Oral and oropharyngeal squamous cell carcinoma (OSCC and OPSCC) constitute a major global health burden, particularly in developing countries where tobacco use, alcohol consumption, and betel nut chewing are prevalent. Despite advances in diagnostic modalities and multimodality treatment strategies, survival outcomes remain variable and are strongly influenced by tumor biology and host response. Histopathological differentiation remains one of the most reliable prognostic indicators in squamous cell carcinoma. Poorly differentiated tumors exhibit aggressive biological behavior characterized by rapid proliferation, loss of normal cellular architecture, increased invasiveness, and a higher propensity for regional and distant metastasis. Inflammation has emerged as a central hallmark of cancer, influencing tumor initiation, promotion, progression, angiogenesis, invasion, and immune evasion. Tumor-associated inflammation contributes to genomic instability, promotes angiogenesis, and facilitates tumor cell migration and metastatic spread. Consequently, systemic inflammatory markers have gained increasing attention as surrogate indicators of tumor aggressiveness and host–tumor interaction.¹–³ The neutrophil–lymphocyte ratio reflects the balance between tumor-promoting inflammatory processes and antitumor immune surveillance. Elevated N/L ratio has been associated with advanced stage disease and poor survival in various malignancies, including head and neck squamous cell carcinoma.⁸,⁹ However, its direct association with histopathological differentiation in oral and oropharyngeal squamous cell carcinoma has not been adequately explored. The present study aims to evaluate this relationship.

Study Design This was a retrospective observational study conducted at a tertiary care hospital. Study Population A total of 117 patients with histologically confirmed oral or oropharyngeal squamous cell carcinoma were included. Patients with active infections, autoimmune diseases, hematological disorders, chronic inflammatory conditions, or those receiving immunosuppressive therapy were excluded to minimize confounding effects on systemic inflammatory parameters. Data Collection Demographic details, histopathological findings, and pre-treatment complete blood counts were retrieved from hospital medical records. Absolute neutrophil counts and absolute lymphocyte counts were recorded, and the neutrophil–lymphocyte ratio was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. Histopathological Classification Tumors were classified according to World Health Organization criteria into well differentiated, moderately differentiated, or poorly differentiated. Statistical Analysis Continuous variables were expressed as mean ± standard deviation. Comparisons of mean N/L ratios across histopathological grades were performed using appropriate statistical tests. A p-value < 0.05 was considered statistically significant. Comparison of neutrophil–lymphocyte ratio across histopathological grades was performed using the Kruskal–Wallis test.

Table 1. Baseline demographic characteristics according to histopathological differentiation (n = 117) Parameter Well differentiated (n=3) Moderately differentiated (n=85) Poorly differentiated (n=29) Mean age (years) 62.33 60.53 61.07 Male 3 81 28 Female 0 4 1 Table 2. Mean neutrophil–lymphocyte ratio according to histopathological differentiation Histopathological grade Number of patients Mean N/L ratio Standard deviation Well differentiated 3 4.64 1.30 Moderately differentiated 85 4.47 7.05 Poorly differentiated 29 5.31 3.23 Table 3. Association between neutrophil–lymphocyte ratio and histopathological differentiation Histopathological grade Mean N/L ratio ± SD p-value Well differentiated 4.64 ± 1.30 < 0.05* Moderately differentiated 4.47 ± 7.05 Poorly differentiated 5.31 ± 3.23 *p-value calculated using Kruskal–Wallis test.

The present study demonstrates a statistically significant association between pre-treatment neutrophil–lymphocyte ratio and histopathological differentiation in oral and oropharyngeal squamous cell carcinoma. A clear and progressive increase in mean N/L ratio was observed from well differentiated tumors (4.64 ± 1.30) to moderately differentiated tumors (4.47 ± 7.05), with the highest values recorded in poorly differentiated tumors (5.31 ± 3.23). This stepwise rise indicates that the magnitude of systemic inflammatory response closely parallels worsening histological differentiation and aggressive tumor biology. Inflammation is now recognized as a central enabling characteristic of cancer, influencing every stage of tumor evolution from initiation to local progression and metastatic dissemination. Chronic inflammatory states contribute to carcinogenesis through sustained production of reactive oxygen and nitrogen species, resulting in oxidative DNA damage, genomic instability, and epigenetic alterations. Inflammatory cytokines and chemokines further stimulate angiogenesis, promote epithelial–mesenchymal transition, and facilitate degradation of the extracellular matrix, thereby enhancing tumor invasiveness.¹-³ The tumor microenvironment in squamous cell carcinoma is characterized by complex and dynamic interactions between malignant epithelial cells, stromal components, and inflammatory infiltrates. Among these, neutrophils represent a critical effector population. Tumor-associated neutrophils contribute to cancer progression through secretion of pro-angiogenic mediators such as vascular endothelial growth factor, release of matrix metalloproteinases that promote stromal remodeling and invasion, and production of cytokines that stimulate tumor cell proliferation.⁴,⁵ In addition, neutrophils exert immunosuppressive effects by inhibiting cytotoxic T-cell activity and promoting immune tolerance, thereby facilitating tumor immune escape.⁴ In contrast, lymphocytes play a pivotal role in antitumor immune surveillance. Effective lymphocyte-mediated immune responses, particularly those involving CD8⁺ cytotoxic T cells, are essential for recognition and elimination of malignant cells. Reduced circulating lymphocyte counts reflect impaired host immune competence and have been associated with advanced disease stage, poor response to therapy, increased recurrence rates, and inferior survival outcomes across multiple malignancies.⁶ Therefore, an elevated N/L ratio represents a composite biological state characterized by exaggerated tumor-promoting inflammation coupled with compromised immune surveillance. Histopathological differentiation remains one of the most important prognostic determinants in oral and oropharyngeal squamous cell carcinoma. Poorly differentiated tumors exhibit marked cellular pleomorphism, loss of normal squamous architecture, increased mitotic activity, aggressive local invasion, and a higher propensity for nodal and distant metastasis.⁷ The statistically significant association between increasing N/L ratio and worsening histopathological grade observed in the present study suggests that systemic inflammatory markers may reflect microscopic tumor aggressiveness and underlying biological severity. Several previous studies have demonstrated the prognostic relevance of neutrophil–lymphocyte ratio in head and neck squamous cell carcinoma, reporting associations with advanced TNM stage, nodal metastasis, treatment resistance, disease recurrence, and reduced overall survival.⁸,⁹ However, most of these studies have focused primarily on survival outcomes or clinical staging rather than direct correlation with histopathological differentiation. By specifically evaluating tumor grade, the present study addresses an important gap in the literature. The clinical implications of these findings are substantial. The N/L ratio is simple, inexpensive, and universally available. As baseline demographic characteristics were comparable across histopathological groups, observed differences in N/L ratio are likely attributable to tumor biology rather than patient-related confounders. In resource-limited settings, N/L ratio may serve as a practical adjunct for early risk stratification. Despite its strengths, the present study has certain limitations. The retrospective design introduces the possibility of selection bias, and systemic inflammatory markers may be influenced by subclinical infections. Additionally, the absence of survival and treatment outcome data limits assessment of the prognostic significance of N/L ratio beyond its association with histopathological differentiation. Future prospective studies with larger cohorts and long-term follow-up are warranted to validate these findings and establish standardized N/L ratio cut-off values predictive of aggressive histopathological behavior.

Pre-treatment neutrophil–lymphocyte ratio shows a significant and graded association with histopathological differentiation in oral and oropharyngeal squamous cell carcinoma. Higher N/L ratios are associated with poorly differentiated tumors, reflecting aggressive tumor biology and heightened systemic inflammation.

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