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ERBB2/ERBB3-mutated S100/SOX10-positive uterine sarcoma: something new
Wangpan J Shi1, Oluwole Fadare2
1Department of Pathology, University of California San Diego Health, 9300 Campus Point Drive, Suite 1-200, La Jolla, MC 7723, San Diego, CA, 92037, USA.
Abstract:
A distinctive subset of uterine mesenchymal tumors display recurrent genetic fusions involving receptor tyrosine kinases, including NTRK, PDGFB, FGFR1, and RET, presumably leading to aberrant pathway activation. A pair of recent studies have highlighted the existence of a genetic fusion-negative uterine sarcoma that is characterized by activating mutations in ERBB2/ERBB3, CDKN2A deletion, inactivating ATRX mutation, and a S100 + /SOX10 + immunohistochemical profile. This report describes another case of this emerging entity that was diagnosed in a 57-year-old woman. The 8-cm tumor was centered in the uterine cervix and was comprised mostly of spindle cells configured in fascicles. The tumor was diffusely immunoreactive for SOX10 and S100, with more localized staining for CD68, CD56, MITF, and PRAME. HMB-45, ER, PR, HER2, Melan-A/MART1, STAT6, pan-TRK, ALK, CD34, desmin, CD10, myogenin, and pancytokeratins were all negative, and there was retained expression of H3K27me3. The following molecular alterations were found: ERBB2 p.Val777Leu, ATRX p.F2113Sfs*, CDKN2A deep deletion, NF1 p.W2317*, SMARCA4 p691Sfs*. The authors review the sparse literature on molecular-genetic aberrations involving the epidermal growth factor receptor family of receptor tyrosine kinases (ERBB1/EGFR, ERBB2, ERBB3, and ERBB4) in uterine mesenchymal tumors, a review that suggests that such tumors may be pathologically heterogeneous. The potential clinical significance of demonstrating a targetable ERBB2/ERBB3 tyrosine kinase mutation or other EGFR family aberrations, as well as its distinctive pathologic profile, supports the segregation of the tumor reported herein as a distinct and emerging entity.
Insights
This study identifies a rare uterine sarcoma with specific genetic mutations, including ERBB2/ERBB3, and a distinct S100+/SOX10+ profile. This finding helps classify this emerging tumor entity for better patient care.
Area of Science:
- Oncology
- Pathology
- Molecular Biology
Background:
- Uterine mesenchymal tumors often involve receptor tyrosine kinase fusions.
- A distinct genetic fusion-negative uterine sarcoma subtype has been recently identified.
- This subtype is characterized by ERBB2/ERBB3 mutations, CDKN2A deletion, ATRX mutation, and S100+/SOX10+ immunohistochemistry.
Purpose of the Study:
- To describe another case of this emerging uterine sarcoma entity.
- To review the literature on epidermal growth factor receptor family aberrations in uterine mesenchymal tumors.
- To support the classification of this tumor as a distinct entity based on its molecular and pathological profile.
Main Methods:
- Case report of a 57-year-old woman with an 8-cm cervical tumor.
- Immunohistochemical analysis including SOX10, S100, CD68, CD56, MITF, PRAME, HMB-45, ER, PR, HER2, Melan-A/MART1, STAT6, pan-TRK, ALK, CD34, desmin, CD10, myogenin, pancytokeratins, and H3K27me3.
- Molecular analysis for genetic alterations including ERBB2, ATRX, CDKN2A, NF1, and SMARCA4.
Main Results:
- The tumor exhibited spindle cell morphology and was immunoreactive for SOX10, S100, CD68, CD56, MITF, and PRAME.
- Key molecular findings included ERBB2 p.Val777Leu, ATRX p.F2113Sfs*, CDKN2A deep deletion, NF1 p.W2317*, and SMARCA4 p691Sfs*.
- Retained H3K27me3 expression and negative results for various other markers confirmed the distinct profile.
Conclusions:
- The described case represents another instance of an emerging uterine sarcoma entity with a unique molecular and pathological profile.
- Aberrations in the epidermal growth factor receptor family, particularly ERBB2/ERBB3 mutations, are significant in this tumor type.
- The distinct profile and potential for targeted therapy support its classification as a separate entity.
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