Abstract
To study the prognostic significance of neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) in head and neck cancers. The study included 170 cases of histopathologically diagnosed head and neck cancer patients and 80 control subjects. NLR and PLR of patients with head and neck cancers were compared to the control group. The correlation between NLR and PLR values and factors such as age, gender, duration of symptoms, site of tumour, histological type, histological grading, T-category, N-category and TNM stages in cancer patients were analysed. NLR and PLR were statistically higher in cancer patients compared to control. There was a non-significant increase in both NLR and PLR with advancing degree of differentiation and TNM Stages of the cancer patients. A significant increase in NLR and PLR with increasing T Categories and increasing N Categories of head and neck cancer patients was obtained. NLR and PLR can be used to estimate tumour prognosis in head and neck cancers. Increased NLR and PLR values can be used as a marker for poor prognosis. However further studies with larger study groups including treatment response and surveillance should be carried out to corroborate these results.
Keywords: Neutrophil lymphocyte ratio, Platelet lymphocyte ratio, Head and neck cancer, TNM staging, Degree of differentiation
Introduction
Cancer is the second leading cause of death globally, and was responsible for 8.8 million deaths in 2015. Globally, nearly 1 in 6 deaths is due to cancer. The annual incidence of Head and Neck Cancers worldwide is more than 550,000 cases with around 300,000 deaths each year. About 90% of all head and neck cancers are squamous cell carcinomas (HNSCC). HNSCC is the sixth leading cancer by incidence worldwide. Head and neck cancers are a significant problem in India, constituting approximately one-third of all cancer cases in contrast to 4–5% in the developed world. Lip and Oral Cancer was the leading cancer in males in India, while being the 2nd most common cancer in both sexes in 2018 [1]. Early detection of these lesions can dramatically improve the treatment outcome and prognosis in such patients. The development of newer diagnostic and predictive approaches that are safe, economical and amenable to repeated sampling is imperative. Blood based/serum based tests offer such advantages.
The functional relationship between inflammation and cancer is not new. In 1863, Virchow hypothesized that the origin of cancer was at sites of chronic inflammation, in part based on his hypothesis that some classes of irritants, together with the tissue injury and ensuing inflammation they cause, enhance cell proliferation [2]. There is some data to suggest that neutrophils or neutrophil-derived factors participate in tumourigenesis, tumour cell proliferation and metastasis [3]. The first association between cancer and blood dates back to the Indian surgeon Sushruta, who lived approximately 3000 years ago and who described that tumor entry into the blood stream leads to blood vessel constriction and compression. In 1865, the French clinician Armand Trousseau reported several cases of thrombophlebitis in patients who were later diagnosed with gastric cancer [4]. Since then, thrombocytosis has been shown to be correlated with advanced, often metastatic steps of cancer and appears to be a negative prognostic factor for many human cancers [5]. In contrary to neutrophils and platelets, lymphocyte counts tend to decrease in malignancies. It has been demonstrated that lymphocytes in patients with HNSCC have significantly higher rates of apoptosis in the HNSCC populations compared to disease-free groups [6].
Based on the above changes in the counts of these three inflammatory cells in cancers, interestingly, neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) have recently been investigated in a variety of malignancies. The presence of an elevated preoperative NLR has been validated as a marker of inflammation, and shown to have prognostic significance for a number of tumors, including HNSCC [7, 8]. Rassouli et al. [9], claimed that pretreatment PLR was an independent predictor of mortality and pretreatment NLR could be used as an independent predictor of recurrence [9]. The main basis of this study was to investigate whether neutrophil lymphocyte ratio and platelet lymphocyte ratio can be used as prognostic markers in head and neck malignancies.
Materials and Methods
This study was conducted in a tertiary care centre of Northern India over a period of 2 years. The study included 170 cases of histologically diagnosed head and neck cancer patients and 80 control subjects. Detailed history and clinical examination of patients presenting with head and neck lesions suggestive of malignancy were carried out. A complete blood count (CBC) as well as routine blood investigations were requested. Other associated investigations, such as CT Scan and panendoscopy, when needed, were performed prior to biopsy to avoid the effect of upstaging from edema caused by biopsy trauma. Histopathologically confirmed cases were taken in the study group. The histological type of the tumour was classified under the World Health Organisation Classification of Tumours, Pathology and Genetics of Head and Neck Tumours, IARC Press: Lyon, 2005 whereas AJCC-UICC Cancer Staging 8th Edition, 2017 was used for the histological grading and clinical staging of the tumours.
Eighty randomly selected patients from the surgical archive chart who had undergone tympanoplasty for inactive mucosal chronic otitis media (dry perforation) at our institute in the same time period comprised the control group who were also available with preoperative hemogram test. The control subjects were not suffering from any other systemic illness, active infection, neoplasms and neither they were on any drugs. Neutrophil to lymphocyte ratio and platelet lymphocyte ratio were calculated for each subject and recorded.
The demographic characteristics (age, gender, religion) of all the head and neck patients were studied. Clinical data, such as symptoms, duration of symptoms, location of the tumor, histological type, histological grading and TNM stage were also analysed. Neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) of patients with head and neck cancers were compared to the control group. The correlation between NLR and PLR values and factors such as age, gender, duration of symptoms, site of tumour, histological type, histological grading, T-category, N-category and TNM stages were investigated.
Statistical Analysis
The Statistical Package for Social Sciences (SPSS) 16.0 software program was used to analyse data. The frequency distributions and means were assessed. Moreover the normalcy of distribution between the groups was examined. Comparison of quantitative data was evaluated by using Student T test whereas qualitative data was evaluated by using Chi-square test. While the normally distributed data was assessed with one- way ANOVA test, the non normally distributed data was assessed by using Post- Hoc Dunnett’s test. The significance was set at p < 0.05.
Results
Majority of patients with cancer presented at an age > 40 years (129 in total i.e. 75.9%) with a mean age of 52.1 years. Cancer patients showed a male predominance with a male: female ratio of 5.8:1. Oral lesion (90.32%) and local pain (45.16%) were the most frequently reported symptoms among the patients of oral cavity cancer. Hoarseness/voice change (94.60%) was distinctly the most common symptom for laryngeal cancer whereas dysphagia (75%) was the most common chief complaint for oropharyngeal cancers. Only 15 (8.8%) patients reported within one month of the initial onset of symptoms. The vast majority of patients, a total of 68 (40%), appeared at hospital between 1 and 3 months. Cancers of oral cavity (54.7%) were the most prevalent in this region, followed by larynx (21.8%) and oropharynx (14.1%). Among tumours of oral cavity and oropharynx, tongue (47.3%) was the commonest sub-site of involvement followed by buccal mucosa (31.2%), while in case of larynx, supraglottictumours (48.6%) were much more common. Squamous cell carcinoma was the predominant histological type in head and neck cancer patients accounting for 92.4% of cases. Furthermore based on the AJCC-UICC Cancer Staging 8th Edition, 2017, most of the patients i.e. 128 (75.3%) had well differentiated cancers. Majority of the cancer patients presented at the T2 category (67 cases, 39.6%) and without any cervical lymph node, N0 category (96 patients, 56.8%). It was also seen that cancer patients predominantly reported at TNM Stage II and Stage III (102 patients, 60.4%).
Mean neutrophil lymphocyte ratio of cancer group was 2.76 ± 1.82 whereas for control group it was 2.15 ± 0.90. A mean platelet lymphocyte ratio of 113.20 ± 60.36 was obtained for cancer group, while it was 91.41 ± 38.62 for the control group (Table 1).The mean NLR and PLR were found to be statistically higher in cancer group in comparison to control group (p =0.005 for NLR; p =0.030 for PLR). There was no significant relationship between NLR and PLR in accordance to age and gender of cancer patients. However PLR was found to rise with increasing duration of symptoms. A cut- off value of 6 months was taken in this study and there was a statistically significant increase in PLR in patients presenting ≥ 6 months, compared to < 6 months. There was a non- significant increase in both NLR and PLR with advancing degree of differentiation of the tumours. The mean NLR for well differentiated cancers was 2.66 ± 1.73, 3.21 ± 2.51 for moderately differentiated cancers and 2.84 ± 1.13 for poorly/undifferentiated cancers (p = 0.389); whereas the mean PLR was 109.95 ± 59.02, 120.92 ± 68.22 and 126.33 ± 59.12 with advancing degree of differentiation respectively (p = 0.455). On the other hand, there was a significant increase in NLR and PLR with increasing tumour size (Table 2) and lymph node involvement (Table 3). Also, there was a non significant increase in NLR and PLR with the different TNM Stages of the cancer patients (Table 4).
Table 1.
Mean neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) in head and neck cancers (n = 170) compared to controls (n = 80)
| Cancers (n = 170) | Controls (n = 80) | p value | |
|---|---|---|---|
| Neutrophil–lymphocyteratio (NLR) | 2.76 ± 1.82 | 2.15 ± 0.90 | p = 0.005 |
| Platelet–lymphocyte ratio (PLR) | 113.20 ± 60.36 | 91.41 ± 38.62 | p = 0.030 |
Table 2.
Alteration in neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) in different T Categories of cancers (n = 169*)
| T categories of cancers | NLR | PLR |
|---|---|---|
| T1 (28) | 2.33 ± 1.09 | 88.35 ± 29.02 |
| T2 (67) | 2.56 ± 1.40 | 113.18 ± 55.51 |
| T3 (64) | 2.93 ± 1.93 | 115.40 ± 57.58 |
| T4 (10) | 4.39 ± 3.73 | 169.68 ± 120.78 |
| p value | 0.011 | 0.003 |
* One case of malignant melanoma of external auditory canal, has been excluded from this category
Table 3.
Alteration in neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) in different N categories of cancers (n = 169*)
| N categories of cancers | NLR | PLR |
|---|---|---|
| N0 (96) | 2.55 ± 1.34 | 106.49 ± 52.28 |
| N1 (39) | 2.96 ± 2.39 | 117.39 ± 67.75 |
| N2 (29) | 2.87 ± 1.48 | 117.11 ± 45.41 |
| N3 (5) | 4.95 ± 4.38 | 188.42 ± 150.14 |
| p value | 0.027 | 0.025 |
*One case of malignant melanoma of external auditory canal, has been excluded from this category
Table 4.
Alteration in neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) in different TNM stages of cancers (n = 169*)
| TNM stages of cancers | NLR | PLR |
|---|---|---|
| Stage I (28) | 2.33 ± 1.09 | 88.36 ± 29.02 |
| Stage II (51) | 2.54 ± 1.25 | 113.41 ± 57.25 |
| Stage III (51) | 2.88 ± 2.12 | 114.61 ± 61.77 |
| Stage IV (39) | 3.24 ± 2.32 | 129.15 ± 74.52 |
| p value | 0.154 | 0.057 |
*1 case was that of malignant melanoma of external auditory canal
None of the above cases presented with distant metastasis; M0 category is assigned for all cases
Discussion
In recent years, there has been rising interest in the use of systemic hematological markers as prognostic factors in malignancies. Neutrophil, lymphocyte, and platelet counts, either alone or expressed as ratios, have been associated with cancer prognosis. Various outcome thresholds for these ratios have subsequently been established and implemented in the clinical practice for a handful of neoplasms. However literature review revealed that, there are only a few studies regarding the role of NLR/PLR as either predictive marker for prognosis or diagnosis of malignancy in patients with a head and neck pathology. The main objective of this study was to investigate the prognostic value of neutrophil–lymphocyte ratio and platelet–lymphocyte ratio in head and neck cancers.
Pietrzyk et al. [10], in 2016 found that the mean NLR of gastric cancer patients (3.05 ± 2.09) was statistically higher than that of the control group (2.25 ± 0.87), with a p value of 0.02. It was also seen that difference between the PLR of the gastric cancer patients (187.75 ± 92.97) and the control group (138.77 ± 39.32) was also statistically significant (p = 0.002). Acmaz et al. [11], conducted a study in 2014 where the mean NLR in endometrial cancerous group was 2.89 and in control group it was 1.94 (p = 0.025). Moreover, the difference in the PLR between the cancerous group (144.9) and the control (103.7) was also significant statistically (p < 0.001). Nikolić et al. [12], in 2016 studied 388 patients with lung cancers and obtained a mean NLR of 3.63 and a mean PLR of 171 for the cancer group while for the control group, the mean NLR was 2.07 and the mean PLR was 115.
As far as head and neck malignancies are concerned, the NLR/PLRwere also found to be increased in patients with certain tumors. Duzlu et al. [13], conducted a study in 2015 on 65 patients of laryngeal cancer and 42 controls and the difference in NLR between larynx carcinoma (2.70 ± 1.25) and control group (2.04 ± 0.90) was significant statistically (p = 0.004). Ciftci et al. [14], in 2015, carried out a study in 2015, with a total of 53 laryngeal cancer patients and 50 controls. The median NLR was higher in the malignant group (1.9455) compared to the control group (1.5404) and the difference was statistically significant (p < p = 0.011). Yilmaz et al. [15], in 2016 reviewed retrospectively 242 patients with laryngeal pathology among which 141 were patients with benign pathology and 101 were with malignant pathology. The malignant group (mean PLR = 196.47) had significantly higher PLR values compared to the benign group (mean PLR = 113.34; p < 0.001).
In this study, NLR and PLR of the patients with malignant head and neck lesions have been assessed and compared to that of healthy control subjects. The mean NLR and PLR were statistically lower in healthy controls than the cancer group (Table 1). These findings were consistent with the previous studies indicating the relationship between increased NLR and PLR in various cancer types in humans. Besides, there was a non- significant increase in both NLR and PLRwith advancing degree of differentiation of the tumours; this was consistent with other previous studies [16–18]. However, Yilmaz et al., found statistical difference in PLR values among the different histological grades.
Moreover both the mean NLR and PLR showed a significant increase with increasing T categories of cancers (Table 2).The present study is in accord with Valero et al., Hsueh et al., Rassouli et al. and Tsai et al., indicating that there is a significant relationship between the increasing NLR and PLR with increasing T categories. However Duzlu et al. did not find such significance in their studies (p = 0.141). Additionally there was also a significant increase in NLR and PLR with increasing N categories(Table 3) and this is in accordance with previous studies carried out by Valero et al. and Hsueh et al. Concerning the TNM Stages, it was observed that there was a non significant increase in NLR and PLR with the different TNM Stages of the cancer patients, which is in consensus with Rassouli et al. and Duzlu et al.
The main objective of this study was to investigate the prognostic value of neutrophil–lymphocyte ratio and platelet–lymphocyte ratio in head and neck cancers. NLR and PLR were significantly higher in patients with cancer than in control patients. Hence, both parameters can be used for discrimination of cancer from pathologically normal patients. NLR and PLR had a significant increase with increase in size of tumours (T category of TNM Staging) and also with number and size of lymph nodes involved (N category of TNM Staging). There was also a non significant rise in NLR and PLR with the degree of differentiation of the cancers and also with the TNM Stages. Hence, neutrophil–lymphocyte ratio and platelet–lymphocyte ratio can be used to estimate prognosis in head and neck cancers.
Conclusion
Increased neutrophil–lymphocyte ratio and platelet–lymphocyte ratio levels can be used as a marker for poor prognosis in head and neck cancers. However further studies with larger study groups including treatment response and surveillance should be carried out to corroborate these results and determine a cut-off value for these ratios, in head and neck cancer.
Funding
No any fund is provided for completion of study.
Compliance with Ethical Standards
Informed Consent
Informed consent was obtained from all the individuals who participated in the study group and as well as the control group.
Ethical Approval
Research involved human participation, with prior consent.
Footnotes
Publisher's Note
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