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

Pedram Argani, Raluca Yonescu, Laura Morsberger, Kerry Morris, George J. Netto, Nathan Smith, Nilda Gonzalez, Peter B Illei, Marc Ladanyi, Constance A. Griffin

Research output: Contribution to journalArticle

Abstract

A subset of renal cell carcinomas (RCCs) is characterized by t(6;11)(p21;q12), which results in fusion of the untranslated Alpha (MALAT1) gene to the TFEB gene. Only 21 genetically confirmed cases of t(6;11) RCCs have been reported. This neoplasm typically demonstrates a distinctive biphasic morphology, comprising larger epithelioid cells and smaller cells clustered around basement membrane material; however, the full spectrum of its morphologic appearances is not known. The t(6;11) RCCs differ from most conventional RCCs in that they consistently express melanocytic immunohistochemical (IHC) markers such as HMB45 and Melan A and the cysteine protease cathepsin K but are often negative for epithelial markers such as cytokeratins. TFEB IHC has been proven to be useful to confirm the diagnosis of t(6;11) RCCs in archival material, because native TFEB is upregulated through promoter substitution by the gene fusion. However, IHC is highly fixation dependent and has been proven to be particularly difficult for TFEB. A validated fluorescence in situ hybridization (FISH) assay for molecular confirmation of the t(6;11) RCC in archival formalin-fixed, paraffin-embedded material has not been previously reported. We report herein the development of a break-apart TFEB FISH assay for the diagnosis of t(6;11)(p21;q12) RCCs. We validated the assay on 4 genetically confirmed cases and 76 relevant expected negative control cases and used the assay to report 8 new cases that expand the clinicopathologic spectrum of t(6;11) RCCs. An additional previously reported TFEB IHC-positive case was confirmed by TFEB FISH in 46-year-old archival material. In conclusion, TFEB FISH is a robust, clinically validated assay that can confirm the diagnosis of t(6;11) RCC in archival material and should allow a more comprehensive clinicopathologic delineation of this recently recognized neoplastic entity.

Original languageEnglish (US)
Pages (from-to)1516-1526
Number of pages11
JournalAmerican Journal of Surgical Pathology
Volume36
Issue number10
DOIs
StatePublished - Oct 2012

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Fluorescence In Situ Hybridization
Renal Cell Carcinoma
Paraffin
MART-1 Antigen
Cathepsin K
Endopeptidase K
Epithelioid Cells
Cysteine Proteases
Gene Fusion
Keratins
Basement Membrane
Formaldehyde
Genes

Keywords

  • FISH
  • renal cell carcinoma
  • TFE3
  • TFEB
  • translocation

ASJC Scopus subject areas

  • Anatomy
  • Pathology and Forensic Medicine
  • Surgery

Cite this

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. / Argani, Pedram; Yonescu, Raluca; Morsberger, Laura; Morris, Kerry; Netto, George J.; Smith, Nathan; Gonzalez, Nilda; Illei, Peter B; Ladanyi, Marc; Griffin, Constance A.

In: American Journal of Surgical Pathology, Vol. 36, No. 10, 10.2012, p. 1516-1526.

Research output: Contribution to journalArticle

Argani, Pedram ; Yonescu, Raluca ; Morsberger, Laura ; Morris, Kerry ; Netto, George J. ; Smith, Nathan ; Gonzalez, Nilda ; Illei, Peter B ; Ladanyi, Marc ; Griffin, Constance A. / 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. In: American Journal of Surgical Pathology. 2012 ; Vol. 36, No. 10. pp. 1516-1526.
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abstract = "A subset of renal cell carcinomas (RCCs) is characterized by t(6;11)(p21;q12), which results in fusion of the untranslated Alpha (MALAT1) gene to the TFEB gene. Only 21 genetically confirmed cases of t(6;11) RCCs have been reported. This neoplasm typically demonstrates a distinctive biphasic morphology, comprising larger epithelioid cells and smaller cells clustered around basement membrane material; however, the full spectrum of its morphologic appearances is not known. The t(6;11) RCCs differ from most conventional RCCs in that they consistently express melanocytic immunohistochemical (IHC) markers such as HMB45 and Melan A and the cysteine protease cathepsin K but are often negative for epithelial markers such as cytokeratins. TFEB IHC has been proven to be useful to confirm the diagnosis of t(6;11) RCCs in archival material, because native TFEB is upregulated through promoter substitution by the gene fusion. However, IHC is highly fixation dependent and has been proven to be particularly difficult for TFEB. A validated fluorescence in situ hybridization (FISH) assay for molecular confirmation of the t(6;11) RCC in archival formalin-fixed, paraffin-embedded material has not been previously reported. We report herein the development of a break-apart TFEB FISH assay for the diagnosis of t(6;11)(p21;q12) RCCs. We validated the assay on 4 genetically confirmed cases and 76 relevant expected negative control cases and used the assay to report 8 new cases that expand the clinicopathologic spectrum of t(6;11) RCCs. An additional previously reported TFEB IHC-positive case was confirmed by TFEB FISH in 46-year-old archival material. In conclusion, TFEB FISH is a robust, clinically validated assay that can confirm the diagnosis of t(6;11) RCC in archival material and should allow a more comprehensive clinicopathologic delineation of this recently recognized neoplastic entity.",
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AU - Yonescu, Raluca

AU - Morsberger, Laura

AU - Morris, Kerry

AU - Netto, George J.

AU - Smith, Nathan

AU - Gonzalez, Nilda

AU - Illei, Peter B

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AU - Griffin, Constance A.

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