Sialosyl-Le(x) expression defines invasive and metastatic properties of bladder carcinoma

Abstract

Background: Two types of transitional bladder carcinoma have been distinguished based on macroscopic morphology: type A papillary carcinomas, with papillomatous surface outgrowth without infiltration into muscular layer, and type B nodular carcinomas, with a nonpapillomatous surface appearance, most of which display infiltrative growth through muscular layer, and some of which display lymphatic or blood-borne metastasis. However, there is no specific predictor at early stages for later invasive and metastatic clinical outcome of patients with type B tumors.

Methods: The study included 1) glycosphingolipid (GSL) composition of type A and B tumors; 2) histologic and immunohistologic patterns of nodular (type B) bladder carcinoma from 44 patients based on a special sampling procedure termed whole-layer core biopsy (WLCB) using the antisialosyl-Le(x) (anti-SLe(x); SLe(x): NeuAcalpha3Galbeta4[Fucalpha3]GlcNAcbeta3Galbeta4GlcCer) SNH3 antibody or other antibodies; 3) comparison of the incidence of metastasis in patients with SNH3 positive versus SNH3 negative primary tumors and of 5-year survival curves; 4) comparison of bladder carcinoma cell lines from tumors with high versus low malignancy in terms of expression patterns of SLe(x), SLe(a), and other carbohydrates, E-selectin dependent adhesion, and transcript levels of five fucosyltransferases.

Results: Anti-SLe(x) monoclonal antibody (mAb) SNH3 staining of WLCB samples from 44 type B tumors showed that the majority of tumors (n = 31 patients) were SNH3 positive and the minority (n = 13 patients) were SNH3 negative. SNH3 positive patients had more lymph node or blood-borne metastasis and lower 5-year and 7-year survival rates, as indicated by Kaplan-Meier curves (P = 0.001). Staining of samples with other antibodies, including FH6 and CA19-9, was not correlated with long-term survival. Determination of GSL composition in extracts showed that SLe(x) ganglioside was present in all three patients with nodular tumors but absent in all three patients with papillary tumors tested. Bladder carcinoma cell lines from invasive tumors that maintained their metastatic properties were SNH3 positive, showed high levels of alpha1,3-fucosyltransferase VI (FT-VI) and FT-VII, and displayed E-selectin dependent adhesion. Cell lines from noninvasive tumors or normal bladder epithelia were negative for SNH3 reactivity, FT-VI, and FT-VII, and E-selectin dependent adhesion.

Conclusions: SLe(x) expression in primary bladder carcinoma, defined by the mAb SNH3, is a predictor of invasive and metastatic outcome. No other carbohydrate epitope examined to date has equal prognostic value.