Clear cell carcinomas are the most common type, accounting for 65% of renal cell cancers. Histologically, they are composed of cells with clear cytoplasm. Although most are sporadic, they also occur in familial forms or in association with von Hippel-Lindau (VHL) disease. It is the study of VHL disease that has provided molecular insights into the causation of clear cell carcinomas. VHL disease is inherited as an autosomal dominant trait and is characterized by predisposition to a variety of neoplasms, but particularly to hemangioblastomas of the cerebellum and retina. Hundreds of bilateral renal cysts and bilateral, often multiple, clear cell carcinomas develop in 40% to 60% of affected individuals. Those with VHL disease inherit a germline mutation of the VHL gene on chromosomal band 3p25 and lose the second allele by somatic mutation. The VHL gene also is involved in the majority of sporadic clear cell carcinomas. Cytogenetic abnormalities giving rise to loss of a segment on chromosome 3p that harbors the VHL gene are often seen in sporadic renal cell cancers. The second, non-deleted allele is inactivated by a somatic mutation or hypermethylation in 60% of sporadic cases. Thus, loss or inactivation of both copies of the VHL gene seems to be the common underlying molecular abnormality in both sporadic and familial forms of clear cell carcinomas. The VHL protein causes the degradation of hypoxia-induced factors (HIFs), and in the absence of VHL, HIFs are stabilized. HIFs are transcription factors that contribute to carcinogenesis by stimulating the expression of vascular endothelial growth factor (VEGF), an important angiogenic factor, as well as a number of other genes that drive tumor cell growth (Chapter 6). An uncommon familial form of clear cell carcinoma unrelated to VHL disease also is associated with cytogenetic abnormalities involving the short arm of chromosome 3 (3p). In addition, recent deep sequencing of clear cell carcinoma genomes has revealed frequent loss-of-function mutations in genes that encode proteins that regulate histone methylation, suggesting that changes in the “epigenome” have a central role in the genesis of this subtype of renal carcinoma.
Papillary renal cell carcinomas account for 10% to 15% of all renal cancers and are defined in part by their papillary growth pattern. These neoplasms are frequently multifocal and bilateral and appear as early-stage tumors. Like clear cell carcinomas, they occur in familial and sporadic forms, but unlike these neoplasms, papillary renal cancers are not associated with abnormalities of chromosome 3. The culprit in most cases of hereditary papillary renal cell cancers is the MET proto-oncogene, located on chromosome 7q. The MET gene encodes a tyrosine kinase receptor for hepatocyte growth factor. The increased dosage of the MET gene due to duplications of chromosome 7 seems to spur abnormal growth in the proximal tubular epithelial cell precursors of papillary carcinomas. In familial cases, genetic analysis shows activating mutations of MET in the germ line, along with increased gene dosage in the cancers. Activating mutations of the MET gene also are found in a subset of patients with sporadic forms of papillary renal cell carcinoma.
Chromophobe renal carcinomas are the least common form, representing 5% of all renal cell carcinomas. They arise from intercalated cells of collecting ducts. Their name derives from the observation that the tumor cells stain more darkly (i.e., they are less clear) than cells in clear cell carcinomas. These neoplasms are unique in having multiple losses of entire chromosomes leading to extreme hypoploidy. Because of multiple losses, the “critical hit” has not been determined. In general, chromophobe renal cancers have a favorable prognosis.