Conflicting Immunohistochemistry and Fluorescence In Situ Hybridization Results on Transcription Factor E3 Translocation Status in Renal Cell Carcinoma: A Case Report

Transcription factor E3 (TFE3) translocation-associated renal cell carcinoma (RCC) is a rare entity. However, its clinical course is usually aggressive. Immunohistochemical (IHC) detection of the TFE3 recombinant protein is generally considered a highly sensitive and specific means for the diagnosis of the TFE3 translocation-associated RCC. A 50-year-old woman presented with repeated gross hematuria and right lower quadrant abdominal pain refractory to symptomatic treatment. CT scan showed a large heterogenous and enhancing mass in the lower pole of the right kidney with no clinically significant adenopathy or metastasis. Microscopic examination of the radical nephrectomy specimen revealed an 11.5-cm high-grade renal cell carcinoma with renal vein and sinus involvement and extensive lymphovascular invasion. No low-grade tumor area was identified in the initially submitted sections. The tumor cells were immunoreactive for TFE3 (nuclear), vimentin, EMA, CK7 (focal), and CD10 (focal) and negative for RCC. A fluorescence in situ hybridization (FISH) test, however, failed to identify any rearrangement of TFE3. Follow-up cytogenomic microarray analysis (CMA) on paraffin-embedded tissue revealed losses of 3p (where VHL gene is located), 4q, 9, 10q, 13, 14, and 15 and gains of 5p and 16, in addition to copy-neutral loss of heterozygosity of 5q and 17 in a mosaic state (35% of cells). Paired sequencing of the tumor DNA specimen and the matching normal tissue with a 275-gene panel detected mutations in VHL, BAP1, PIK3R1, IRF4, ARID2, and TP53 genes in tumor cells. The final diagnosis was clear cell RCC, grade 4. The patient developed metastatic RCC to the lung later. Positive nuclear TFE3 immunostain driven by mechanisms other than genetic fusion-like chromosome amplification and in ALK fusion-associated RCC has been reported. This case highlights the necessity to confirm the IHC result by FISH and further molecular testing to differentiate difficult cases.