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TFE3-associated renal cell carcinoma

Thursday 18 September 2003

TFE3 gene fusions associated renal cell carcinoma, pediatric renal cell carcinomas with Xp11.2 rearrangements; Xp11 Translocation Renal Cell Carcinoma (RCC); xp11 translocation renal cell carcinomas

Definition: The renal cell carcinomas (RCCs) associated with Xp11.2 translocations (TFE3 transcription factor gene fusions) are rare tumors predominantly reported in children.


- TFE3-associated renal cell carcinoma

- TFE3 RCC, typical architecture with pasammoma bodies

- cystic Xp11-associated RCC

Digital cases

- HPC:169 : Pulmonary metastasis of a TFE3+ juvenile renal cell carcinoma
- HPC:360 : Nodal metastasis of a TFE3+ juvenile renal cell carcinoma


- cystic Xp11-associated RCC

TFE3-associated renal cell carcinomas comprise at least one-third of pediatric RCCs and only few adult cases have been reported.


- possibly cystic tumor with multiple friable mural nodules on its inner surface
- well encapsulated


- clear and eosinophilic/oncocytic voluminous cells arranged in papillary, trabecular, and nested/alveolar patterns.
- occasional hyaline nodules
- numerous psammoma bodies

Xp11 translocation renal cell carcinoma (RCC) harbor various TFE3 gene fusions, and are known to underexpress epithelial immunohistochemical (IHC) markers such as cytokeratin and EMA relative to usual adult type RCC.

However, their profile in reference to other IHC markers that are differentially expressed in other subtypes of RCC has not been systematically assessed. Few therapeutic targets have been identified in these aggressive cancers.


- strong nuclear positivity for TFE3.
- Epithelial membrane antigen, CD10, and E-cadherin are strongly positive.
- Cytokeratin AE1/AE3, cytokeratin CAM-5.2, calveolin, and parvalbumin are moderately positive.
- Cytokeratin 7, renal cell carcinoma antigen, and colloidal iron are focally weakly positive.
- BerEP4 and carbonic anhydrase IX are negative.
- Xp11 translocation RCC usually express PAX2 and PAX8 but do not usually express MiTF. Although they may express HIF-1alpha, they only focally express the downstream target CA IX. (20679884)
- They inconsistently express markers associated with other RCC subtypes, further highlighting the lack of specificity of the latter markers. (20679884)
- TFE3 and Cathepsin K remain the most sensitive and specific markers of these neoplasms. (20679884)
- Elevated expression of phosphorylated S6 in Xp11 translocation RCC suggests the mTOR pathway as an attractive potential therapeutic target for these neoplasms. (20679884)

Cathepsin K expression

Cathepsin K (CTSK) is a protease whose expression is driven by microphthalmia transcription factor (MITF) in osteoclasts. TFE3 and TFEB are members of the same transcription factor subfamily as MITF and all three have overlapping transcriptional targets.

All t(6;11) renal cell carcinomas, which harbor an Alpha-TFEB gene fusion, as well as a subset of the Xp11 translocation renal carcinomas, which harbor various TFE3 gene fusions, express cathepsin K (CTSK), while no other common renal carcinoma does. (21602817)

The difference in expression of cathepsin K (CTSK) between the PRCC-TFE3 and ASPSCR1-TFE3 carcinomas, together with the observed clinical differences between these subtypes of Xp11 translocation carcinomas, suggests the possibility of functional differences between these two related fusion proteins. (21602817)


- ASPL/TFE3 by t(X;17)(p11.2;q25)
- CLTC/TFE3 by t(X;17)(p11.2;q23) CLTC coding for a major subunit of clathrin
- t(X;19)(p11.2;q13.1)

- chromosomal copy number alterations

  • High chromosomal copy number alterations in xp11 translocation renal cell carcinomas detected by array comparative genomic hybridization are associated with aggressive behavior. doi : 10.1097/PAS 0b013e318293d872 (23759936)


TFE3 gene fusions by Xp11.2 translocations

- ASPL/TFE3 by t(X;17)(p11.2;q25)
- CLTC/TFE3 by t(X;17)(p11.2;q23) CLTC coding for a major subunit of clathrin
- t(X;19)(p11.2;q13.1) (20679884)


- High chromosomal copy number alterations in xp11 translocation renal cell carcinomas detected by array comparative genomic hybridization are associated with aggressive behavior. Pan CC, Sung MT, Huang HY, Yeh KT. Am J Surg Pathol. 2013 Jul;37(7):1116-9. doi : 10.1097/PAS.0b013e318293d872 PMID: 23759936

- Differential expression of cathepsin K in neoplasms harboring TFE3 gene fusions. Martignoni G, Gobbo S, Camparo P, Brunelli M, Munari E, Segala D, Pea M, Bonetti F, Illei PB, Netto GJ, Ladanyi M, Chilosi M, Argani P. Mod Pathol. 2011 May 20. PMID: 21602817

- Xp11 Translocation Renal Cell Carcinoma (RCC): Extended Immunohistochemical Profile Emphasizing Novel RCC Markers. Argani P, Hicks J, De Marzo AM, Albadine R, Illei PB, Ladanyi M, Reuter VE, Netto GJ. Am J Surg Pathol. 2010 Sep;34(9):1295-303. PMID: 20679884

- Xp11.2 translocation renal cell carcinoma occurring during pregnancy with a novel translocation involving chromosome 19: a case report with review of the literature. Armah HB, Parwani AV, Surti U, Bastacky SI. Diagn Pathol. 2009 May 18;4:15. PMID: 19450277 [Free]

- Rakheja D, Kapur P, Tomlinson GE, Margraf LR. Pediatric renal cell carcinomas with Xp11.2 rearrangements are immunoreactive for hMLH1 and hMSH2 proteins. Pediatr Dev Pathol. 2005 Nov-Dec;8(6):615-20. PMID: 16328670

- 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 Sep;28(9):1117-1132. PMID: 15316311

- 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 Jun;27(6):750-61. PMID: 12766578

- Tonk V, Wilson KS, Timmons CF, Schneider NR, Tomlinson GE. Renal cell carcinoma with translocation (X;1). Further evidence for a cytogenetically defined subtype. Cancer Genet Cytogenet. 1995 May;81(1):72-5. PMID: 7773963

- Tomlinson GE, Nisen PD, Timmons CF, Schneider NR. Cytogenetics of a renal cell carcinoma in a 17-month-old child. Evidence for Xp11.2 as a recurring breakpoint. Cancer Genet Cytogenet. 1991 Nov;57(1):11-7. PMID: 1684532