There is increasing evidence to show that the presence of systemic inflammation is
correlated with poorer cancer-specific survival in several solid tumors, such as colorectal
carcinoma 6], 15]–20]. Moreover, non-steroidal anti-inflammatory medications have been suggested to reduce
the risk of developing bladder cancer, which implies a critical correlation between
inflammation and bladder tumorigenesis 16], 21]. This study revealed systemic inflammation including CRP was an independent risk
factor to estimate the prognosis. The presence of an inflammatory response can be
determined by both the expression of CRP and an elevation in the NLR 4], 6], 22]. The latter has indeed been shown to be associated with a poorer prognosis in patients
with some solid tumors 4], 6], 11], 23], 24]. The proposed mechanisms include increasing the supply of growth factors, survival
factors, pro-antigenic factors, extracellular matrix-modifying enzymes that can facilitate
invasion and metastasis, and inductive signals that may lead to epithelial-to-mesenchymal
transition 25], 26].. The interaction between the tumor and the immune system of the host not only promotes
tumor cell proliferation and metastasis but also activates the inflammatory cascade
in the host, which leads to the further deterioration of the general condition of
cancer patients 27]. The NLR, as an independent parameter, has been shown to be significantly correlated
with serum CRP levels 28]. However, another study 2], found that the NLR was not a powerful predictor of survival. Thus, there is a biological
rationale for using the NLR, as a measure of systemic host response when evaluating
the association between inflammation and cancer outcomes 26].
It has been proposed that the NLR can be used to estimate the magnitude of systemic
inflammation in cancer patients 5], 29]–31]. It can easily be calculated from routine CBCs with differentials 26]. CBCs are usually determined in the clinical check-ups, thus it is possible to apply
the NLR to all patients, both preoperatively and postoperatively. Thus, the NLR is
a useful tool when considering additional therapy after radical cystectomy. We also
attempted to investigate the numbers of CD66b-positive neutrophils and CD8-positive
lymphocytes in separate sets of bladder cancer tissues. An immunohistochemical analysis
showed that CD8-positive cells were present in the majority of cases, whereas CD66b-positve
cells were seen only in a few cases. Higher numbers of CD8-positive lymphocytes were
strongly correlated with a higher tumor grade or stage. In a previous immunohistochemical
study involving 56 cystectomy cases, a high CD8 density (defined as the presence of
?60 intra-tumoral CD8-positive cells per high-power field) was observed in 10 of 45
(22Â %) muscle-invasive tumors, while it was not observed in any of 11 non-muscle-invasive
tumors 32]. In contrast, although all of the cystectomy cases in which the NLR was assessed
in the present study exhibited muscle-invasive tumors, we found no significant difference
in the NLRs of patients with different pT or pN stages. Thus, there appeared to be
no strong correlation between the number of CD8-positive lymphocytes in the tissue
specimens and the NLR in blood in bladder cancer patients. Nevertheless, in a previous
study using tissue specimens, a high CD8 density was only associated with a favorable
prognosis in???pT1 tumors, which supports the prognostic significance of the NLR via
CBCs 32].
The present study showed that the NLR was an independent prognostic factor in bladder
cancer patients who underwent radical cystectomy. Tumor characteristics are known
to assist in the prediction of the risk of disease recurrence and progression 33]. The European Organization for Research and Treatment of Cancer (EORTC) risk table
has been commonly used to predict progression 33]–36]. In order to further improve the prediction, new biomarkers are needed. In bladder
cancer, several studies have shown the NLR to be a prognostic factor 2], 26], 28], 37]–39]. On the other hand, the association between the NLR and tumor progression remains
controversial (Table 3). These studies showed that a higher NLR was correlated with a worse prognosis in
patients with bladder cancer, while others indicated that the NLR was not recognized
to be correlated with OS 2], 26], 28], 37], 38]. In patients with non-muscle-invasive bladder cancer, an NLR of 2.41 tended to be
correlated with recurrence and progression after transurethral resection of bladder
tumors 33]. In the present study, a high NLR was found to be a risk factor for death in patients
with invasive bladder cancer who underwent radical cystectomy.
The AUROC determined the cut-off value of the NLR to be 2.38 in the present study.
Kayner et al. reported that MIBC showed a higher NLR compared with NMIBC, and the
cut-off point was set as 2.50 in their study 40]. Several studies in advanced pancreatic cancer showed NLR cut-off values of approximately
5 5]. In intrahepatic cholangiocarcinoma 6], and in patients with liver metastasis from colorectal carcinoma 25], the NLR cut-off value was also set as 5. In urologic cancers, NLR cut-off values
of approximately 5 (prostate cancer) or from 2 to 5 (renal cell carcinoma) have been
used 41]. In urothelial carcinoma, NLR cut-off values of 2.41-3.0 have been reported 2], 26], 37], 38], 40], 42]. Our cut-off point for the NLR was thus somewhat lower than the values of previous
reports.
The present study is associated with several limitations. First, this is a retrospective
study, which may have led selection bias. Second, we did not perform mechanistic experiments
to determine the roles of neutrophils and/or lymphocytes in bladder cancer progression.
Nonetheless, the current results support the findings of previous studies which indicate
correlations between NLR/inflammation and the clinical outcome of patients with muscle-invasive
bladder cancer. The NLR may thus be useful in the prediction of prognosis in bladder
cancer patients after radical cystectomy.