Evaluation of different lymph node (LN) variables as prognostic markers in patients undergoing radical cystectomy and extended LN dissection to the level of the inferior mesenteric artery.

OBJECTIVE: To evaluate the prognostic impact of lymph node (LN) variables in patients undergoing radical cystectomy (RC) and extended LN dissection. PATIENTS AND METHODS: From January 2004 to January 2009, 167 patients with bladder cancer underwent RC and extended LN dissection to the level of the inferior mesenteric artery in a surgery-only series with no neoadjuvant or adjuvant chemotherapy. Correlation to prognosis of different LN variables according to presence of LN metastasis, number, localization, extracapsular extension (ECE), size, volume, LN density and N-stage according to two different Tumour-Node-Metastasis (TNM) classifications were analysed. RESULTS: In all, 43 patients (26%) had LN metastases. In univariate analysis, gender, T-stage and several different LN variables stratified by presence of LN metastasis, number of positive LNs, anatomical localisation, ECE, LN density, size and volume of positive LNs, were significant prognostic predictors. Female gender, advanced T-stage, presence of LN metastasis, non-regional LN metastases (M-positive) and number of positive LNs (1 vs >1) were significant adverse prognostic predictors in multivariate analysis, whereas the other LN variables were not. Inclusion of the common iliac LNs in the regional LNs as suggested in the seventh edition of the TNM classification was relevant regarding prognosis. However, subclassification based on location was not correlated to prognosis. The new N3 category therefore seems superfluous. CONCLUSIONS: LN-positive patients have a poor prognosis, especially if >1 positive LN is present. Despite several different suggestions of new LN-dependent prognostic factors, none of the tested variables were independently significant in the present series.

Lymph node mapping in patients with bladder cancer undergoing radical cystectomy and lymph node dissection to the level of the inferior mesenteric artery.

OBJECTIVE: To evaluate extended lymph node dissection (LND) as a nodal staging tool in the treatment of invasive carcinoma of the urinary bladder and to suggest a reasonable proximal limit of the dissection. PATIENTS AND METHODS: In all, 170 patients underwent radical cystectomy with extended LND up to the level of the inferior mesenteric artery. Specimens were evaluated as 13 separate packages from pre-designated anatomical locations. The number of LNs and presence of positive LNs (LN+) at each location was prospectively registered. RESULTS: The median (range) number of LNs removed was 24 (6-62). In all, 25.3% of the patients had LN+. The median (range) number of LN+ was 2 (1-20). Advanced T-stage was correlated with a higher risk of LN+ but not to the specific location of the LN+. Two patients had LN+ above the common iliac bifurcation with no LN+ more distally located within the pelvic region. All other patients with LN+ above the common iliac bifurcation had more distally located LN+. There were no skip lesions to LNs above the aortic bifurcation. CONCLUSIONS: Extended LND above the common iliac bifurcation including the presacral area provides a more accurate LN staging compared with a standard pelvic LND. Extending the limits above the aortic bifurcation is not necessary from a staging perspective.

Emmprin and survivin predict response and survival following cisplatin-containing chemotherapy in patients with advanced bladder cancer.

PURPOSE: Cisplatin-containing chemotherapy is the standard of care for patients with locally advanced and metastatic transitional cell carcinoma of the urothelium. The response rate is approximately 50% and tumor-derived molecular prognostic markers are desirable for improved estimation of response and survival. EXPERIMENTAL DESIGN: Affymetrix GeneChip expression profiling was carried out using tumor material from 30 patients. A set of genes with an expression highly correlated to survival time after chemotherapy was identified. Two genes were selected for validation by immunohistochemistry in an independent material of 124 patients receiving cisplatin-containing therapy. RESULTS: Fifty-five differentially expressed genes correlated significantly to survival time. Two of the protein products (emmprin and survivin) were validated using immunohistochemistry. Multivariate analysis identified emmprin expression (hazard ratio, 2.23; P < 0.0001) and survivin expression (hazard ratio, 2.46; P < 0.0001) as independent prognostic markers for poor outcome, together with the presence of visceral metastases (hazard ratio, 2.62; P < 0.0001). In the clinical good prognostic group of patients without visceral metastases, both markers showed significant discriminating power as supplemental risk factors (P < 0.0001). Within this group of patients, the subgroups of patients with no positive, one positive, or two positive immunohistochemistry scores (emmprin and survivin) had estimated 5-year survival rates of 44.0%, 21.1%, and 0%, respectively. Response to chemotherapy could also be predicted with an odds ratio of 4.41 (95% confidence interval, 1.91-10.1) and 2.48 (95% confidence interval, 1.1-5.5) for emmprin and survivin, respectively. CONCLUSIONS: Emmprin and survivin proteins were identified as strong independent prognostic factors for response and survival after cisplatin-containing chemotherapy in patients with advanced bladder cancer.

Gene expression signatures predict outcome in non-muscle-invasive bladder carcinoma: a multicenter validation study.

PURPOSE: Clinically useful molecular markers predicting the clinical course of patients diagnosed with non-muscle-invasive bladder cancer are needed to improve treatment outcome. Here, we validated four previously reported gene expression signatures for molecular diagnosis of disease stage and carcinoma in situ (CIS) and for predicting disease recurrence and progression. EXPERIMENTAL DESIGN: We analyzed tumors from 404 patients diagnosed with bladder cancer in hospitals in Denmark, Sweden, England, Spain, and France using custom microarrays. Molecular classifications were compared with pathologic diagnosis and clinical outcome. RESULTS: Classification of disease stage using a 52-gene classifier was found to be highly significantly correlated with pathologic stage (P < 0.001). Furthermore, the classifier added information regarding disease progression of T(a) or T(1) tumors (P < 0.001). The molecular 88-gene progression classifier was highly significantly correlated with progression-free survival (P < 0.001) and cancer-specific survival (P = 0.001). Multivariate Cox regression analysis showed the progression classifier to be an independently significant variable associated with disease progression after adjustment for age, sex, stage, grade, and treatment (hazard ratio, 2.3; P = 0.007). The diagnosis of CIS using a 68-gene classifier showed a highly significant correlation with histopathologic CIS diagnosis (odds ratio, 5.8; P < 0.001) in multivariate logistic regression analysis. CONCLUSION: This multicenter validation study confirms in an independent series the clinical utility of molecular classifiers to predict the outcome of patients initially diagnosed with non-muscle-invasive bladder cancer. This information may be useful to better guide patient treatment.