We report for the first time the occurrence of synchronous bilateral kidney tumors of different histological subtypes (clear cell RCC and papillary RCC) in a patient whom the genetic analysis showed the presence of a germline mutation in the MET oncogene, p.(Val1238Ile).
HPRCC is a very rare inherited syndrome characterized by the development of numerous papillary adenomas or papillary type 1 carcinomas [2, 5]. Germline mutations within the MET gene were first identified by a genome-wide analysis of HPRCC families then somatic MET mutations were also found in some sporadic papillary type 1 RCC [3, 6, 7]. The MET proto-oncogene is located on chromosome 7q31 and encodes the receptor for hepatocyte growth factor (HGF). HGF binding to MET results in autophosphorylation of tyrosines in the met kinase domain leading to activation of MAPKinase and PI3K-AKT signal cascades that drive effectors involved in cell proliferation, migration, and invasion [8, 9]. In cases of germline MET mutations, there is a ligand-independent constitutive kinase activation [3, 10]. Cytogenetic studies showed that the papillary renal carcinomas harboring MET mutations also had trisomy of chromosome 7, resulting from duplication of the chromosome harboring the mutated MET allele [11].
Classically, a specific histological type is described according to each inherited syndrome; for example, clear cell RCC in VHL disease and papillary tumors in HPRCC syndrome. However, recently, two cases of biphasic squamoid RCC (BSARCC) mixed with type 1 papillary RCC have been reported in a familial context of hereditary papillary RCC associated with MET mutation. Immunohistochemical features with expression in both populations of CK7, AMACR and vimentin were consistent with a link between BSARCC and type I papillary RCC [12]. Several hypotheses could be considered to explain the occurrence of various histological types: (1) common metabolic pathway but other cases of mixed histological subtypes should then have been reported; (2) specific histological type according to the type of mutation as described previously for clinical manifestations in VHL disease [13]. Against this possibility, to date, it has not been described any genotype-phenotype correlations in HPRCC. Furthermore, the patient presented one the most frequent MET known mutations. No report has described clear cell RCC or coexistence of other histologic subtypes in the same kidney of a patient with HPRCC except the report of a biphasic squamoid RCC; and (3) both clear cell RCC and papillary RCC are originated from proximal tubules and we can not exclude that additional genetic events of key regulatory genes may push a tumor towards a particular phenotype.
FISH analysis showed trisomy 7 and/or 17 in 3 out of 4 tested cases of papillary RCC and more unexpectedly in the clear cell RCC metastasis. This data would be in favor of a molecular link between both histological subtypes. Trisomy 7 and/or 17 were not observed in the papillary adenomas, perhaps influenced by difficulty evaluating sufficient numbers of tumor cells in microscopic papillary adenomas and a potential lower rate of these alterations in adenomas compared to papillary carcinomas. Interestingly, among the 3 clear cell RCC, VHL deletion was observed in only one case.
In summary, it is important to remember that some genomic alterations might be associated with synchronous bilateral kidney tumors with different histological types. The pathologist must be aware that the presence of a non-papillary RCC associated with numerous papillary adenomas or type I carcinomas should not exclude the diagnostic suspicion of HPRCC and thus to perform a thorough genomic study.