DICER1 and FOXL2 Mutation Status Correlates With Clinicopathologic Features in Ovarian Sertoli-Leydig Cell Tumors

Abstract

Sertoli-Leydig cell tumors (SLCTs) are rare ovarian sex cord-stromal neoplasms. The only known recurrent genetic abnormality is DICER1 mutation, with rare mutations reported in FOXL2. We set out to establish a molecular classifier using DICER1 and FOXL2 somatic mutation status and clinicopathologic features in 42 SLCTs. Five tumors (12%) were well differentiated, 31 (74%) moderately differentiated, and 6 (14%) poorly differentiated. Eight (19%) had heterologous elements, and 2 (5%) showed retiform differentiation; all 10 were moderately differentiated. DICER1 RNase IIIb domain mutations were identified in 18/41 (44%; 17 moderately, 1 poorly differentiated), including all cases with retiform or heterologous elements. FOXL2 c.402C>G (p.C134W) mutation was identified in 8/42 (19%) tumors (5 moderately, 3 poorly differentiated). DICER1 and FOXL2 mutations were mutually exclusive. Median age for the cohort was 47 years (range, 15 to 90 y). Patients with DICER1 mutations were younger (median, 24.5 y; range, 15 to 62 y) than patients with FOXL2 mutation (median, 79.5 y; range, 51 to 90 y) (P<0.0001). Nine of 10 tumors with retiform or heterologous elements occurred in premenopausal patients (median, 26.5 y; range, 15 to 57 y). Patients with tumors that were wild type for DICER1 and FOXL2 (15/42, 37%) had an intermediate age (median, 51 y; range, 17 to 74 y). All tumors were FOXL2 positive by immunohistochemistry. Patients with FOXL2 mutation trended toward presenting more often with abnormal bleeding (P=0.13); DICER1-mutant patients trended toward having more androgenic symptoms (P=0.22). Our data suggest at least 3 molecular subtypes of SLCT with distinct clinicopathologic features: DICER1 mutant (younger, more androgenic symptoms, moderately/poorly differentiated, retiform or heterologous elements), FOXL2 mutant (postmenopausal, abnormal bleeding, moderately/poorly differentiated, no retiform or heterologous elements), and DICER1/FOXL2 wild type (intermediate age, no retiform or heterologous elements, including all well-differentiated tumors).

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

“…In one study, no FOXL2 mutations were detected in 34 SCLTs, whereas DICER1 mutation was identified in all of the moderately and poorly differentiated tumours . In contrast, another study of 42 SLCTs reported a 19% incidence of FOXL2 mutation, a finding that was exclusive to women who were postmenopausal (median age of 79.5 years), which contrasts with the typical clinical presentation of SLCT in the second and third decades of age . None of these eight women had androgenic clinical symptoms, which are commonly found in women with SLCT, but almost half presented with uterine bleeding, which is commonly found in women with AGCT.…”

“…Patient age was younger in women with SLCTs containing a somatic hotspot DICER1 mutation in four of five studies; this might be explained by the younger age of patients with a germline mutation. DICER1 mutation appears to be restricted to moderately or poorly differentiated tumours (Figure B); no mutations have been reported in well‐differentiated SLCTs, although only 12 cases of well‐differentiated SLCT have been evaluated to date . There are conflicting data on whether or not the presence of heterologous elements and/or retiform growth is associated with DICER1 mutation status .…”

“…The discovery of this association led to a landmark sequencing study in 2012 that identified somatic missense mutations in the RNase IIIB domain of DICER1 in a majority of ovarian SLCTs . Subsequent studies have confirmed that somatic or germline mutations of DICER1 constitute a common signature of ovarian SLCTs . The practical implications for pathologists include the diagnostic role for DICER1 mutation testing in tumours with a differential diagnosis that includes SLCT, and the screening role of molecular testing to triage patients with SLCT for genetic counselling and formal risk assessment for DICER1 syndrome.…”

“…An alternative strategy is to test all SLCT patients for somatic DICER1 hotspot mutations, and refer women with DICER1 ‐mutant tumours for formal genetic evaluation. Although the current literature suggests that well‐differentiated SLCTs are not associated with DICER1 syndrome, only a small number of women with well‐differentiated SLCTs have been studied . Thus, it may be prudent to also include them in referral for formal genetic evaluation until larger studies confirm the absence of an association with DICER1 syndrome.…”

“…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.…”