The relationship between MET expression and subtypes of RCC has not been well elucidated in sporadic RCC. In present study, diffuse and strong MET expression was found in papillary RCC and collecting duct carcinoma, whereas clear cell RCC and chromophobe RCC showed negative or focal cytoplasmic staining. Inoue et al. (17
) reported that all 20 RCC with tubulo-papillary histology showed positive staining for MET, and 98% (88 out of 90) of clear cell RCC showed negative or focal staining, which well corresponds to our result. There was a few reports showing no association with the subtypes of RCC and MET expression (18
). The number of cases in those reports, however, is thought to be relatively small to reveal the relationship of the subtypes of RCC and MET expression. Diffuse and strong immunoexpression of MET in papillary RCC and collecting duct carcinoma might be helpful in discriminating from the other subtypes of RCC with tubulo-papillary growth.
Renal neoplasm has been a major subject of cytogenetic and molecular genetic studies. Papillary RCC was characterized by trisomy of chromosomes 7, 16, 17 and loss of Y chromosome in male patients in cytogenetics (20
). A germline mutation of met
gene of 7q31 has been detected in patients with hereditary papillary renal carcinoma (8
) as well as a small portion of sporadic papillary RCC (9
). In present study, the over expression of MET was detected in 90% of sporadic papillary RCC by the method of immunohistochemistry, which was much higher than the result of the previous study using molecular method that identified met
mutations in 13% of sporadic RCC (9
). Our result is consistent with that of a recent study reporting MET over expression in 80% of sporadic RCC by the immunohistochemistry (11
). Trisomy of chromosome 7 has been reported in 95% of sporadic RCC (20
), and it may result in an increased met
mRNA copy number, as described by Glukhova et al. (21
). The increased met
mRNA copy number may lead to MET overexpression in protein level. The significance of chromosome 7 trisomy observed in sporadic papillary RCC is that the trisomy may serve to increase the dosage of the met
allele. The tumorigenesis by met
is known to be quantitatively related to its level of activation (22
). Thus, it appears that in addition to met
mutation, MET overexpression contributes to the sporadic RCC.
Regarding the subtypes of papillary RCC, no significant difference of MET expression between two subtypes was observed in our study. In type 1 and type 2 papillary RCC, 92% and 86% of the cases, respectively, showed immunoexpression of MET (). Delahunt and Eble proposed subdividing papillary RCC into two subtypes, type 1 with small cells and pale cytoplasm and type 2 with large cells and eosinophilic cytoplasm (13
). In the study by Lubensky et al. (23
), all 6 sporadic RCC with met
mutations demonstrated type 1, whereas 10 papillary RCC without met
mutations demonstrated both types equally. In the recent immunohistochemical study by Sweeney et al. (11
), however, no significant difference of MET expression between two subtypes was found. In their study, MET was expressed in 81.1% and 76.9% of type 1 and type 2 papillary RCC, respectively, which was consistent with our results. There might be some discrepancies between the changes in molecular level and the immunoexpression of MET in ours.
It is of interest that the diffuse and strong expression of MET was observed in all cases of collecting duct carcinoma, while the majority of chromophobe RCC and all oncocytomas did lack in the expression of MET. The molecular characteristics of renal tumors originating from non-proximal tubules, including collecting duct carcinoma, chromophobe RCC and oncocytoma are not well known. Polascik et al. (24
) showed that the loss of heterozygosity of chromosomal arm 3p that is known to be associated with clear cell RCC was infrequent in both collecting duct carcinoma and oncocytoma, and concluded that the molecular events contributing to the development of non-proximal nephron tumors were distinct from those associated with renal tumors originating from the proximal tubules. It is unclear why MET expression was different between in collecting duct carcinoma and in chromophobe RCC or oncocytoma. We suspected that this might be due to the difference in the origin of collecting duct carcinoma and the others. The collecting duct carcinoma is thought to arise from the distal segment of the collecting duct of Bellini, while renal oncocytoma and chromophobe renal carcinoma appears to arise in the cortex from the intercalated cells of the proximal connecting segment of the collecting ducts (25
). It was not apparent, however, whether the collecting duct of MET overexpression was in the distal segment of Bellini or the proximal connecting segment of the collecting ducts. Further investigations on the staining localization in normal renal structure and molecular studies seem to explain the difference of MET overexpression between collecting duct carcinoma and chromophobe RCC and oncocytoma.
Most cases (92%) of urothelial carcinoma included in our study exhibited strong (2+) MET expression. Li et al. showed MET immunoreactivity in all 49 urothelial carcinomas of the urinary bladder (27
) and Tamatani et al. demonstrated that HGF stimulated migration and invasion of the rat tumorigenic urothelial cell lines in vitro (28
), while in a study by Natali et al., all 5 urothelial carcinoma of renal pelvis did not display MET expression (19
). As pointed out by Pisters et al. (18
), this difference may be related to the fact that we used a polyclonal antibody which could theoretically detect more epitopes of the MET protein, whereas the antibody used in the study by Natali et al. (19
) was monoclonal antibody against the extracellular domain of the MET protein.
We demonstrated that MET expression in clear cell RCC were correlated with several clinicopathological parameters, such as infiltrative growth pattern, tumoral necrosis, pelvic or ureteral involvement, calyceal involvement, and lymphatic invasion, which were thought to be related to the invasiveness or aggressiveness of the tumor (). In addition, there was a significant relationship between MET immunoreactivity and the higher Fuhrman's nuclear grade, which is an important prognostic factor (p
<0.001). These results are comparable to those of a few studies demonstrating strong expression of MET in more than 80% of RCC with higher grades (18
). HGF/SF-MET pathway was reported to enhance the invasive properties in the chemoinvasion assay and inhibit Fas-induced apoptosis in vitro (7
). In present study, MET expression was more frequently found in the tumors of advanced stage (stage 3 or 4) than in localized stage (stage 1 or 2), and all three clear cell RCC with distant metastasis expressed MET, although it was not statistically significant.
In conclusion, we demonstrated that MET was diffusely and strongly expressed in papillary RCC, collecting duct carcinoma, and urothelial carcinoma of renal pelvis, whereas no or focal expression of MET was observed in clear cell RCC, chromophobe RCC and oncocytoma. Diffuse and strong immunoexpression of MET in papillary RCC and collecting duct carcinoma might be helpful in discriminating from the other subtypes of RCC with tubulo-papillary growth. In clear cell RCC, there was a significant relationship between MET expression and high nuclear grade, as well as several clinicopathological parameters including infiltrative growth, tumoral necrosis, pelvic or ureteral involvement, calyceal involvement, and lymphatic invasion, implying invasiveness or aggressiveness of the tumor.