A Narrative Review on Oral Squamous Cell Carcinoma

ABSTRACT

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity, accounting for nearly 90% of all oral cancers. It remains a significant global health concern due to the high morbidity and mortality, often diagnosed at advanced stages despite advancements in diagnostic tools such as biopsy, imaging, and molecular markers. OSCC is driven by genetic and molecular alterations, including TP53 mutations, EGFR overexpression, and dysregulated signaling pathways that promote tumor progression. While treatment primarily includes surgery, radiotherapy, and chemotherapy, emerging approaches such as targeted therapy and immunotherapy are showing promise. However, challenges such as recurrence, metastasis, and treatment resistance persist. Improving early detection strategies, identifying novel biomarkers, and incorporating precision medicine approaches are crucial for enhancing survival outcomes and quality of life in OSCC patients.

INTRODUCTION

Oral squamous cell carcinoma (OSCC) accounts for nearly 90% of oral malignancies and is associated with the aggressive progression, high recurrence rates, and poor prognosis. Risk factors include tobacco and alcohol use, betel quid chewing, and human papillomavirus (HPV) infection, compounded by genetic predisposition and environmental carcinogens.[1] The disease is driven by chronic inflammation, oxidative stress, and molecular alterations such as TP53 mutations and EGFR overexpression, leading to tumor initiation, invasion, and metastasis. Despite advancements in early detection techniques and treatment modalities, OSCC’s five-year survival rate remains low due to delayed diagnosis and therapy resistance. Addressing these challenges through precision medicine, improved screening programs, and biomarker-based risk stratification is critical to improving patient outcomes.[2]

Epidemiology and risk factors

OSCC has a rising global incidence, particularly in developing countries, with higher prevalence in men due to greater exposure to risk factors. Tobacco use, including smoking and smokeless forms, remains the strongest risk factor, with alcohol acting synergistically to enhance carcinogen penetration. Betel quid chewing, common in South Asia and Southeast Asia, contributes to DNA damage and malignant transformation. Recently, HPV-16 and HPV-18 infections have been identified as independent risk factors, particularly in oropharyngeal OSCC. Other contributing factors include poor oral hygiene, chronic inflammation, genetic mutations, and immunosuppression. Implementing tobacco cessation programs, HPV vaccination, and targeted screening initiatives could significantly reduce OSCC incidence and improve long-term prognosis.[3]

Molecular pathogenesis of OSCC

OSCC develops through a series of genetic, epigenetic, and environmental alterations that disrupt normal cell cycle regulation and apoptosis. TP53 mutations impair DNA repair, allowing uncontrolled proliferation, while EGFR overexpression enhances tumor growth, invasion, and therapy resistance. Other oncogenic pathways, including PI3K/AKT/mTOR activation and cyclin D1 dysregulation, contribute to tumor aggressiveness and metastasis. Additionally, epigenetic modifications such as DNA methylation, histone changes, and microRNA dysregulation alter gene expression, accelerating OSCC progression. Chronic inflammation from poor oral hygiene, bacterial infections, and HPV oncogenes (E6 and E7) further promotes tumorigenesis by fostering immune evasion and cellular proliferation. Understanding these molecular mechanisms is essential for developing biomarker-driven diagnostics and targeted therapies to improve treatment response.[4]

Clinical presentation and diagnosis

OSCC typically manifests as non-healing ulcers, leukoplakia, erythroplakia, or exophytic growths, often accompanied by pain, dysphagia, bleeding, and speech difficulties. Advanced cases may present with regional lymphadenopathy and weight loss, worsening prognosis. Histopathological examination via biopsy remains the gold standard for diagnosis, providing insights into tumor differentiation and depth of invasion.[5] Adjunctive tools, including toluidine blue staining, fluorescence imaging, and cytobrush biopsy, enhance early detection. Imaging modalities such as contrast-enhanced CT and MRI assess tumor extent and lymph node involvement, while PET scans aid in metastasis detection. Emerging molecular approaches, such as liquid biopsy and circulating tumor DNA (ctDNA) analysis, offer potential for non-invasive OSCC screening and monitoring. However, late-stage diagnosis remains a challenge, necessitating improved screening programs and biomarker-based risk assessments for early intervention.[6]

Treatment modalities

OSCC treatment is guided by tumor stage, location, and patient health status, with surgery, radiotherapy, and chemotherapy forming the cornerstone of management. Surgical resection is the preferred approach for localized tumors, often supplemented by neck dissection in cases with lymph node involvement. Adjuvant radiotherapy or chemoradiotherapy is recommended for high-risk cases exhibiting perineural invasion, lymphovascular involvement, or extracapsular spread.[7] Radiotherapy (EBRT, IMRT) plays a pivotal role in locally advanced or inoperable OSCC, often combined with cisplatin-based chemotherapy to enhance therapeutic response. Targeted therapies, such as EGFR inhibitors (cetuximab), block tumor proliferation pathways, while immunotherapy using checkpoint inhibitors (pembrolizumab, nivolumab) is proving beneficial in recurrent and metastatic OSCC. Despite advances, treatment resistance, recurrence, and functional impairments post-surgery remain major challenges, highlighting the need for personalized and biomarker-driven therapeutic approaches.[8]

Emerging therapies and future directions

Targeted therapy, immunotherapy, and biomarker-driven treatments are revolutionizing OSCC management. EGFR inhibitors (cetuximab) effectively block tumor growth, while immune checkpoint inhibitors (pembrolizumab, nivolumab) offer promising results in recurrent and metastatic cases.[9] Biomarkers such as ctDNA, microRNAs, and exosome markers facilitate non-invasive early detection and real-time treatment monitoring. Precision medicine approaches, integrating genomic profiling and personalized treatment regimens, aim to optimize therapeutic response and minimize side effects. However, challenges in cost, accessibility, and patient variability hinder widespread implementation. Future research must focus on large-scale clinical trials, AI-driven diagnostics, and affordable screening programs to enhance OSCC detection and management.[10]

Challenges and limitations

OSCC management is hindered by late-stage diagnosis, treatment resistance, and high recurrence rates. Many cases remain asymptomatic in early stages, leading to delayed intervention and poor survival outcomes. Tumor heterogeneity, genetic mutations, and adaptive resistance mechanisms further complicate radiotherapy and chemotherapy effectiveness. Additionally, surgical interventions often result in the speech impairment, dysphagia, and aesthetic concerns, significantly impacting quality of life. The limited availability of molecular diagnostics, biomarker-driven therapies, and immunotherapy in low-resource settings restricts treatment options. There is an urgent need for cost-effective screening programs, public awareness campaigns, and AI-based diagnostic models to facilitate early detection and personalized therapy selection. Overcoming treatment resistance and improving post-treatment rehabilitation remains key to enhancing long-term OSCC outcomes.

CONCLUSION

OSCC remains a major global health challenge, with high morbidity, late-stage diagnosis, and therapy resistance limiting survival rates. While surgical, radiotherapy, and systemic treatments have improved management, early detection and personalized medicine remain the most effective strategies for better prognosis. Integrating biomarker-driven diagnostics, AI-based screening, and precision oncology approaches can enhance treatment efficacy and patient survival. Future research must focus on cost-effective screening, innovative therapeutic strategies, and personalized interventions to reduce OSCC burden and improve long-term outcomes.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.