J Korean Med Sci.  2006 Aug;21(4):672-677. 10.3346/jkms.2006.21.4.672.

MET Expression in Sporadic Renal Cell Carcinomas

• Choi JS
• Kim MK
• Seo JW
• Choi YL
• Kim DH
• Chun YK
• Ko YH

• KMID: 2157819
• DOI: http://doi.org/10.3346/jkms.2006.21.4.672

Abstract

Although germline mutations of met proto-oncogene on human chromosome 7q31-34 have been known as useful molecular markers of hereditary papillary renal cell carcinoma (RCC), the expression of MET, a product of met proto-oncogene, has not been fully studied in sporadic RCC, along with its clinical significance. We investigated the expression of MET by immunohistochemistry in 182 cases of renal neoplasm encompassing 145 RCC, 25 urothelial carcinomas of renal pelvis, and 12 oncocytomas. MET was diffusely and strongly expressed in 90% of papillary RCC, all collecting duct carcinomas, and 92% of urothelial carcinomas of renal pelvis. On the contrary, clear cell RCC, chromophobe RCC, and oncocytomas were negative or focally positive for MET expression. In clear cell RCC, MET expression was positively correlated with high nuclear grade, presence of infiltrative growth, tumoral necrosis, papillary architecture, sarcomatoid component, tumoral involvement of the renal pelvis or ureter, involvement of the calyx, and lymphatic invasion. In conclusion, diffuse and strong expression of MET in papillary RCC and collecting duct carcinoma might be helpful in discriminating from the other subtypes of RCC with tubular or papillary growth. In case of MET expression observed in clear cell RCC, it might correlate with those clinicopathological parameters implying aggressive behavior.

Keyword

Proto-Oncogene Proteins c-met; Carcinoma, Renal Cell; Kidney Neoplasms; Kidney; Immuno-histochemistry

MeSH Terms

Urothelium/chemistry/pathology
Receptors, Growth Factor/*biosynthesis
Proto-Oncogene Proteins/*biosynthesis
Neoplasm Staging
Kidney Pelvis/chemistry/pathology
Kidney Neoplasms/metabolism/*pathology
Immunohistochemistry
Humans
Carcinoma, Renal Cell/metabolism/*pathology
Adenoma, Oxyphilic/metabolism/pathology

Figure

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  Fig. 1 Immunohistochemical staining for MET shows strong reactivity in the cell membrane with cytoplasmic staining in papillary renal cell carcinoma (A, ×200), collecting duct carcinoma (B, ×400) and urothelial carcinoma of renal pelvis (C, ×400). No reactivity was found in 55% of clear cell renal cell carcinomas (D, ×200).

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  Fig. 2 Immunohistochemical staining for MET shows focal and weak reactivity in the cell membrane with or without cytoplasmic staining in chromophobe renal cell carcinoma (A, ×400). Focal and weak cytoplasmic staining is observed in less than 5% of tumor cells in 11 cases of renal oncocytoma (B, ×400).

Reference

1. Gonzatti-Haces M, Seth A, Park M, Copeland T, Oroszlan S, Vande Woude GF. Characterization of the TPR-MET oncogene p65 and the MET protooncogene p140 protein-tyrosine kinases. Proc Natl Acad Sci USA. 1988. 85:21–25.

2. Rubin JS, Chan AM, Bottaro DP, Burgess WH, Taylor WG, Cech AC, Hirschfield DW, Wong J, Miki T, Finch PW, Aaronson SA. A broad-spectrum human lung fibroblast-derived mitogen is a variant of hepatocyte growth factor. Proc Natl Acad Sci USA. 1991. 88:415–419.

3. Stoker M, Gherardi E, Perryman M, Gray J. Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature. 1987. 327:239–242.

4. Tsarfaty I, Resau JH, Rulong S, Keydar I, Faletto DL, Vande Woude GF. The met proto-oncogene receptor and lumen formation. Science. 1992. 257:1258–1261.

5. Woolf AS, Kolatsi-Joannou M, Hardman P, Andermarcher E, Moorby C, Fine LG, Jat PS, Noble MD, Gherardi E. Roles of hepatocyte growth factor/scatter factor and the met receptor in the early development of the metanephros. J Cell Biol. 1995. 128:171–184.

6. Sonnenberg E, Meyer D, Weidner KM, Birchmeier C. Scatter factor/hepatocyte growth factor and its receptor, the c-met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development. J Cell Biol. 1993. 123:223–235.

7. Horie S, Aruga S, Kawamata H, Okui N, Kakizoe T, Kitamura T. Biological role of HGF/MET pathway in renal cell carcinoma. J Urol. 1999. 161:990–997.

8. Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJ, Walther MM, Tsui LC, Geil L, Orcutt ML, Stackhouse T, Lipan J, Slife L, Brauch H, Decker J, Niehans G, Hughson MD, Moch H, Storkel S, Lerman MI, Linehan WM, Zbar B. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 1997. 16:68–73.

9. Schmidt L, Junker K, Nakaigawa N, Kinjerski T, Weirich G, Miller M, Lubensky I, Neumann HP, Brauch H, Decker J, Vocke C, Brown JA, Jenkins R, Richard S, Bergerheim U, Gerrard B, Dean M, Linehan WM, Zbar B. Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene. 1999. 18:2343–2350.

10. Fischer J, Palmedo G, von Knobloch R, Bugert P, Prayer-Galetti T, Pagano F, Kovacs G. Duplication and overexpression of the mutant allele of the MET proto-oncogene in multiple hereditary papillary renal tumours. Oncogene. 1998. 17:733–739.

11. Sweeney P, EL-Naggar AK, Lin S, Pisters LL. Biological significance of c-met overexpression in papillary renal cell carcinoma. J Urol. 2002. 168:51–55.

12. The World Health Organization Working Group. Eble JN, Sauter G, Epstein JI, Sesterhenn IA, editors. Tumours of the kidney. World Health Organization Classification. Pathology and Genetics of Tumours of the urinary system and male genital organs. 2004. Lyon: IARC Press;9–87.

13. Delahunt B, Eble JN. Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. Mod Pathol. 1997. 10:537–544.

14. Thoenes W, Störkel S, Rumpelt HJ, Moll R, Baum HP, Werner S. Chromophobe cell renal carcinoma and its variants-a report on 32 cases. J Pathol. 1988. 155:277–287.

15. American Joint Committee on Cancer. Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM, Haller DG, Morrow M, editors. Genitourinary Sites. AJCC Cancer staging manual. 2002. 6th ed. Chicago: Springer;301–346.

16. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982. 6:655–663.

17. Inoue K, Karashima T, Chikazawa M, Iiyama T, Yoshikawa C, Furihata M, Ohtsuki Y, Shuin T. Overexpression of c-met proto-oncogene associated with chromophilic renal cell carcinoma with papillary growth. Virchows Arch. 1998. 433:511–515.

18. Pisters LL, el-Naggar AK, Luo W, Malpica A, Lin SH. C-met proto-oncogene expression in benign and malignant human renal tissues. J Urol. 1997. 158:724–728.

19. Natali PG, Prat M, Nicotra MR, Bigotti A, Olivero M, Comoglio PM, Di Renzo MF. Overexpression of the met/HGF receptor in renal cell carcinomas. Int J Cancer. 1996. 69:212–217.

20. Kovacs G. Molecular cytogenetics of renal cell tumors. Adv Cancer Res. 1993. 62:89–124.

21. Glukhova L, Lavialle C, Fauvet D, Chudoba I, Danglot G, Angevin E, Bernheim A, Goguel AF. Mapping of the 7q31 subregion common to the small chromosome 7 derivatives from two sporadic papillary renal cell carcinomas: Increased copy number and overexpression of the MET protooncogne. Oncogene. 2000. 19:754–761.

22. Jeffers M, Schmidt L, Nakaigawa N, Webb CP, Weirich G, Kishida T, Zbar B, Vande Woude GF. Activating mutations for the met tyrosine kinase receptor in human cancer. Proc Natl Acad Sci USA. 1997. 94:11445–11450.

23. Lubensky IA, Schmidt L, Zhuang Z, Weirich G, Pack S, Zambrano N, Walther MM, Choyke P, Linehan WM, Zbar B. Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. Am J Pathol. 1999. 155:517–526.

24. Polascik TJ, Cairns P, Epstein JI, Fuzesi L, Ro JY, Marshall FF, Sidransky D, Schoenberg M. Distal nephron renal tumors: microsatellite allelotype. Cancer Res. 1996. 56:1892–1895.

25. Störkel S, Steart PV, Drenckhahn D, Thoenes W. The human chromophobe cell renal carcinoma: its probable relation to intercalated cells of the collecting duct. Virchows Arch B Cell Pathol Incl Mol Pathol. 1989. 56:237–245.

26. Morra MN, Das S. Renal oncocytoma: a review of histogenesis, histopathology, diagnosis, and treatment. J Urol. 1993. 150:295–302.

27. Li B, Kanamaru H, Noriki S, Fukuda M, Okada K. Differential expression of hepatocyte growth factor in papillary and nodular tumors of the bladder. Int J Urol. 1998. 5:436–440.

28. Tamatani T, Hattori K, Iyer A, Tamatani K, Oyasu R. Hepatocyte growth factor is an invasion/migration factor of rat urothelial carcinoma cells in vitro. Carcinogenesis. 1999. 20:957–962.