RBM10–TFE3 renal cell carcinoma characterised by paracentric inversion with consistent closely split signals in break‐apart fluorescence in‐situ hybridisation: study of 10 cases and a literature review

Abstract

Aims Xp11 rearrangement in renal cell carcinoma (RCC) typically involves gene fusion to the gene encoding transcription factor E3 (TFE3), a member of the microphthalmia‐associated transcription factor family on chromosome Xp11.2. Dual‐colour break‐apart fluorescence in‐situ hybridisation (FISH) is recommended to confirm histological diagnoses. Recently, RNA‐binding motif protein 10 (RBM10), encoded by a gene on chromosome Xp11.3, was identified as a chimeric partner of TFE3; thus, RBM10–TFE3 fusion results from paracentric inversion. RBM10–TFE3 RCC may yield a false‐negative result in FISH analysis of TFE3 expression. The aim of the present study was to investigate the clinicopathological features of RBM10–TFE3 RCC. Methods and results Ten patients with RBM10–TFE3 RCC aged 31–71 years were investigated. Histological analysis, immunostaining, dual‐colour break‐apart FISH for TFE3, reverse transcription polymerase chain reaction and sequencing analysis were performed. No patient had a history of exposure to chemotherapy. Two of these patients died of RCC, and three were alive but developed metastases. Microscopically, the tumours were composed of a mixed architecture of tubulocystic and papillary patterns with scattered psammoma bodies. The tumours showed strong nuclear immunoreactivity for TFE3. FISH showed consistent closely spaced split signals in the RCCs of four patients, and polysomic signals with occasional closely spaced split signals in the RCCs of six patients. Of the latter six patients, five had renal failure, and four developed tumours in kidneys subjected to haemodialysis. Conclusions The present study suggests that the carcinogenesis of RBM10–TFE3 RCC in some, but not all, patients may be associated with chronic kidney disease. The aggressive nature of RBM10–TFE3 RCC should be considered, as five patients experienced metastases.

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].…”

Clinicopathological Findings on 28 Cases with XP11.2 Renal Cell Carcinoma

“…However, FISH analysis has its own limitations as well, whereas poor fixation, inappropriate hybridization, and/or extensive contamination with normal stromal cells can lead to negative results. It must be stated that break-apart FISH test has low sensitivity for intrachromosomal or paracentric inversions like in RBM10-TFE3 and NonO-TFE3 RCCs [ 33 ]. In these cases, despite the typical microscopic appearance and the characteristic immunophenotype, FISH can provide equivocal or even negative results.…”

“…In these cases, despite the typical microscopic appearance and the characteristic immunophenotype, FISH can provide equivocal or even negative results. In this particular scenario, one must be really cautious about setting the diagnosis as Xp11.2 RCC, and fusion partner analysis (if available) by RT-PCR or RNA sequencing should be considered [ 33 ].…”

MiT Family Translocation Renal Cell Carcinoma: from the Early Descriptions to the Current Knowledge

“…It is important to keep in mind that the FISH assay is unable to detect subtle TFE3 gene inversions, such as those that result in the RBM10-TFE3 gene fusion [20]. In the experience of the authors, minimally split fluorescent signals in which fluorescent signals were separated by a signal diameter or less were observed in few cases [21]. Recently, it has been argued whether TFE3 gene rearrangement is the key event in tumorigenesis [22,23,24].…”