Original article
Lymphopenia is an independent predictor of inferior outcome in papillary renal cell carcinoma

https://doi.org/10.1016/j.urolonc.2014.06.004Get rights and content

Highlights

  • This is the first study, evaluating the role of preoperative absolute lymphocyte count (ALC) as a prognostic factor in PRCC tumors.

  • Preoperative ALC can be an important independent prognosticator of clinical outcomes and survival in patients with PRCC.

  • In patients with Papillary Renal Cell Carcinoma (PRCC), lymphopenia is associated with lower overall survival independent of TNM stage, age, histological subtype, and comorbidity index. ALC may contribute to already established prognostic factors and can be helpful for patient counseling. It may enhance the development of specific immunomodulatory approaches or design of clinical trials for management of patients with RCC.

Abstract

Purpose

Lymphopenia as a likely index of poor systemic immunity is an independent predictor of inferior outcome in patients with clear cell renal cell carcinoma (RCC). We sought to evaluate the prognostic relevance of preoperative absolute lymphocyte count (ALC) in a cohort of patients with papillary RCC (PRCC).

Materials and methods

A prospectively maintained, renal cancer database was analyzed. Patients with preoperative ALC, within 3 months before surgery, were eligible for the study. Those with multifocal or bilateral renal tumors were excluded. Correlations between ALC and age, gender, smoking, Charlson comorbidity index, pathologic T category, PRCC subtype, and TNM stage were evaluated. Differences in overall survival (OS) and cancer-specific survival by ALC status were assessed using the log-rank test and cumulative incident estimators, respectively. Cox proportional hazards model was used for multivariable analyses.

Results

A total of 192 patients met the inclusion criteria. As a continuous variable, preoperative ALC was associated with higher TNM stage (P = 0.001) and older age (P = 0.01). As a dichotomous variable, lymphopenia (<1,300 cells/µl) was associated with higher TNM stage (P = 0.003). On multivariable analyses, controlling for covariates, after a median follow-up of 37.3 months, lymphopenia was associated with inferior OS (hazard ratio = 2.3 [95% CI: 1.2–4.3], P = 0.011) and trended to significance for cancer-specific survival (P = 0.071). Among patients with nonmetastatic disease and lymphopenia, OS at 37.5 months was shorter compared with those with normal ALC (83% vs. 93%, P = 0.0006).

Conclusions

In patients with PRCC, lymphopenia is associated with lower survival independent of TNM stage, age, and histology. ALC may provide an additional preoperative prognostic factor.

Introduction

Kidney cancer, predominantly renal cell carcinoma (RCC), is among the most lethal of urologic malignancies, and in 2014, in the United States, 63,920 new cases are estimated, with approximately 22% rate of cancer-specific mortality [1]. Although 20% to 30% of patients can experience relapse within the first 3 years, surveillance is the standard of care after the curative-intent surgery for localized or locally advanced RCC [2]. Existing preoperative RCC models that risk stratify patients are useful guides after surgery but are of limited value in a preoperative setting. To estimate the risk of disease recurrence for localized RCC, only a limited number of models and nomograms based on TNM stage, nuclear grade, tumor necrosis, microvascular invasion, and performance status have been proposed [2], [3], [4], [5], [6]. Moreover, the most commonly used prognostic factor models for RCC are derived from the era of immunotherapy and are limited to a population of patients with advanced RCC [7], [8].

Over the past several years, prognostic systemic inflammatory markers such as erythrocyte sedimentation rate [9], platelet count [10], C-reactive protein [11], vascular endothelial growth factors [12], and serum IL-6 levels [13] related to RCC outcomes have been described. More recently, there has been an increased interest in evaluating the host׳s inflammatory and immune response to tumors. One routinely obtained and readily available maker of the systemic inflammatory response is the absolute lymphocyte count (ALC), and its preoperative prognostic value as an independent predictor of disease-free survival and all-cause overall survival (OS) in clear cell RCC (ccRCC) has been previously described by our group [14].

Papillary RCC (PRCC) is the second most common histologic subtype of RCC that originates from a different biological pathway, and along with clear cell histology, they make up most cases of RCC seen in clinical settings [15]. To our knowledge, the role of ALC as a biomarker has not yet been fully evaluated as a predictor of survival in patients with PRCC. The aim of our study was to evaluate the prognostic significance of preoperative ALC in our large uniform PRCC series, as our group has done for ccRCC before [14]. We hypothesized that preoperative ALC may be a significant predictor of PRCC outcome as well. If preoperative ALC is indeed a significant predictor of outcome in PRCC, and because ccRCC and PRCC constitute the vast majority of RCCs, then ALC can be used as a useful preoperative predictor of RCC outcome even if the histology is not known yet.

Section snippets

Material and methods

The institutional, prospectively maintained, renal tumor database at the Fox Chase Cancer Center was used to identify patients with PRCC who underwent surgery from 2000 to 2013. Patients who did not have ALC values within 3 months preoperatively were excluded from the analysis. Because the outcome could have been affected by another primary tumor rather than the PRCC index tumor, the patients who had more than 1 surgery for management of multifocal or bilateral renal tumors were also excluded.

Patient characteristics

Of 293 patients with a pathologic diagnosis of PRCC, 101 were excluded: 44 owing to multiple surgeries for either bilateral or multifocal tumors, 55 owing to absence of ALC on record, and 2 because of high ALC considered suspicious for chronic lymphocytic leukemia. Except for slightly lower nuclear tumor grade in the excluded cases, all the characteristics of tumors and patients were not statistically different between the exclusion and the final cohorts. A total of 192 patients met the

Discussion

To our knowledge, this is the first study to evaluate the role of preoperative ALC as a prognostic factor in PRCC tumors. Our current analysis of a large and uniform cohort suggests that preoperative ALC can be an important independent prognosticator of clinical outcomes and survival in patients with PRCC. On MVA, lymphopenia was found to be a strong predictor of inferior all-cause mortality (OS) along with advanced TNM stage.

Although several novel molecular changes in RCC have been identified,

Conclusions

Similar to our cohort of ccRCC, in patients with PRCC, lymphopenia was associated with lower OS, independent of TNM stage, age, PRCC subtype, and CCI. ALC may contribute to already established prognostic factors and can be helpful for patient counseling. It may enhance the development of specific immunomodulatory approaches or design of clinical trials for the management of patients with RCC.

Acknowledgment

The authors would like to thank Debra Kister and Michelle Collins for their management of the Fox Chase Kidney Cancer Keystone Database.

References (30)

Cited by (43)

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    Albumin is the most abundant protein in the plasma, and its level represents the nutritional and inflammatory statuses [15]. Therefore, low levels of albumin and lymphocytes, leading to a low PNI value, can result in tumor development, progression, and metastasis [16,17]. Because prognosis of RCC is not explained only by 1 factor, prognostic models including many factors are used in clinical setting.

  • Prognostic value of preoperative prognostic nutritional index in patients with renal cell carcinoma after nephrectomy

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    Furthermore, a low lymphocyte level may indicate a preexisting immunosuppressed status, which is a beneficial microenvironment for tumor development and progress [31,32]. Several studies found that lymphopenia was associated with poor survival outcomes in patients with RCC [33,34]. Conversely, several studies demonstrated that increased tumor-infiltrating lymphocyte was associated with better outcomes in patients with RCC [35,36].

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    Tumor associated eosinophils recently were shown to facilitate the anti-tumor immune response by enhancing CD8+ T cell infiltration and have been linked to favorable prognosis in oral squamous cell carcinomas [36,37]. Several studies analyzing absolute lymphocyte count (ALC) in pre-operative patients with solid tumors have demonstrated that lower lymphocyte counts, as we observed with low DEK plasma concentrations, are associated with decreased survival rates [38–41]. Additional studies are needed in order to determine if the lower eosinophil and lymphocyte counts on CBC from patients with low plasma DEK concentrations correlate with limited intratumoral immune responses and poor survival.

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This publication was supported in part by the Grant no. P30 CA006927 from the National Cancer Institute, USA. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. Additional funds were provided by Fox Chase Cancer via institutional support of the Kidney Cancer Keystone Program.

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