Transcription factor EB (TFEB) is the second more frequent gene of microphthalmia transcription factor family (MiTF) implicated in renal cell carcinoma (RCC).^1,2 TFEB -translocation RCC (t-TFEB RCC) is reported more frequently in children/adolescents and young adults with indolent behavior, while TFEB amplification (TFEB amp) is more frequently observed in adults as aggressive disease

 t-TFEB RCC: Cases most commonly occur in children/adolescents and young adults, without significant sex predominance

TFEB amp: Cases generally occur in significantly older patients (6-7th decade) with locally advanced or metastatic disease (high stage).

Patients with t-TFEB RCC may present with hematuria, abdominal pain or an abdominal mass. It can be found as an incidental finding but may also occur in patients who have received previous cytotoxic chemotherapy for other disorders. In contrast, TFEB amp RCC occurs in an older patient population with an average age in the 7th decade. ³

t-TFEB RCC: Tumors are well-circumscribed, cystic or solid masses, and occasionally have a mahogany-brown cut surfaces similar to that seen in oncocytoma

TFEB amp: Tumors are large, uncircumscribed, and often occupy the entire kidney, usually with visible necrosis and evidence of venous invasion.

t-TFEB RCC: Typical biphasic morphology, with isolated or clustered eosinophilic cells, which is a morphology clue for any t-TFEB RCC. Atypical morphologic features can show alveolar architecture, papillary structures, psammoma bodies and pigment. However, morphologic assessment alone is not sufficient for the diagnosis of any t-TFEB RCC, as it often resembles other subtypes of RCC. ⁴ The Cancer Genome Atlas (TCGA) studies identified TFEB gene fusions in 1.2% of phenotypically clear cell RCC cases ⁵ and 5% of papillary RCC cases. ⁶

TFEB amp: Nests of high-grade epithelioid cells with pseudopapillary formation and necrosis or true papillary formations with aberrant melanocytic marker expression; necrosis may be present. ² TFEB amplification was most prevalent in RCCs initially diagnosed as either papillary or unclassified RCC. ^7,8 TFEB amplification was seen in only 1% of cases in the TCGA papillary RCC study.⁵

t-TFEB RCC: Melanocytic biomarker such as HMB45, Melan-A, and Cathepsin K are overexpressed⁹.Staining for TFEB is considered highly sensitive for this tumor (Fig.1A); but it is not entirely specific as it also stains TFEB amp.

TFEB amp: TFEB and melanocytic marker, such as HMB45, MelanA and Cathepsin K expression, is more variable, but often at least focally positive (Fig.1B), suggesting that the level of TFEB amplification may correlate with aberrant melanocytic marker expression. ¹⁰

Fig. 1. Immunohistochemistry with TFEB. ( A) The neoplastic cells show strong nuclear staining and week cytoplasmatic staining in cases with t(6;11); the surrounding stroma is negative. (B) The neoplastic cells show moderate nuclear staining and weal cytoplasmatic staining, the surrounding stroma is negative, in cases with TFEB amplification (Images courtesy of Dr. P Argani)

t-TFEB RCC: Usually a more indolent neoplasm; metastatic disease is less frequently than with Xp11/TFE3 translocation RCCs.

TFEB amp: Aggressive behavior, which might be secondary to other co-amplified genes at 6p21.1 locus e.g. VEGFA and CCND3,¹¹ suggesting the possible usefulness of VEGFR-targeted therapy in a few cases of RCC with TFEB/VEGFA co-amplification. ¹²

t-TFEB  

t(6;11)(p21;q12) associated with MALAT1::TFEB (Fig.2A) are mainly seen in children and young adults ^13,14, but have been also rarely recognized in adults. ¹⁵ Overexpression of the intact TFEB protein is a result of promotor swapping, as the breakpoint in TFEB is within intron 1 which is upstream of the ATG initiation codon. ^16,17 

Variant translocations with several partner genes, including SERPINA3, EWSR1, CLTC, PPP1R10, KHDRBS2, COL21A1, CADM2, have been reported, mainly as single case reports. ¹⁸FISH analysis is an important tool to detect t-TFEB RCC. However, a potential diagnostic pitfall in detecting TFEB gene rearrangement which can occur on intrachromosomal inversions of TFEB, such as fusions with PPP1R10, KHDRBS2, or COL21A1 demonstrate by NGS, consistent with “negative” TFEB split FISH results.¹⁸

Fig. 2. (A) Partial GTG- banded karyotype showing a t(6;11)( p21;q12) (Courtesy by Dr J. Bridge). (B) TFEB amplification by FISH, using the TFEB break -apart probe at 6p21 (Courtesy by Dr C. Antonescu) 

TFEB amp:

FISH analysis using break apart probe (Fig. 2B) and array-CGH (Fig. 3) have allowed the emergence of a specific group of RCC harboring TFEB amplification have been reported. However, there is no established consensus for the amount of amplified TFEB required in tumor cells harboring the amplification. ^11,12

Fig.3. Chromosomal Microarray Analysis can easily identify recurrent, focal amplification of TFEB at 6p21.1 (Courtesy of DR. Adrian M Dubuc).

TFEB amp can occur with and without concurrent TFEB rearrangement and is associated with co-amplifications of VEGFA and CCND3 at 6p21, very close located to the TFEB locus. ^8,10-12