Introduction: The prognostic value of tumor infiltrating lymphocytes (TIL) is well established in pure urothelial carcinoma. Amongst variant histologies of bladder cancer squamous cell carcinoma (SCC) is the most frequent subtype. However, tumor infiltration of B- and T-cells and its impact on survival of patients after radical cystectomy has not been analyzed in SCC until today.
Methods: Patients with SCC undergoing radical cystectomy were retrospectively selected from a large single center cohort. Patients were followed-up according to the guidelines of the European Association of Urology (EAU) and at least once per year by mail.
The institute of pathology of our academic center reevaluated all samples from our cohort according to the latest classification of the American Joint Committee on Cancer (AJCC) in order to confirm SCC. Also, immunohistochemical staining for B- and T-cell markers (CD3, CD4, CD8 and CD20) were conducted.
Statistical analysis for overall survival (OS) and progression free survival (PFS) was performed using Kaplan-Meier-Method and cox-regression model for multivariate analysis.
Results: A total of 1600 patients underwent radical cystectomy at our academic center. 61 patients revealed SCC of the bladder in the final histological specimen and had available samples for analysis as well as complete follow-up. Median age of our cohort is 65 (range: 37-85) years and median follow-up of all patients was 16 (range 0-175) months.
27 tumors of our cohort were positive for CD3, 28 for CD4, 26 for CD8 and 27 for CD20. In twelve samples all B- and T-cell receptors were expressed, whereas 20 samples revealed no expression for B- and T-cell receptors.
Expression of CD3 (2-year OS: 72.4% vs 21.7%, p<0.001), CD4 (2-year OS: 56.7% vs 36.9%, p=0.045), CD8 (2-year OS: 68.9% vs 30.2%, p=0.001), and CD20 (2-year OS: 64.5% vs 30.4%, p<0.001) was associated with favorable OS. Detection of CD3 (2-year PFS: 66.3% vs 29.6%, p=0.025) and CD20 (2-year PFS: 68.5% vs 22.6%, p=0.002) showed prolonged PFS. In contrast, CD4 positive (2-year PFS: 55.7% vs 39.1%, p=0.292) and CD8 positive tumors (2-year PFS: 64.5% vs 33.5%, p=0.069) had no significant differences in PFS.
In the multivariate analysis, CD3 (HR: 0.163, CI: 0.044-0.614), CD8 (HR: 0.265, CI: 0.081-0.864), high-grade histology (HR: 5.189, CI: 1.288-20.901) and lymph node metastases (HR: 14.178, CI: 3.075-65.376) were independent predictors of OS. However, CD20 (HR: 0.095, CI: 0.019-0.464), high-grade histology (HR: 5.285, CI: 1.437-19.436), lymph node metastases (HR: 4.625, CI: 1.410-15.171) and distant metastases (HR: 15.765, CI: 2.676-92.865) were independent predictive parameters for PFS.
Conclusions: TILs hold potential to predict oncological outcome in SCC. Expression of CD3 and CD8 predicts OS whereas CD20 predicts PFS in our cohort. Therefore, further research is urgently needed to understand immunoregulation in SCC and thereby path the way towards personalized treatment in variant histologies of bladder cancer.
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