ERBB2/ ERBB3-mutated S100/ SOX10-positive unclassified high-grade uterine sarcoma: first detailed description of a novel entity

Abstract

With the increasing use of innovative next generation sequencing (NGS) platforms in routine diagnostic and research settings, the genetic landscape of uterine sarcomas has been dynamically evolving during the last two decades. Notably, the majority of recently recognized genotypes in uterine sarcomas represent gene fusions, while recurrent oncogene mutations of diagnostic and/ or therapeutic value have been rare. Recently, a distinctive aggressive uterine sarcoma expressing S100 and SOX10, but otherwise lacking diagnostic morphological, immunophenotypic and molecular features of other uterine malignancies has been presented in a scientific abstract form (USCAP, 2023), but detailed description and delineation of the entity is still missing. We herein describe two high-grade unclassified uterine sarcomas characterized by spindle to round cell morphology and diffuse expression of S100 and SOX10, originating in the uterine body and cervix of 53- and 45-year-old women and carrying an ERBB3 (p.Glu928Gly) and an ERBB2 (p.Val777Leu) mutation, respectively. Both tumors harbored in addition genomic HER2 amplification, ATRX mutation and CDKN2A deletion. Methylation studies revealed a methylome most similar to MPNST-like tumors, but distinct from melanoma, MPNST, clear cell sarcoma, and endometrial stromal sarcoma. Case 1 died of progressive peritoneal metastases after multiple trials of chemotherapy 47 months after diagnosis. Case 2 is a recent case who presented with a cervical mass, which was biopsied. This study defines a novel heretofore unrecognized aggressive uterine sarcoma with unique phenotypic and genotypic features. Given the potential value of targeting HER2, recognizing this tumor type is mandatory for appropriate therapeutic strategies and for better future delineation of the entity.

Keywords: EGFR; Molecular profiling; nerve sheath tumor; Targeted therapy; Tyrosine kinase fusions; Undifferentiated uterine sarcoma.

Fig. 1

Representative examples of the histological findings in Case 1. A: peritoneal metastasis showing solid neoplasm infiltrating the fat tissue. B: less cellular spindle cell areas with slightly myxoid appearing stromal background. C: diffuse sheets of ovoid to fusiform cells lacking any specific features of ESS. D: higher magnification shows small round to ovoid cells with scanty cytoplasm and brisk mitotic activity

Fig. 2

Representative examples of the immunohistochemical findings in Case 1. A: diffuse strong nuclear expression of SOX10. B: diffuse nucleocytoplasmic reactivity with S100. C: moderate diffuse nuclear expression of Cyclin D1. D: strong circular membranous expression of HER2

Fig. 3

Representative examples of the histological and immunohistochemical findings in Case 2. A: diffuse solid sheets and fascicles of monotonous spindle cells imparting a “fibrosarcoma-like” pattern. B: higher magnification of A. C: diffuse nucleocytoplasmic reactivity with S100. D: strong nuclear expression of SOX10

Fig. 4

Unsupervised hierarchical clustering of methylation profiles comparing the 2 cases of ERBB2/3-mutated sarcomas to melanoma, MPNST, MPNST-like tumors, clear cell sarcoma, low-grade and high-grade endometrial stromal sarcomas