Multidimensional Profiling of GLI1-Altered Mesenchymal Tumors in Soft Tissue

Objectives: To characterize the clinical and pathological features, molecular genetic alterations, diagnostic criteria, and differential diagnosis of three cases of mesenchymal tumors harboring GLI1 gene alterations. Methods: Retrospective analysis of 3 cases of GLI1 gene altered mesenchymal tumors, using routine hematoxylin and eosin (HE) staining and immunohistochemistry (IHC) , Fluorescence in situ hybridization (FISH) and Next-generation sequencing (NGS) methods to explore the molecular changes, and review of relevant literature. Results: We herein report three cases of GLI1-altered mesenchymal tumors: two arising in deep soft tissues and one located within the myometrium. Histologically, the tumor cells exhibited nested, reticular, nodular, cribriform, microcystic, or pseudoglandular architectural patterns, with a prominent network of branching thin-walled capillaries in the stroma. The tumor cells displayed relatively uniform morphology, predominantly comprising round to oval cells with a minor spindle cell component. The immunophenotype was nonspecific; most cases demonstrated diffuse or focal expression of CD56, S-100, Cyclin-D1, and CD10. CD34, ERG, SMA, desmin, AE1/AE3, Syn, and CgA were typically negative. Cases with GLI1 amplification frequently exhibited positivity for MDM2, CDK4, and STAT6. All three tumors demonstrated GLI1 gene alterations by FISH, with Case 3 additionally showing gene amplification by NGS. During follow-up (17–35 months), no recurrence or metastasis was observed. Conclusions: These tumors predominantly affect young to middle-aged adults,with a median onset age of 38–40 years (range: 1–79 years), with no significant sex predilection. Approximately one-third of cases arise in the head and neck region, most frequently involving the tongue (accounting for approximately 70% of head and neck cases). The remaining cases are distributed across the deep soft tissues of the extremities, gastrointestinal tract, kidneys, female reproductive tract (ovaries, uterus, and cervix), thoracic cavity, and retroperitoneum; primary bone involvement is exceedingly rare. Definitive diagnosis requires confirmation of molecular genetic alterations.