SPORADIC BILATERAL PAPILLARY RENAL CARCINOMA EXHIBITINGC-MET MUTATION IN THE LEFT KIDNEY TUMOR

YASUYUKI TAKAKI, MUTSUO FURIHATA,* CHIAKI YOSHIKAWA, TAKESHI KISHIDA,MASAHIRO YAO AND TARO SHUIN

From the Departments of Urology and Pathology II, Kochi Medical School, Nankoku, Kochi and Department of Urology, Yokohama CityUniversity School of Medicine, Fuku-ura, Kanazawa-ku, Yokohama, Japan

KEY WORDS: carcinoma, papillary; kidney; genes; mutation

Papillary renal carcinoma is rare and has recently beenrecognized as a new clinicopathological subtype of humanrenal cell carcinoma. Hereditary papillary renal carcinoma isan inherited kidney cancer characterized by multiple andbilateral papillary renal carcinomas. Studies indicate thatmissense mutations of a c-met proto-oncogene lead to consti-tutive activation of c-met protein and contribute to tumori-genesis in a subset of sporadic papillary renal carcinoma.1–3

However, c-met mutations may be present at a low frequencyand not detectable in small sets of papillary renal carcino-mas. We report a case of sporadic bilateral papillary renalcarcinoma with c-met protein over expression exhibiting mis-sense mutation of a c-met proto-oncogene in only the leftkidney tumor.

CASE REPORT

A 70-year-old man was referred to us for bilateral renaltumors detected incidentally on abdominal ultrasonographyand computerized tomography in June 1997 (fig. 1). Medicaland family histories, including family history of renal cellcarcinoma, were not remarkable. With the clinical diagnosisof bilateral renal tumors right radical and left partial ne-phrectomies were performed.

On gross examination the right tumor was 11 3 10 3 9 cm.and weighed 600 gm., and the left tumor was 3 3 2.5 3 2 cm. andweighed 40 gm. The right tumor was dark brown and tan withmulticystic, multiple necrotic and hemorrhagic areas. The left tu-mor was solid, cystic and milk white. Histologically, both tumorswere composed of eosinophilic cuboidal tumor cells with prominentpapillary growth. Stromal infiltration of foam cells and lympho-cytes were also observed. Immunohistochemical examination re-vealed cytoplasmic immunostaining with anti c-met antibody oftumor cells in both tumors (fig. 2).

DNA samples from the peripheral blood and each tumorwere purified and analyzed for mutation at exons 16 to 19 ofthe tyrosine kinase domain of c-met, which are mutation hotspots detected in papillary renal carcinoma, using polymer-ase chain reaction-single strand conformational polymor-phism and DNA sequencing analysis. 2, 3 We identified only abase substitution exhibiting a T to C transition at nucleotideAccepted for publication November 12, 1999.

* Requests for reprints: Department of Pathology II, Kochi MedicalSchool, Nankoku, Kochi, 783-8505, Japan.

FIG. 3. A, polymerase chain reaction-single strand conformationalpolymorphism analysis of c-met demonstrates mutant alleles at exon19 (arrowhead) detected only in left tumor. B, direct DNA sequencinganalysis leveling detected missense mutation of c-met at nucleotide3997 in exon 19 (arrow), resulting in transition from T to C.

FIG. 1. Abdominal computerized tomography shows solid righttumor (arrow) with vast areas of low density and focal high density,and left tumor (arrowhead) with high density.

FIG. 2. Anti c-met antibody by streptavidin-biotin-peroxidasecomplex method reveals positive cell membrane and cytoplasmicimmunostaining of tumor cells with papillary growth. Reduced from3300.

0022-5347/00/1634-1241/0THE JOURNAL OF UROLOGY® Vol. 163, 1241–1242, April 2000Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.® Printed in U.S.A.

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3997 in exon 19 of c-met from the left tumor. This missensemutation results in an amino acid change from methionine tothreonine (fig. 3). No mutations at any exons of c-met weredetected in either tumor or peripheral blood DNA. At 25-month followup there was no evidence of recurrence or me-tastasis.

DISCUSSION

The c-met gene, located in chromosome 7q31.1–34, encodesa receptor tyrosine kinase. Over expression of the c-met pro-tein has been detected in a number of carcinomas, suggestingthat c-met has a role in their carcinogenesis. Schmidt et alreported c-met mutations in the tyrosine kinase domain,including a T to C transition at nucleotide 3997 in exon 19 inboth tumors of patients with sporadic bilateral papillaryrenal carcinoma.2 A recent study indicated that missensemutations of c-met leading to constitutive activation of c-metprotein were infrequent (13%), and that most papillary renalcarcinomas with c-met activation were characterized by tri-somy of chromosome 7 without c-met mutations.3

Our case also demonstrated c-met mutation with over ex-pression of its product only in the left papillary renal carci-noma corresponding to the same missense mutation at thesame codon of c-met reported by Schmidt et al.2 However, the

right papillary renal carcinoma demonstrated over expres-sion of c-met protein but no mutation. These findings suggestthat each papillary renal carcinoma exhibited c-met overexpression. The right tumor was large and focally necroticwith no c-met mutation, while the left tumor was small andlocalized with c-met mutation. They may have progressedindependently by different mechanisms in c-met activation tocontribute to macroscopic and pathological characteristic fea-tures of each papillary renal carcinoma. Additional studies ofbilateral papillary renal carcinoma, including sporadic andhereditary types of tumors, are needed to evaluate thesefindings.

REFERENCES

1. Zbar, B., Glenn, G., Lubensky, I. et al: Hereditary papillary renalcarcinoma: clinical studies in 10 families. J Urol, 153: 907,1995

2. Schmidt, L., Duh, F. M., Chen, F. et al: Germline and somaticmutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet, 16: 68,1997

3. Schmidt, L., Junker, K., Nakaigawa, N. et al.: Novel mutation ofthe MET proto-oncogene in papillary renal carcinomas.Oncogene, 18: 2343, 1999

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