation in the FOXL2 gene, whereas fibromas and thecomas lack this mutation. The aim of our study was to assess the FOXL2 mutation status of ovarian granulosa theca cell tumors and to correlate the mutation status with morphologic and clinical characteristics. A FOXL2 mutation was detected in 6 of 12 (50%) granulosa theca cell tumors. Tumors with higher cellularity of granulosa cells were more likely to harbor a FOXL2 mutation as were tumors in which the granulosa cells formed large lobules. No conclusions could be drawn regarding the clinical and prognostic significance of the presence of a mutation given the small number of cases and limited clinical follow-up. Our study shows that half of granulosa theca cell tumors harbor the same FOXL2 mutation that characterizes adult granulosa cell tumors but there is no outcome evidence to guide whether mutation status should alter the classification of the tumor or the management of the patient.

Practical roles for molecular diagnostic testing in ovarian adult granulosa cell tumour, Sertoli–Leydig cell tumour, microcystic stromal tumour and their mimics

“…The category in between these two ends of the spectrum, fibromatous tumours containing 10–50% granulosa cell proliferation, is uncommon and not well studied. Some have referred to such tumours as granulosa theca cell tumours, although the long‐term outcome of such tumours has not been described . In theory, FOXL2 mutation status could be used to classify such tumours as ovarian fibroma with minor sex cord elements in the absence of mutation versus AGCT in the presence of a mutation.…”

“…One study of granulosa theca cell tumours reported that FOXL2 mutation was present in nine of 12 tumours composed of 30–50% granulosa cells but not in three cases for which the granulosa cell population constituted 10–30% of the overall tumour. The tumours with a mutation were more likely to show larger nested, lobular growth of the granulosa cell proliferation . Although none of the cases recurred, follow‐up was not available for several patients and was of limited duration in the rest.…”

“…6,11,14 Among ovarian sex cord-stromal tumours, no FOXL2 C134W mutations have been identified in cellular fibromas, 20 sclerosing stromal tumours, 6,9,11 MCSTs, 21,22 steroid cell tumours, 1,6,9 Sertoli cell tumours, 9 sex cord tumours with annular tubules (SCTATs), 6,9,11 or gynandroblastomas. 18 The C134W FOXL2 mutation has been identified in 1.6% (1/62) of conventional fibromas, 1,6,8,9,11,18 20% (7/35) of thecomas, 1,6,11 3% (2/59) of juvenile granulosa cell tumours (JGCTs), 1,6,[9][10][11][12]16,17 13% (12/90) of SLCTs, 1,6,8,9,11,18,23 50% (6/12) of granulosa theca cell tumours, 24 and 8% (2/24) of gynandroblastomas. 18,25,26 These observations raise a nosological dilemma regarding the gold standard for tumour classification: morphology, immunophenotype, molecular phenotype, or some combination thereof.…”

“…Some have referred to such tumours as granulosa theca cell tumours, although the long-term outcome of such tumours has not been described. 24 In theory, FOXL2 mutation status could be used to classify such tumours as ovarian fibroma with minor sex cord elements in the absence of mutation versus AGCT in the presence of a mutation. One study of granulosa theca cell tumours reported that FOXL2 mutation was present in nine of 12 tumours composed of 30-50% granulosa cells but not in three cases for which the granulosa cell population constituted 10-30% of the overall tumour.…”

“…The tumours with a mutation were more likely to show larger nested, lobular growth of the granulosa cell proliferation. 24 Although none of the cases recurred, followup was not available for several patients and was of limited duration in the rest. Therefore, although FOXL2 mutation status is a reproducible variable with which to segregate fibromatous tumours with variable amounts (10-50%) of sex cord elements, the clinical significance of obtaining FOXL2 mutation status remains to be studied.…”