Tumor microenvironment inflammation plays an important role in both tumor recurrence and progression. Neutrophils within tumor nests can behave as an anti-tumor (N1) phenotype; by inducing cytotoxicity, tumor rejection and anti-tumor immune memory or Pro-tumour phenotype (N2) which promotes tumour progression through enhancing angiogenesis, invasion, metastasis and immunosuppression [22–24]. Moreover, lymphocytes located around tumor cells have dual regulatory roles in both anti-tumor immune responses, by inhibiting tumor growth and tumor progression or by creating a microenvironment, which stimulates tumor outgrowth and protection the tumour from the immunological events [20, 24]. The present study investigated the association between TINs and CD8 + T lymphocytes with early recurrence in patients newly diagnosed with non-muscle invasive bladder urothelial carcinoma.
Our study demonstrated that TINs had pro-carcinogenic effects on tumor recurrence and progression, as by using Kaplan-Meier survival analysis, it showed that TIN were statistically significantly related to the short RFS (p = 0.03). This finding was agreeing with that previously reported in malignancy as regards; UB carcinoma , renal cell carcinoma , non-small cell lung cancer , and esophageal carcinoma , suggesting the associations between the presence of TINs and poor prognosis. Moreover, in the present study, regarding the prognosis, high level of TINs was significantly associated with early recurrence not progression. At the early stage of carcinoma development, neutrophils show anti-tumor activity which causes cell lysis and stimulates T cell mediated immunity through enhancing the CD4 + and CD8 + T lymphocyte proliferation and activation. Under certain conditions, neutrophils may release certain endogenous mediators, growth-stimulating signals and matrix-degrading proteases during carcinogenesis .
Regarding TILs, we found that in patients with NMIBC, the group with recurrent disease had higher of CD8 + lymphocytes than the group without recurrent disease. In the present study, recurrence as well as progression were statistically significantly higher in the high CD8 + TILs group in comparison to low CD8 TILs group (p = 0.012 and 0.049 respectively). Kaplan-Meier survival analysis showed that TILs were statistically significantly related to the short RFS (p = 0.001). This finding is consistent with that reported in Liu et al.  they showed that low CD8 + TILs were an independent favorable prognostic factor in NMIBC, However, the association between TILs and recurrence RFS of NMIBC patients was non-significant in their study. Krpina et al,  reported that the abundant CD8 + TILs were related to higher risks of recurrence. On the other hand, it has been reported that patients with progressive BC, who showed higher numbers of CD8 + TIL had better disease-free survival than did patients with similar-staged of BC and fewer numbers of CD8 TIL . Such conflicting data necessitate larger sample studies to confirm such results and to highlight the possibility of other factors in determining the fate of CD8 TIL in tumour biology.
Neutrophil to lymphocyte ratio (NLR) reflects the immune response against tumor cells, with both its innate (neutrophils) and adaptive (lymphocytes) immune responses, with a high NLR value indicates a potent inflammatory reaction, which in turn, correlates with decreased tumor-specific immunity [28, 29]. It has been reported that NLR was considered as a prognostic marker in urothelial bladder cancer, as well as metastatic and advanced disease . In addition, Morizawa et al.  showed that NLR was significantly associated with recurrence-free survival, cancer-specific survival, and overall survival. Moreover, Krane et al.  reported that the patients with elevated NLR before radical cystectomy have worse overall survival than patients without elevated NLR. Other studies reported that a low NLR was related to better response to neoadjuvant chemotherapy [32, 33] and there was a significant relationship between NLR and both pathological response and survival . In the present study, we found that NLRs showed no statistically significant relation to short RFS and recurrence, but only high NLR is associated with an increased risk of tumour progression in NMIBC. Again, such discrepancy in the results highlight the complexity of inflammatory response in urothelial carcinogenesis and that other factors could potentiate or attenuate the role of inflammatory cells as an anti-tumor or pro-tumor cells.
As regards tumour stage and grade, our study showed that there was a significant correlation between higher stage and grade and increased tumour recurrence and progression and this findings constancy with the previous studies [3, 5]. In Ta LG, the rate of recurrence was significantly correlated to higher (TINs, TILs and NLR), this results was in agreement with others. [19, 20] The Ta HG did not show any progression, or recurrence that limits the ability to statistically analyze the corresponding association. In T1 LG tumour: low TINs, high TILs, and low NLR were associated lower recurrence and progression rate, and clinically the recurrent rate was high in high TINs (4/10), low TILs (4/9) and high NLR (4/8). In T1 HG tumours: high TINs and high NLR were associated clinical and statistically lower recurrence rate. while, clinically in T1 HG higher recurrent rate was seen low TINs (10/20) and NLR (10/20), this finding was agreeing with that previously reported in UB carcinoma , and others carcinomas [15, 25–27]
The major limitations in this study were the limited numbers of the study population and the short term follow up. Further studies with large sample size are needed to demonstrate the correlation between tumour infiltration immunological cells and the clinical-pathological features, with long term follow up are required to demonstrate the prognostic effect of such immunological cells in tumour behavior