Renal Cell Carcinoma, Papillary, 1

A number sign (#) is used with this entry because papillary renal cell carcinoma-1 (RCCP1) can be caused by heterozygous germline mutation in the MET protooncogene (164860) on chromosome 7q31. Somatic mutations in the MET gene have also been found in papillary renal cell carcinomas.

Description

Hereditary papillary renal cell carcinoma is characterized by the development of multiple, bilateral papillary renal tumors (Zbar et al., 1995). The transmission pattern is consistent with autosomal dominant inheritance with incomplete penetrance.

Papillary renal cell carcinoma is histologically and genetically distinct from 2 other forms of inherited renal carcinoma, von Hippel Lindau disease (193300), caused by mutation in the VHL gene (608537) on chromosome 3, and a form associated with the chromosome translocation t(3;8), as described by Cohen et al. (1979). Bodmer et al. (2002) reviewed the molecular genetics of familial and nonfamilial cases of renal cell carcinoma, including the roles of VHL, MET, and translocations involving chromosomes 1, 3, and X.

For background information and a discussion of genetic heterogeneity of nonpapillary renal cell carcinoma, see RCC (144700).

See also a hereditary syndrome of predisposition to uterine leiomyomas and papillary renal cell carcinoma (HLRCC; 150800) caused by germline mutation in the FH gene (136850).

Clinical Features

In a review of 224 renal cell carcinomas, Mancilla-Jimenez et al. (1976) found that 34 were papillary and 190 of other histologic types. The majority of papillary tumors (85.3%) were in pathologic stage I, whereas more than half of the nonpapillary tumors had extended beyond the limits of the kidney. Follow-up data revealed that the survival for papillary RCC was significantly higher than that for nonpapillary tumors. This difference held true even when tumors in the same pathologic stage were compared. Many papillary tumors, particularly those with a favorable course, were massively necrotic, densely infiltrated by macrophages, or both. In view of these findings, the possibility that host mechanisms are involved in destruction and confinement of the tumor was discussed. Examination of kidney tissue distant from the tumor disclosed, in some cases, atypical hyperplastic changes of collecting tubules; this raised the possibility that some papillary tumors arise from distal tubular epithelium. Hypo- or avascularity was present in all papillary RCCs studied by angiography.

Zbar et al. (1994) described a 3-generation family with members affected with papillary renal cell carcinoma, an uncommon histologic type of renal cell carcinoma. Multiple tumors of varying size were present in both kidneys of affected family members. The disorder was not linked to polymorphic markers on chromosome 3p and there was no loss of heterozygosity at loci on 3p in renal tumors. The authors considered the inherited disorder in this family to be different from recognized hereditary cancer syndromes.

Zbar et al. (1995) sought other families with papillary renal cell carcinoma to determine whether the large family reported by Zbar et al. (1994) represented a distinct class of inherited cancer. They identified an additional 9 families with multiple affected members. Including the affected members of the original family (designated family 150), there were 29 affected male and 12 affected female subjects. Papillary renal cell carcinomas were often detected incidentally in asymptomatic individuals or during screening of asymptomatic members of renal cell carcinoma families. The penetrance, i.e., the proportion of obligate gene carriers that showed medical evidence of the disease, was reduced. The median survival of affected individuals was 52 years. Several instances of male-to-male transmission were observed in these families. The carcinomas were often multiple and bilateral in these cases.

Papillary renal carcinomas are recognized histologically by the presence of vascularized connective tissue stalks surrounded by neoplastic cells (Schmidt et al., 1997).

Pathologic Features

Papillary renal cell carcinoma accounts for about 10 to 15% of all renal cell tumors. It is characterized histologically by the presence of fibrovascular cores with tumor cells arranged in a papillary configuration. Papillary renal cell carcinoma has been morphologically classified into 2 subtypes: type 1 shows small cuboidal cells covering thin papillae with small uniform nuclei and basophilic cytoplasm, whereas type 2 shows large tumor cells with eosinophilic cytoplasms and pseudostratification. Type 2 is generally associated with a poorer prognosis than type 1. However, some tumors show a mixed histologic pattern and the classification of the 2 types is controversial (summary by Yang et al., 2005). RCCP1 due to MET mutations is usually associated with the type 1 pattern (review by Kuroda et al., 2003), whereas papillary renal cell carcinoma in HLRCC is usually associated with the type 2 pattern (review by Lehtonen, 2011).

Cytogenetics

Somatic Abnormalities

Kovacs et al. (1991) found that papillary renal cell carcinoma is characterized by trisomy of chromosomes 3q, 7, 8, 12, 16, 17, or 20, and in men by loss of the Y chromosome. In combined trisomy of chromosomes 7 and 17, the only karyotypic change was found in several tumors, including some with size of less than 2 mm in diameter (Kovacs, 1993). These observations strongly suggested that duplication of genes on chromosomes 7 and 17 are associated with early stage of development of RCCP.

Fischer et al. (1998) found duplication of the same parental allele of chromosome 7 in multiple papillary renal cell carcinomas arising in hereditary RCCP families without germline mutation of the MET protooncogene. In the vast majority of papillary renal cell carcinomas, a polysomy of chromosome 7 is accompanied by trisomy of chromosome 17. Chromosome, comparative genomic hybridization, and allelotyping studies revealed either a full trisomy of chromosome 17, an isochromosome 17q with monosomy of 17p, or a duplication of the 17q21-qter region.

To determine a tumor suppressor gene locus, Balint et al. (1999) analyzed 37 papillary renal cell carcinomas at 25 loci on chromosome 17 by fluorescence microsatellite assay. They found an overlapping duplication of 17q21.32 in 3 cases. They further analyzed this region in DNA obtained from paraffin-embedded tissues of 118 papillary RCCs and narrowed the gene locus to the segment between D17S787 and D17S1799. Altogether, 92% of papillary RCCs showed allelic duplication of this region. They found no RCCP-causing mutations in coding sequences or altered expression of the hepatic leukemia factor gene (HLF; 142385), which maps to the same region. Therefore, another gene within the 300-kb region may be responsible for the development of papillary renal cell carcinoma.

Molecular Genetics

Heterozygous germline mutations in the MET tyrosine kinase gene on 7q32 were detected in families with hereditary RCCP (see, e.g., 164860.0001) and also in cells of some sporadic tumors (164860.0006); see Schmidt et al. (1997) and Zhuang et al. (1998).

Pathogenesis

Cohen and McGovern (2005) noted that in hereditary papillary renal cell carcinoma, the MET receptor tyrosine kinase domain undergoes autoactivating amino acid substitutions, which promote cellular transformation. Subsequently, chromosome 7 harboring the MET mutation is duplicated, increasing the gene dose. Only a small percentage of the cases of the sporadic papillary type have MET mutations. Thus, the pathogenesis of hereditary papillary renal cell carcinoma is usually different from that of sporadic papillary renal cell carcinoma.

Nomenclature

The term 'papillary' is preferred over 'chromophilic' to describe tumors of this type because of the variable affinity of the cytoplasm for routine stains (Kovacs et al., 1997).