Perivascular Epithelioid Cell Tumors (PEComas) Harboring TFE3 Gene Rearrangements Lack the TSC2 Alterations Characteristic of Conventional PEComas: Further Evidence for a Biological Distinction

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To the Editor:Perivascular epithelioid cell neoplasms (PEComas) are a group of lesions composed of distinctive perivascular epithelioid cells that typically demonstrate both melanocytic and muscular differentiation. This family includes the common renal angiomyolipoma, pulmonary clear cell sugar tumor, lymphangioleiomyomatosis, and less common neoplasms of the soft tissue, gynecologic, and gastrointestinal tracts.7–10,14,16,19 The cells comprising these lesions may be variably epithelioid or spindled in shape and have variable cytoplasm ranging from clear to eosinophilic. By immunohistochemistry (IHC), PEComas typically express the melanocytic markers HMB45 and melan-A and the protease cathepsin K18 and also typically label for smooth muscle actin and may express desmin. Some members of the PEComa family (specifically angiomyolipoma and lymphangioleiomyomatosis) are seen with high frequency in the genetic syndrome tuberous sclerosis complex (TSC),16 and a high frequency of syndromic and sporadic PEComas have demonstrated inactivation of the TSC1 or TSC2 genes12,20,21 with subsequent activation of the mammalian target of rapamycin (mTOR) pathway.15 Specifically, mutation in and loss of heterozygosity (LOH) of TSC2 with loss of expression of tuberin, the protein encoded by TSC2, is consistently found in conventional PEComas.TFE3 is a member of the MiT family of transcription factors, which includes MiTF, TFEB, TFEC, and TFE3.11TFE3 gene fusions are known to occur in several types of neoplasia. Alveolar soft part sarcoma, a rare epithelioid cell soft tissue sarcoma of uncertain histogenesis, characteristically demonstrates a der (17) t(X;17)(p11;q25) resulting in an ASPL-TFE3 gene fusion.17 In addition, a group of recently described renal cell carcinomas (RCCs) that often occur in children bears various TFE3 gene fusions; these are designated the Xp11 translocation RCC.1,2,5,6 Moreover, a distinctive subgroup of renal cancers in young patients with overlapping features of melanoma, RCC, and PEComas have also been proven to harbor TFE3 gene fusions.3 Finally, we have recently identified a subgroup of lesions currently characterized as PEComas that, in contrast to conventional PEComas, harbor TFE3 gene fusions.4 Although the number of cases identified is small, distinctive features of these TFE3-rearranged PEComas include a tendency to young age, absence of an association with tuberous sclerosis, predominant alveolar architecture and epithelioid cytology, minimal immunoreactivity for muscle markers, and strong (3+) TFE3 immunoreactivity. In contrast, conventional PEComas frequently have a spindle cell component, typically label for muscle markers, lack strong TFE3 immunoreactivity, and in young patients are frequently associated with tuberous sclerosis.As conventional PEComas frequently demonstrate TSC2 LOH and loss of expression of the tuberin protein that this gene encodes,13 we evaluated TFE3-rearranged PEComas for TSC2 LOH and for tuberin expression by IHC. The study cohort consisted of 4 PEComas (previously shown to harbor TFE3 gene fusions)4 and 4 conventional PEComas, which lacked TFE3 alterations. To assess LOH or allelic loss we analyzed 3 microsatellite markers STR3, KG8, and STR7 in the region of the TSC2 gene on paraffin-extracted DNA from tumor and normal tissue as described elsewhere.21 IHC was performed by standard techniques using Target Retrieval Solution pH 6.1 (Dako), incubation with antituberin antibody (1:200 dilution, Cell Signaling, #4308), and development with horseradish peroxidase-conjugated secondary antibody and DAB (Dako Envision System). Slides were counterstained with hematoxylin.By IHC, all 4 of the conventional non-TFE3 PEComas demonstrated loss of tuberin protein labeling by IHC, with the surrounding normal tissue serving as an internal control (Fig. 1, top row).

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