Clinicopathologic and Molecular Insights Into ERBB2-Altered S100/SOX10-Positive Uterine Sarcoma: A Report of 6 Cases

A novel entity of ERBB2/ERBB3-mutated S100/SOX10-positive uterine sarcoma has recently been proposed. However, the detailed clinicopathologic spectrum and molecular features of this emerging entity remain to be further elucidated. Here, we describe 6 cases of ERBB2-altered uterine sarcoma. The patients' age ranged from 41 to 65 years (median, 48 years). Most tumors (5/6, 83.3%) were centered in the cervical stroma. An infiltrative, interdigitating border was a consistent finding, with neoplastic cells intimately admixed with entrapped preexisting smooth muscle fascicles. The tumor exhibits alternating hypercellular and hypocellular areas. Most cases (5/6, 83.3%) showed a predominantly spindled architecture arranged in a fascicular, herringbone, or storiform pattern. The tumor cells typically showed mild-to-moderate cytologic atypia, scant cytoplasm, and a brisk mitotic count (median, 28.5/10 high-power fields). Intriguingly, the remaining case (1/6, 16.7%) harbored a concurrent TP53 nonsense mutation and exhibited a predominantly epithelioid architecture with marked cytologic atypia. Notably, another distinctive finding was the presence of neoplastic multinucleated giant cells exhibiting a characteristic floret-like nuclear arrangement in all cases. The background stroma exhibited focal myxoid change, hyalinization, and variable inflammatory infiltrates. All cases exhibited strong and diffuse positivity for S100 and SOX10. Next-generation sequencing revealed a highly recurrent molecular signature characterized by universal oncogenic ERBB2 missense mutations (including the canonical V777L variant and other activating mutations) and CDKN2A copy number loss, frequently accompanied by inactivating ATRX mutations (66.7%), CDKN2B (66.7%), MTAP (50.0%) copy number loss, ERBB3 mutations (50.0%), and concurrent ERBB2 amplification (33.3%). Of the 6 patients, 1 patient (harboring a TP53 nonsense mutation) had bone metastasis at diagnosis and was lost to follow-up, 2 progressed at 3.5 and 5 months (1 death at 10 months), and 3 remained alive with no evidence of disease at 10 to 12 months. Our results support this emerging entity as a distinct, aggressive gynecologic mesenchymal neoplasm harboring actionable ERBB2 alterations.