Promising role of preoperative neutrophil-to-lymphocyte ratio in patients treated with radical nephroureterectomy

In the present study, we assessed the significance of preoperative NLR in a large multi-institutional cohort of patients with UTUC treated by RNU. We demonstrated that abnormal NLR was not only associated with adverse pathological features and worse oncologic outcomes, but also predicted the presence of lymph node metastases, muscle-invasive and NOC disease. Therefore, the potential of NLR could be in the preoperative clinical decision making regarding lymphadenectomy indication and extent, and patient counseling regarding conservative therapy.

Using a ratio of 2.7, we observed that almost two-thirds of the patients had an altered preoperative NLR. Altered NLR was associated with features of biologically and clinically aggressive UTUC such as advanced tumor stage, LVI, tumor necrosis, sessile architecture and lymph node metastases. These findings confirm the results reported in smaller cohorts [13‐15]. The potential reasons for such associations remain hypothetical. NLR could reflect a balance between neutrophilia and lymphopenia that results from the relationship between the immune system and tumorigenesis. On the one hand, the secretion of granulocyte colony-stimulating factor (G-CSF) by tumor cells may promote neutrophils production in bone marrow and recruitment of the neutrophils in the tumor environment. De Larco et al. [7] showed that these “tumor-associated neutrophils” could have a role in the tumor microenvironment and local angiogenesis. Neoangiogenesis could therefore promote tumor progression and migration of tumor cells. On the other hand, lymphopenia may be responsible for poor immune response against tumor and favor tumor aggressiveness and progression [17]. Even if this association is of great interest, it does not ensure the independent value of NLR to predict adverse pathological features at final pathology.

We demonstrated, therefore, the ability of NLR to independently predict lymph node metastasis, muscle-invasive and NOC disease in a preoperative model that included patient age, gender, tumor location and architecture. This preoperative model may help physicians identify patients who should be proposed a radical treatment with RNU or a lymphadenectomy during RNU [18]. Previous models have been proposed to identify such patients and adapt clinical decision making [19‐21]. Margulis et al. [19] developed a model to predict muscle-invasive disease using preoperative clinicopathologic features such as age, gender, tumor location, architecture and grade at biopsy. Another predictive model combined high grade, tumor location, local invasion and hydronephrosis on imaging and achieved 71 and 70 % accuracies for predicting muscle-invasive and NOC disease, respectively [20]. We constructed a model including NLR but did not consider, however, grade at biopsy and data from the preoperative imaging. Our model only relies on easy accessible factors and demonstrates accuracies of 68–72.5 % for the prediction of NOC, muscle-invasive or positive lymph node disease. Further improvement of these models may be obtained, however, by the combination of NLR with other routinely available biomarkers as CRP [22].

We demonstrated NLR was associated with worse oncologic outcomes such as RFS and CSS. However, adjusted for standard pathologic prognostic factors in UTUC, NLR did not retain statistical significance. Most of the previous studies reported, however, independent predictive value for RFS [15], CSS [13, 14] and OS [14]. The discrepancies between these studies and our findings could be explained by several reasons. First, initial studies defined the optimal cutoff for NLR as 2.7 [14] or 3 [13] based on the interpretations of iterative Cox or ROC analysis observed in the cohorts. Only one study externally validated the prognostic value of NLR using a predefined threshold of 3 [15]. To our knowledge, we are the first to propose an external validation with the 2.7 cutoff proposed by Dalpiaz et al. [14]. Second, the parameters used in multivariable analysis proposed in these studies varied widely. For example, Tanaka et al. only adjusted on age, N status, stage and LVI. We performed a multivariable analysis using most of the clinicopathologic parameters published in the literature [3, 23, 24]. When we limited our multivariable analysis to the parameters used in established prognostic models [3, 23‐25], NLR did not demonstrate independent prognostic value, however (data not shown). Third, populations were different regarding the clinicopathologic characteristics. Luo et al. [13] only included patients with pT stage <4 and without lymph node metastases. Conversely, half cohort of Tanaka et al. [15] had locally advanced disease. However, none of the subgroup analyses we performed with advanced disease or localized disease demonstrated independent prognostic value for NLR.

We demonstrated, however, that NLR would be an independent prognostic factor regarding CSS in patients who were treated with lymphadenectomy. In previous studies, status of lymphadenectomy was not routinely performed [13‐15]. Staging benefit of lymphadenectomy in UTUC is noteworthy [26]. Xylinas et al. [27] showed, therefore, that all patients treated with RNU for UTUC should receive LND to ensure accurate nodal staging. In the future, metastatic patients may also receive immune checkpoint inhibitors such as anti-PDL1. Preliminary results in bladder cancer suggest that circulating inflammatory markers may predict response to immune checkpoint inhibitors [28]. Therefore, NLR could be of great value in the identification of patients with metastatic status that may benefit from immune checkpoint inhibitors.

Although this is the largest study that investigated the predictive and prognostic value of pretreatment NLR with outcomes after RNU, our study has some limitations that should be considered. First, its retrospective and multicentric status may be responsible for variations in laboratory, pathological and surgical workup that could confound the results. In the present study, NLR was determined preoperatively with a predefined cutoff and analyzed as a categorical variable. We did not complete these investigations with exact levels of NLR as neutrophils and lymphocytes counts were measured with different assays. Continuously coded NLR or different thresholds may have provided different conclusions. Assessment of NLR at different points in time may also have excluded confounders, such as occult infectious diseases without any symptoms preoperative, autoimmune diseases responsible for temporally changes. Finally, we only investigated NLR. A growing evidence suggests that derivatives of NLR or its combination with other preoperative markers of systemic inflammation may be helpful in the prediction of oncologic outcomes in UTUC and warrants further investigations [29‐31].