Cervical cancer is the third most common malignancy and the fourth leading cause of cancer-related death in women worldwide, with more than 85% occurring in developing countries.1 Approximately 500,000 new cases of cervical cancer are diagnosed annually, and 275,000 deaths are estimated to occur from this disease.2 The prognostic factors affecting the survival of patients with cervical cancer mainly include the International Federation of Obstetricians and Gynecologists (FIGO) tumor staging system, lymph node (LN) status, tumor size, and depth of invasion.3,4 Except the stage of disease, other variables can only be evaluated after surgery. Therefore, a noninvasive and readily accessible preoperative test to estimate survival probability and prognosis in cervical cancer is necessary.
On the basis of the theory that inflammation has an important function in the development of cancer and its progression,5 prognostic and predictive values of systemic inflammatory markers have been demonstrated in various malignant tumors. Serum C-reactive protein (CRP), an index of systemic inflammation, has been shown to be associated with poor prognosis in patients with ovarian cancer6 and hepatocellular carcinoma,7 but it is not routinely measured as part of preoperative test. Neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) are 2 nonspecific markers of systemic inflammation that have been investigated to be associated with many types of cancer such as non–small-cell lung,8 pancreatic,9 gastric,10 and renal11 cancers. To our knowledge, a few studies have evaluated the function of systemic inflammation in cervical cancer. However, little is known about the prognostic values of preoperative NLR and PLR in cervical cancer patients treated with initial radical surgery without neoadjuvant chemotherapy or primary radiation therapy. Given this reason, we evaluated the prognostic and predictive values of preoperative NLR and PLR in cervical cancer patients receiving initial radical hysterectomy with pelvic lymphadenectomy.
MATERIALS AND METHODS
Retrospective data were collected from patients with cervical carcinoma treated with radical hysterectomy and pelvic lymphadenectomy from February 2005 to June 2008 at the Department of Gynecology, the Third Affiliated Hospital of Harbin Medical University, China. This study was approved by the institutional review board. All the patients were histologically confirmed with cervical cancer and staged according to the FIGO staging system. Clinicopathologic variables were collected from the medical records of the enrolled patients. The inclusion criteria were patients histologically diagnosed with cervical cancer, initially treated with radical hysterectomy and pelvic lymphadenectomy, and with histological types of squamous cell carcinoma and adenocarcinoma. Patients who underwent fertility-saving surgery; received chemotherapy, radiotherapy, or immunotherapy before surgery; with hematologic, autoimmune, or infectious diseases; and/or with other cancers were excluded.
The patients were followed up every 3 months for the first 2 years, in 6-month intervals for the next 3 years, and every year thereafter. Follow-up of patients included a pelvic magnetic resonance imaging, a color Doppler ultrasound of the liver and kidney, cervical smears, and chest x-rays. Overall survival (OS) time was defined as the interval between the date of surgery and death or the last follow-up, and progression-free survival (PFS) time was as the period from the date of surgery to the occurrence of local recurrence or distant metastasis or the last follow-up. Patient follow-up was maintained until death or the cutoff date of June 2013.
Blood Parameters and Calculation of NLR and PLR
All preoperative white cells and differential counts were obtained within 7 days before surgery by Sysmex XE-5000 TM Automated Hematology System (Harbin, China). The NLR was defined as the absolute neutrophil count divided by the absolute lymphocyte count, and PLR was evaluated as platelet measurement divided by lymphocyte measurement. The patients were divided at the median values of NLR and PLR.
The associations between NLR or PLR and the clinicopathologic variables were analyzed by a χ2 test. The Kaplan-Meier method and the log-rank test were carried out to evaluate OS and PFS and assess the statistical significance in the univariate analyses, respectively. Prognostic factors with significance values of P < 0.05 in a univariate analysis were entered into a multivariate analysis, which was conducted using the Cox proportional hazards model with the backward likelihood method to test for independent prognostic parameters. Statistical Package for Social Science (SPSS) 18.0 software was used for the statistical analysis. A P = 0.05 or less was considered statistically significant, and all the tests were 2 sided.
This study enrolled 460 patients with cervical cancer who received radical hysterectomy and pelvic lymphadenectomy from February 2005 to June 2008 and met all of our inclusion criteria. The age of the patients ranged from 24 to 78 years, with a median of 44 years. The median follow-up time was 69 (range, 6–100) months. At the last follow-up time, 72 patients were recurrent, and 63 patients were dead. Of the 460 patients, 279 (60.7%) were diagnosed with FIGO stage I, and 181 (39.3%) with FIGO stage II. A total of 411 patients (89.3%) with squamous cell carcinoma and 49 patients (10.7%) with adenocarcinoma were included. By histologic grading, 330 (71.7%) and 130 (28.3%) cases were assessed as G1/G2 and G3, respectively. The LN metastasis was observed in 94 patients (20.4%).
Correlations Between NLR, PLR, and Clinicopathologic Factors of Cervical Cancer
The clinicopathologic characteristics were compared between patients grouped by NLR, as shown in Table 1. The median of preoperative NLR was 2.213, which was the cutoff point. A total of 230 patients with NLR of 2.213 or greater and 230 patients with NLR of less than 2.213 were found. The association between NLR and depth of stromal infiltration (P = 0.007) and LN metastasis (P = 0.003) was statistically significant. In contrast, no significant relationships were noted between NLR and age, stage, histologic grade, histologic type, tumor size, and postoperative radiotherapy.
Table 2 summarizes the patient characteristics at baseline according to PLR. The median of preoperative PLR was 150.9. The PLR was divided based on the 2 different cutoff points (≥150 or < 150). Nearly 228 patients (49.6%) had a PLR of less than 150, and 232 patients (50.4%) had a PLR greater than or equal to 150. The PLR was significantly correlated with tumor size (P = 0.020) and LN metastasis (P = 0.027). However, no significant association was found between PLR with age, stage, histologic type, histologic grade, depth of stromal infiltration, and postoperative radiotherapy.
Prognostic Variables for PFS and OS
As shown in Table 3, univariate analysis revealed that stage, tumor size, depth of stromal infiltration, LN metastasis, postoperative radiotherapy, and NLR were correlated with PFS and OS. Patients with elevated NLR had a significantly shorter PFS and shorter OS than those with low NLR (Ps = 0.008 and 0.014, respectively; Fig. 1). However, increased PLR cannot predict poorer OS (P = 0.110) or PFS (P = 0.075; Fig. 2).
We assessed the independent prognostic factors for PFS and OS using multivariate Cox proportional hazard analysis. Multivariate analysis showed that high NLR was an independent factor associated with worse PFS (P = 0.027; hazard ratio (HR), 1.799; 95% confidence interval [CI], 1.069–3.028], but not an independent prognostic significance for OS (P = 0.066; HR, 1.631; 95% CI, 0.968–2.750) (Table 4). The FIGO stage and LN metastasis were also proved to be independent prognostic markers for OS and PFS.
To our knowledge, this study is the first to investigate the association between the pretreatment NLR/PLR and clinicopathologic characteristics and the prognostic significance in cervical carcinoma patients undergoing initial radical hysterectomy and pelvic lymphadenectomy without chemotherapy, radiotherapy, or immunotherapy before surgery. Our findings showed that both preoperative NLR and PLR significantly correlated with LN metastasis. The NLR and PLR were also associated with depth of stromal infiltration and tumor size, respectively. These results suggest that inflammation including neutrophil, lymphocyte, and platelet may be involved in the development of cervical cancer and its progression.
On the basis of the findings aforementioned, we further analyzed the prognostic value of NLR and PLR on OS and PFS in cervical cancer by univariate and multivariate analyses. Kaplan-Meier analysis confirmed that patients with high NLR had a significantly poorer PFS and OS compared with patients with low NLR. Moreover, Cox regression analysis revealed that NLR was an independent prognostic indicator of PFS of patients with cervical cancer, but not of OS. By contrast, PLR exhibited no significant effect on OS and PFS. These results showed that NLR is superior to PLR as an adverse prognostic and predictive parameter for cervical cancer. In addition, assessment of the inflammatory response to the tumor, such as neutrophil, lymphocyte, and platelet, may be easier and more cost effective in clinical practice. Thus, NLR will be used as an auxiliary indicator of prognostic factors currently used to predict the prognosis of cervical cancer. Similarly, inflammatory markers can be used as a novel target for cervical cancer treatment.
Our results were consistent with those of previous studies that elevated NLR is associated with poor prognosis for survival. These studies include colorectal cancer,12 gastric cancer treated with FOLFOX chemotherapy10 or neoadjuvant chemotherapy,13 and small hepatocellular carcinoma undergoing radiofrequency ablation.14 In cervical cancer, some reports showed that low circulating lymphocytes,15 elevated levels of neutrophil counts,16 or high pretreatment NLR17 is a risk indicator for prognosis. However, Wang et al18 found that pretreatment NLR and PLR failed to predict the survival of patients with cervical cancer treated with neoadjuvant chemotherapy and radical hysterectomy. The possible reason for the failure may be attributed to the changes caused by chemotherapy on host inflammatory response, immune response, and their balance. These results were similar to that demonstrated by Hailong,13 that high NLR values were normalized after neoadjuvant chemotherapy in 11 patients and the normalization of high NLR indicated improved PFS and OS.
Although the mechanisms by which elevated NLR can predict poor survival in patients with various types of cancers are not clearly elucidated, the following points can help in the explanation. Pretreatment neutrophil and lymphocyte numbers indicate the level of systemic inflammation or stress, and neutrophils and lymphocytes play different roles in the tumor. On one hand, neutrophilia may establish an adequate environment for the development and progression of tumor cells. Circulating neutrophils have been proved to contain and secrete vascular endothelial growth factor, IL-18, and matrix metalloproteinases,19,20 which contribute to tumor-related angiogenesis, tumor growth, and metastasis. Thus, the high-density circulating neutrophils may adversely affect the tumor-bearing host, resulting in a negative association between neutrophil density and patient survival. On the other hand, circulating lymphocyte has been shown to secrete cytokines, which prevent proliferation and metastasis of tumor cells and have an important function in cytotoxicity.21 It was confirmed that more CD4+ T lymphocytes at tumor margins resulted in less patient’s risk for recurrence and better prognosis in colorectal cancer.22 Meanwhile, subsets of lymphocytes, such as CD4+, CD8+, CD3−, and CD56+ T cells, were reduced in patients with advanced disease, despite the increased white blood cells in advanced stages.23 Thus, a decreased number of lymphocytes may result in a weaker lymphocyte-mediated antitumor cellular immune response. Moreover, the antitumor immune responses of activated T cells and natural killer cells may be restrained by the increased number of neutrophils.24 When considered together, NLR can reflect the balance between host inflammatory response and immune response. Increase in NLR indicates that the balance is upset for protumor inflammatory response and leads to a negative association with oncologic outcome. These findings were confirmed in the present study.
Platelet count is also a marker of host systemic inflammation. Under some proinflammatory cytokine, actions including IL-1, IL-6, and megakaryocyte proliferate, which lead to the increasing number of platelets.25,26 Other researchers have proved that activated platelets may promote invasion of ovarian cancer cells through activation of urokinase plasminogen activator and vascular endothelial growth factor,27 which is similar to our results that PLR was correlated with tumor size and LN metastasis in cervical cancer patients.
The limitations of this study are as follows. First, it is a retrospective, single-institution study with relatively small number of patients. A well-designed, prospective study with larger number of patients with cervical cancer who underwent radical surgery is needed. Second, CRP, an inflammatory marker, was not regularly carried out in our situation. So, we were not able to evaluate the relationship between CRP and the prognosis of cervical cancer patients. Third, some differences may exist in host’s immune condition between human papillomavirus (HPV)-negative cervical cancer patients and HPV-positive cervical cancer patients. Some heterogeneity may be found in this study because we included cervical cancer patients with HPV infection and patients without HPV infection. However, HPV test was not regularly performed in our hospital from February 2005 to June 2008. So we cannot divide the patients into the HPV-positive group and the HPV-negative group. Finally, the postoperative NLR and the dynamic change of NLR should also be investigated, which may reflect the dynamic change of balance between host inflammatory response and immune response.
In conclusion, preoperative routine hematological factors, including NLR and PLR, were associated with unfavorable pathologic characteristics in patients with cervical caner who had been treated with initial radical hysterectomy and pelvic lymphadenectomy. A high pretreatment NLR independently predicts poor survival in resectable cervical carcinoma. Therefore, NLR can act as a potential factor to guide systemic therapy and predict the treatment outcome for cervical cancer. The cost-effective and easy accessibility and reproducibility of a full blood count can facilitate its application in clinical practice.
1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin
. 2011; 61: 69–90.
2. Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J Clin
. 2013; 63: 11–30.
3. Brenner DE, Whitley NO, Prempree T, et al. An evaluation of the computed tomographic scanner for the staging of carcinoma of the cervix. Cancer
. 1982; 50: 2323–2328.
4. Rosa DD, Medeiros L, Edelweiss MI, et al. Adjuvant platinum-based chemotherapy for early stage cervical cancer. Cochrane Database Syst Rev
. 2012; 6:CD005342.
5. Mantovani A, Allavena P, Sica A, et al. Cancer-related inflammation. Nature
. 2008; 454: 436–444.
6. Hefler LA, Concin N, Hofstetter G, et al. Serum C-reactive protein as independent prognostic variable in patients with ovarian cancer. Clin Cancer Res
. 2008; 14: 710–714.
7. Gomez D, Farid S, Malik H, et al. Preoperative neutrophil-to-lymphocyte ratio as a prognostic predictor after curative resection for hepatocellular carcinoma. World J Surg
. 2008; 32: 1757–1762.
8. Yildirim M, Yildiz M, Duman E, et al. Prognostic importance of the nutritional status and systemic inflammatory response in non-small cell lung cancer. J BUON
. 2013; 59: 59.
9. Sugiura T, Uesaka K, Kanemoto H, et al. Elevated preoperative neutrophil-to-lymphocyte ratio as a predictor of survival after gastroenterostomy in patients with advanced pancreatic adenocarcinoma. Ann Surg Oncol
. 2013; 20: 4330–4337.
10. Lee S, Oh SY, Kim SH, et al. Prognostic significance of neutrophil lymphocyte ratio and platelet lymphocyte ratio in advanced gastric cancer patients treated with FOLFOX chemotherapy. BMC Cancer
. 2013; 13: 350.
11. Pichler M, Hutterer GC, Stoeckigt C, et al. Validation of the pre-treatment neutrophil-lymphocyte ratio as a prognostic factor in a large European cohort of renal cell carcinoma patients. Br J Cancer
. 2013; 108: 901–907.
12. Jankova L, Dent OF, Chan C, et al. Preoperative neutrophil/lymphocyte ratio predicts overall survival but does not predict recurrence or cancer-specific survival after curative resection of node-positive colorectal cancer. BMC Cancer
. 2013; 13: 442.
13. Jin H, Zhang G, Liu X, et al. Blood neutrophil-lymphocyte ratio predicts survival for stages III-IV gastric cancer treated with neoadjuvant chemotherapy. World J Surg Oncol
. 2013; 11: 112.
14. Dan J, Zhang Y, Peng Z, et al. Postoperative neutrophil-to-lymphocyte ratio change predicts survival of patients with small hepatocellular carcinoma undergoing radiofrequency ablation. PLoS One
. 2013; 8: e58184.
15. Choi CH, Kang H, Kim WY, et al. Prognostic value of baseline lymphocyte count in cervical carcinoma treated with concurrent chemoradiation. Int J Radiat Oncol Biol Phys
. 2008; 71: 199–204.
16. Fernandes P, Garcia C, Micheli D, et al. Circulating neutrophils may play a role in the host response in cervical cancer. Int J Gynecol Cancer
. 2007; 17: 1068–1074.
17. Lee Y-Y, Choi CH, Kim H-J, et al. Pretreatment neutrophil: lymphocyte ratio as a prognostic factor in cervical carcinoma. Anticancer Res
. 2012; 32: 1555–1561.
18. Wang D, Wu M, Feng F, et al. Pretreatment neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios do not predict survival in patients with cervical cancer treated with neoadjuvant chemotherapy and radical hysterectomy. Chin Med J (Engl)
. 2013; 126: 1464–1468.
19. Ardi VC, Kupriyanova TA, Deryugina EI, et al. Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis. Proc Natl Acad Sci U S A
. 2007; 104: 20262–20267.
20. Jablonska E, Puzewska W, Grabowska Z, et al. VEGF, IL-18 and NO production by neutrophils and their serum levels in patients with oral cavity cancer. Cytokine
. 2005; 30: 93–99.
21. Ding P-R, An X, Zhang R-X, et al. Elevated preoperative neutrophil to lymphocyte ratio predicts risk of recurrence following curative resection for stage IIA colon cancer. Int J Colorectal Dis
. 2010; 25: 1427–1433.
22. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science
. 2006; 313: 1960–1964.
23. Ray-Coquard I, Cropet C, Van Glabbeke M, et al. Lymphopenia as a prognostic factor for overall survival in advanced carcinomas, sarcomas, and lymphomas. Cancer Res
. 2009; 69: 5383–5391.
24. Shau H, Kim A. Suppression of lymphokine-activated killer induction by neutrophils. J Immunol
. 1988; 141: 4395–4402.
25. Klinger MH, Jelkmann W. Role of blood platelets in infection and inflammation. J Interferon Cytokine Res
. 2002; 22: 913–922.
26. Alexandrakis MG, Passam FH, Moschandrea IA, et al. Levels of serum cytokines and acute phase proteins in patients with essential and cancer-related thrombocytosis. Am J Clin Oncol
. 2003; 26: 135–140.
27. Holmes C, Levis J, Ornstein D. Activated platelets enhance ovarian cancer cell invasion in a cellular model of metastasis. Clin Exp Metastasis
. 2009; 26: 653–661.