|Year : 2021 | Volume
| Issue : 2 | Page : 243-249
|Diagnostic efficacy of neutrophil to lymphocyte ratio (NLR) in oral potentially malignant disorders and oral cancer
Shruti Singh1, Jaya Singh1, Roop Ganguly2, Shaleen Chandra1, Fahad M Samadi1, Shaista Suhail1
1 Department of Oral Pathology and Microbiology, Faculty of Dental Sciences, King George's Medical University, Lucknow, Uttar Pradesh, India
2 Department of Oral and Maxillofacial Surgery, Faculty of Dental Sciences, King George's Medical University, Lucknow, Uttar Pradesh, India
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|Date of Submission||16-Feb-2020|
|Date of Decision||16-Mar-2020|
|Date of Acceptance||17-Jun-2020|
|Date of Web Publication||9-Apr-2021|
| Abstract|| |
Background and Aims: Inflammation is considered to be the seventh hallmark of cancer and plays a pivotal role in all stages of tumor development. Systemic inflammatory responses in particular neutrophil to lymphocyte ratio (NLR) have garnered immense attention of current researchers and its role is well proven in various solid malignancies. Its prognostic role in oral cancer have been extensively studied. However, its diagnostic role is yet to be explored. The current study aims to investigate diagnostic utility of NLR in oral potentially malignant disorders and oral cancer, when compared to normal subjects. Methods: A total of 150 subjects were involved in the study, a total of 2.5 ml of blood was drawn from the median cubital vein of the patient in an EDTA vial and hematological parameters were assessed using Erba-Transasia B7256 Autoanalyzer and reassessed manually by two experts. Statistical Analysis: The NLR values were recorded and tabulated as Mean ± S.D. and comparisons were analyzed using Kruskal Wallis and Mann Whitney post hoc U test. ROC curve analysis was performed to estimate cut-off values. Results: The NLR values when compared between the 3 groups were statistically significant (P < 0.001). The cut off value between disease and normal subject was 2.33, while the cut-off value between potentially malignant and malignant condition is 3.20. Conclusion: NLR can be a valuable diagnostic adjunct in oral cancer and potentially malignant disorders of oral cavity.
Keywords: Biomarker, diagnostic, neutrophil to lymphocyte ratio, oral cancer, oral potentially malignant disorders
|How to cite this article:|
Singh S, Singh J, Ganguly R, Chandra S, Samadi FM, Suhail S. Diagnostic efficacy of neutrophil to lymphocyte ratio (NLR) in oral potentially malignant disorders and oral cancer. Indian J Pathol Microbiol 2021;64:243-9
|How to cite this URL:|
Singh S, Singh J, Ganguly R, Chandra S, Samadi FM, Suhail S. Diagnostic efficacy of neutrophil to lymphocyte ratio (NLR) in oral potentially malignant disorders and oral cancer. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 May 7];64:243-9. Available from: https://www.ijpmonline.org/text.asp?2021/64/2/243/313266
| Introduction|| |
Cancer of lip and oral cavity, according to GLOBOCAN 2018, stands 18th and 14th most common cancer worldwide according to incidence and mortality, respectively, with an estimated 354,864 (2.0%) new cases diagnosed leading to 1,77,384 (1.9%) number of deaths in 2018. South central Asia procures 2nd highest place for incidence of lip and oral cavity cancer (17.4%). Despite advancement in therapeutic modalities, the 5 year survival rate still remain close to 50%, with recurrence rate of oral cancer still at 35%.
Oral Potentially Malignant Disorders are those lesions which have increased risk of malignant transformation when compared with the healthy mucosa. Oral Potentially Malignant Disorders consist of leukoplakia, erythroplakia, oral lichen planus, oral submucous fibrosis and various other oral lesions. Majority of oral squamous cell carcinoma develop from preceding potentially oral malignant disorders. The need for effective biomarker to predict Oral Squamous cell Carcinoma and potentially malignant lesions of oral cavity is inevitable in order to avail early diagnosis and therapeutic intervention, thus providing better outcome and good prognosis of the disease.
Hanahan and Weinberg proposed 6 hallmarks of cancer jointly encompassed an organizing principle that provides a rational scaffold for comprehending the multi-stages of carcinogenesis. This includes sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Recent evidence suggests that the tumor-associated inflammatory response had the unexpected, paradoxical effect of enhancing tumorigenesis and progression, Inflammation is now considered to be seventh hallmark of carcinogenesis. The neutrophil-to-lymphocyte ratio (NLR) is a simple and effective marker of inflammation and immunity and reflects patient's immunity status. NLR has been shown to be a valuable marker in patients with various other malignancies such as hepatocellular carcinoma, gastric cancer, soft tissue sarcoma, esophageal cancer, breast cancer, and oral carcinoma. However, the cutoff value of NLR is not consistent. Also, To the best of our knowledge, no study has been done till date to compare pre-operative neutrophil to lymphocyte ratio in oral squamous cell carcinoma, potentially oral malignant disorders and normal oral mucosa. The current study aims to assess pre-operative neutrophil to lymphocyte ratio in oral squamous cell carcinoma, potentially oral malignant disorders of oral cavity and normal oral mucosa.
| Methods|| |
The study was undertaken as prospective case-control study.Institutional ethical clearence and informed consent were duly obtained. A total of 150 subjects participated in the study. The subjects were divided into three groups. Group I: 50 subjects with clinical and histopathologically confirmed cases of Oral Cancer; Group II: 50 subjects with clinical and histopathologically confirmed cases of Oral Potentially Malignant Disorders (Includes Oral Leukoplakia, Erythroplakia, Oral Lichen Planus and Oral Submucous Fibrosis) with histopathologically confirmed Epithelial Dysplasia; Group III: 50 subjects of normal healthy control. Only subjects with established cases of oral squamous cell carcinoma and oral pre-cancer were included in the case groups and normal healthy control with no habit history were included in the control group. Subjects with acute or chronic infections, autoimmune disorders, and any hematological disorder history with corticosteroid therapy or chronic renal insufficiency and subjects who consumed antibiotics in last 6 months were excluded from the study.
Histopathological grading of Oral epithelial dysplasia was done according to WHO Grading System (2017). Clinical Staging and histopathological grading of Oral Squamous Cell Carcinoma was done according to American Joint Committee on Cancer (AJCC) TNM staging and Broder's histopathological grading system (1927) respectively.
A thorough personal history, habit history, clinical examination were done and recorded. Incisional biopsy of subject cases were performed and only confirmed cases were included in the study. A total of 2.5 ml of blood was drawn from the median cubital vein of the patient in an EDTA vial and hematological parameters were assessed using Erba-Transasia B7256 Autoanalyzer.
Descriptive analysis includes expression of all explanatory and Outcome parameters in terms of Mean and SD for continuous variables, whereas in terms of frequency and proportions for categorical variables. Descriptive analysis includes expression of all explanatory and Outcome parameters in terms of Mean and SD for continuous variables, whereas in terms of frequency and proportions for categorical variables. Kruskal Wallis Test followed Mann Whitney U post hoc test was used to compare the mean NLR values between the 3 groups. Mann Whitney test was used to compare the mean NLR values between genders in each study group. ROC curve analysis was performed to establish the cut-off for NLR values between normal and disease conditions, and also between pre-malignant and malignant conditions. The level of significance [P-Value] was set at P < 0.05. Kruskal Wallis test were used to assess NLR values within three grades of oral epithelial dysplasia, clinical stages of Oral Cancer and histopathological grading of oral cancers (P < 0.05).
| Results|| |
The mean age in oral cancer group is 50.2 ± 15.4 years; in oral potentially malignant disorder group is 45.3 ± 14.0 years and in normal control group is 38.3 ± 15.2 years [Table 1] and [Figure 1]a. There were 37 males and 13 females in group I; 38 and 12 males and females respectively in oral potentially malignant disorder groups and 25 males and 25 females in group three cases [Table 1] and [Figure 1]b. The mean neutrophil to lymphocyte ratio in oral cancer subjects is 4.332 ± 1.330; in oral potentially malignant disorder group is 2.879 ± 1.192 and in normal healthy control is 1.825 ± 0.575 [Table 2] and [Figure 1]c. Comparison between NLR values in the three groups using Kruskal Wallis test was statistically significant (P < 0.001) [Table 2] and [Figure 1]d. Multiple comparison of mean difference in NLR Values between three groups using Mann Whitney U Post hoc Test was statistically significant. (P < 0.001) [Table 3] while gender wise comparisons of NLR value between three groups were non-significant.) [Table 4] and [Figure 1]e The cut off NLR value in between normal and diseased conditions is 2.33 (Area under curve-0.88; sensitivity 74%; specificity: 80%) [Table 5]a and [Figure 1]f. The cut off NLR value in between potentially malignant and malignant condition is 3.20 (Area under curve-0.79; sensitivity-82%; specificity-62%) [Table 5]b and [Figure 1]f.
|Figure 1: (a) Age wise distribution among study groups; (b) Gender wise distribution among study groups; (c) Mean NLR value between three groups; (d) Gender wise distribution of mean NLR values among three groups; (e) ROC curve between cases and control; (f) ROC curve between potentially malignant and malignant group|
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|Table 2: Comparison of mean NLR values b/w three groups using Kruskal Wallis Test|
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|Table 3: Multiple comparison of mean difference in NLR Values between three groups using Mann Whitney U Post hoc Test|
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|Table 4: Genderwise comparison of mean NLR values among three study groups using Mann Whitney Test|
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When compared within the group, the NLR values between the three grades of dysplasia, that is, mild; moderate and severe epithelial dysplasia using Kruskal Wallis test were non-significant (P = 0.85) [Table 6] and [Figure 2]c. Amongst the oral cancer group, the group was further subdivided according to clinical staging and histopathological grading. The NLR values when compared within these groups were statistically non-significant. (P = 0.86; P = 0.86) [Table 7], [Table 8] and [Figure 2]a, [Figure 2]b.
|Table 6: Comparison of mean NLR values b/w varying H/P grades in Potentially Pre-malignant lesion Group using Kruskal Wallis Test|
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|Table 7: Comparison of mean NLR values b/w varying clinical stages in Oral Cancer Group using Kruskal Wallis Test|
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|Table 8: Comparison of mean NLR values b/w varying H/P grades in Oral Cancer Group using Kruskal Wallis Test|
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|Figure 2: (a) Mean NLR Values Between Varying Clinical Stages Of Oral Cancer Group; (b) Mean NLR Values Between Varying Histopathological Grades Of Oral Cancer Group (c) Mean NLR Values Between Varying Histopathological Grades In Potentially Pre-Malignant Lesions Group|
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ROC is a plot of the true positive rate against the false positive rate for the different possible cut points of a diagnostic test.
Accuracy is measured by the area under the ROC curve. An area of 1 represents a perfect test; an area of 0.5 represents a worthless test. A rough guide for classifying the accuracy of a diagnostic test is the traditional academic point system:
0.90-1 = excellent (A), 0.80-0.90 = good (B), 0.70-0.80 = fair (C), 0.60-0.70 = poor (D), 0.50-0.60 = fail (F).
| Discussion|| |
The association of inflammation with oral cancer dates back to 1963 when Rudolph Virchow observed role of inflammation with carcinogenesis. Different studies have confirmed the role of inflammation in tumor initiation and promotion by impairing cell homeostasis and metabolism causing genomic changes thereby leading to carcinogenesis. The changes occurring in pro-inflammatory cells and cytokine production links inflammation and cancer are well proven by literature. The current researchers have emphasized the role of systemic inflammatory response in cancer. Neutrophil-to-lymphocyte ratio (NLR) is one of the most studied markers in different malignancies. While a majority of the studied prognostic role of NLR in carcinomas, the diagnostic role of NLR is still scarcely reported. Since prevention is anytime better than cure, an early treatment reduces the morbidity and mortality, hence early detection implies favorable prognosis.
Neutrophils and macrophages aids in tumor initiation through various cytokines and chemokines. Initial tumor growth depends on increased cell proliferation and reduced cell death and this is majorly contributed by inflammation-guided process.,,,, Various other chemical mediator aids in tumor growth. Inflammation also aids in neo-angiogenesis and metastatic growth. Apart from tumor cells, tumor microenvironment contains innate immune cells such as neutrophils and adaptive immune cells such as lymphocytes. These cells regulate the tumor growth through cytokines and chemokine. A schematic representation of role of inflammatory and immune cells in carcinogenesis has been illustrated in [Figure 3] and [Figure 4].
|Figure 3: Role of inflammatory cells in oral carcinogenesis,,,,,|
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Dunn et al. put forth immunoediting concept, according to which cancer cells restrain the host anti-tumor immune response and immune response in return controls tumor immunogenicity and clonal selection. Tumor growth occurs when there is tumor-promoting response proceeds than anti-tumor response. Cancer cell edits its repertoire of tumor antigens towards lower immunogenicity and also re-shapes the tumor microenvironment to become immunosuppressive. Consistent with this hypothesis, cancers that have evolved in alymphocytic mice are more immunogenic than cancers grown in immunocompetent mice.
The basis of the NLR is to associate and compare the inflammatory response to the immune response of the host. An increased neutrophil count and a decreased lymphocyte count indicate a high NLR. Lymphocytes and neutrophils have a reverse effect on cancer progression.
Initial tumor growth depends on increased cell proliferation and decreased cell death. Neutrophil Count can act as both tumor promoting and tumoricidal function depending upon their differentiation status and effect of TGF-Beta. Neutrophil subsets can repress T-cell proliferation by integrin Mac-1 and hydrogen peroxide. Lymphocytes, predominantly the T-lymphocytes inhibit the proliferation and metastatic spread of tumor cells by cytotoxic cell death and production of cytokines respectively. Body's immune response can be reduced due to a decrease in the lymphocyte count. The NLR generally remain steady with a change in various physiological, pathological, and physical factors, although there can be a change in the neutrophil and lymphocytic count. Therefore higher the NLR, poorer is the prognosis of cancer.The possible pathomechanism of NLR in Oral cancer is elucidated in [Figure 5].
|Figure 5: Possible Pathomechanism of NLR in Oral Cancer (Adapted from: Mahalakshmi R, Boaz K, Srikant N, Baliga M, Shetty P, Prasad M, et al. Neutrophil-to-lymphocyte ratio: A surrogate marker for prognosis of oral squamous cell carcinoma. Indian J Med Paediatr Oncol 2018;39:8-12)|
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A systematic review by Guthrie et al. showed that NLR is increased in patients with advanced and aggressive cancers. Likewise, Perisanidis et al. analyzed 97 patients with OSCC with local invasion who were preoperatively treated with chemotherapy and observed that NLR is an independent marker for an unfavorable prognosis. Takenaka et al. conducted a meta-analysis on neutrophil to lymphocyte ratio in head and neck squamous cell carcinoma and concluded that elevated NLR predicts worse outcome in patients with HNSCC.
The diagnostic value of NLR in oral cancer has not been studied in depth. Duzlu et al. studied NLR as diagnostic marker in 95 subjects suffering from oral cavity cancers. He observed that NLR were high in case of oral cancers with a cutoff value of 2.88. Phulari et al. conducted a study on 100 cases of oral cancer observed a high NLR in oral cavity cancers and obtained a cut off value of 2.84. Cut off NLR value in our study to differentiate between control and disease condition came out as 2.33 consistent with other studies. The cut off NLR value between pre-malignant and malignant condition was 3.20.
Kum et al. showed that neutrophil-to lymphocyte ratio elevated in squamous cell carcinoma of larynx compared to benign and precancerous laryngeal lesions. Our finding is similar when compared in oral cancers.
The mean NLR values when compared within different grades of oral epithelial dysplasia, different clinical stages and different histopathological grades of Oral Squamous Cell Carcinoma came out to be non-significant. Mahalaxmi R et al. compared NLR values within different grades of Oral Cancers and obtained higher NLR values with increasing grades of Carcinoma but the values were statistically non-significant.
| Conclusion|| |
To our knowledge, this is the first study conducted to compare NLR in oral potentially malignant disorders, oral malignant disorders and healthy controls. The comparison of NLR values between the three groups was statistically significant. The cut off value between normal and cases is lesser when compared with cut off NLR value in the case of potentially malignant and malignant disorders. Further studies with larger sample size are needed to establish NLR as a definite diagnostic adjunct in oral potentially malignant and malignant disorders.
The non-significant findings of the mean NLR values within different grades of oral epithelial dysplasia, different clinical stages and different histopathological grades of Oral Squamous Cell Carcinoma can be attributed to the smaller sample size of our study. Hence, further cross-sectional studies with a larger sample size may be required to establish some significance.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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Senior Resident, Department of Oral Pathology & Microbiology, King George's Medical University, Chowk, Lucknow, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]
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