This report describes a malignant superficial soft tissue neoplasm arising in the thigh of a 45-year-old woman. The lesion was classified as a perivascular epithelioid cell tumor (PEComa) based on morphologic and ancillary study findings and was notable for harboring a previously unreported in-frame EEF1A1::MITF gene fusion.
The case was presented as a malignant cutaneous/soft tissue neoplasm with features that differ from classic PEComa, prompting integrated histopathologic, immunophenotypic, and molecular analyses to clarify lineage and potential oncogenic drivers.
Microscopically the tumor was composed of epithelioid to plump spindle cells arranged in sheets, nests, and short fascicles. Prominent capillary vasculature was observed throughout the lesion. There was marked cytologic atypia, brisk mitotic activity, and areas of tumor necrosis, supporting a malignant histologic grade.
This architectural and cytologic pattern—epithelioid/spindle morphology with rich capillary network and high mitotic rate—was a key reason the authors classified the lesion as a high-grade PEComa-like neoplasm and pursued molecular characterization.
Immunostaining showed diffuse, strong nuclear expression of MITF and diffuse expression of GPNMB. Smooth muscle actin (SMA) staining was patchy; desmin was present in scattered cells; cathepsin K showed multifocal positivity. Markers more typically associated with melanocytic differentiation and other lineages were negative, including S100, SOX10, HMB45, Melan A, PRAME, and tyrosinase. Pancytokeratin, CD34, and TFE3 were also negative.
This immunophenotype is atypical for classic PEComa (which often shows coexpression of melanocytic markers and smooth muscle markers) but resembles the profile described in other recently reported MITF-overexpressing PEComas, where nuclear MITF and GPNMB are prominent and conventional melanocytic markers may be absent.
Comprehensive molecular studies identified several genomic alterations in this tumor. The defining event was an in-frame EEF1A1::MITF fusion, representing a novel partner fusion with MITF in the context of PEComa. In addition to the fusion, the tumor harbored an ATRX frameshift mutation and a homozygous deletion of CDKN2A/CDKN2B. Copy-number profiling revealed multiple complex copy-number alterations.
Importantly, no canonical alterations in TSC1, TSC2, or FLCN were detected in this case. These genes are recurrently altered in many PEComas and in related lesions such as angiomyolipoma; their absence here suggests a distinct molecular subset.
The combination of diffuse nuclear MITF expression and the presence of an MITF fusion supports classification of this lesion within the expanding category of MITF-rearranged or MITF-overexpressing PEComas. Although the immunophenotype did not match classic PEComa in every respect, it parallels descriptions of previously reported PEComas driven by MITF-related alterations.
The additional alterations—ATRX frameshift and homozygous CDKN2A/CDKN2B loss—are markers often associated with aggressive behavior across tumor types and align with the malignant histologic features observed (high mitotic index, necrosis, cytologic atypia). The complex copy-number alterations further reflect genomic instability in this malignant tumor.
This case broadens the recognized molecular heterogeneity of PEComa by adding EEF1A1::MITF to the list of MITF fusion partners. It provides additional evidence that a subset of cutaneous or superficial PEComas may be driven by MITF rearrangements rather than canonical TSC1/TSC2/FLCN alterations.
From a diagnostic standpoint, the case highlights that diffuse nuclear MITF and GPNMB expression with absence of conventional melanocytic markers can indicate an MITF-rearranged PEComa and should prompt molecular testing for fusions. The presence of ATRX mutation and CDKN2A/CDKN2B deletion may have prognostic relevance, though direct correlations with outcome were not reported in this single case.
Therapeutic and prognostic implications specific to the EEF1A1::MITF fusion were not described in the source. As a single-case report, the findings are hypothesis-generating and underscore the need for larger series and functional studies to clarify oncogenic mechanisms, potential targeted vulnerabilities, and clinical behavior of MITF-rearranged PEComas.
A malignant superficial PEComa of the thigh in a 45-year-old woman was found to harbor a novel EEF1A1::MITF fusion along with an ATRX frameshift mutation, homozygous CDKN2A/CDKN2B deletion, and complex copy-number alterations, and lacked TSC1/TSC2/FLCN alterations. The tumor’s immunophenotype—diffuse nuclear MITF and GPNMB with absent conventional melanocytic markers—parallels other MITF-overexpressing PEComas and supports the concept of a distinct molecular subset of PEComa driven by MITF rearrangements. The report expands the molecular taxonomy of PEComa but does not provide outcome or therapeutic-response data for this specific fusion.