Molecular Signaling Pathways in Nasopharyngeal Carcinoma

TL;DR: Nasopharyngeal carcinoma (NPC) is a unique type of head and neck cancer characterized by heavy infiltration of lymphocytes and association with Epstein–Barr virus (EBV) infection. The majority of NPC is non-keratinizing and exhibits high sensitivity to ionizing radiation and chemotherapy. However, patients often develop local failure and distant metastases, and chemotherapy has limited efficacy in recurrent and metastatic disease. Recent advancements in immunotherapy have shown promise in improving patient survival.

Abstract: Nasopharyngeal carcinoma (NPC) is a unique type of head and neck cancer arising from the nasopharyngeal epithelium. The incidence rate of NPC is notably high in southern China and Southeast Asia, but low in most other parts of the world (Tsang et al. 2020). The recent World Health Organization classification categorizes NPC into two major histological subtypes, keratinizing and non-keratinizing squamous cell carcinoma, which differ considerably in epidemiology and pathogenesis. Keratinizing NPC shares similar histological and clinical features to other types of head and neck squamous cell carcinoma (HNSCC). The non-keratinizing subtype (either squamous or undifferentiated), which accounts for the majority of NPC, is characterized by heavy infiltration of lymphocytes and is consistently associated with Epstein–Barr virus (EBV) infection (Tsao et al. 2015; El-Naggar et al. 2017). Compared with other HNSCCs, non-keratinizing NPC is more sensitive to ionizing radiation and chemotherapy, suggesting a unique tumorigenesis. For EBV-associated NPC, patients with early disease are often successfully treated with radiotherapy or concurrent chemoradiotherapy. However, more than 60% of these patients are diagnosed at an advanced stage (stages II–IV) and frequently develop local failure and distant metastases subsequent to conventional treatments. For recurrent and metastatic NPC, chemotherapy is the main treatment but has limited efficacy (Chen et al. 2019; Wong et al. 2021). Recently, immune checkpoint inhibitor therapy targeting PD-L1 and combined with conventional chemotherapy has demonstrated promising improvements in patient survival (Ma et al. 2018; Mai et al. 2021; Yang et al. 2021). Nevertheless, the high mortality rate of patients who are resistant to these treatments is a challenge. The development of new effective therapeutic strategies targeting recurrent and metastatic disease is important for the clinical management of NPC. Understanding the molecular basis of NPC tumorigenesis will aid in the development of novel targeted therapies and personalized treatment options for patients.