Ovarian Sertoli-Leydig Cell Tumors with Heterologous Rhabdomyosarcoma: Clinicopathologic Features and Molecular Analysis Highlighting Recurrent Genetic Alterations

In 11 cases of this exceptionally rare ovarian tumor type, 100% harbored DICER1 mutations and 86% carried double mutations, pointing to DICER1 as the primary driver.

Journal: Histopathology | Published: 2025-12-15 | Type: Journal Article | PMID: 41395670 Authors: Zou Ying S, Mohammed Sanobar Yasmeen, Zhu Jing, Dashti Nooshin K, Smith Colton, Sun Ying, Vang Russell, McCluggage W Glenn, Xing Deyin (Johns Hopkins Medical Institutions; Dartmouth-Hitchcock Medical Center; Belfast Health and Social Care Trust) Funding/COI: Not disclosed

Summary

This retrospective case series from Johns Hopkins and collaborating institutions characterizes 11 ovarian Sertoli-Leydig cell tumors (SLCTs) containing heterologous rhabdomyosarcoma (RMS) — one of the rarest gonadal tumor combinations in the pathology literature. Molecular analysis of 7 of the 11 cases found DICER1 hotspot mutations in all of them, with 6 of 7 additionally carrying a second loss-of-function DICER1 mutation. Additional mutations in TERT promoter or TP53 were identified in all molecularly tested cases and were mutually exclusive with each other, suggesting distinct oncogenic trajectories within this tumor type.

Claims

• All 7 cases that underwent next-generation sequencing (100%) harbored hotspot DICER1 mutations
• 6 of 7 cases (86%) had double DICER1 mutations: a hotspot mutation plus a nonsense or frameshift loss-of-function mutation
• TERT promoter c.-124C>T mutations were found in 4 cases; TP53 mutations in 3 cases — mutually exclusive in this cohort
• 8 of 11 cases (73%) contained additional heterologous elements beyond RMS: gastrointestinal-type mucinous epithelium (5 cases) and immature cartilage (3 cases)
• Patients showed a bimodal age distribution: 7 patients (64%) aged ≤33 years (mean age 20), and 4 patients (36%) aged ≥52 years (mean age 60)
• All 11 tumors were unilateral
• Component-specific sequencing in 2 cases showed shared DICER1 hotspot mutations across both the SLCT and RMS components, supporting clonal origin
• In 1 of those 2 cases, BRAF p.V600E was exclusive to the RMS component, indicating divergent somatic evolution after a common clonal ancestor

Study Quality

This is a retrospective case series — by design, not a controlled study. With only 11 clinical cases and 7 undergoing molecular analysis, no statistical conclusions are possible. The component-specific findings that speak to clonal evolution come from just 2 cases. For a tumor this rare, an 11-case series is a meaningful contribution, but the molecular picture is necessarily preliminary. Immunohistochemistry (desmin and myogenin positivity) was used to confirm RMS differentiation, which is standard practice. NGS methodology is not described in detail in the available abstract, which is a gap in reproducibility. Multi-institutional collaboration (Johns Hopkins, Dartmouth, Belfast) adds some credibility to the pathological rigor.

Red Flags

• N=11 for the clinical cohort; N=7 for molecular analysis — far too small to draw generalizable conclusions
• Component-specific sequencing performed in only 2 cases; clonal evolution findings cannot be extrapolated
• Funding and conflicts of interest not disclosed — unusual for a molecular pathology study from a major academic center
• Sequencing methods not described in detail in the available abstract
• No survival, recurrence, or treatment outcome data reported
• Retrospective case ascertainment across an unspecified time span likely means some cases pre-date current NGS standards, introducing inconsistency in molecular data quality

Strengths

• Largest published cohort of SLCTs with heterologous RMS — prior reports are single cases
• Molecular analysis goes beyond prior purely morphological descriptions of this tumor type
• Multi-institutional authorship reduces single-center selection bias
• Component-specific sequencing, even in just 2 cases, provides preliminary mechanistic signal about clonal origin that has not previously been reported for this tumor combination
• Near-universal DICER1 association aligns with the established DICER1 tumor predisposition syndrome literature and carries direct clinical implications for genetic counseling

Verdict

For pathologists and gynecologic oncologists, this is a useful reference paper — the kind that gets cited whenever someone encounters one of these tumors in practice. The DICER1 finding (7/7 tested cases) is internally consistent and fits well within the broader DICER1 tumor biology literature. But with N=7 for genomics and N=2 for component-specific analysis, this establishes a pattern, not a proof. The paper's real value is in anchoring the clinical recommendation that heterologous elements in SLCTs — particularly RMS — should trigger DICER1 genetic counseling; that inference is well-supported even at this sample size. Read it as carefully documented groundwork, not as definitive molecular characterization.