TFE3 activation in a TSC1‐altered malignant PEComa: challenging the dichotomy of the underlying pathogenic mechanisms

Abstract

Perivascular epithelioid cell tumors (PEComas) form a family of rare mesenchymal neoplasms that typically display myomelanocytic differentiation. Upregulation of mTOR signaling due the inactivation of TSC1/2 (Tuberous Sclerosis 1 and 2) is believed to be a key oncogenic driver in this disease. Recently, a subgroup of PEComas harboring TFE3 (Transcription Factor E3) rearrangements and presenting with a distinctive morphology has been identified. TSC1/2 and TFE3 aberrations are deemed to be mutually exclusive in PEComa, with two different pathogenic mechanisms assumed to lead to tumorigenesis. Here, we challenge this dichotomy by presenting a case of a clinically aggressive TCS1-mutated PEComa displaying a TFE3-altered phenotype. FISH analysis was suggestive of a TFE3 inversion; however, RNA and whole genome sequencing was ultimately unable to identify a fusion involving the gene. However, a copy number increase of the chromosomal region encompassing TFE3 was detected and transcriptome analysis confirmed upregulation of TFE3, which was also seen at the protein level. Therefore, we believe that the TSC1/2-mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa. Our comprehensive genetic analyses add to the understanding of the complex pathogenic mechanisms underlying PEComa and harbor insights for clinical treatment options.

Natural History and Treatment Strategies of Advanced PEComas: A Systematic Review

“…In the literature, different partners of TFE3 have been described and keep on being described. The presence of the TFE3 fusion protein probably substitutes MiTF in these PEComas, explaining the absence of MiTF expression and the lower expression of Melan A. TFE3 rearrangements and TSC1/2 alterations were, for a long time, considered to be mutually exclusive [10], but recently a case of TCS1-mutated PEComa displaying a TFE3-altered phenotype was reported, challenging this conclusion [112]. Hence, developing molecular biology analysis in PEComas is mandatory both to decipher the tumor pathogenesis and to select for the most relevant therapy.…”

A rare metastatic mesenteric malignant PEComa with TSC2 mutation treated with palliative surgical resection and nab-sirolimus: a case report

“…Two major molecular subgroups have recently been identified for PEComas: those with TSC1 or TSC2 alterations and those with TFE3 fusions [ 3 , 4 , 18 ]. Interestingly, Schmeister et al recently reported a case of aggressive PEComa with simultaneous TSC1 mutation and TFE3 inversion, which suggests that these two pathways may not be mutually exclusive [ 19 ]. Loss of heterozygosity in the TSC2 locus, such as deletion of 16p or TSC2 mutations, resulting in loss of function of the tuberin protein are commonly found in PEComas [ 18 ].…”

A rare case of primary cutaneous malignant perivascular epithelioid cell tumor and review of the literature

“…Loss of function in tuberous sclerosis complex 1 ( TSC1 ) or 2 ( TSC2 ) in extracutaneous PEComas may occur as germline or sporadic mutations and subsequently cause an upregulation of the mTOR signaling pathway; however, this association is not typically seen in cutaneous PEComas, 1 although it has been described 15 . Transcription factor E3 ( TFE3 ) gene rearrangements have also been identified in a group of extracutaneous PEComas 16 ; however, in two separate reviews of primary cutaneous PEComas, TFE3 immunohistochemistry was uniformly negative 1,10 . Additionally, the presence of positive TFE3 immunostaining does not always represent a TFE3 genetic event 15 .…”