Intratumoral lymphatics and lymphatic vessel invasion detected by D2-40 are essential for lymph node metastasis in bladder transitional cell carcinoma.

Bladder cancer is frequently associated with regional lymph node metastasis at the time of diagnosis or after initial treatment, and lymph node metastasis is crucial for clinical therapeutic strategies. Lymphangiogenesis, detected by antibodies specific for lymphatic endothelial cells, is correlated with cancer spread, but the mechanisms that underlie lymphatic spread and the role of lymphangiogenesis in cancer metastasis has been less clear. The aim of this study was to investigate the association of vascular endothelial growth factor (VEGF)-D expression, intratumoral lymphatics, and lymphatic invasion associated with lymph node metastasis as well as the prognostic analysis in patients with bladder transitional cell carcinoma (TCC). The VEGF-D expression was evaluated by immunohistochemistry in 72 specimens, and tumoral lymphatic vessels were measured by D2-40. Counts of lymph vessels were taken in intratumoral and peritumoral areas. Survival analyses and their independent roles were investigated using univariate and multivariate analysis models. The high expression of VEGF-D was closely associated with the intratumoral lymphatic vessels, tumoral lymphatic invasion, and lymph node metastasis as well as a shorter overall survival. Higher lymphatic vessel density, intratumoral lymphatics, and lymphatic invasion showed a significant association with lymph node metastasis. Univariate analysis indicated that VEGF-D, intratumoral lymphatics, and lymphatic invasion were associated with overall survival, but they were not independent prognostic factors for bladder TCC in multivariate analysis. We conclude that VEGF-D plays an essential role in tumoral lymphangiogenesis. Intratumoral lymphatics and lymphatic invasion are important predictive factors of pelvic lymph node metastasis in patients with bladder cancer.

Ma Y ，Hou Y ，Liu B ，Li X ，Yang S ，Ma J ... -  《-》

Vascular endothelial growth factor D and intratumoral lymphatics as independent prognostic factors in epithelial ovarian carcinoma.

Li L ，Liu B ，Li X ，Yang S ，Xiao J ，Chen M ，Zhang Y ，Ma J ... -  《-》

Vascular endothelial growth factor-C (VEGF-C) expression predicts lymph node metastasis of transitional cell carcinoma of the bladder.

It has been found that expression of vascular endothelial growth factor-C (VEGF-C) in several carcinomas is significantly associated with angiogenesis, lymphangiogenesis and regional lymph node metastasis. However, VEGF-C expression in bladder transitional cell carcinoma (TCC) has not yet been reported. To elucidate the role of VEGF-C in bladder TCC, we examined VEGF-C expression in bladder TCC and pelvic lymph node metastasis specimens obtained from patients who underwent radical cystectomy. Eighty-seven patients who underwent radical cystectomy for clinically organ-confined TCC of the bladder were enrolled in the present study. No neoadjuvant treatments, except transurethral resection of the tumor, were given to these patients. The VEGF-C expressions of 87 bladder tumors and 20 pelvic lymph node metastasis specimens were examined immunohistochemically and the association between VEGF-C expression and clinicopathological factors, including angiogenesis as evaluated by microvessel density (MVD), was also examined. Vascular endothelial growth factor-C expression was found in the cytoplasm of tumor cells, but not in the normal transitional epithelium. Vascular endothelial growth factor-C expression was significantly associated with the pathological T stage (P = 0.0289), pelvic lymph node metastasis (P < 0.0001), lymphatic involvement (P = 0.0008), venous involvement (P = 0.0002) and high MVD (P = 0.0043). The multivariate analysis demonstrated that VEGF-C expression and high MVD in bladder TCC were independent risk factors influencing the pelvic lymph node metastasis. Moreover, the patients with VEGF-C-positive tumors had significantly poorer prognoses than those with the VEGF-C-negative tumors (P = 0.0087) in the univariate analysis. The multivariate analysis based on Cox proportional hazard model showed that the independent prognostic factors were patient age (P = 0.0132) and pelvic lymph node metastasis (P = 0.0333). The present study suggests that VEGF-C expression is an important predictive factor of pelvic lymph node metastasis in bladder cancer patients.

Suzuki K ，Morita T ，Tokue A 《INTERNATIONAL JOURNAL OF UROLOGY》

[New markers for pharmacological targeting in bladder cancer with lymph node metastasis].

VECF-C, -D and their receptor Flt-4 are associated with lymph node metastasis and a poor prognosis in many tumour entities. We have analysed the expression of these factors in transitional cell carcinoma of the bladder with positive lymph nodes. We constructed "tissue microarrays" (TMAs) from bladder cancer specimens (BC-array) and corresponding lymph node metastases (LN-array) of 73 patients, who all underwent radical cystectomy and bilateral lymphadenectomy. After immunohistochemical staining, semiquantitative analysis was performed using polyclonal antibodies for VEGF-C, -D and Flt-4. The results were correlated with various histopathological and clinical variables. VEGF-C (p = 0.007) and Flt-4 (p = 0.019) were significantly higher expressed in the LN-array compared to the BC-array. In the LN-array VEGF-D correlated with T-(p = 0.013) and N-stage (p = 0.030) Flt-4 correlated with N-stage (p = 0.011) and distant metastasis (p = 0.011) in the BC-array, as well as with T-(p = 0.004) and N-stage (p = 0.014) in the LN-array. Accordingly, in the LN-array VEGF-D positive patients showed both a shorter disease-free survival (p = 0.028) and a poorer overall survival (p = 0.014). Similarly, Flt-4 positive patients had a shorter overall survival (p = 0.033). Patients with transitional bladder cancer and lymph node metastasis have a poorer prognosis when they overexpress VEGF-D and Flt-4 in their lymph nodes. Pharmacological targeting of these factors could improve their overall survival.

Herrmann E ，Eltze E ，Köpke T ，Bolenz C ，Bierer S ，Neumann J ，Hertle L ，Wülfing C ... -  《AKTUELLE UROLOGIE》

Prognostic implications of lymphangiogenesis in muscle-invasive transitional cell carcinoma of the bladder.

Fernández MI ，Bolenz C ，Trojan L ，Steidler A ，Weiss C ，Alken P ，Grobholz R ，Michel MS ... -  《EUROPEAN UROLOGY》