Preoperative neutrophil-lymphocyte ratio predicts death among patients with localized clear cell renal carcinoma undergoing nephrectomy

Abstract

Objectives

The neutrophil-lymphocyte ratio (NLR) is an indicator of the systemic inflammatory response. An increased pretreatment NLR has been associated with adverse outcomes in other malignancies, but its role in localized (M0) clear cell renal cell carcinoma (ccRCC) remains unclear. As such, we evaluated the ability of preoperative NLR to predict oncologic outcomes in patients with M0 ccRCC undergoing radical nephrectomy (RN).

Methods and materials

From 1995 to 2008, 952 patients underwent RN for M0 ccRCC. Of these, 827 (87%) had pretreatment NLR collected within 90 days before RN. Metastasis-free, cancer-specific, and overall survival was estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate models were used to analyze the association of NLR with clinicopathologic outcomes.

Results

At a median follow-up of 9.3 years, 302, 233, and 436 patients had distant metastasis, death from ccRCC, and all-cause mortality, respectively. Higher NLR was associated with larger tumor size, higher nuclear grade, histologic tumor necrosis, and sarcomatoid differentiation (all, P<0.001). A NLR≥4.0 was significantly associated with worse 5-year cancer-specific (66% vs. 85%) and overall survival (66% vs. 85%). Finally, after controlling for clinicopathologic features, NLR remained independently associated with risks of death from ccRCC and all-cause mortality (hazard ratio for 1-unit increase: 1.02, P< 0.01).

Conclusions

Our results suggest that NLR is independently associated with increased risks of cancer-specific and all-cause mortality among patients with M0 ccRCC undergoing RN. Accordingly, NLR, an easily obtained marker of biologically aggressive ccRCC, may be useful in preoperative patient risk stratification.

Introduction

There has been an increase in the incidence of renal cell carcinoma (RCC) in the last 3 decades [1] with most patients with RCC (>80%) presenting with the clear cell (cc) histologic subtype [2]. Although surgical resection remains the “gold standard” treatment for patients with clinically localized disease, approximately 10% to 60% of such patients develop recurrence following surgical extirpation [3], and of these patients, a significant proportion die of their disease [4]. Therefore, advancements in patient risk stratification are needed to appropriately identify patients at highest risk of cancer-related mortality who may be candidates for adjuvant therapy trial enrollment.

One significant challenge in the identification of the patients at highest risk is the limited pretreatment risk data that are available for patients presenting with a solid renal mass. Not surprisingly, then, most current predictive models rely almost exclusively on postoperative pathologic analysis of the surgical specimen with minimal consideration for associated patient-related variables [5], [6], [7]. As such, the potential exists that the prognostic accuracy of these models may be significantly improved with the addition of inflammatory and molecular tumor biomarkers [8]. Nevertheless, a paucity of preoperative data exists to facilitate appropriate patient counseling and guide clinic trial enrollment, and thereby there remains a need to identify biomarkers that will incrementally improve preoperative risk stratification.

The neutrophil-lymphocyte ratio (NLR) represents an easily measured, reproducible, and inexpensive marker of systemic inflammation that has been associated with oncologic outcomes in multiple malignancies, including colorectal and gastric cancers [9], [10]. It has been hypothesized that the synthesis of inflammatory cytokines triggered by the tumor microenvironment alters acute phase reactants and hematological components including serum neutrophil and lymphocyte counts [11], [12]. Evaluation of NLR in ccRCC might be particularly relevant as inflammation has been correlated with tumor stage, grade, and proliferative index and, moreover, has been associated with disease-free and overall survival as well [13], [14]. Indeed, ccRCC is currently one of the few malignancies in which immunotherapy has been employed, in some cases (high-dose IL-2), with remarkable responses. In fact, both lymphocytosis and C-reactive protein have been observed to be predictive of oncologic outcomes in patients treated for advanced RCC [15], [16].

For those with RCC undergoing curative resection, lymphocytopenia and an elevated CRP have been associated with worse cancer-related outcomes, suggesting a correlation between inflammation and disease biology [17], [18]. Nevertheless, limited data exist regarding the potential prognostic value of NLR in nonmetastatic (M0) ccRCC [19], [20], [21]. Moreover, these studies have been limited by relatively small patient numbers, heterogeneous histologic subtypes, short-term follow-up, and differing clinical end points.

We hypothesize that a greater preoperative NLR is associated with adverse outcomes among patients treated for RCC. Accordingly, we sought to determine the association between pretreatment NLR and oncologic outcomes in a large cohort of patients with M0 ccRCC treated with radical nephrectomy (RN) with long-term follow-up.