Ovarian Sertoli-Leydig cell tumors with heterologous rhabdomyosarcoma: Clinicopathologic features and molecular analysis highlighting recurrent genetic alterations.
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AIMS: Ovarian Sertoli-Leydig cell tumor (SLCT) with heterologous rhabdomyosarcoma (RMS) is exceptionally rare. While the presence of heterologous elements in SLCT is highly predictive of an underlying DICER1 mutation, the molecular alterations in these tumors, including in SLCTs with heterologous RMS, remain largely unknown. In this study, we aimed to characterize the clinicopathologic features of these rare tumors, and in a subset of cases, we analyzed in detail their molecular changes to investigate potential recurrent and component-specific genetic alterations. METHODS AND RESULTS: We report clinicopathologic features of 11 ovarian SLCTs with heterologous RMS (positivity for desmin and myogenin); 10 were in keeping with embryonal and 1 with pleomorphic RMS. The patients showed a bimodal age distribution: seven patients (64%) were aged 33 years or younger (mean 20) and four patients (36%) were aged 52 years or older (mean 60). All tumors were unilateral. In addition to the RMS components, 8 of 11 cases (73%) contained other heterologous elements, including gastrointestinal-type mucinous epithelium (5 cases) and immature cartilage (3 cases). Seven of 11 cases (64%) underwent next-generation sequencing analysis. All tumors tested molecularly (7/7, 100%) harbored hotspot DICER1 mutations. Of these, six cases (86%) also carried a second nonsense or frameshift loss-of-function DICER1 mutation. One case had only a p.D1810Y hotspot mutation and consisted of high-grade sarcoma with focal rhabdomyoblastic differentiation (focal expression of desmin and myogenin) in keeping with pleomorphic RMS; the pleomorphic sarcoma component also exhibited mutation-type p53 expression. In addition to DICER1 mutations, TERT c.-124C>T promoter (4 cases) or TP53 mutations (3 cases) were present in all cases and were mutually exclusive. Component-specific analysis in two cases revealed shared common DICER1 hotspot mutations in both the SLCT and RMS components, supporting a clonal origin. In 1 case, a TERT promoter c.-124C>T somatic mutation was present only in the RMS component. In the other case, the TERT promoter mutation was found in both components, while a BRAF p.V600E mutation was exclusive to the RMS component. CONCLUSION: Our study demonstrates that the majority (86%) of SLCTs with heterologous RMS harbor double DICER1 mutations (a hotspot mutation and a nonsense or frameshift loss-of-function mutation), supporting the existing knowledge on DICER1 mutations associated with RMS heterologous elements, the presence of which should trigger genetic counselling. Our findings also suggest that molecular alterations other than DICER1, namely, TERT promoter and TP53 mutations, may contribute to component-specific oncogenic transformation.