Abstract
This present study aimed to assess the predictive significance of two systemic inflammatory markers, the neutrophilic to lymphocytic ratio (NLR) and platelet to lymphocytic ratio (PLR), in evaluating the prognosis of individuals. The research involved 47 patients diagnosed with head and neck squamous cell carcinoma, all of whom were histo-pathologically confirmed and aged over 18 years. The patients were monitored every 6 months for a period of 18 months. The average age of the study participants was 57.66 ± 13.5 years, with 42 (89.36%) being male and 5 (10.64%) female. After 6 months, the mean PLR in patients with residual/recurrence was 161.5 ± 8.5, which was significantly, exceeded that of patients without residual/recurrence (109.07 ± 36.29; p value < 0.0001). However, no significant correlation was seen between the NLR (p value = 0.822) and residual/recurrence after 6 months. After 12 months, the mean NLR in patients with recurrence was 4.89 ± 0.69, which was significantly higher compared to patients without recurrence (3.48 ± 1.01; p value = 0.025). Conversely, no significant association was found between the PLR (p value = 0.751) and recurrence after 12 months. Notably, there were no significant associations observed in NLR and PLR at the 18-month mark. Elevated levels of the NLR and PLR can serve as indicators of poor prognosis and the presence of residual/recurrent disease in head and neck malignancies.
Keywords: Head and neck cancer, Neutrophilic to lymphocytic ratio, Platelet to lymphocytic ratio
Introduction
Cancer, the 2nd leading cause of death worldwide, claimed the lives of 8.8 million individuals in 2015. It accounts for over 1/6th of global fatalities. Each year, more than 550,000 new cases of head and neck cancer are diagnosed globally, resulting in approximately 300,000 deaths. Among head and neck malignancies, squamous cell carcinomas (HNSCC) constitute over 90% of cases. HNSCC is the 6th most common cancer globally. However, in India, head and neck cancers comprise nearly 1/3rd of all cancer incidences, a much higher proportion compared to the industrialized world's 4–5%. In India, lip and oral cancer ranked highest among male cancers and 2nd overall in 2018. Early detection of these abnormalities plays a crucial role in improving treatment outcomes and prognosis. The development of modern, safe, affordable, and repeatable diagnostic and prescriptive methods is therefore essential, with blood- or serum-based diagnostics offering significant advantages [1, 2].
Oral squamous cell carcinoma (OSCC) is a type of cancer that arises from the mucosal epithelium of the tongue and oral cavity and exhibits squamous differentiation. Its incidence is notably increasing in individuals in their thirties and forties. Factors contributing to this rise include smoking, alcohol consumption, lifestyle changes, increased awareness and early diagnosis, and genetic factors. Men are more susceptible to oral cancer, with the highest incidence occurring in individuals aged between their fifties and sixties. The survival rate for oral cancer stands at approximately 50%. Currently, traditional histologic factors, such as tumor size, depth of invasion, pattern of invasion and nodal status, are important for predicting cancer progression or recurrence. Researchers have investigated numerous novel biomarkers to enhance risk stratification for adjuvant treatment or more aggressive therapy in patients with distant metastasis [2–6].
Tumors significantly influence the inflammatory response, and various malignancies severely disrupt hematopoiesis. The growth, development and spread of tumors are closely associated with cellular mediation. Inflammatory markers, including C-reactive protein (CRP), peripheral blood cell count, erythrocyte sedimentation rate (ESR), monocyte tolymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR) and neutrophil to lymphocyte ratio (NLR) have been utilized to measure the inflammatory response. Chronic inflammation has been studied as a hallmark of host variables in cancer genesis and progression. Research on the interaction between tumor development and systemic inflammation suggests that chronic inflammation can promote carcinogenesis, with the level of systemic inflammation correlating with oncologic outcomes. Peripheral blood sampling is a simple and valuable method for assessing systemic inflammation in clinical settings [7, 8].
Several composite indices incorporating peripheral blood differential counts have been proposed as prognostic indicators. Survival in oral squamous cell carcinoma is closely linked to systemic inflammatory markers (SIMs) such as the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR). However, there are discrepancies in the prognostic impact and cutoff values among these systemic inflammatory markers for oral squamous cell carcinoma.
Hence, this study aimed to assess the predictive significance of two systemic inflammatory markers, the Neutrophilic/Lymphocytic ratio (NLR) and Platelet/Lymphocytic ratio (PLR), in evaluating the prognosis of individuals.
Materials and methods
All eligible patients with confirmed Head and Neck Squamous Cell Carcinoma (HNSCC) were included in the study while those who did not meet the inclusion criteria or had exclusion criteria were excluded. The inclusion criteria required patients to be aged over 18 years, have histopathologically confirmed HNSCC, and provide their consent to participate. Exclusion criteria consisted of the presence of synchronous tumors, inflammatory conditions (such as neck fistula, pneumonia, wound infection, abscess, cholecystitis, sepsis, endocarditis, urinary tract infection, etc.), thromboembolic events, corticosteroid therapy, and treatment with platelet aggregation inhibitors within one month prior to blood sampling.
Patients of any gender who met the inclusion criteria and visited the Department of Otorhinolaryngology—Head and Neck Surgery at I.G.M.C. Shimla, Himachal Pradesh within the first three months of the study's initiation were enrolled. Alternatively, a minimum sample size of 30 patients was considered due to the ongoing COVID-19 pandemic. Informed consent was obtained from all participants. Detailed medical history and clinical examination were conducted for patients presenting with head and neck lesions. Routine blood investigations, including complete blood count, were performed. Additional investigations, such as CT scans, were conducted before biopsy to prevent the impact of biopsy-induced edema on upstaging. Patients with histologically confirmed tumors were included in the study, with tumor type classified according to the World Health Organization's classification of tumors, pathology, and genetics of head and neck tumors (IARC Press: Lyon, 2005). The AJCC-UICC Cancer staging 8th edition, 2017, was used for histological grading and clinical staging of tumors.
Inflammatory markers, including neutrophil, lymphocyte, and platelet levels, were collected from routine full blood counts before initiating treatment. Patients were followed up every 6 months for 18 months, with clinical examinations, complete blood counts, and CT or USG neck scans performed as necessary to detect recurrence.
The demographic characteristics (age, gender, etc.) of all patients with head and neck squamous cell carcinoma were analyzed. The NLR, PLR, and other hematological values were assessed at 6 months, 12 months, and 18 months, and patients were evaluated for residual/recurrent disease. The correlation between NLR, PLR, and disease was examined.
Statistical analysis
Categorical variables were presented as numbers and percentages, while quantitative data were expressed as means ± standard deviation (SD) or median with 25th and 75th percentiles (interquartile range). Independent t-tests were used for comparing quantitative variables between two groups, ANOVA for more than two groups, and paired t-tests for comparisons across follow-up. Chi-square tests were employed for analyzing qualitative variables, and Fisher's exact test was used if any cell had an expected value of less than 5.
Data entry was performed in Microsoft Excel, and the final analysis was conducted using the Statistical Package for Social Sciences (SPSS) software, IBM manufacturer, Chicago, USA, version 25.0. A p value of less than 0.05 was considered statistically significant.
Ethical Consideration
The study was done after taking due permission from Institutional ethical committee of Indira Gandhi Medical College, Shimla, Himachal Pradesh vide letter No. HFW(MC-II) B(12)ETHICS/2021-362 dated 07-01-2022.Informed consent was obtained from all the participants before their enrollment in the study. Participant confidentiality and anonymity were strictly maintained throughout the research process.
Results
Patient Demographics for Total Population
Out of the total 47 patients, the highest proportion of individuals, 16 (34.04%), fell into the age group of 61–70 years. This was followed by the age groups of 41–50 years with 13 patients (27.66%), 51–60 years with 9 patients (19.15%), > 70 years with 6 patients (12.77%), and 18–40 years with 3 patients (6.38%). The mean age of the study participants was 57.66 ± 13.5 years, and the median age (25th–75th percentile) was 60 (47–68.5).
The majority of patients, 28 (59.57%), had a body mass index (BMI) within the range of 18.5–24.9 kg/m2, categorized as "Normal." This was followed by 18 patients (38.30%) who fell into the "Underweight" category with a BMI of 16–18.4 kg/m2. Only one patient (2.13%) had a BMI below 16 kg/m2, indicating "Severe underweight." The mean BMI of the study participants was 18.91 ± 1.91, and the median BMI (25th–75th percentile) was 19 (18–20).
Among the patients, 42 (89.36%) were male, while 5 (10.64%) were female (Table 1).
Table 1.
Distribution of demographic characteristics of study subjects
| Demographic characteristics | Frequency | Percentage |
|---|---|---|
| Age (years) | ||
| 18–40 | 3 | 6.38 |
| 41–50 | 13 | 27.66 |
| 51–60 | 9 | 19.15 |
| 61–70 | 16 | 34.04 |
| > 70 | 6 | 12.77 |
| Mean ± SD | 57.66 ± 13.5 | |
| Median (25th–75th percentile) | 60 (47–68.5) | |
| Range | 18–90 | |
| Body mass index (kg/m2) | ||
| < 16 kg/m2 (severely underweight) | 1 | 2.13 |
| 16–18.4 kg/m2 (underweight) | 18 | 38.30 |
| 18.5–24.9 kg/m2 (normal) | 28 | 59.57 |
| Mean ± SD | 18.91 ± 1.91 | |
| Median (25th–75th percentile) | 19 (18–20) | |
| Range | 15–23 | |
| Gender | ||
| Female | 5 | 10.64 |
| Male | 42 | 89.36 |
NLR and PLR Associations with Patient Demographics
There was no significant correlation observed between the neutrophil lymphocyte ratio (NLR) and the presence of residual/recurrence at 6 months (p value = 0.822). The mean NLR in patients with residual/recurrence was 2.86 ± 0.95, while in patients without residual/recurrence, it was 2.99 ± 1.14. These values did not show any significant association between them.
However, a significant association was found between the platelet lymphocyte ratio (PLR) and the presence of residual/recurrence at 6 months (p value < 0.05). The mean PLR in patients with residual/recurrence was 161.5 ± 8.5, which was significantly higher compared to patients without residual/recurrence (109.07 ± 36.29) (p value < 0.0001) (Table 2).
Table 2.
Association of NLR and PLR at 6 months with residual/recurrence at 6 months
| NLR/PLR at 6 months | With residual/recurrence | Without residual/recurrence | Total | p value |
|---|---|---|---|---|
| Neutrophil lymphocyte ratio | ||||
| Mean ± SD | 2.86 ± 0.95 | 2.99 ± 1.14 | 2.98 ± 1.11 | 0.822‡ |
| Median (25th–75th percentile) | 2.88 (2.22–3.52) | 3 (1.845–4) | 3 (1.845–4) | |
| Range | 1.8–3.88 | 1.45–5 | 1.45–5 | |
| Platelet lymphocyte ratio | ||||
| Mean ± SD | 161.5 ± 8.5 | 109.07 ± 36.29 | 114.44 ± 38 | < 0.0001‡ |
| Median (25th–75th percentile) | 163 (158.25–166.25) | 107 (78–143) | 113 (80–150.3) | |
| Range | 150–170 | 44–164 | 44–170 | |
‡Independent t test
There was no significant correlation observed between the platelet lymphocyte ratio (PLR) and the presence of recurrence at 12 months (p value = 0.751). The mean PLR in patients with recurrence was 123.22 ± 75.49, while in patients without recurrence, it was 132.08 ± 43.17. These values did not show any significant association between them.
However, a significant association was found between the neutrophil lymphocyte ratio (NLR) and the presence of recurrence at 12 months (p value < 0.05). The mean NLR in patients with recurrence was 4.89 ± 0.69, which was significantly higher compared to patients without recurrence (3.48 ± 1.01) (p value = 0.025) (Table 3).
Table 3.
Association of NLR and PLR at 12 months with recurrence at 12 months
| NLR/PLR at 12 months | With recurrence (n = 3) | Without recurrence (n = 31) | Total | p value |
|---|---|---|---|---|
| Neutrophil lymphocyte ratio | ||||
| Mean ± SD | 4.89 ± 0.69 | 3.48 ± 1.01 | 3.6 ± 1.06 | 0.025‡ |
| Median (25th–75th percentile) | 5.17 (4.635–5.285) | 3.52 (2.775–4.2) | 3.74 (3–4.3) | |
| Range | 4.1–5.4 | 1.57–5.4 | 1.57–5.4 | |
| Platelet lymphocyte ratio | ||||
| Mean ± SD | 123.22 ± 75.49 | 132.08 ± 43.17 | 131.3 ± 45.24 | 0.751‡ |
| Median (25th–75th percentile) | 87 (79.83–148.5) | 133 (104.5–156.5) | 132.85 (101–156.75) | |
| Range | 72.66–210 | 56–238 | 56–238 | |
‡Independent t test
There were no significant associations observed between the neutrophil lymphocyte ratio (NLR) (p value = 0.858) and platelet lymphocyte ratio (PLR) (p value = 0.925) with recurrence at 18 months. The mean NLR and PLR in patients with recurrence were 3 ± 0 and 117 ± 0, respectively. In contrast, in patients without recurrence, the mean NLR and PLR were 3.28 ± 1.51 and 109.71 ± 75.03, respectively. These values did not show any significant associations between them (Table 4).
Table 4.
Association of NLR and PLR at 18 months with recurrence at 18 months
| Hematological parameters at 18 months | With recurrence (n = 1) | Without recurrence (n = 27) | Total | p value |
|---|---|---|---|---|
| Neutrophil lymphocyte ratio | ||||
| Mean ± SD | 3 ± 0 | 3.28 ± 1.51 | 3.27 ± 1.48 | 0.858‡ |
| Median (25th–75th percentile) | 3 (3–3) | 3.03 (2.125–4.05) | 3.01 (2.188–4.025) | |
| Range | 3–3 | 1.38–7.4 | 1.38–7.4 | |
| Platelet lymphocyte ratio | ||||
| Mean ± SD | 117 ± 0 | 109.71 ± 75.03 | 109.97 ± 73.64 | 0.925‡ |
| Median (25th–75th percentile) | 117 (117–117) | 80.66 (58.395–142) | 81.38 (58.668–141.5) | |
| Range | 117–117 | 32–353 | 32–353 | |
‡Independent t test
The distribution of recurrence showed comparable patterns with various hematological parameters. Neutrophil count (%) exhibited no significant association with recurrence when comparing low (< 50%) versus normal (50–70%) versus elevated (> 70%) levels (p value = 0.511). Similarly, platelet count (×103/µL) did not show a significant association with recurrence when comparing low (< 150 ×103/µL) versus normal (150–410 ×103/µL) versus elevated (> 410 ×103/µL) levels (p value = 0.457). The lymphocyte count (%) also did not display a significant association with recurrence when comparing low (< 20%) versus normal (20–40%) versus elevated (> 40%) levels (p value = 0.316). Hemoglobin (g/dL), RBC (×1012/µL), WBC (×103/µL), and hematocrit (%) also did not exhibit significant associations with recurrence.
Furthermore, no significant associations were found between neutrophil lymphocyte ratio (NLR) (p value = 0.35) and platelet lymphocyte ratio (PLR) (p value = 0.805) with overall recurrence. The mean NLR and PLR in patients with recurrence were 2 ± 0.81 and 103.55 ± 55.5, respectively. In patients without recurrence, the mean NLR and PLR were 2.88 ± 2.24 and 111.78 ± 77.16, respectively. These findings suggest no significant association between NLR and PLR values and recurrence (Table 5).
Table 5.
Association of hematological parameters at presentation with overall recurrence
| Hematological parameters at Presentation | With recurrence (n = 6) | Without recurrence (n = 33) | Total | p value |
|---|---|---|---|---|
| Neutrophil count (%) | ||||
| Low (< 50%) | 0 (0%) | 2 (100%) | 2 (100%) | 0.511* |
| Normal (50–70%) | 3 (11.11%) | 24 (88.89%) | 27 (100%) | |
| Elevated (> 70%) | 3 (30%) | 7 (70%) | 10 (100%) | |
| Platelet count (×103/µL) | ||||
| Low (< 150 × 103/µL) | 0 (0%) | 8 (100%) | 8 (100%) | 0.457* |
| Normal (150–410 × 103/µL) | 5 (20%) | 20 (80%) | 25 (100%) | |
| Elevated (> 410 × 103/µL) | 1 (16.67%) | 5 (83.33%) | 6 (100%) | |
| Lymphocyte count (%) | ||||
| Low (< 20%) | 0 (0%) | 4 (100%) | 4 (100%) | 0.316* |
| Normal (20–40%) | 4 (13.79%) | 25 (86.21%) | 29 (100%) | |
| Elevated (> 40%) | 2 (33.33%) | 4 (66.67%) | 6 (100%) | |
| Hemoglobin (g/dL) | ||||
| Low (< 12 g/dL) | 2 (11.76%) | 15 (88.24%) | 17 (100%) | 0.723* |
| Normal (12–15 g/dL) | 4 (19.05%) | 17 (80.95%) | 21 (100%) | |
| Elevated (> 15 g/dL) | 0 (0%) | 1 (100%) | 1 (100%) | |
| RBC (× 1012/µL) | ||||
| Low (< 3.8 × 1012/µL) | 2 (10.53%) | 17 (89.47%) | 19 (100%) | 0.549* |
| Normal (3.8–4.8 × 1012/µL) | 3 (18.75%) | 13 (81.25%) | 16 (100%) | |
| Elevated (> 4.8 × 1012/µL) | 1 (25%) | 3 (75%) | 4 (100%) | |
| WBC (× 103/µL) | ||||
| Normal (4–10 × 103/µL) | 3 (13.64%) | 19 (86.36%) | 22 (100%) | 1* |
| Elevated (> 10 × 103/µL) | 3 (17.65%) | 14 (82.35%) | 17 (100%) | |
| Hematocrit (%) | ||||
| Low (< 36%) | 2 (12.50%) | 14 (87.50%) | 16 (100%) | 0.772* |
| Normal (36–46%) | 4 (19.05%) | 17 (80.95%) | 21 (100%) | |
| Elevated (> 46%) | 0 (0%) | 2 (100%) | 2 (100%) | |
| Neutrophil lymphocyte ratio | ||||
| Mean ± SD | 2 ± 0.81 | 2.88 ± 2.24 | 2.75 ± 2.1 | 0.35‡ |
| Median (25th–75th percentile) | 2 (1.608–2.075) | 2 (2–3.08) | 2 (2–2.765) | |
| Range | 1–3.42 | 1.2–12 | 1–12 | |
| Platelet lymphocyte ratio | ||||
| Mean ± SD | 103.55 ± 55.5 | 111.78 ± 77.16 | 110.52 ± 73.68 | 0.805‡ |
| Median (25th–75th percentile) | 88.5 (74.75–136) | 93 (69.76–133) | 91 (70.38–139.5) | |
| Range | 35.29–187 | 33–407 | 33–407 | |
‡Independent t test
*Fisher's exact test
Discussion
The primary objective of this study was to investigate the importance of systemic inflammatory markers in predicting residual/recurrent head and neck squamous cell cancer. The markers examined were the platelet-lymphocyte ratio (PLR) and the neutrophil–lymphocyte ratio (NLR).
In a study on osteosarcoma, Liu et al. [9] concluded that both high NLR and PLR were indicative of a poor prognosis in non-small cell lung cancer. Higher NLR/PLR was likewise linked to a poor prognosis in the study done by Song et al. [10]. Another study by Jiang et al. [11] found that NLR/PLR had similar predictive value for esophageal cancer.
Pietrzyk et al. [12] conducted a study in 2016 and found that the mean NLR of patients with gastric cancer (3.05 ± 2.09) was significantly higher than that of the control group (2.25 ± 0.87) with a p value of 0.02. Acmaz et al. [13] conducted a study in 2014 and reported a mean NLR of 2.89 in the endometrial malignant group compared to 1.94 in the control group (p = 0.025). Duzlu et al. [14] conducted a study in 2015 involving laryngeal cancer patients and controls, and they found a statistically significant difference in NLR between the larynx carcinoma group (2.70 ± 1.25) and the control group (2.04 ± 0.90) with a p value of 0.004.
In 2015, Seetohul et al. [15] conducted a study involving 53 laryngeal cancer patients and 50 healthy controls. The malignant group had a higher median NLR (1.9455) compared to the control group, and this difference was statistically significant (p = 0.011). Nikolic et al. [16] conducted a study in 2016 with lung cancer patients and found that the mean NLR was 3.63 and the mean PLR was 171 in the cancer group, while the control group had a mean NLR of 2.07 and a mean PLR of 115. Yilmaz et al. [17] retrospectively evaluated individuals with laryngeal pathology in 2016 and found significantly higher PLR values in the malignant group (mean PLR = 196.47; p < 0.001) compared to the benign group (mean PLR = 113.34).
In our study, we observed a significant association between the platelet-lymphocyte ratio and residual/recurrence at 6 months (p < 0.05). The mean ± SD of the platelet-lymphocyte ratio in patients with residual/recurrence was 161.5 ± 8.5, which was significantly higher than in patients without residual/recurrence (109.07 ± 36.29, p < 0.0001). Similarly, a significant association was found between the neutrophil–lymphocyte ratio and recurrence at 12 months (p < 0.05). The mean ± SD of the neutrophil–lymphocyte ratio in patients with recurrence was 4.89 ± 0.69, which was significantly higher compared to patients without recurrence (3.48 ± 1.01, p = 0.025). However, no significant association was observed between the neutrophil–lymphocyte ratio (p = 0.858) and platelet-lymphocyte ratio (p = 0.925) with recurrence at 18 months.
Conclusion
The primary objective of this study was to assess the predictive value of the platelet-lymphocyte ratio (PLR) and neutrophil–lymphocyte ratio (NLR) in predicting residual/recurrent head and neck malignancies. Patients diagnosed with cancer exhibited significantly higher NLR and PLR values compared to individuals without pathological conditions. These metrics have the potential to differentiate between individuals with cancer and those who are disease-free, thus enabling the prediction of prognosis for head and neck tumors using the NLR and PLR.
Therefore, elevated levels of the neutrophil–lymphocyte ratio and platelet-lymphocyte ratio can serve as indicators of an unfavorable prognosis in head and neck malignancies. Nevertheless, further investigations involving larger study populations and continuous monitoring are necessary to corroborate these findings.
Funding
None.
Declarations
Conflict of interest
None.
Footnotes
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