Title : The expanding spectrum of GREB1 Fusions in UTROSCT: A clinicopathological and molecular analysis of four cases, Including a novel GREB1-SS18 variant
Abstract:
Background: Uterine Tumors Resembling Ovarian Sex Cord Tumors (UTROSCT) are rare mesenchymal neoplasms with diagnostic challenges due to morphological heterogeneity and variable immunohistochemistry (IHC). Gene fusions involving GREB1 and nuclear receptor coactivators (NCOA1/2/3) are increasingly recognized, but the full spectrum and clinical implications, especially of rarer GREB1 partners, remain to be elucidated.
Methods: We retrospectively reviewed four UTROSCT cases from our archives. All cases underwent detailed histopathological and IHC evaluation. RNA-based next-generation sequencing (NGS) using a sarcoma fusion panel (86 genes) was performed to identify driver fusions. Clinical data, imaging, and follow-up were collated.
Results: The patients’ ages were 46, 37, 70, and 56 years. All presented with abnormal uterine bleeding or uterine masses. Histology consistently showed sex cord-like patterns.
- Case 1 (46 y/o): Atypical IHC (negative for most sex cord markers except CD99). NGS revealed a GREB1(E7)-SS18(E6) fusion.
- Case 2 (37 y/o): IHC positive for multiple sex cord markers (Calretinin, WT-1, CD99, FOXL2, focal α-Inhibin). NGS identified a GREB1(E3)-NCOA2(E15) fusion.
- Case 3 (70 y/o): IHC positive for WT-1, CD56, focal Calretinin & CD99. NGS detected a GREB1(E6)-NCOA1(E15) fusion.
- Case 4 (56 y/o): (Detailed IHC pending full review). NGS identified a GREB1(E3)-NCOA2(E15) fusion, identical to Case 2.
- The GREB1-SS18 fusion is an exceptionally rare finding. The recurrence of the specific GREB1(E3)-NCOA2(E15) fusion in two unrelated patients is also noteworthy.
Conclusion: This series expands the understanding of GREB1-rearranged UTROSCT, highlighting SS18 as a rare but significant fusion partner. The findings underscore the critical role of molecular diagnostics, particularly RNA sequencing, in confirming UTROSCT diagnosis, especially with atypical IHC, and in uncovering the diverse landscape of GREB1 fusions. The potential link between GREB1 rearrangements and aggressive behavior warrants further investigation through larger cohorts and longer follow-up.
Keywords: Uterine Tumor Resembling Ovarian Sex Cord Tumor; GREB1; SS18; Gene Fusion; Molecular Pathology; Uterine Sarcoma.
