A distinctive renal neoplasm with epithelioid morphology, basement membrane production focal HMB45 immunoreactivity.

The t(6;11) renal cell carcinomas (RCCs) harbor a specific Alpha (MALAT1)-TFEB gene fusion. Xp11 translocation RCCs harbor gene fusions involving TFE3 transcription factor. TFEB and TFE3 belong to the same MiT subfamily of transcription factors. Because of similarities at the clinical, morphologic, immunohistochemical, and genetic levels, the Xp11 translocation RCCs and t(6;11) RCCs are currently grouped together under the category of MiT family translocation renal cell carcinoma.

Not clear, but a subset of confirmed cases have occurred in children who were exposed to prior cytotoxic chemotherapy, raising the possibility that this tumor may be induced by chemotherapy.

There are approximately 50 reported cases, the Male: Female ratio is 1.4:1. The median age is 31 years (range: 3-68 years).

On microscopic examination, these neoplasms feature nests and tubules of polygonal epithelioid cells, separated by thin capillaries. Papillary architecture may be seen. The majority of the tumor cells have abundant clear to granular eosinophilic cytoplasm, well-defined cell borders and round nuclei with small nucleoli. However, a second population of smaller epithelioid cells is also characteristic, typically (but not always) clustered around nodules of hyaline basement membrane material within larger acini. Mitoses are rare and necrosis is usually absent. The cases examined have generally been negative for cytokeratins by immunohistochemistry, but all have labeled at least focally for HMB45 and Melan A. The t(6;11) renal carcinomas demonstrate specific nuclear labeling for TFEB protein by IHC while other neoplasms and normal tissues do not. Hence, nuclear labeling for TFEB is a sensitive and specific diagnostic marker for this renal neoplasm with a TFEB gene fusion. TFEB break-apart FISH is generally more reliable in variably-fixed archival material.

Nephrectomy

Unclear at the current time. One case has metastasized and killed the patient, proving that these are malignant neoplasms.

TFEB (transcription factor EB)

6p21.1

TFEB has 10 exons, with the ATG protein initiation codon located within exon 3.

TFEB is a transcription factor with a basic helix-loop-helix DNA binding domain, a leucine zipper dimerization domain18, and a nuclear localization signal, thought to be located C-terminal to the helix-loop-helix domain. TFEB is ubiquitously expressed.
TFEB, TFE3, TFEC and Mitf comprise the members of the microphthalmia transcription factor subfamily, which have homologous DNA binding domains and can bind to a common DNA sequence. These four transcription factors may homo- or heterodimerize to bind DNA, and they may have functional overlap.

MALAT1 (metastasis associated lung adenocarcinoma transcript 1 (non-protein coding))

11q13.1

MALAT1 (Alpha) is an intronless, untranslated gene of unknown function.

The breakpoint on TFEB is within its second intron, just upstream of the TFEB initiation ATG codon, which results in retention of the entire TFEB coding region in the fusion gene. Although the MALAT1 promoter drives expression of the fusion gene, the MALAT1 gene does not contribute to the open reading frame. Therefore, the consequence of the MALAT1-TFEB fusion is dysregulated expression of the normal full-length TFEB protein. The TFEB-MALAT1 fusion gene is also expressed.

In the t(6;11)(p21;q12), the lack of splicing between MALAT1 and TFEB results in a different and unique fusion transcript in each case that can vary considerably in size (over 1 kb) from case to case. Based on the sizes of these two breakpoint cluster regions, RT-PCR product sizes using a primer at the 5 end of MALAT1 in combination with a reverse primer in exon 3 of TFEB could range in size to over 1.5 kb. This is a technical drawback for molecular diagnosis that could be addressed by using several assays with different MALAT1 primers scattered from the 5 to the 3 end of the gene. However the unique features of the MALAT1 gene as a translocation partner should result in a lack of splicing across the intron rearranged by the translocation. Indeed, this seems to be the case, since in all three cases with data on both the genomic junction sequence and the fusion transcript, the sequences have been identical. This indicates that the DNA PCR and RT-PCR products will be identical if a reverse primer that binds to TFE3 exon 3 is used. Because it is easier to isolate and amplify 1 to 1.5 kb target DNAs from clinical tumor samples than target RNAs of the same size (given the greater lability of RNA), detecting this fusion by long range DNA PCR may be a useful alternative for molecular diagnosis.

The MALAT1-TFEB gene fusion results in dysregulated expression of native TFEB protein.

TFEB protein that is overexpressed as a result of the MALAT1-TFEB gene fusion localizes to the nucleus as determined by immunohistochemistry. While it is ubiquitously expressed, native TFEB in cells without this translocation is not detectable by this assay.