**Abstract**

Nasopharyngeal carcinoma (NPC) is a malignancy with unique biological and clinical characteristics. It has highly associated with Epstein–Barr virus (EBV) infection and is sensitive to radiotherapy. Due to the extreme relevance between EBV infection and incidence of NPC, testing antibodies against EBV has been applied to screening "high-risk" populations of NPC. The pathological diagnosis of nasopharyngeal biopsy is the gold standard for the diagnosis of NPC. Radiotherapy has been recognized as the first choice for NPC treatment. With the improvement of intensity-modulated radiation therapy (IMRT), the 5-year disease-specific survival rate in NPC patients at an early stage has reached 95%. However, the efficacy brought by radiotherapy has reached the bottleneck in advanced patients. Recently, the 5-year overall survival rate was increased around 60-80% in locoregionally advanced NPC patients by introducing concurrent chemoradiotherapy. In addition, molecular targeted therapy and immunotherapy have been introduced to many clinical trials. In this chapter, we mainly focus on the current early screening and diagnosis of NPC patients, and the development of therapeutic approaches.

**Keywords:** nasopharyngeal carcinoma, population-based screening, symptoms, diagnosis, treatment

## **1. Introduction**

As a part of the pharynx, the nasopharynx lies behind and communicates with the nasal cavities. It is up to the cranial base, down to the soft palate plane, forward through the back of the nose to the nasal cavity, and pharynx tonsils in the backward. Behind the inferior turbinate, there is an opening of the eustachian tube, which leads through the nasopharynx to the tympanic cavity. A recess in the lateral of the pharyngeal wall extending posteriorly to the opening of the eustachian tubal torus, which is called Fossa of Rosenmüller, is the predilection site of nasopharyngeal carcinoma (NPC).

As one of the malignant head and neck cancer, NPC arises from epithelial cells within the nasopharyngeal mucosa, with a unique geographical and ethnic distribution.. Epstein–Barr virus (EBV) infection, carcinogen exposure, and genetic susceptibility contribute to the carcinogenesis of NPC. In the endemic area, more than 95% of NPC patients were EBV positive, therefore, testing antibodies against EBV or cell-free EBV DNA has been established for screening assays targeted "high-risk" populations of NPC. Nasopharyngeal endoscopy is recommended for EBV-seropositive individuals to find out NPC patients at an early stage. The common clinical symptoms of NPC were nasal congestion, bloody nose, hearing loss,

and headache, but not specific at early stages. At present, the pathological diagnosis of nasopharyngeal biopsy remains the golden standard for NPC. Most undifferentiated NPC is moderately sensitive to radiation therapy, leading it the first choice for NPC treatment. Taking advantage of accurate staging systems, modern radiotherapy techniques, and concurrent chemotherapy, the locoregional control and overall survival of NPC patients have substantially improved along with the decline of treatment-induced toxicity in the past two decades. However, residual/recurrent disease and metastatic disease are still crucial challenges in managing NPC.

#### **1.1 Epidemiology**

Globally, NPC is uncommon cancer with approximately 129,000 new cases reported in 2018 and accounting for 0.7% of all cancers [1]. The incidence of NPC is relatively concentrated, about 80% of NPC occurs in Asia, and China accounts for almost half of the total [2]. For instance, the incidence rate in North America and Europe is less than 1/100,000 person-years, but greater than 20/100,000 personyears in Southern China and Southeast Asia [3, 4]. Importantly, NPC incidence is higher in males than in females, with a ratio of 2-3 [5]. The age-specific incidence of NPC is different from other types of cancer as well. The bimodal distribution of age showed two peaks between 16 and 20 and 45-60 years [3]. Besides, family aggregation is a characteristic of NPC in the endemic area which is well documented [6, 7]. Even people migrate from Southern China to non-endemic areas, the incidence remains high, suggesting that genetic inheritance is one of the main factors for NPC pathogenesis. However, the reduced incidence has been observed in second-generation migrants [8]. In addition, according to recent epidemiology studies, the global incidence of NPC is also declining gradually [9–11]. These findings indicate that lifestyle alterations are highly correlated with the pathogenesis of NPC.

#### **1.2 Etiology**

So far, the etiology of NPC is not fully clear. It is widely accepted that genetic susceptibility, EBV infection, and exposure to harmful carcinogens such as intake of salted fish and preserved food, etc., are the main pathogenic factors for NPC. The single factor mentioned above can not induce the occurrence of NPC in animal models, therefore all these factors contribute together and their interaction might be more important and worth deeply understanding [12]. Recently, poor oral hygiene has been proposed as a risk factor for NPC [13]. The composition of the oral microbiome is shown to be different between NPC patients and their populationbased controls [14]. Moreover, the anaerobic metabolites of *F. nucleatum*, *n*-butyrate acid is a strong lytic-cycle inducer of EBV [15]. More potential pathogenic factors are being discovered.

In the endemic area, almost all NPC patients are associated with EBV infection and are more sensitive to radiotherapy [16]. Besides, it is difficult to achieve effective treatment by surgery in NPC patients, because the anatomy of the nasopharynx is concealed and the peripheral nerves and blood vessels, and more than 80% of patients show lymph node metastasis at the time of diagnosis [17, 18]. Therefore, radiotherapy is the first choice in the treatment of NPC. At present, the local control rate of NPC patients under radiotherapy exceeds 90%, and the 5-year survival rate is close to 80% [19, 20]. It is noteworthy that early diagnosis is a key point. The earlier diagnosis of NPC patients, the greater improvement of survival [21]. To date, distant organ metastasis remains the largest obstacle and the main factor of failure. In this chapter, we mainly introduce the early population screening of NPC in the endemic area, as well as the approaches for NPC diagnosis and treatment.
