Neutrophil-to-lymphocyte ratio is a prognostic marker in bladder cancer patients after radical cystectomy

Urinary bladder cancer is one of the most commonly diagnosed malignancies [1]. Two-thirds to three-fourths of patients with bladder tumor initially present with non-muscle-invasive (pTa or pT1) disease that can often be treated with conservative approaches, however, many patients suffer from recurrence, occasionally with grade and/or stage progression. In contrast, for patients with muscle-invasive bladder cancer the gold standard treatment is radical cystectomy. Radical cystectomy is also occasionally performed in patients with stage Ta-1 or Tis tumors that are resistant to intravesical instillation therapy [2]. Though radical cystectomy has some therapeutic benefits, it is a potentially invasive surgery which requires urinary diversion. Thus, a new marker to predict the prognosis is needed to determine whether patients should receive radical cystectomy.

Previous reports have indicated a variety of tissue- or urine-based biomarkers that can be used for predicting the recurrence and progression of bladder cancer; these have often been PCR- or immunohistochemistry-based methods [3]. A simple, inexpensive and highly accurate method would be preferable for daily clinical use. The neutrophil-to-lymphocyte ratio (NLR), which can be easily calculated from routine complete blood counts (CBCs) in peripheral blood samples has been suggested as a predictor, not only for the systemic inflammatory response in critical care patients [4] but also for the prognosis of some solid malignancies including bladder cancer [2, 5‐13]. Additionally, the NLR can be obtained retrospectively even in the postoperative follow-up because CBCs are routinely examined in various stages of bladder cancer therapy. In the current study, we assessed the utility of the NLR in the prediction of the prognosis of patients with bladder cancer who underwent radical cystectomy.

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 (22 %) 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.

The current study demonstrated the usefulness of the NLR in the prediction of OS in patients with advanced stage bladder cancer. The NLR was thus found to be an independent prognostic marker for predicting the prognosis. The preoperative NLR predicted prognosis in patients who underwent radical cystectomy and might therefore function as a reliable biomarker for invasive bladder cancer.

Due to ethical restrictions, the raw data underlying this paper are available upon request to the corresponding author.