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Clear-cell papillary renal cell carcinoma: molecular and immunohistochemical analysis with emphasis on the von Hippel-Lindau gene and hypoxia-inducible factor pathway-related proteins.
- Source :
-
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc [Mod Pathol] 2011 Sep; Vol. 24 (9), pp. 1207-20. Date of Electronic Publication: 2011 May 20. - Publication Year :
- 2011
-
Abstract
- Over the past few years several investigators have independently described unique low-grade renal epithelial neoplasms with clear cytoplasm, focal to diffuse papillary architecture, and occasional leiomyomatous stromal metaplasia that are not currently recognized in the World Health Organization classification of renal tumors. These tumors have been referred to by a variety of names including clear-cell papillary renal cell carcinoma and recently "clear-cell tubulopapillary renal cell carcinoma". On the basis of the available data, such tumors are positive for cytokeratin 7 (CK7) and carbonic anhydrase IX (CA9), while being negative for CD10, α-methylacyl-CoA racemase (AMACR), and TFE3. These tumors reportedly lack trisomies of chromosomes 7 and 17, deletions of 3p25, von Hippel-Lindau (VHL) gene mutations, and VHL promoter hypermethylation. Herein, we report on nine cases of this tumor emphasizing detailed studies of the VHL gene and hypoxia-inducible factor (HIF) pathway. Molecular studies performed included VHL mutational analysis, copy number changes assessed using single-nucleotide polymorphism arrays, and qRT-PCR for VHL mRNA expression. Immunohistochemical stains for markers of HIF pathway activation (HIF-1α, CA9, and glucose transporter-1 (GLUT-1)) as well as other relevant markers (CK7, CD10, AMACR, and TFE3) were performed. None of our tumors harbored VHL gene mutations, losses of chromosomal region 3p25, or trisomies of chromosomes 7 or 17. VHL mRNA was overexpressed in our tumors relative to normal renal tissue and clear-cell renal cell carcinoma. All cases showed strong co-expression of CK7, HIF-1α, GLUT-1, and CA9. No expression of TFE3, CD10, or AMACR was seen. The morphological, immunophenotypic, and molecular features of these unique low-grade tumors are sufficiently distinct to allow separation from other renal cell carcinoma subtypes. The co-expression of CA9, HIF-1α, and GLUT-1 in the absence of VHL gene alterations in clear-cell papillary renal cell carcinoma suggests activation of the HIF pathway by non-VHL-dependent mechanisms.
- Subjects :
- Aged
Carcinoma, Papillary genetics
Carcinoma, Papillary metabolism
Carcinoma, Papillary pathology
Carcinoma, Renal Cell pathology
DNA Mutational Analysis
Female
Gene Dosage
Humans
Immunohistochemistry
Immunophenotyping
Kidney Neoplasms pathology
Male
Middle Aged
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction physiology
Tissue Array Analysis
Von Hippel-Lindau Tumor Suppressor Protein metabolism
Carcinoma, Renal Cell genetics
Carcinoma, Renal Cell metabolism
Hypoxia-Inducible Factor 1 metabolism
Kidney Neoplasms genetics
Kidney Neoplasms metabolism
Von Hippel-Lindau Tumor Suppressor Protein genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1530-0285
- Volume :
- 24
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
- Publication Type :
- Academic Journal
- Accession number :
- 21602815
- Full Text :
- https://doi.org/10.1038/modpathol.2011.80