Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype

Germline mutations of c-met oncogene at 7q31 have been detected in patients with hereditary papillary renal cell carcinoma. In addition, c-met mutatio ns were shown to play a role in 13% of patients with papillary renal cell c arcinoma and no family history of renal tumors. The histopathology of papil lary renal cell carcinoma with c-met mutations has not been previously desc ribed, We analyzed the histopathology of 103 bilateral archival papillary r enal cell carcinomas and 4 metastases in 29 patients from 6 hereditary papi llary renal cell carcinoma families with germline c-met mutations and 6 pap illary renal cell carcinomas with c-met mutations from 5 patients with no f amily history of rectal tumors. Twenty-five sporadic renal tumors with prom inent papillary architecture and without somatic c-met mutations were evalu ated for comparison. All papillary renal cell carcinomas with c-met mutatio ns were 75 to 100% papillary/tubulopapillary in architecture and showed chr omophil basophilic, papillary renal cell carcinoma type 1 histology. Fuhrma n nuclear grade 1-2 was seen in tumors from 23 patients, and nuclear grade 3 was observed focally in 8 patients. Seventeen patients had multiple papil lary adenomas and microscopic papillary lesions in the surrounding renal pa renchyma Clear cells with intracytoplasmic Lipid and glycogen were focally present in tumors of 94% papillary renal cell carcinoma patients. Clear cel ls of papillary renal. cell carcinoma had small basophilic nuclei, and clea r cell areas lacked a fine vascular network characteristic of conventional (clear) cell renal cell carcinoma. We conclude that papillary renal cell ca rcinoma patients with c-met mutations develop multiple, bilateral, papillar y macroscopic and microscopic renal lesions. Renal tumors with c-met genoty pe show a distinctive papillary renal cell carcinoma type 1 phenotype and a re genetically and histologically different from renal tumors seen in other hereditary renal syndromes and most sporadic renal tumors with papillary a rchitecture. Although all hereditary and sporadic papillary renal cell carc inomas with c-met mutations share papillary renal cell carcinoma type 1 his tology, not all type 1 sporadic papillary renal cell carcinomas harbor c-me t mutations.