|Year : 2021 | Volume
| Issue : 2 | Page : 322-326
Neutrophil-to-lymphocyte ratio as a prognostic factor in oral squamous cell carcinoma – A single-institutional experience from a developing country
Vigyan Mishra1, Subhranshu Hota1, Subrat Kumar Sahu2, Ranjana Giri1, Urmila Senapati1
1 Department of Pathology, Kalinga Institute of Medical Sciences, KIIT, Bhubaneswar, Odisha, India
2 Department of Surgical Oncology, Kalinga Institute of Medical Sciences, KIIT, Bhubaneswar, Odisha, India
|Date of Submission||31-Jul-2020|
|Date of Acceptance||18-May-2021|
|Date of Web Publication||31-Aug-2021|
Department of Pathology, Kalinga Institute of Medical Sciences, KIIT, Bhubaneswar, Odisha
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Cell-mediated inflammatory response, neutrophils, lymphocytes and monocytes are being recognized as an important role in carcinogenesis. Neutrophil-to-lymphocyte ratio (NLR) has been used as an independent prognostic factor in varieties of cancers. NLR can be easily determined from complete blood count, and it could be considered as a simple and inexpensive prognostic marker.
Aim: In this study, we evaluate the prognostic significance of NLR in patients with oral squamous cell carcinoma (OSCC).
Materials and Methods: Clinical and epidemiological data of all biopsy-proven nonmetastatic OSCC treated between 2014 and 2018 were taken into consideration. Pretreatment absolute neutrophil and lymphocyte counts were used to get NLR. Using univariate and multivariate analysis, the impact of NLR on overall survival (OS) and progression-free survival (PFS) was investigated.
Results: A total of 50 patients of OSCC with median pretreatment NLR ratio of 2.52 were identified. Based on the median NLR as a cutoff, patients were classified into two groups, i.e., high NLR and low NLR. Elevated NLR was significantly associated with lymph node metastasis (P = 0.01). Four-year OS and PFS were significantly better for patients with low NLR when compared with high NLR group (51.4% vs. 100%, P = 0.001). Four-year PFS for high and low NLR groups was 38.8% and 87.8% (P = 0.002). Multivariate analysis confirmed that NLR is an independent prognostic factor (P = 0.003).
Conclusion: Pretreatment NLR provides a simple, cheap and early predictor of outcome in this group of patients. However, an optimal cutoff value of NLR should be determined, for which larger sample size and prospective studies are required.
Keywords: Neutrophil-to-lymphocyte ratio, oral squamous cell carcinoma, prognostic factor
|How to cite this article:|
Mishra V, Hota S, Sahu SK, Giri R, Senapati U. Neutrophil-to-lymphocyte ratio as a prognostic factor in oral squamous cell carcinoma – A single-institutional experience from a developing country. J Oral Maxillofac Pathol 2021;25:322-6
|How to cite this URL:|
Mishra V, Hota S, Sahu SK, Giri R, Senapati U. Neutrophil-to-lymphocyte ratio as a prognostic factor in oral squamous cell carcinoma – A single-institutional experience from a developing country. J Oral Maxillofac Pathol [serial online] 2021 [cited 2021 Dec 8];25:322-6. Available from: https://www.jomfp.in/text.asp?2021/25/2/322/325235
| Introduction|| |
Oral squamous cell carcinoma (OSCC) is one of the most common head and neck cancers worldwide. Despite recent advances in the treatment of OSCC, 5-year survival rate is unsatisfactory because of treatment failure. Recent studies have confirmed the role of host inflammatory response on tumor development and progression of cancer. Neutrophil-to-lymphocyte ratio (NLR) has shown correlation with outcomes in several malignancies, such as breast cancer, lung cancer, nasopharyngeal cancer, ovarian cancer and renal cell cancer.
NLR will be very much useful because it is an inexpensive, easily measured and reproducible marker. Till now, only very few studies have evaluated the prognostic role of NLR in OSCC. The aim is to evaluate the prognostic significance of pretreatment NLR in patients with OSCC.
| Materials and Methods|| |
A total of 50 histologically diagnosed cases of OSCC treated radically during 2014–2018 were collected. Patients with nonsquamous histology, distant metastasis at the time of presentation, incomplete data, other inflammatory conditions or clinical evidence of infection and history of recent steroid intake were excluded from the study.
Demographic data and clinical characteristics were retrieved for all cases from medical records. Tumor-node-metastasis staging was done according to the 2010 American Joint Committee on Cancer system, and grading was done by Border's criteria and categorized as well, moderately and poorly differentiated. Information about pretreatment hematologic parameters was collected. NLR was calculated as the ratio of absolute neutrophil count to absolute lymphocyte count.
All patients were subjected to standard treatment protocols according to primary tumor site, stage and patient general conditions. After receiving primary treatment, patients were followed in the oncosurgery department in every 3 months for the 1st year, every 4 months in the 2nd year and every 6 months till completing 5 years, then annually. Clinical examination was performed at each visit. Radiological evaluation of response performed after the first posttreatment visit by computed tomography (CT), positron emission tomography-CT or magnetic resonance imaging. Local or regional recurrence was confirmed by pathological examination.
Survival times were calculated from the day of diagnosis. Overall survival (OS) was calculated at the date of death, and progression-free survival (PFS) was calculated at the date of relapse or the last date of follow-up. Survival rates were calculated by Kaplan–Meier method. The level of significance was set at P ≤ 0.05. The Chi-square test was used to determine the associations between the pretreatment NLR and different variables. Statistical analysis was performed on SPSS Software version 23.
| Results|| |
We identified 50 patients of OSCC with a median age of 45 years. Median pretreatment NLR ratio was 2.52. According to the median NLR as a cutoff value, patients were classified into two groups: high NLR group and low NLR group. The correlations between NLR and selected variables showed that elevated NLR (>2.52) was significantly associated with lymph node metastases (P = 0.01) [Table 1].
|Table 1: Correlation between neutrophil-to-lymphocyte ratio and different variables|
Click here to view
In our patients, 4-year OS and PFS were significantly better for patients with low NLR when compared with high NLR group 51.4% versus 100% (P = 0.001) [Figure 1].
|Figure 1: Overall survival according to neutrophil-to-lymphocyte ratio, high neutrophil-to-lymphocyte (>2.52) and low neutrophil-to-lymphocyte (<2.52). Mantel-Cox test, P = 0.001|
Click here to view
Four-year PFS for high and low NLR groups was 38.8% and 87.8% (P = 0.002) [Figure 2].
|Figure 2 : Progression- free survival according to neutrophil-to-lymphocyte ratio, high neutrophil-to-lymphocyte (>2.52) and low neutrophil-to-lymphocyte (<2.52). Mantel-Cox test, P = 0.002|
Click here to view
[Table 2] shows the univariate analysis of the other prognostic factors. Multivariate analysis confirmed that NLR is an independent prognostic factor for PFS (P = 0.003) [Table 3].
|Table 2: Univariate analysis for 4 years overall and progression-free survival in relation to different prognostic factors|
Click here to view
|Table 3: Cox-regression multivariate analysis for overall and progression-free survivals|
Click here to view
| Discussion|| |
Association between NLR and prognosis of cancer is not fully understood. Regarding the link between inflammation and cancer, till now, very few evidence is there. The neutrophils may act as tumor-promoting leukocytes as well as participate in metastatic cascade. Through the enzymatic actions, the tumor associated neutrophils promote remodelling of the extracellular matrix. It causes release of basic fibroblast growth factors, migration of endothelial cells and dissociation of tumor cells. This events result in enhanced angiogenesis, tumor growth and progression to metastatic cascade. Neutrophil also inhibit apoptosis or tumor cells by activation of nuclear factor kappa B (NF-kB).
Inflammation can generate not only a cancer-prone microenvironment but also a systemic change in the host that accelerates cancer growth. An elevated NLR can cause neutrophilia linked to tumor granulocyte colony-stimulating factor and can accelerate tumor development and increase plasma cytokine (such as interleukin-6 and tumor necrosis factor-α) level, while lymphopenia is associated with disease severity and immune escape of tumor cells from tumor-infiltrating lymphocytes. In contrast, tumor infiltration by lymphocytes has been reported to indicate generation of an effective antitumor cellular immune response. It also has role in cytotoxic cell death and cytokines production that inhibits tumor cell proliferation and metastasis. The increased count of neutrophils and/or decreased count of lymphocytes may suppress lymphokine-activated killer cells. It may be a possible mechanism for decreased survival in cancer patients. Depressed immune function due to lymphocytopenia may be the cause of decreased survival of the patient.
In our present study, the cutoff value to define low and high NLR we used median NLR as 2.52. The way of choosing cutoff values differs among studies. Cutoff values on the basis of the median, higher quartile or values determined by the use of receiver operating characteristic curve analysis were used. As a result, different cutoff values are reported; however, the vast majority of cutoffs were in the ranges of 2–4. However, the optimal cutoff levels for NLR remain to be established. A study was done by Phulari et al. in 2019 found that mean value of NLR in OSCC cases and control was 2.8 and 1.95, respectively, where the value was statistically significant.
In our work, high NLR was associated with the presence of LN metastases (P = 0.01). The association between high NLR with poor prognostic features such as positive nodal involvement has been observed in breast cancer patients. We can speculate that our findings are due to similar reasons as described in other tumor types. Another study by Mattavelli et al. in 2019 that reviewed naive OSCC cases for a period of 14 years from 2000 to 2014 showed that median value of NLR was 2.5. In this study, association between NLR and clinical pathological variables is described. Patients with advanced T classification tend to show higher NLR values, while no correlation was demonstrated with tumor stage, number of positive nodes and perineural and lymphovascular invasion.
Our present study demonstrates a positive correlation between low pretreatment NLR and survival outcome and PFS in patients with OSCC. These findings are consistent with study done by Nakashima et al. in 2016. Malik et al. in 2019 told that decreased OS with increasing NLR was found to be significant only for the group which received adjuvant chemotherapy (P = 0.01).
The limitations of our study are its retrospective nature and the limited number of patients. Prospective studies with larger number cases are needed to accurately define the cutoff value to discriminate the prognostic group.
| Conclusion|| |
Although evidences are there for the prognostic role of NLR, still the optimal cutoff levels for NLR remains to be established. Prospective studies are still needed for further evaluation of its benefit and clinical importance. Mechanism underlying high NLR and response to anticancer treatment should also be explored. It would also help the selection of patients who are more likely to be benefited from specific surgical approach or drugs. Whenever selecting a prognostic marker always, a cost-effective analysis and accessibility should be taken into consideration, NLR qualities an excellent one. In oral carcinoma, NLR can be potentially used as an independent prognostic marker for OS and PFS, and it should be assessed before any type of surgical and drug treatment.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Global Burden of Disease Cancer Collaboration; Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, et al.
Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: A systematic analysis for the global burden of disease study. JAMA Oncol 2017;3:524-48.
Taghavi N, Yazdi I. Prognostic factors of survival rate in oral squamous cell carcinoma: Clinical, histologic, genetic and molecular concepts. Arch Iran Med 2015;18:314-9.
Yamanaka T, Matsumoto S, Teramukai S, Ishiwata R, Nagai Y, Fukushima M. The baseline ratio of neutrophils to lymphocytes is associated with patient prognosis in advanced gastric cancer. Oncology 2007;73:215-20.
Azab B, Bhatt VR, Phookan J, Murukutla S, Kohn N, Terjanian T, et al.
Usefulness of the neutrophil-to-lymphocyte ratio in predicting short - and long-term mortality in breast cancer patients. Ann Surg Oncol 2012;19:217-24.
Tomita M, Shimizu T, Ayabe T, Yonei A, Onitsuka T. Preoperative neutrophil to lymphocyte ratio as a prognostic predictor after curative resection for non-small cell lung cancer. Anticancer Res 2011;31:2995-8.
An X, Ding PR, Wang FH, Jiang WQ, Li YH. Elevated neutrophil to lymphocyte ratio predicts poor prognosis in nasopharyngeal carcinoma. Tumour Biol 2011;32:317-24.
Chen S, Zhang L, Yan G, Cheng S, Fathy AH, Yan N, et al.
Neutrophil-to-lymphocyte ratio is a potential prognostic biomarker in patients with ovarian cancer: A meta-analysis. Biomed Res Int 2017;2017:7943467.
Na N, Yao J, Cheng C, Huang Z, Hong L, Li H, et al.
Meta-analysis of the efficacy of the pretreatment neutrophil-to-lymphocyte ratio as a predictor of prognosis in renal carcinoma patients receiving tyrosine kinase inhibitors. Oncotarget 2016;7:44039-46.
Noh H, Eomm M, Han A. Usefulness of pretreatment neutrophil to lymphocyte ratio in predicting disease-specific survival in breast cancer patients. J Breast Cancer 2013;16:55-9.
Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013;19:1423-37.
Denkert C, Loibl S, Noske A, Roller M, Müller BM, Komor M, et al.
Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 2010;28:105-13.
Teramukai S, Kitano T, Kishida Y, Kawahara M, Kubota K, Komuta K, et al
. Pretreatment neutrophil count as an independent prognostic factor in advanced non-small-cell lung cancer: An analysis of Japan Multinational Trial Organisation LC00-03. Eur J Cancer 2009;45:1950-8.
Clark EJ, Connor S, Taylor MA, Madhavan KK, Garden OJ, Parks RW. Preoperative lymphocyte count as a prognostic factor in resected pancreatic ductal adenocarcinoma. HPB (Oxford) 2007;9:456-60.
Phulari RG, Rathore RS, Shah AK, Agnani SS. Neutrophil: Lymphocyte ratio and oral squamous cell carcinoma: A preliminary study. J Oral Maxillofac Pathol 2019;23:78-81.
Faria SS, Fernandes PC Jr., Silva MJ, Lima VC, Fontes W, Freitas-Junior R, et al.
The neutrophil-to-lymphocyte ratio: A narrative review. Ecancermedicalscience 2016;10:702.
Mattavelli D, Lombardi D, Missale F, Calza S, Battocchio S, Paderno A, et al.
Prognostic nomograms in oral squamous cell carcinoma: The negative impact of low neutrophil to lymphocyte ratio. Front Oncol 2019;9:339.
Nakashima H, Matsuoka Y, Yoshida R, Nagata M, Hirosue A, Kawahara K, et al
. Pre-treatment neutrophil to lymphocyte ratio predicts the chemoradiotherapy outcome and survival in patients with oral squamous cell carcinoma: A retrospective study. BMC Cancer 2016;16:41.
Malik A, Mishra A, Mair M, Chakrabarti S, Garg A, Singhvi H, et al
. Role of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as prognostic markers in oral cavity cancers. Indian J Med Paediatric Oncol 2019;401:94.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]