MiT Family Translocation Renal Cell Research Articles

Case – Long-term remission after repeated courses of palliative radiotherapy in a patient with metastatic MiT family translocation renal cell carcinoma

Case – Long-term remission after repeated courses of palliative radiotherapy in a patient with metastatic MiT family translocation renal cell carcinoma

"Oncocytoid Renal Cell Carcinomas After Neuroblastoma" Represent TSC -mutated Eosinophilic Solid and Cystic Renal Cell Carcinomas : Association With Prior Childhood Malignancy and Multifocality With Therapeutic Implications.

The concept of oncocytoid renal cell carcinoma in patients who have survived neuroblastoma as a distinct biologic entity has been controversial since its original description in 1999. This is in part because similar oncocytoid renal cell carcinomas have been described in association with other pediatric cancers, and also because other renal cell carcinoma subtypes (such as MiT family translocation renal cell carcinoma) have been described in children who have survived neuroblastoma. We identified an index case of a child who survived medulloblastoma and developed multifocal bilateral oncocytoid renal cell carcinomas with morphology and immunophenotype compatible with eosinophilic solid and cystic renal cell carcinoma (ESC RCC) and demonstrated that both neoplasms harbored distinctive mutations in the TSC1/TSC2 genes. Remarkably, the child's remaining bilateral multifocal renal neoplasms completely responded to MTOR inhibitor therapy without need for further surgery. To confirm our hypothesis that oncocytoid renal cell carcinomas after childhood cancer represent ESC RCC, we obtained formalin-fixed paraffin-embedded tissue blocks from 2 previously published cases of oncocytoid renal cell carcinoma after neuroblastoma, confirmed that the morphology and immunophenotype was consistent with ESC RCC, and demonstrated that both cases harbored somatic TSC gene mutations. Both expressed markers previously associated with neoplasms harboring TSC gene mutations, glycoprotein nonmetastatic B, and cathepsin K. Of note, one of these patients had 2 ESC RCC which harbored distinctive TSC2 mutations, while the background kidney of the other patient had multiple small cysts lined by similar oncocytoid cells which showed loss of TSC2 protein. We then reviewed 3 of 4 cases from the original 1999 report of oncocytoid renal cell carcinomas after neuroblastoma, found that all 3 demonstrated morphology (including basophilic cytoplasmic stippling) that is characteristic of ESC RCC, showed that all 3 overexpressed glycoprotein nonmetastatic B, and showed that both cases with adequate material demonstrated loss of TSC2 protein and expressed cytokeratin 20 and cathepsin K by immunohistochemistry. In summary, "oncocytoid renal cell carcinomas after neuroblastoma" represent ESC RCC which are often multifocal in patients who have survived childhood cancer, likely representing an incompletely characterized tumor predisposition syndrome. MTOR-targeted therapy represents an effective therapeutic option for such patients to preserve functional nephrons.

Racial Disparities in MiT Family Translocation Renal Cell Carcinoma.

Racial disparities have been documented in the biology and outcome of certain renal cell carcinomas (RCCs) among Black patients. However, little is known about racial differences in MiT family translocation RCC (TRCC). To investigate this issue, we performed a case-control study using data from The Cancer Genome Atlas (TCGA) and the Chinese OrigiMed2020 cohort. A total of 676 patients with RCC (14 Asian, 113 Black, and 525 White) were identified in TCGA, and TRCC was defined as RCC with TFE3/TFEB translocation or TFEB amplification, leading to 21 patients with TRCC (2 Asian, 8 Black, 10 White, and 1 unknown). Asian (2 of 14 [14.3%] vs 10 of 525 [1.9%]; P = .036) and Black (8 of 113 [7.1%] vs 1.9%; P = .007) patients with RCC showed significantly higher prevalence of TRCC compared with White patients with RCC. The overall mortality rate of TRCC was slightly higher in Asian and Black patients compared with White patients (HR: 6.05, P = .069). OrigiMed2020 Chinese patients with RCC had a significantly higher proportion of TRCC with TFE3 fusions than TCGA White patients with RCC (13 of 250 [5.2%] vs 7 of 525 [1.3%]; P = .003). Black patients with TRCC were more likely to exhibit the proliferative subtype than White patients (6 of 8 [75%] vs 2 of 9 [22.2%]; P = .057) for those who had RNA-seq profiles. We present evidence of higher prevalence of TRCC in Asian and Black patients with RCC compared with White patients and show that these tumors in Asian and Black patients have distinct transcriptional signatures and are associated with poor outcomes.

Immune Checkpoint Therapy Combinations in Adult Advanced MiT Family Translocation Renal Cell Carcinomas.

There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC). This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US, France, and Belgium. Only cases with confirmed fluorescence in situ hybridization (FISH) were included. Objective response rates (ORR) and progression-free survival (PFS) were assessed by RECIST, and overall survival (OS) was estimated by Kaplan-Meier methods. There were 29 patients identified with median age of 38 (21-70) years, and F:M ratio 0.9:1. FISH revealed TFE3 and TFEB translocations in 22 and 7 patients, respectively. Dual ICT and ICT + VEGF TT were used in 18 and 11 patients, respectively. Seventeen (59%) patients received ICT combinations as first-line therapy. ORR was 1/18 (5.5%) for dual ICT and 4/11 (36%) for ICT + VEGF TT. At a median follow-up of 12.9 months, median PFS was 2.8 and 5.4 months in the dual ICT and ICT + VEGF TT groups, respectively. Median OS from metastatic disease was 17.8 and 30.7 months in the dual ICT and ICT + VEGF TT groups, respectively. In this retrospective study of advanced tRCC, limited response and survival were seen after frontline dual ICT combination therapy, while ICT + VEGF TT therapy offered some efficacy. Due to the heterogeneity of tRCC, insights into the biological underpinnings are necessary to develop more effective therapies.

MiT/TFE Family Renal Cell Carcinoma.

The microphthalmia-associated transcription factor/transcription factor E (MiT/TFE) family of transcription factors are evolutionarily conserved, basic helix-loop-helix leucine zipper (bHLH-Zip) transcription factors, consisting of MITF, TFEB, TFE3, and TFEC. MiT/TFE proteins, with the exception of TFEC, are involved in the development of renal cell carcinoma (RCC). Most of the MiT/TFE transcription factor alterations seen in sporadic RCC cases of MiT family translocation renal cell carcinoma (tRCC) are chimeric proteins generated by chromosomal rearrangements. These chimeric MiT/TFE proteins retain the bHLH-Zip structures and act as oncogenic transcription factors. The germline variant of MITF p.E318K has been reported as a risk factor for RCC. E 318 is present at the SUMOylation consensus site of MITF. The p.E318K variant abrogates SUMOylation on K 316, which results in alteration of MITF transcriptional activity. Only a few cases of MITF p.E318K RCC have been reported, and their clinical features have not yet been fully described. It would be important for clinicians to recognize MITF p.E318K RCC and consider MITF germline testing for undiagnosed familial RCC cases. This review outlines the involvement of the MiT/TFE transcription factors in RCC, both in sporadic and hereditary cases. Further elucidation of the molecular function of the MiT/TFE family is necessary for better diagnosis and treatment of these rare diseases.

1461P Impact of first-line (1L) therapy on outcomes of adult patients (pts) with metastatic MiT family translocation renal cell carcinomas (TRCC) treated in the contemporary immune checkpoint therapy (ICT) era

TRCC represent a rare and aggressive subgroup of RCC. While 1L therapy recommendations and clinical prognostication of pts with clear-cell RCC are well-known, data on TRCC clinical behavior are limited. TRCC is reported to be an immune cold tumor and the data surrounding 1L ICT is scarce.

Advanced nccRCC: what therapeutic options in 2022?

Non-clear-cell renal cell carcinomas (nccRCC) represent around 25% of all renal cancers and are a very heterogeneous group of tumours in terms of both biological features and prognosis. Papillary renal cell carcinomas (pRCC) are the most frequent subtype with 15% to 20% of all kidney cancers. Improved biological knowledge of these tumours has led to better identification of each subtype. Among pRCC, some exhibit mutations of the MET oncogene and others mutations of the gene coding for fumarate hydratase. The management of nccRCC, in particular the pRCC subtype, has evolved considerably in recent times, spearheaded by the advent of targeted therapies including anti-angiogenics but also new immunotherapy agents. Several studies have in the last few years prompted a new standard of care for these nccRCC. We propose to present throughout this article the latest available efficacy data on different compounds assessed in the treatment of the most frequent nccRCC, including the pRCC, chromophobe carcinoma, collecting duct carcinoma, MiT family translocation renal cell carcinoma and renal medullary carcinoma subtypes.

Immuno-oncology (IO) combinations +/- VEGF targeted therapy (VEGF TT) in patients (pts) with advanced mit family translocation renal cell carcinomas (tRCC): Results from an international multicenter study.

343 Background: IO combinations are standard of care for first-line therapy of clear-cell RCC; however, non-clear cell histologies including tRCC were not included in the registrational trials. We previously reported a modest efficacy (objective response rate [ORR] <20%) with IO monotherapy (PD-1 blockade) in tRCC (Boilève et al, JITC. 2018). The efficacy of IO combinations +/- VEGF TT has not been reported. Methods: This is a retrospective, international, multicenter study of pts with tRCC treated with IO-IO or IO+VEGF TT at 11 centers in the US, France, and Belgium. Only pts with confirmed TFE3 or TFEB translocation by fluorescent-in-situ hybridization (FISH) were included. ORR and progression-free survival (PFS) were assessed by RECIST. Overall survival (OS) was assessed by Kaplan-Meier methods. OS was measured from initiation of therapy till death or last follow up. We also assessed the association between OS and baseline prognostic variables. Results: 29 patients with metastatic tRCC were included in this analysis. Median age at starting therapy was 38 (IQR 27, 53) years. Female:Male ratio was 0.9:1. FISH revealed a translocation involving TFE3 and TFEB in 22 and 7 patients, respectively. Most frequent metastatic sites at diagnosis were lungs (76%), liver (52%), retroperitoneal adenopathy (48%), and bone (38%). IMDC risk at diagnosis was favorable (31%), intermediate (45%) and poor (24%). Combinations of IO+VEGF TT and anti-PD1 (L1) + anti-CTLA-4 (IO+IO) were used in 11 and 18 pts, respectively. 17 (59%) pts received IO combinations as 1L, 7 (24%) pts as 2L and 5 (17%) pts as ≥3L. ORR in the IO+IO group was 1/18 (5.5%), while in IO+VEGF TT group was 4/11 (36%). For 20 (69%) pts, progressive disease was the best overall response. At a median follow-up of 12.9 months (mo), median PFS was 3.2 mo and median OS was 13.5 mo for all 29 pts (Table). Median PFS in the IO+IO group was 2.8 mo, and 5.4 mo in IO+VEGF TT group (HR=0.81, 95% CI: 0.35-1.84). Conclusions: In this small retrospective study of tRCC, IO+IO therapy produced modest activity based on low ORR and short PFS while IO+VEGF TT produced numerically higher ORR and longer PFS. Insights into the biological basis of tRCC are necessary to develop more effective therapies for this rare and aggressive RCC variant.[Table: see text]

Diagnostic utility of one-stop fusion gene panel to detect TFE3/TFEB gene rearrangement and amplification in renal cell carcinomas

MiT family translocation renal cell carcinoma (MiT-RCC) harbors translocations involving the TFE3 or TFEB genes. RCC with TFEB amplification is also identified and is associated with a more aggressive clinical course. Accurate diagnosis of MiT-RCC is crucial for patient management. In this study, we evaluated the performance of the Archer FusionPlex assay for detection of MiT-RCC with TFE3 or TFEB translocations and TFEB amplifications. RNA was extracted from 49 RCC FFPE tissue samples with known TFE3/TFEB status (26 TFE3 FISH positive, 12 TFEB FISH positive, 4 TFEB amplified (1 case both split and amplified), and 8 FISH negative) using the Covaris extraction kit. Target enriched cDNA libraries were prepared using the Archer FusionPlex kit and sequenced on the Illumina NextSeq 550. We demonstrate that the age of the specimen, quality of RNA, and sequencing metrics are important for fusion detection. Fusions were identified in 20 of 21 cases less than 2 years old, and TFE3/TFEB rearrangements were detected in all cases with Fusion QC ≥ 100. The assay identified intrachromosomal inversions in two cases (TFE3-RBM10 and NONO-TFE3), usually difficult to identify by FISH assays. TFEB mRNA expression and the TFEB/TFE3 mRNA expression ratio were significantly higher in RCCs with TFEB fusion and TFEB gene amplification compared to tumors without TFEB fusion or amplification. A cutoff TFEB/TFE3 ratio of 0.5 resulted in 97.3% concordance to FISH results with no false negatives. Our study demonstrates that the FusionPlex assay successfully identifies TFE3 and TFEB fusions including intrachromosomal inversions. Age of the specimen and certain sequencing metrics are important for successful fusion detection. Furthermore, mRNA expression levels may be used for predicting cases harboring TFEB amplification, thereby streamlining testing. This assay enables accurate molecular detection of multiple subtypes of MiT-RCCs in a convenient workflow.

Mit family translocation renal cell carcinoma: a rare variant of renal cell carcinoma showing unusual aggressive pathological features

Mit family translocation renal cell carcinoma: a rare variant of renal cell carcinoma showing unusual aggressive pathological features

Efficacy of cabozantinib in advanced MiT family translocation renal cell carcinomas (TRCC).

274 Background: MiT family translocation renal cell carcinomas (TRCC) represent a rare and aggressive subgroup of RCC harboring high expression of c-MET. While response rates of VEGF receptor-tyrosine kinase inhibitor and immune checkpoint inhibitors are limited, efficacy of cabozantinib (a TKI that inhibits VEGFR, MET, and AXL) in this subgroup is unclear. Methods: We performed a multicentre, retrospective, international cohort study of patients with TRCC treated with cabozantinib regardless the line of treatment at 7 centers (3 in France and 4 in the US). The main objectives were to estimate response rate according to RECIST criteria, and to analyze progression-free survival (PFS) and overall survival (OS). Results: Among 31 metastatic patients treated in the participating centers, 24 were evaluable for response and were included in this study (21 with TFE3 and 3 with TFEB translocations). Median age at diagnosis was 43.5 years (range, 22–70). Most frequent metastatic sites at diagnosis were lungs (62.5%), retroperitoneal lymph nodes (45.8%) and bone (37.5%). Patient’s IMDC risk group at diagnosis was favourable (20,8%), intermediate (62,5%) and poor (16,7%). Seven (29%) patients received cabozantinib at first line, 9 (37.5%) at second line and 8 (33%) at third line and beyond. The proportion of patients who achieved an objective response was 16.6%, including 1 complete response and 3 partial responses. For 11 (45.8%) patients, stable disease was the best response. With a median follow-up of 14 months (IQR 5-23), median PFS was 8.4 months (range, 1-34+) and median OS was 17 months (range, 2-43). No PFS difference was detected overall or in any subgroup except in patients with bone metastasis which harbored a median PFS of 3.6 months as compared to 9.1 months for those without (p=0.03). Conclusions: This real-world study provides evidence supporting activity of cabozantinib in TRCC, with more durable responses to therapy than those observed with of VEGF receptor-tyrosine kinase inhibitor and immune checkpoint inhibitors. International collaborations and prospective studies are necessary to identifies efficacious therapies for this rare disease that lacks evidence-based treatment options.

Stimulator of interferon genes (STING) immunohistochemical expression in the spectrum of perivascular epithelioid cell (PEC) lesions of the kidney

Angiomyolipoma is the prototype of renal perivascular epithelioid cell (PEC) lesions whose pathogenesis is determined by mutations affecting TSC genes, with eventual deregulation of the mTOR pathway. It is well known that mTOR complex protein is involved in autophagy, and recently the role of STING in this process has been demonstrated. Based on this background, we sought to investigate STING immunohistochemical expression in a series of PEC lesions of the kidney. Fifty classic angiomyolipomas, 14 epithelioid angiomyolipomas/pure epithelioid PEComas, two angiomyolipomas with epithelial cysts (AMLEC), and two intraglomerular PEC lesions were collected. Immunostaining for STING was carried out in all cases and FISH analysis using dual colour break apart TFE3 and TFEB probes was performed in all pure epithelioid PEComas and AMLEC. Control cases including 20 normal adult kidneys, five fetal kidneys, and 30 MiT family translocation renal cell carcinomas (the main differential diagnosis with epithelioid angiomyolipoma/pure epithelioid PEComa) were also immunohistochemically stained with STING. Strong and diffuse cytoplasmic expression of STING was observed in 100% of classic angiomyolipomas, AMLEC, and intraglomerular lesions, and in 79% (11/14) of epithelioid angiomyolipomas/pure epithelioid PEComas. TFE3 gene rearrangement was demonstrated in two epithelioid angiomyolipomas/pure epithelioid PEComas, both completely negative for STING. None of the MiT family translocation renal cell carcinomas expressed STING. In conclusion, we demonstrate the expression of STING in almost all PEC lesions of the kidney. This result provides novel insights into the possible role of autophagy in PEC lesions of the kidney. Moreover, this finding may be useful for diagnostic purposes, particularly in distinguishing epithelioid angiomyolipoma/pure epithelioid PEComa from MiT family translocation renal cell carcinoma and detecting intraglomerular PEC lesions.

Secondary renal neoplasia following chemotherapy or radiation in pediatric patients

Renal neoplasia occurring as a second malignancy following childhood cancer has been most closely associated with neuroblastoma and Wilms tumor. While some cases have been associated with a genetic predisposition, nearly all are thought to result from "late effects" of therapy-related toxicity that involves chemotherapy or radiation. It is unclear if these tumors are enriched for specific molecular or morphologic characteristics. A query of our institutional nephrectomy registry of 8295 patients for renal neoplasia occurring post-treatment for childhood cancer revealed 6 patients with Wilms tumor, 4 with neuroblastoma, and 1 with acute lymphoblastic leukemia (ALL). Three additional cases of MiT family translocation renal cell carcinoma (RCC), from 2 patients, following chemotherapy for neuroblastoma and systemic lupus erythematosus and another of clear cell RCC post-ALL were included. The most common tumor type was clear cell RCC: 9/19 cases (47.4%), followed by metanephric adenoma and MiT family translocation RCC (3/19, 15.8%). There were no characteristic features to indicate a unique renal neoplasia subtype. Potential syndromic renal neoplasia occurred in 2 patients, metanephric adenomas and oncocytoma in a patient with hyperparathyroidism-jaw tumor syndrome post-treatment of Wilms tumor and a fumarate hydratase-deficient RCC in a patient post-treatment for ALL. The mean age at diagnosis of childhood neoplasia or treatment with chemotherapy or radiation was 4.7 years, and the average time to subsequent renal neoplasia was 31 years. Five (of 14) patients developed metastatic RCC, and there were 2 RCC-related deaths. These results indicate the need for extended clinical follow-up of these patients.

Comprehensive analysis of 34 MiT family translocation renal cell carcinomas and review of the literature: investigating prognostic markers and therapy targets

Recently cabozantinib, a tyrosine kinase inhibitor with activity against VEGF, MET, AXL, and downregulating cathepsin K invitro, has been proposed for the treatment of advanced clear and non-clear renal cell carcinomas. Since it is well known that cathepsin K is expressed in the majority of MiT family translocation renal cell carcinomas, we investigated cathepsin K, MET, AXL, and VEGF in a large series of those tumours, looking for possible predictive markers. We collected the clinicopathological features of 34 genetically confirmed MiT family translocation renal cell carcinomas [26 Xp11 and 8 t(6;11) renal cell carcinomas] and studied them using an immunohistochemical panel including PAX8, cathepsin K, HMB45, Melan-A, CD68 (PG-M1), CK7, CA9, MET, AXL and by FISH for VEGFA and MET. Cathepsin K was expressed in 14 of 26, HMB45 in 8 of 25, and Melan-A in 4 of 23 Xp11 renal cell carcinomas, whereas labelling for CK7 and CA9 was minimal. In t(6;11) renal cell carcinoma, cathepsin K and melanogenesis markers were constantly positive, whereas CK7 and CA9 were negative. None of the 34 carcinomas showed CD68 (PG-M1) and AXL expression. One aggressive Xp11 renal cell carcinoma showed increased VEGFA gene copy number (4-5 copies) with concurrent gains of TFE3 and TFEB. None of the 34 carcinomas showed MET gene amplification, whereas staining for MET was found in 7 of 8 t(6;11) and in 16 of 24 Xp11 renal cell carcinomas, and in the latter cases, when the expression was >50%, correlated with aggressiveness (p=0.0049). In Xp11 renal cell carcinomas, the aggressiveness was also correlated with larger tumour size (p=0.0008) and the presence of necrosis (p=0.027) but not nucleolar grading (p=1). Interestingly, in patients with tumours exhibiting two of three parameters (necrosis, larger tumour size and MET immunolabelling >50%) an aggressive clinical behaviour was observed in 88% of cases. In conclusion, cathepsin K, CD68 (PG-M1), CK7, CA9, and PAX8 is a useful panel for the diagnosis. Larger tumour size, the presence of necrosis and MET immunohistochemical expression correlate with aggressive behaviour in Xp11 renal cell carcinomas, especially in combination. VEGF, MET, cathepsin K but not AXL may be potential predictive markers for targeted therapy in MiT family translocation renal cell carcinomas.

Les carcinomes du rein à translocation de la famille MiT : histoire naturelle, caractéristiques moléculaire et prise en charge multidisciplinaire

MiT family translocation renal cell carcinomas (tRCC) represent a rare subtype of renal cell carcinomas. These tumors have been introduced for the first time in the World Health Classification (WHO) classification of kidney cancers in 2004. tRCC are characterized by reccurent translocations involving members of the MiT family transcription factors, mainly TFE3 and TFEB. The estimated incidence of these tumors is ∼1-5% among all renal cell carcinomas, with female prodominance. tRCC were initially described in children, and the spectrum has been expanded over time to encompass adolescents and adults. TFE3- and TFEB-rearranged RCC harbor characteristic clinicopathological and immunohistochemical features and fluorescent hybridization in situ is considered the gold standard for their diagnosis, although it has some limitations especially when the partners are located in the vicinity of TFE3. Nephron-sparing surgery is an efficient treatment of localized cases when achievable. In metastatic setting, targeted agents and immunotherapy showed modest efficacy, with response rates and median overall survival inferior to those observed in clear-cell renal cell carcinomas. Management of tRCC necessite a multidisciplinary team and accrual in clinical trials have to be encouraged when possible. Novel biological insights are urgently awaited to better understand the mechanisms associated with kidney oncogenesis in this setting, and ultimately help to identify therapeutic targets.

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

The new category of MiT family translocation renal cell carcinoma has been included into the World Health Organization (WHO) classification in 2016. The MiT family translocation renal cell carcinoma comprises Xp11 translocation renal cell carcinoma harboring TFE3 gene fusions and t(6;11) renal cell carcinoma harboring TFEB gene fusion. At the beginning, they were recognized in childhood; nevertheless, it has been demonstrated that these neoplasms can occur in adults as well. In the nineties, among Xp11 renal cell carcinoma, ASPL, PRCC, and SFPQ (PSF) were the first genes recognized as partners in TFE3 rearrangement. Recently, many other genes have been identified, and a wide spectrum of morphologies has been described. For this reason, the diagnosis may be challenging based on the histology, and the differential diagnosis includes the most common renal cell neoplasms and pure epithelioid PEComa/epithelioid angiomyolipoma of the kidney. During the last decades, many efforts have been made to identify immunohistochemical markers to reach the right diagnosis. To date, staining for PAX8, cathepsin K, and melanogenesis markers are the most useful identifiers. However, the diagnosis requires the demonstration of the chromosomal rearrangement, and fluorescent in situ hybridization (FISH) is considered the gold standard. The outcome of Xp11 translocation renal cell carcinoma is highly variable, with some patients surviving decades with indolent disease and others dying rapidly of progressive disease. Despite most instances of t(6;11) renal cell carcinoma having an indolent clinical course, a few published cases demonstrate aggressive behavior. Recently, renal cell carcinomas with TFEB amplification have been described in connection with t(6;11) renal cell carcinoma. Those tumors appear to be associated with a more aggressive clinical course. For the aggressive cases of MiT family translocation carcinoma, the optimal therapy remains to be determined; however, new target therapies seem to be promising, and the search for predictive markers is mandatory.

TFE3-Expressing Perivascular Epithelioid Cell Tumor of the Breast.

Perivascular epithelioid cell tumor (PEComa) is a very rare mesenchymal tumor with a distinctive morphology and immunophenotype. PEComas usually harbor TSC2 alterations, although TFE3 translocations, which occur in MiT family translocation renal cell carcinoma and alveolar soft part sarcoma, are also possible. We recently experienced a case of PEComa with TFE3 expression arising in the breast. An 18-year-old female patient presented with a right breast mass. Histologically, the tumor consisted of epithelioid cells with alveolar structure and showed a diffuse strong expression of HMB45 and TFE3. TSC2 was preserved. Melan A and smooth muscle actin were negative. To our knowledge, this is the first Korean case of PEComa of the breast that intriguingly presented with TFE3 expression.

Comprehensive genetic characterization of TFE3-positive renal cell carcinoma.

635 Background: MiT family translocation renal cell carcinoma (RCC) is very rare variant which has translocation of Xp11.2/TFE3 gene or t(6;11)/TFEB gene. Xp11.2 translocation RCC is predominantly reported in younger age and has aggressive features. However, its pathophysiology or genetic characteristics are rarely understood. The aim of the study is to describe the comprehensive genetic characteristics of TFE3-positive RCC diagnosed by immunohistochemistry. Methods: We identified patients who were clinically diagnosed as Xp11.2 translocation RCC by immunostaining positive of TFE3 from two tertiary referral hospitals. Among them, a total of 19 patients whose fresh frozen tissue and normal DNA were achieved were included in the analysis. Whole exome sequencing (WES) was performed to evaluate somatic mutations and copy-number variation (CNV). We also performed RNAseq on the TFE3-positive RCC, 7 clear cell RCC, and 4 normal kidney tissue for comparison. Fusion partners were identified and clustering analysis was done by RNAseq. Results: Mutational landscape of TFE3-positive RCC is unique by low somatic mutation rate and very rare COSMIC variants. High prevalence of CNV with loss of 3p, 6q, 9, gain of 5, 7, and 12 were most frequent. We identified NONO, RBM10, SFPQ, ASPSCR1 and PRCC as fusion partner as previously described. We could not find TFE3 fusion in 6 out of 19 patients by RNAseq, and they were older and had more mutations than the others. They were also genetically clustered with clear cell RCC. Oxidative reducatase pathway was upregulated and immune response and cell adhesion were downregulated by gene ontology results from heatmap clusters. These may promote metastasis, resistant to immunity and cell survival in poorer condition which could be potential mechanism of Xp11.2 translocation RCC aggressiveness. Conclusions: TFE3-positive RCC showed distinctive mutation pattern with low somatic mutation and rare common driver gene. One-third clinically diagnosed Xp11.2 translocation RCC (6/19) did not have real gene fusion even in TFE3 overexpression. They were older and had more somatic mutations than the others. Furthermore, they were clustered with clear cell RCC.

MiT family translocation renal cell carcinoma.

The MiT subfamily of transcription factors includes TFE3, TFEB, TFC, and MiTF. Gene fusions involving two of these transcription factors have been identified in renal cell carcinoma (RCC). The Xp11 translocation RCCs were first officially recognized in the 2004 WHO renal tumor classification, and harbor gene fusions involving TFE3. The t(6;11) RCCs harbor a specific Alpha-TFEB gene fusion and were first officially recognized in the 2013 International Society of Urologic Pathology (ISUP) Vancouver classification of renal neoplasia. These two subtypes of translocation RCC have many similarities. Both were initially described in and disproportionately involve young patients, though adult translocation RCC may overall outnumber pediatric cases. Both often have unusual and distinctive morphologies; the Xp11 translocation RCCs frequently have clear cells with papillary architecture and abundant psammomatous bodies, while the t(6;11) RCCs frequently have a biphasic appearance with both large and small epithelioid cells and nodules of basement membrane material. However, the morphology of these two neoplasms can overlap, with one mimicking the other. Both of these RCCs underexpress epithelial immunohistochemical markers like cytokeratin and epithelial membrane antigen (EMA) relative to most other RCCs. Unlike other RCCs, both frequently express the cysteine protease cathepsin k and often express melanocytic markers like HMB45 and Melan A. Finally, TFE3 and TFEB have overlapping functional activity as these two transcription factors frequently heterodimerize and bind to the same targets. Therefore, on the basis of clinical, morphologic, immunohistochemical, and genetic similarities, the 2013 ISUP Vancouver classification of renal neoplasia grouped these two neoplasms together under the heading of "MiT family translocation RCC." This review summarizes our current knowledge of these recently described RCCs.