Translocation Renal Cell Carcinoma
About Translocation Carcinoma
MiT Family Translocation Renal Cell Carcinoma
The MiT subfamily of transcription factors includes TFE3, TFEB, TFEC, and MITF. Gene fusions involving two of these transcription factors have been identified in renal cell carcinoma (RCC). The Xp11 translocation RCC 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 RCC 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 RCC underexpress epithelial immunohistochemical markers like cytokeratin and epithelial membrane antigen (EMA) relative to most other RCC. Unlike other RCC, 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", and this is carried forward in the 2016 World Health Organization Renal Cell Carcinoma classification.
The Xp11 translocation renal cell carcinomas (RCCs) harbor gene fusions involving TFE3. The t(6;11) RCCs harbor a specific Alpha-TFEB gene fusion. On the basis of clinical, morphologic, immunohistochemical and genetic similarities, these two neoplasms are now grouped together under the heading of "MiT family translocation RCC". This website is intended to be a resource on these recently described RCC and related tumors.
What are Xp11 translocation renal cell carcinomas?
Xp11 translocation renal cell carcinomas (RCCs) are a distinctive subtype of RCC characterized by chromosomal translocations with breakpoints involving the TFE3 transcription factor gene, which maps to the Xp11.2 locus. The result is a fusion of the TFE3 transcription factor gene with one of multiple reported genes including ASPSCR1 ( ASPL), PRCC, NonO (p54nrb), SFPQ (PSF), and CLTC (Table 1). The three most common Xp11 translocation RCCs are those bearing the t(X;1)(p11.2;q21) which fuses the PRCC and TFE3 genes, the t(X;17)(p11.2;q25) which fuses the ASPSCR1 and TFE3 genes , and the t(X;1)(p11.2;p34) which fuses the SFPQ (PSF) and TFE3 genes. The ASPSCR1-TFE3 gene fusion is the same gene fusion found in alveolar soft part sarcoma (ASPS), a rare pediatric neoplasm of uncertain histogenesis. However, the translocation in Xp11 translocation RCC is balanced, which may contribute to the differences seen at the clinical and histopathologic levels between Xp11 translocation RCC and ASPS. Other reported but rare translocations are the inv (X)(p11.2;q12) which fuses the NonO (p54nrb) and TFE3 genes; the t(X;17)(p11.2;q23) which fuses the CLTC and TFE3 genes5 , and the t(X;3)(p11.2;q23)6 which fused the PARP14 and TFE3 genes. Variant translocations with no known fusion partner include t(X;10)(11.2;q23).Clinical Features +
Xp11 translocation RCC were first recognized in children. Although RCC accounts for less than 5% of renal neoplasms in children, Xp11 translocation RCCs constitute a significant percentage of these cases. Approximately 40% of pediatric RCC have been classified as Xp11 translocation RCC, with a range from 20% to 75% of pediatric RCC cases among different series. The higher frequencies have generally come from single institution series, which may be less biased than multi-institution, tumor-repository based series.
The frequency of Xp11 translocation RCC in adults may be underestimated, perhaps due to morphological overlap with more common adult RCC subtypes, such a conventional clear cell RCC and papillary RCC. The frequency ranges from 1-4% in different studies. While Xp11 translocation RCC is therefore on a percentage basis rare in adults, RCC is overall much more common in adults than in children. If there are approximately 30,000 new cases of RCCs in adults each year, 4.2 % of 30,000 cases would total 1,260 adult Xp11 translocation RCC per year. In contrast, 40% of the 25 pediatric RCC in the United States would total 10 pediatric Xp11 translocation RCC per year. Thus, adult Xp11 translocation RCC may outnumber pediatric Xp11 translocation RCC by orders of magnitude due to the much higher incidence of RCC in the adult population.
Prior exposure to cytotoxic chemotherapy is currently the only known risk factor for development of Xp11 translocation RCC: up to 15% of patients with these tumors had a history of prior chemotherapy exposure. Indications for chemotherapy have included Wilms tumor, Ewing sarcoma, systemic lupus erythematosus (SLE), acute leukemia, and bone marrow transplant. The post-chemotherapy interval ranged from 4-13 years, though more recent studies have documented occurrence of Xp11 translocation RCC within 2 years of chemotherapy. All reported patients received either a DNA topoisomerase II inhibitor and/or an alkylating agent. Although they have differing mechanisms of action, both cytotoxic agents break DNA, which may initiate repair or recombination mechanisms that permit a chromosome translocation to occur.
In contrast to most RCC, Xp11 translocation RCC underexpresses epithelial markers such as cytokeratins and EMA. Vimentin is often negative. In contrast, Xp11 translocation RCC do consistently express CD10 and RCC marker as well as PAX2 and PAX8, similar to both clear cell RCC and papillary RCC. Occasionally, Xp11 translocation RCCs may express melanocytic markers such as Melan-A and HMB-45, particularly in cases associated with less common gene fusions.
The most sensitive and specific immunohistochemical marker for the Xp11 translocation RCC is strong nuclear TFE3 immunoreactivity using an antibody to the C-terminal portion of TFE3. The fusion products found in Xp11 translocation RCC retain the C-terminal portion of the TFE3 transcription factor, including its DNA binding domain, leucine-zipper dimerization domain and nuclear localization signal. Although native TFE3 protein is ubiquitously expressed, its normal levels are generally undetectable by immunohistochemistry. However, the TFE3 gene fusion partners in the Xp11 translocation RCC contribute strong promoters leading to overexpression of the fusion protein and strong nuclear labeling for TFE3 by immunohistochemistry. Adjacent renal tubules and stroma should be negative by this assay. When properly performed with overnight antibody incubation, the TFE3 immunohistochemical assay is very sensitive and specific for neoplasms bearing TFE3 gene fusions. Using moderate and strong immunoreactivity as a positive result, the initial study found sensitivity of 97.5% (39 of 40 of positive control tumors) and specificity of 99.6 % (6 of 1476 negative controls). However, a major drawback is that the assay is technically challenging, and suboptimal fixation can permit detection of native TFE3 protein resulting in high background staining. TFE3 break-apart fluorescence in situ hybridization (FISH) assays can provide molecular confirmation of Xp11 translocation RCC in paraffin embedded tissue. Hybridization with probes centromeric and telomeric to TFE3 normally yields a fusion signal but TFE3 rearrangement results in a split signal. The TFE3 break-apart FISH assay has proven to be very useful for detecting TFE3 gene fusions in Xp11 translocation RCC, and suffers less from the technical and fixation issues associated with the TFE3 immunohistochemical assay.
Cathepsin K is also useful as a specific marker for the MiT family translocation RCC. Expression of cathepsin K is mediated by expression of MiTF in osteoclasts. Since TFE3 overlaps functionally with MiTF, overexpressed TFE3 fusion proteins in the Xp11 translocation RCC are hypothesized to function like MiTF and mediate cathepsin K expression. Among cytogenetically confirmed Xp11 translocation RCCs, approximately 60% label for cathepsin K; interestingly, PRCC-TFE3 RCC label more frequently for cathepsin K than do the ASPSCR1-TFE3 RCC in the limited number of cases tested. In contrast, none of the conventional clear cell RCCs (210 cases), papillary RCCs (40 cases), chromophobe RCCs (25 cases), oncocytomas (30 cases) or adjacent non-neoplastic renal tissue showed immunoreactivity for cathepsin K. t(6;11) RCC also consistently express cathepsin K, likely due to the similar effects of overexpressed native TFEB (see below). Hence, cathepsin K can be considered highly specific for the diagnosis of an MiT family translocation RCC. However, the sensitivity is less than that of TFE3 IHC or FISH.
Since Xp11 translocation RCC was recognized as a distinct entity by the WHO only 10 years ago, outcome data on Xp11 translocation RCC are still premature at this time. Outcomes have been highly variable, with some patients surviving decades with indolent disease and others dying rapidly of progressive disease. Overall, survival is similar to that of patients with clear cell RCC, and significantly worse than those of patients with papillary RCC. Ellis et al. reviewed the published literature on Xp11 translocation RCC with the ASPSCR1-TFE3 and PRCC-TFE3 gene fusions. In multivariate analysis, only advanced stage (specifically distant metastasis) and older age at diagnosis independently predicted death. Fusion subtype impacted presentation; ASPSCR1-TFE3 RCC were more significantly more likely to present with regional lymph node metastasis (24 of 32 evaluable cases, 75%) than were PRCC-TFE3 RCC (5 of 14 cases, 36%); however, most of the former patients remained disease free without adjuvant therapy. Hence, locally advanced stage may not predict adverse outcomes. However, all patients who presented with distant metastases had ASPSCR1-TFE3 RCC and these patients have poor outcomes.
Children with locally-advanced disease (regional nodal metastases but without hematogenous spread) have a favorable short-term prognosis. In a literature review, over 90% of these patients remained disease free at last follow-up having a median of 4.4 years and a mean of 6.3 years. However, likely reflecting their usually low proliferative indices, Xp11 translocation RCC have the potential to metastasize late, as many as 20 or 30 years after diagnosis. Therefore, good long-term follow up data are necessary before any favorable short-term outcome can be confirmed. Adults do poorly when presenting with systemic metastases. Unfortunately, Xp11 translocation RCCs in adults often present this way. Mean survival after diagnosis in one study was 18 months with a range of 10-24 months. Another adult series with at least one year of follow-up reported that five of six patients developed hematogenous spread and two patients died within a year of diagnosis.
Xp11 Translocation PEComa and Melanotic Xp11 Translocation Renal Cancer
A subset of perivascular epithelioid cell tumors (PEComa) in extra-renal sites have recently been shown to harbor TFE3 gene fusions. Although the cases are few (less than 10 cases reported in the literature), distinctive features included young age, absence of association with tuberous sclerosis, minimal muscle marker immunoreactivity, and prominent epithelioid clear cell morphology. Most cases have demonstrated an SFPQ(PSF)-TFE3 gene fusion.
Another unusual malignant melanotic epithelioid cell renal neoplasm bearing a TFE3 gene fusion has also been reported. The two initial cases occurred in children and presented with widespread metastatic disease. The neoplastic cells were Melan-A and HMB-45 positive but negative for cytokeratins, renal tubular markers and muscle markers. Most cases have demonstrated an SFPQ(PSF)-TFE3 gene fusion. Around 10 total cases have now been reported, but Dr. Argani has seen more in his unpublished consultation material. These neoplasms are difficult to classify, overlapping with Xp11 translocation RCC, melanoma and perivascular epithelioid cell neoplasm (PEComa). While they are immunoreactive to TFE3, all reported cases were negative for renal tubular markers CD10, PAX2 and PAX8, in contrast to the typical Xp11 translocation RCC. The neoplastic cells are not immunoreactive to MiTF, in contrast to melanoma. PEComas represent the most closely associated phenotype. Both melanotic Xp11 translocation cancer and Xp11 translocation PEComas may represent distinct entities which overlap with Xp11 translocation RCC, and broaden the spectrum of TFE3-associated cancers.
What are the t(6;11) Renal Cell Carcinomas?
Renal cell carcinomas (RCC) harboring the t(6;11) (p21;q12) translocation were first described by Dr. Argani in 2001. While their lineage was initially unclear, the t(6;11) RCC have now been accepted by the 2013 International Society of Urological Pathology Vancouver classification of renal neoplasia and the 2016 World Health Organization Renal Tumor Classification as a subtype of the MiT family of translocation RCC, which includes the more common Xp11 translocation RCC. The t(6;11) translocation fuses the gene for transcription factor EB (TFEB), a transcription factor related to microphthalmia transcription factor (MITF), with Alpha (MALAT1), an untranslated gene of unknown function, resulting in overexpression of native TFEB.Clinical Features +
The t(6;11) RCC are less common than the Xp11 translocation RCC; only approximately 50 cases have been reported in the world literature. While the original cases were reported in children and young adults, it is now clear that these neoplasms can present in adults. The reported age range has ranged from 3 to 68 years. The mean and median age is 31 years, which is significantly lower than that of more common clear cell and papillary RCC of adults. There has been a slight male predominance of cases with a male to female ratio approximately 1.4:1. Similar to the Xp11 translocation RCC, a subset of cases have occurred in patients who have received cytotoxic chemotherapy for other disorders.
Microscopically, the t(6;11) RCC typically demonstrates a distinctive biphasic morphology, comprising larger epithelioid cells and small cells clustered around basement membrane material. The larger epithelioid cells may have clear to eosinophilic cytoplasm, and their nested architecture is similar to that of clear cell RCC. The smaller cells clustered around basement membrane material resemble the Call-Exner bodies of adult granulosa cell tumor. These neoplasms typically do not show prominent cytologic atypia or mitotic activity. While these lesions appear well delineated grossly, microscopically they characteristically entrap single native renal tubules at their periphery
The t(6;11) RCC have a distinctive immunophenotype. These neoplasms express the renal tubular transcription factor PAX8, and most cases at least focally express RCC marker, CD10, and low molecular weight cytokeratin Cam5.2, which supports ultrastructural evidence that these neoplasms demonstrate renal tubular differentiation and thus qualify as RCC. In contrast to other subtypes of RCC, the t(6;11) RCC consistently and diffusely express the melanoma marker Melan A, and consistently demonstrate patchy labeling for HMB45. Unlike malignant melanoma, these neoplasms are negative for MITF and S100 protein. The t(6;11) RCC consistently express the cysteine protease cathepsin K. Other renal tubular markers demonstrate inconsistent immunoreactivity.
The t(6;11)(p21;q12) has been shown to result in a fusion of the intronless, untranslated Alpha gene with TFEB, a gene belonging to the same transcription factor family as MiTF and TFE3. The consequence of the Alpha-TFEB fusion is dysregulated expression of the normal full-length TFEB protein. Along these lines, the t(6;11) RCCs (also known as Alpha-TFEB RCCs) demonstrate specific nuclear labeling for TFEB protein by immunohistochemistry, whereas other neoplasms and normal tissues do not. Hence, nuclear labeling for TFEB is a sensitive and specific diagnostic marker for this neoplasm bearing a TFEB gene fusion, just as nuclear labeling for TFE3 is a sensitive and specific marker for neoplasms bearing TFE3 gene fusions. More recently, a break-apart fluorescence in situ hybridization (FISH) assay to detect TFEB gene rearrangements has been validated on formalin-fixed tissues, and appears to be superior to the TFEB IHC assay. The TFEB break-apart FISH assay is less affected by variable fixation than the TFEB immunohistochemical assay, and thus represents the preferred diagnostic test for establishing the diagnosis of t(6;11) RCC in formalin-fixed, paraffin embedded material.
The differential diagnosis for t(6;11) RCC is broad, reflecting the variable morphology which genetically confirmed cases may demonstrate. In fact, Dr. Argani has seen cases in adults which overlap greatly with clear cell RCC, such that the author would have not suspected the diagnosis of t(6;11) RCC had immunohistochemistry not been performed. Since standard practice is not to perform immunohistochemistry on adult RCC which are morphologically consistent with clear cell RCC, some adult MiT family translocation carcinomas are likely misclassified as clear cell RCC in daily practice.
The t(6;11) RCC have generally been more indolent neoplasms than the Xp11 translocation RCC. Of the approximately 50 cases in the published literature, only four have developed metastases, leading to patient death in three cases. Most neoplasms have presented at low stage (pT1 or pT2) and have had benign follow-up. Like the Xp11 translocation RCC, these neoplasms have demonstrated the capacity to recur late (up to eight years after diagnosis), so long term follow-up is important for these patients.
At the current time, there is so standard treatment protocol for patients with MiT family translocation RCC. Future studies will utilize emerging genomic technologies to identify prognostic factors and therapeutic targets in these neoplasms. One study found that high chromosome copy number alterations in Xp11 translocation RCC are associated with aggressive behavior. Another found that chromosome 17q gain correlated with older age and worse outcome which corroborates the effect of age reported by Ellis et al. Expression profiling studies have demonstrated that the MET receptor tyrosine kinase is induced by TFE3 gene fusions, and this represents a targetable protein. Whole genome DNA and RNA sequencing studies have recently been performed on a small number of cases, and it is hoped that these studies and others will identify therapeutic targets. MiT family translocation RCC do express high levels of phosphorylated S6, a marker of activation of the mammalian target of rapamycin (mTOR) pathway This finding suggests that the potential utility of mTOR inhibitors in MiT family translocation RCC, and several case reports have documented their efficacy though others have not. Two other genetically Xp11 confirmed Xp11 translocation RCC reported in the literature have responded to sunitinib, suggesting possible efficacy of tyrosine kinase inhibitors in treating these neoplasms.
- Argani P, Antonescu CR, Couturier J, Fournet J, Sciot R, Debiec-Rychter M, Hutchinson B, Reuter VE, Boccon-Gibod L, Timmons C, Hafez N, Ladanyi M. PRCC-TFE3 renal carcinomas: Morphologic, immunohistochemical, ultrastructural, and molecular analysis of an entity associated with the t(X;1)(p11.2;q21). Am J Surg Pathol 2002;26:1553-66.
- Argani P, Antonescu CR, Illei PB, Lui MY, Timmons CF, Newbury R, Reuter VE, Garvin AJ, Perez-Atayde AR, Fletcher JA, Beckwith JB, Bridge JA, Ladanyi M. Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: A distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol 2001;159:179-92.
- Ladanyi M, Lui MY, Antonescu CR, Krause-Boehm A, Meindl A, Argani P, Healey JH, Ueda T, Yoshikawa H, Meloni-Ehrig A, Sorensen PH, Mertens F, Mandahl N, van den Berghe H, Sciot R, Dal Cin P, Bridge J. The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene 2001;20:48-57.
- Clark J, Lu YJ, Sidhar SK, Parker C, Gill S, Smedley D, Hamoudi R, Linehan WM, Shipley J, Cooper CS. Fusion of splicing factor genes PSF and NonO (p54nrb) to the TFE3 gene in papillary renal cell carcinoma. Oncogene 1997;15:2233-9.
- Argani P, Lui MY, Couturier J, Bouvier R, Fournet J, Ladanyi M. A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X;17)(p11.2;q23). Oncogene 2003;22:5374-8.
- Argani P, Olgac S, Tickoo SK, Goldfischer M, Moch H, Chan DY, Eble JN, Bonsib SM, Jimeno M, Lloreta J, Billis A, Hicks J, De Marzo AM, Reuter VE, Ladanyi M. Xp11 translocation renal cell carcinoma in adults: Expanded clinical, pathologic, and genetic spectrum. Am J Surg Pathol 2007;31:1149-60.
- Dijkhuizen T, van den Berg E, Wilbrink M, Weterman M, Geurts van Kessel A, Storkel S, Folkers RP, Braam A, de Jong B. Distinct Xp11.2 breakpoints in two renal cell carcinomas exhibiting X;autosome translocations. Genes Chromosomes Cancer 1995;14:43-50.
- Chian-Garcia CA, Torres-Cabala CA, Eyler R et al. Renal cell carcinoma in children and young adults: A clinicopathologic and immunohistochemical study of 14 cases [abstract]. Mod Pathol 2003(16):145A.
- Bruder E, Passera O, Harms D, Leuschner I, Ladanyi M, Argani P, Eble JN, Struckmann K, Schraml P, Moch H. Morphologic and molecular characterization of renal cell carcinoma in children and young adults. Am J Surg Pathol 2004;28:1117-32.
- Altinok G, Kattar MM, Mohamed A, Poulik J, Grignon D, Rabah R. Pediatric renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions and clinicopathologic associations. Pediatr Dev Pathol 2005;8:168-80.
- Ramphal R, Pappo A, Zielenska M, Grant R, Ngan BY. Pediatric renal cell carcinoma: Clinical, pathologic, and molecular abnormalities associated with the members of the mit transcription factor family. Am J Clin Pathol 2006;126:349-64.
- Geller JI, Argani P, Adeniran A, Hampton E, De Marzo A, Hicks J, Collins MH. Translocation renal cell carcinoma: Lack of negative impact due to lymph node spread. Cancer 2008;112:1607-16
- Komai Y, Fujiwara M, Fujii Y, Mukai H, Yonese J, Kawakami S, Yamamoto S, Migita T, Ishikawa Y, Kurata M, Nakamura T, Fukui I. Adult Xp11 translocation renal cell carcinoma diagnosed by cytogenetics and immunohistochemistry. Clin Cancer Res 2009;15:1170-6.
- Zhong M, De Angelo P, Osborne L, Keane-Tarchichi M, Goldfischer M, Edelmann L, Yang Y, Linehan WM, Merino MJ, Aisner S, Hameed M. Dual-color, break-apart FISH assay on paraffin-embedded tissues as an adjunct to diagnosis of Xp11 translocation renal cell carcinoma and alveolar soft part sarcoma. Am J Surg Pathol 2010;34: 757-766.
- Argani P, LaÃ© M, Ballard ET, Amin M, Manivel C, Hutchinson B, Reuter VE, Ladanyi M. Translocation carcinomas of the kidney after chemotherapy in childhood. J Clin Oncol 2006;24:1529-34.
- Rais-Bahrami S, Drabick JJ, De Marzo AM, Hicks J, Ho C, Caroe AE, Argani P. Xp11 translocation renal cell carcinoma: Delayed but massive and lethal metastases of a chemotherapy-associated secondary malignancy. Urology 2007;70:178.e3-6.
- Parikh J, Wahid F, McCarville B. Translocation carcinoma of the kidney developing with a short latency period after cytotoxic chemotherapy for pediatric cancer. Mod Pathol 2014;27(S2):252A.
- Medeiros LJ, Palmedo G, Krigman HR, Kovacs G, Beckwith JB. Oncocytoid renal cell carcinoma after neuroblastoma: A report of four cases of a distinct clinicopathologic entity. Am J Surg Pathol 1999;23:772-80.
- Green WM, Yonescu R, Morsberger L, Morris K, Netto GJ, Epstein JI, Illei PB, Allaf M, Griffin C, Argani P. Utilization of a TFE3 break-apart FISH assay in a renal tumor consultation service. Am J Surg Pathol 2013;37: 1150-1163.
- Rao Q, Williamson SR, Zhang S, Eble JN, Grignon DJ, Wang M, Zhou XJ, Huang W, Tan PH, Maclennan GT, Cheng L. TFE3 break-apart FISH has a higher sensitivity for Xp11.2 translocation associated renal cell carcinoma compared with TFE3 or cathepsin K immunohistochemical staining alone: expanding the morphologic spectrum. Am J Surg Pathol 2013; 37:804-15.
- Argani P, Hicks J, DeMarzo A, Albadine R, Illei P, Ladanyi M, Reuter VE, Netto G. Xp11 Translocation Renal Cell Carcinoma (RCC): Extended Immunohistochemical (IHC) Profile Emphasizing Novel RCC Markers. Am J Surg Pathol 2010; 34: 1295-1303.
- Argani P, Lal P, Hutchinson B, Lui MY, Reuter VE, Ladanyi M. Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: A sensitive and specific immunohistochemical assay. Am J Surg Pathol 2003;27:750-61.
- Motyckova G, Weilbaecher KN, Horstmann M, Rieman DJ, Fisher DZ, Fisher DE. Linking osteopetrosis and pycnodysostosis: Regulation of cathepsin K expression by the microphthalmia transcription factor family. Proc Natl Acad Sci U S A 2001 ;98:5798-803.
- Martignoni G, Pea M, Gobbo S, Brunelli M, Bonetti F, Segala D, Pan CC, Netto G, Doglioni C, Hes O, Argani P, Chilosi M. Cathepsin-K immunoreactivity distinguishes MiTF/TFE family renal translocation carcinomas from other renal carcinomas. Mod Pathol 2009;22:1016-22.
- Martignoni G, Gobbo S, Camparo P, Brunelli M, Munari E, Segala D, Pea M, Bonetti F, Illei PB, Netto G, Ladanyi M, Chilosi M, Argani P. Differential expression of cathepsin-K in neoplasms harbouring TFE3 gene fusions. Mod Pathol 2011:24: 1313-1319.
- Ross H, Martignoni G, Argani P. Renal cell carcinomas with clear cell and papillary features. Arch Path Lab Med 2012;136: 391-9.
- Tickoo SK, dePeralta-Venturina MN, Harik LR, Worcester HD, Salama ME, Young AN, Moch H, Amin MB. Spectrum of epithelial neoplasms in end-stage renal disease: An experience from 66 tumor-bearing kidneys with emphasis on histologic patterns distinct from those in sporadic adult renal neoplasia. Am J Surg Pathol 2006;30:141-53.
- Aydin H, Chen L, Cheng L, et al. Clear cell tubulopapillary renal cell carcinoma: A study of 36 distinctive low-grade epithelial tumors of the kidney. Am J Surg Pathol. 2010;34:1608-1621.
- Sukov WR, Hodge JC, Lohse CM, et al. TFE3 rearrangements in adult renal cell carcinoma: clinical and pathologic features with outcome in a large series of consecutively treated patients. Am J Surg Pathol 2012; 36:663-670.
- Ellis CL, Eble JN, Subhawong AP, Martignoni G, Zhong M, Ladanyi M, Epstein JI, Netto GJ, Argani P. Clinical heterogeneity of Xp11 translocation renal cell carcinoma: impact of fusion subtype, age and stage. Mod Pathol 2014;27:875-86
- Geller JI, Dome JS. Adjuvant therapy in pediatric patients with completely resected renal cell carcinoma. Pediatr Blood Cancer 2006;46:527.
- Meyer PN, Clark JI, Flanigan RC, Picken MM. Xp11.2 translocation renal cell carcinoma with very aggressive course in five adults. Am J Clin Pathol 2007;128:70-9.
- Argani P, Illei P, Netto G, Ro J, Cho HY, Dogan S, Ladanyi M, Martignoni G, Aulmann S, Weiss SW. A Distinctive Subset of PEComas Harbor TFE3 Gene Fusions. Am J Surg Pathol 2010; 34: 1395-1406.
- Tanaka M, Kato K, Gomi K, Matsumoto M, Kudo H, Shinkai M, Ohama Y, Kigasawa H, Tanaka Y. Perivascular epithelioid cell tumor with SFPQ/PSF-TFE3 gene fusion in a patient with advanced neuroblastoma. Am J Surg Pathol 2009;33:1416-20.
- Argani P, Aulmann S, Karanjawala Z, Fraser RB, Ladanyi M, Rodriguez MM. Melanotic Xp11 translocation renal cancers: A distinctive neoplasm with overlapping features of PEComa, carcinoma, and melanoma. Am J Surg Pathol 2009;33:609-19.
- Chang IW, Huang HY, Sung MT. Melanotic Xp11 translocation renal cancer: A case with PSF-TFE3 gene fusion and up-regulation of melanogenetic transcripts. Am J Surg Pathol 2009;33:1894-901.
- Argani P, Hawkins A, Griffin CA, et al. A distinctive pediatric renal neoplasm characterized by epithelioid morphology, basement membrane production, focal HMB45 immunoreactivity, and t(6;11)(p21.1;q12) chromosome translocation. Am J Pathol 2001;158:2089-2096.
- Srigley JR, Delahunt B, Eble JN, et al. The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia. Am J Surg Pathol 2013;37: 1469-1489.
- Davis IJ, Hsi BL, Arroyo JD, et al. Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation. Proc Natl Acad Sci U S A 2003;100:6051-6056.
- Kuiper RP, Schepens M, Thijssen J, et al. Upregulation of the transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell carcinomas due to promoter substitution. Hum Mol Genet 2003;12:1661-1669.
- Smith N, Illei P, Allaf M, Gonzalez N, Morris K, Hicks J, De Marzo A, Reuter VE, Amin MB, Epstein JI, Netto G, Argani P. t(6;11) renal cell carcinoma (RCC): Expanded immunohistochemical profile exphasizing novel RCC markers and report of ten new genetically-confirmed cases. Am J Surg Pathol 2014;38:604-14.
- Argani P, Lae M, Hutchinson B, et al. Renal carcinomas with the t(6;11)(p21;q12): clinicopathologic features and demonstration of the specific Alpha-TFEB gene fusion by immunohistochemistry, RT-PCR, and DNA PCR. Am J Surg Pathol 2005;29:230-240.
- Argani P, Yonescu R, Morsberger L, et al. Molecular confirmation of t(6;11)(p21;q12) renal cell carcinoma in archival paraffin-embedded material using a break-apart TFEB FISH assay expands its clinicopathologic spectrum. Am J Surg Pathol 2012;36:1516-1526.
- Rao Q, Liu B, Cheng L, et al. Renal cell carcinomas with t(6;11)(p21;q12): A clinicopathologic study emphasizing unusual morphology, novel Alpha-TFEB gene fusion point, immunobiomarkers, and ultrastructural features, as well as detection of the gene fusion by fluorescence in situ hybridization. Am J Surg Pathol 2012;36:1327-1338.
- Zhan HQ, Wang CF, Zhu XZ, et al. Renal cell carcinoma with t(6;11) translocation: a patient case with a novel Alpha-TFEB fusion point. J Clin Oncol 2010;28:e709-13.
- Rao Q, Zhang XM, Tu P, Xia QY, Shen Q, Zhou XJ, Shi QL. Renal cell carcinomas with t(6;11)(p21;q12) presenting with tubulocystic renal cell carcinoma-like features. Int J Clin Exp Pathol. 2013;6:1452-7.
- Pan CC, Sung M-T, Huang H-Y, Yeh K-T. High chromosomal copy number alterations in Xp11 tranlocation renal cell carcinomas detected by comparative genomic hybridization are associated with aggressive behavior. Am J Surg Pathol 2013; 37: 1116-1119.
- Malouf GG, Monzon FA, Couturier J, et al. Genomic heterogeneity of translocation renal cell carcinoma. Clin Cancer Res 2013;19:4673-84.
- Tsuda M, Davis IJ, Argani P, et al. TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition. Cancer Res 2007; 67: 919-929.
- Kobos R, Nagai M, Tsuda M, Merl MY, Saito T, Lae M, Mo Q, Olshen A, Lianoglou S, Leslie C, Ostrovnaya I, Antczak C, Djaballah H, Ladanyi M. Combining integrated genomics and functional genomics to dissect the biology of a cancer-associated, aberrant transcription factor, the ASPSCR1-TFE3 fusion oncoprotein. J Pathol 2013; 229:743-54.
- Pflueger D, Sboner A, Storz M, Roth J, Comperat E, Bruder E, Rubin MA, Schraml P, Moch H. Identification of molecular tumor markers in renal cell carcinomas with TFE3 protein expression by RNA sequencing. Neoplasia. 2013;15:1231-40.
- Malouf GG, Camparo P, Oudard S, Schleiermacher G, Theodore C, Rustine A, Dutcher J, Billemont B, Rixe O, Bompas E, Guillot A, Boccon-Gibod L, Couturier J, Molinie V, Escudier B.Targeted agents in metastatic Xp11 translocation/TFE3 gene fusion renal cell carcinoma (RCC): a report from the Juvenile RCC Network. Ann Oncol. 2010; 21:1834-8.
- Numakura K, Tsuchiya N, Yuasa T, Saito M, Obara T, Tsuruta H, Narita S, Horikawa Y, Satoh S, Habuchi T. A case study of metastatic Xp11.2 translocation renal cell carcinoma effectively treated with sunitinib. Int J Clin Oncol. 2011; 16:577-80.
- Choueiri TK, Mosquera JM, Hirsch MS. A case of adult metastatic Xp11 translocation renal cell carcinoma treated successfully with sunitinib. Clin Genitourin Cancer. 2009; 7:E93-4.
- Antonescu CR, Le Loarer F, Mosquera JM, Sboner A, Zhang L, Chen CL, Chen HW, Pathan N, Krausz T, Dickson BC, Weinreb I, Rubin MA, Hameed M, Fletcher CD. Novel YAP1-TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma. Genes Chromosomes Cancer. 2013;52:775-84.
- Rao Q, Shen Q, Xia QY, Wang ZY, Liu B, Shi SS, Shi QL, Yin HL, Wu B, Ye SB, Li L, Chen JY, Pan MH, Li Q, Li R, Wang X, Zhang RS, Yu B, Ma HH, Lu ZF, Zhou XJ. PSF/SFPQ is a very common gene fusion partner in TFE3 rearrangement-associated perivascular epithelioid cell tumors (PEComas) and melanotic Xp11 translocation renal cancers: clinicopathologic, immunohistochemical, and molecular characteristics suggesting classification as a distinct entity. Am J Surg Pathol. 2015;39:1181-96.
© Copyright 2002-2017 Johns Hopkins University All Rights Reserved