DICER1 Mutations Are Consistently Present in Moderately and Poorly Differentiated Sertoli-Leydig Cell Tumors

Abstract

Ovarian Sertoli-Leydig cell tumors (SLCTs) are uncommon sex cord-stromal tumors associated with both germ-line and somatic DICER1 mutations, the frequency of which has varied widely in different studies (0% to 62.5%). The current World Health Organization Classification includes 3 histologic types of SLCTs (well-differentiated, moderately differentiated, and poorly differentiated); heterologous elements and/or retiform patterns may be present in moderately and poorly differentiated neoplasms. We investigated the frequency of DICER1 mutations in a series of 38 ovarian tumors initially diagnosed as SLCTs, and explored whether identified mutations were associated with specific morphologic features. Specialist pathology review performed blinded to molecular results confirmed 34 tumors to be SLCTs (22 moderately differentiated, 8 poorly differentiated; 4 well-differentiated), while the remaining 4 neoplasms were considered not to represent SLCTs. Of the 34 cases diagnosed as SLCTs, 30 (88%) harbored ≥1 DICER1 mutation. All 30 moderately differentiated/poorly differentiated SLCTs contained mutations, but we did not find deleterious DICER1 mutations in the 4 well-differentiated SLCTs. Our study reports the highest DICER1 mutation frequency to date in SLCTs, with 100% of moderately differentiated and poorly differentiated tumors being DICER1-mutated. This suggests that DICER1 mutation may be a defining feature of these neoplasms. Although the number of cases is limited, well-differentiated SLCTs appear to be DICER1-independent. Moderately differentiated and poorly differentiated SLCT components often coexist with each other and form part of a spectrum, while well-differentiated SLCTs usually occur in pure form, suggesting that fundamentally, these represent 2 separate and independent tumor types with a different pathogenesis. We suggest that all patients with ovarian SLCTs undergo germ-line DICER1 mutation testing.

DICER1 hot‐spot mutations in ovarian gynandroblastoma

“…This is interesting, given that areas resembling jGCT may be present in moderately and poorly differentiated SLCTs (personal observations, W.G.M.). de Kock et al . identified DICER1 mutations in all 30 moderately and poorly differentiated SLCTs, two of which had areas resembling jGCT.…”

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

“…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.…”

“…Loss of DICER1 in humans and in mouse models is associated with progression of tumour development and adverse outcomes . Germline mutation of DICER1 causes the rare eponymous autosomal dominant syndrome associated with pleuropulmonary blastoma, cystic nephroma, nodular hyperplasia of the thyroid (multinodular goitre, occasionally with differentiated thyroid carcinoma), or, rarely, pineoblastoma, pituitary blastoma, nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma, and anaplastic sarcoma of the kidney . Two gynaecological tumours are also associated with DICER1 syndrome: ovarian SLCT and embryonal rhabdomyosarcoma of the cervix .…”

Paediatric ovarian tumours and their associated cancer susceptibility syndromes

“…In non-hereditary cases of DICER1-related tumours, patients have two somatic mutations in DICER1 with no germline mutation. SLCTs are by far the most common gynaecological manifestation of the DICER1 syndrome and a recent study showed that 100% of moderately and poorly differentiated SLCTs contain either germline or somatic DICER1 mutations 22. Conversely, this same study suggested that well-differentiated SLCTs are not associated with germline or somatic DICER1 mutations 22.…”

“…SLCTs are by far the most common gynaecological manifestation of the DICER1 syndrome and a recent study showed that 100% of moderately and poorly differentiated SLCTs contain either germline or somatic DICER1 mutations 22. Conversely, this same study suggested that well-differentiated SLCTs are not associated with germline or somatic DICER1 mutations 22. However, the number of well-differentiated SLCTs was small and currently we recommend that all patients with SLCT should be referred to a genetics service for consideration of DICER1 testing.…”