FOXL2 molecular status in adult granulosa cell tumors of the ovary: A study of primary and metastatic cases

Abstract

Abstract. Granulosa cell tumors (GCTs) of the ovary are uncommon neoplasms, accounting for ~5% of all malignant ovarian tumors. GCTs are a relatively homogeneous group of tumors, categorized into two distinct subtypes, juvenile GCT and adult GCT (AGCT), likely arising from a limited set of molecular events usually involving the disruption of pathways that regulate granulosa cell proliferation. In the present study, the presence of forkheadbox L2 (FOXL2) c.402C>G mutation was investigated in a series of 42 samples of primary and metastatic AGCT of the ovary. The samples consisted of 37 primary and 5 metastatic ovarian AGCTs from 37 patients. FOXL2 mutational status was evaluated using a pyrosequencing approach on 2.5-µm sections of formalin-fixed paraffin-embedded tissue. FOXL2 c.402C>G mutation was found in 33/37 (89.2%) primary AGCTs and in 4/5 (80.0%) metastases, with the molecular status of the metastases recapitulating that of the primary tumors (4 mutated cases and 1 wild-type case). Overall, FOXL2 mutation is present in the majority of primary and metastatic AGCTs, and could be used as a valid tool in the diagnosis of the disease and in cases of metastatic lesions from an unknown primary origin. Moreover the concordance of FOXL2 molecular status in primary and associated metastases suggests its early appearance and genomic stability in AGCT tumorigenesis.

Aggressive adult granulosa cell tumor of the ovary without a FOXL2 mutation: A case report

“…D'Angelo et al reported that the group with more frequent expression of wild‐type FOXL2 has different sex‐cord components (thecoma, luteinized thecoma, Sertoli‐Leydig and sex‐cord tumor with annular tubules) compared with the group with mutated FOXL2 , but no difference was found in the prognosis between the two groups. Zannoni et al reported FOXL2 mutations in 89.2% (33/37) of primary AGCT and that four wild‐type tumors presented with a high Ki‐67 index. A high mitotic index in AGCT is generally associated with worse prognosis, and previously reported aggressive AGCT also had a high mitotic index, as high as 25/10 HPFs…”

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

“…Regarding prognosis, two studies found no difference in tumour stage between AGCTs with FOXL2 mutation and those without FOXL2 mutation . Tumour recurrence has been reported in a small number of AGCTs without FOXL2 mutation . Two studies reported that the rate of recurrence/metastasis was not different between AGCTs with FOXL2 mutation and those without FOXL2 mutation, nor was there a difference in overall survival between AGCTs with FOXL2 mutation and those without FOXL2 mutation in two studies .…”

“…First, the collective body of literature on AGCT outcome and management has been based on cases defined by morphology (in some cases supported by immunophenotype). Second, as discussed earlier, it is expected that a small percentage of classic‐appearing AGCTs will not harbour FOXL2 mutation, but may still recur or metastasise . Third, FOXL2 mutation status is not associated with tumour stage, recurrence or overall survival in morphologically classic AGCT .…”

“…The clinicopathological features of AGCTs lacking FOXL2 mutation are not fully enough described to determine whether these tumours are prognostically different from AGCTs with FOXL2 mutation. Four studies of 47 AGCTs without FOXL2 mutation reported no unique morphological findings as compared with AGCTs with FOXL2 mutation but did not provide details about which features were evaluated . In contrast, two studies reporting six AGCTs without FOXL2 mutation described a more dominant fibrothecoma‐like or thecoma‐like growth pattern .…”

“…6 Subsequent validation studies using various molecular techniques confirmed that a majority of AGCTs carry the C134W FOXL2 mutation. Eleven studies reported that the incidence is 89-97%, 1,[6][7][8][9][10][11][12][13][14][15] whereas four studies reported that the incidence is 61-80%. [16][17][18][19] The variable incidence remains to be explained, but could be due to differences in molecular test techniques, to observer variation in morphological classification of tumours as AGCT, and to differences in study design.…”