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Primary Cutaneous SWI/SNF-Deficient Carcinomas: Morphologic, Immunohistochemical, and Molecular Analysis of Seven
Shira Ronen1, Julien Masliah-Planchon2, Kristof Cokelaere3
1Department of Pathology, Cleveland Clinic, Cleveland, OH.
Abstract:
Mutations in genes encoding proteins of the SWI/SNF complex are highly recurrent in select tumor entities. Among primary cutaneous tumors, only 4 SMARCA4- deficient undifferentiated neoplasms and 3 primary cutaneous SMARCB 1 -deficient carcinomas have been documented. In this report, we describe the morphologic, immunohistochemical, genomic, and methylation profile features of 5 additional SMARCA4 -deficient undifferentiated neoplasms and 2 SMARCB1 -deficient carcinomas of the skin. The patients (6M;1F) had a median age of 82 years (range: 60 to 94). Morphologically, all lesions showed poorly differentiated, dermal-based neoplasms, 5 of which were associated with subcutaneous involvement. The tumor cells were organized into nests, strands, and solid sheets. These cells displayed moderate to abundant cytoplasm, large, round vesicular nuclei, and prominent nucleoli. Immunohistochemical analysis revealed expression of cytokeratin AE1/AE3 in all cases, along with loss of SMARCA4 expression in 5 cases. Loss of SMARCB1 expression was identified in 2 cases and was mutually exclusive with SMARCA4 alterations. DNA sequencing revealed a high tumor mutation burden and a prominent UV signature in 4 of the 5 analyzed cases. Methylation analysis, in which tumors were compared with a control group of 68 SNF/SWI-deficient neoplasms and 18 cutaneous squamous cell carcinomas, revealed that primary cutaneous SMARCA4 -deficient and SMARCB1- deficient neoplasms, along with SMARCA4 -deficient carcinomas of other organs, constitute a unique group of neoplasms, distinct from other analyzed tumor entities. These results support the theory that these primary cutaneous SWI/SNF-deficient tumors represent a distinctive group of morphologically undifferentiated cutaneous carcinoma.
Insights
This study characterizes rare skin cancers with SWI/SNF complex gene mutations (SMARCA4, SMARCB1). These undifferentiated cutaneous carcinomas represent a distinct tumor group with unique genomic and methylation profiles.
Area of Science:
- Oncology
- Genetics
- Dermatopathology
Background:
- Mutations in SWI/SNF complex genes are common in certain cancers.
- Primary cutaneous SWI/SNF-deficient neoplasms are exceptionally rare, with few cases documented.
- Understanding these rare tumors is crucial for diagnosis and treatment.
Purpose of the Study:
- To describe the clinicopathologic, immunohistochemical, genomic, and methylation features of additional primary cutaneous SMARCA4- and SMARCB1-deficient neoplasms.
- To determine if these cutaneous tumors represent a distinct entity within the spectrum of SWI/SNF-deficient malignancies.
Main Methods:
- Morphological and immunohistochemical analysis of tumor samples.
- DNA sequencing to assess tumor mutation burden and mutational signatures.
- Methylation profiling to compare with other SWI/SNF-deficient neoplasms and cutaneous squamous cell carcinomas.
Main Results:
- Five SMARCA4-deficient and two SMARCB1-deficient cutaneous neoplasms were characterized.
- Tumors exhibited poor differentiation, dermal-based growth, and specific cytologic features.
- Genomic analysis revealed high tumor mutation burden and UV signatures in some cases.
- Methylation profiling indicated these tumors form a unique group distinct from other entities.
Conclusions:
- Primary cutaneous SMARCA4- and SMARCB1-deficient undifferentiated carcinomas are a distinct group of neoplasms.
- These findings support their classification as a unique category of morphologically undifferentiated cutaneous carcinoma.
- Further research is warranted to elucidate their pathogenesis and clinical behavior.
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