A novel RBMX‐TFE3 gene fusion in a highly aggressive pediatric renal perivascular epithelioid cell tumor

Abstract

We report an Xp11 translocation perivascular epithelioid cell tumor (PEComa) with a novel RBMX-TFE3 gene fusion, resulting from a paracentric X chromosome inversion, inv(X)(p11;q26). The neoplasm occurred in an otherwise healthy 12-year-old boy who presented with a large left renal mass with extension into the inferior vena cava.The patient was found to have multiple pulmonary metastases at diagnosis and died of disease 3 months later. The morphology (epithelioid clear cells with alveolar and nested architecture) and immunophenotype (TFE3 and HMB45 strongly positive; actin, desmin, and PAX8 negative) was typical of an Xp11 translocation PEComa; however, TFE3 rearrangement was initially not detected by routine TFE3 break-apart fluorescence in situ hybridization (FISH). Further RNA sequencing revealed a novel RBMX-TFE3 gene fusion, which was subsequently confirmed by fusion assay FISH, using custom design RBMX and TFE3 come-together probes. This report describes a novel TFE3 gene fusion partner, RBMX, in a pediatric renal PEComa patient associated with a fulminant clinical course. As documented in other intrachromosomal Xp11.2 inversions, such as fusions with NONO, RBM10, or GRIPAP1 genes, the TFE3 break-apart might be below the FISH resolution, resulting in a false negative result. K E Y W O R D S renal neoplasm, TFE3, translocation

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

“…The other examined cells did not meet the break-apart cutoff values, but several cells displayed one co-localization signal and one small separation of the 5 0 TFE3 and 3 0 TFE3 probes ( Figure 2B). Similar subtle break-apart patterns have been described in tumors harboring TFE3 inversions rather than translocations [12,13,14].…”

Malignant melanotic Xp11 neoplasms exhibit a clinicopathologic spectrum and gene expression profiling akin to alveolar soft part sarcoma: a proposal for reclassification

“…This patient died of disease 7 months after surgery [52]. Argani et al [15] also reported a highly aggressive Xp11 mesenchymal neoplasm bearing a novel RBMX partner. These clinical malignant reports combined with the outcome analysis in our study cohort clearly demonstrate that survival for patients with melanotic Xp11 neoplasm is significantly worse than that for patients with Xp11 translocation RCC, which is similar to clear cell RCC.…”

“…Since then, fewer than 40 similar cases have been reported in the literature, chiefly in the form of case reports or small series [2][3][4][5][6][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. Indeed, it has been identified that these neoplasms share similar clinicopathologic characteristics (younger patients and female predominance), morphology (alveolar architecture and purely epithelioid clear cell morphology), immunoprofile (PAX8 negative, cathepsin K positive, HMB45/Melan-A positive) and oncogenic activation of TFE3 gene fusions (SFPQ is the most common fusion partner; lack of TSC1 or TSC2 gene alterations [27]), suggesting that they belong to a single clinicopathologic spectrum and notably differ from conventional PEComa [5,15]. On the basis of these findings, we and others have proposed the term 'melanotic Xp11 neoplasm' or 'Xp11 neoplasm with melanocytic differentiation' to designate this unique entity, rather than the originally proposed term 'Xp11 translocation PEComa' [4][5][6].…”

“…Before the existence of ‘Xp11 translocation PEComa’, two similar cases occurring in the kidney were initially described in 2009 under the designation ‘melanotic Xp11 translocation renal cancer’ [8]. Since then, fewer than 40 similar cases have been reported in the literature, chiefly in the form of case reports or small series [2–6,9–26]. Indeed, it has been identified that these neoplasms share similar clinicopathologic characteristics (younger patients and female predominance), morphology (alveolar architecture and purely epithelioid clear cell morphology), immunoprofile (PAX8 negative, cathepsin K positive, HMB45/Melan‐A positive) and oncogenic activation of TFE3 gene fusions ( SFPQ is the most common fusion partner; lack of TSC1 or TSC2 gene alterations [27]), suggesting that they belong to a single clinicopathologic spectrum and notably differ from conventional PEComa [5,15].…”

Perivascular epithelioid cell tumors (PEComa) of the gynecologic tract

“…Similarly, in a recent series of 31 malignant PEComas subjected to DNA and RNA profiling, 5 (16%) tumors harbored a TFE3 fusion, but were wildtype for TSC1 , TSC2 , and FLCN 79 . Other fusion partners that have been detected include NONO , 79,85‐87 RBMX , 88 PRCC , 79,89 RBM10 , 79 and ZC3H4 , 79 but overall SFPQ/PSF appears to be the most recurring gene associated with TFE3 ‐rearranged PEComas 90 …”