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(American Journal of Pathology. 1999;155:517-526.)
© 1999 American Society for Investigative Pathology

Regular Articles

Hereditary and Sporadic Papillary Renal Carcinomas with c-met Mutations Share a Distinct Morphological Phenotype

Irina A. Lubensky^*, Laura Schmidt, Zhengping Zhuang^*, Gregor Weirich, Svetlana Pack^*, Norman Zambrano^§, McClellan M. Walther^§, Peter Choyke^¶, W. Marston Linehan^§ and Berton Zbar

From the Laboratory of Pathology,^*
National Cancer Institute, Bethesda, Maryland; the Intramural Research Support Program,
Science Applications International Corporation Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland; the Laboratory of Immunobiology,
National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland; the Urologic Oncology Branch,^§
National Cancer Institute, Bethesda, Maryland; and the Department of Radiology,^¶
Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland

Germline mutations of c-met oncogene at 7q31 have been detected in patients with hereditary papillary renal cell carcinoma. In addition, c-met mutations were shown to play a role in 13% of patients with papillary renal cell carcinoma and no family history of renal tumors. The histopathology of papillary renal cell carcinoma with c-met mutations has not been previously described. We analyzed the histopathology of 103 bilateral archival papillary renal cell carcinomas and 4 metastases in 29 patients from 6 hereditary papillary renal cell carcinoma families with germline c-met mutations and 6 papillary renal cell carcinomas with c-met mutations from 5 patients with no family history of renal tumors. Twenty-five sporadic renal tumors with prominent papillary architecture and without somatic c-met mutations were evaluated for comparison. All papillary renal cell carcinomas with c-met mutations were 75 to 100% papillary/tubulopapillary in architecture and showed chromophil basophilic, papillary renal cell carcinoma type 1 histology. Fuhrman 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 papillary adenomas and microscopic papillary lesions in the surrounding renal parenchyma. Clear cells with intracytoplasmic lipid and glycogen were focally present in tumors of 94% papillary renal cell carcinoma patients. Clear cells of papillary renal cell carcinoma had small basophilic nuclei, and clear cell areas lacked a fine vascular network characteristic of conventional (clear) cell renal cell carcinoma. We conclude that papillary renal cell carcinoma patients with c-met mutations develop multiple, bilateral, papillary macroscopic and microscopic renal lesions. Renal tumors with c-met genotype show a distinctive papillary renal cell carcinoma type 1 phenotype and are genetically and histologically different from renal tumors seen in other hereditary renal syndromes and most sporadic renal tumors with papillary architecture. Although all hereditary and sporadic papillary renal cell carcinomas with c-met mutations share papillary renal cell carcinoma type 1 histology, not all type 1 sporadic papillary renal cell carcinomas harbor c-met mutations.

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