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Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma

Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma
Literature review current through: Jan 2024.
This topic last updated: Oct 20, 2023.

INTRODUCTION — Nasopharyngeal carcinoma is the predominant tumor type arising in the nasopharynx, the tubular passage behind the nasal cavity that connects to the oropharynx below (figure 1). It differs from other head and neck squamous cell carcinomas in epidemiology, histology, natural history, and response to treatment.

This topic discusses the epidemiology, etiology, diagnosis, and staging of nasopharyngeal carcinoma. The pathology and treatment of nasopharyngeal carcinoma are presented elsewhere:

(See "Treatment of early and locoregionally advanced nasopharyngeal carcinoma".)

(See "Treatment of recurrent and metastatic nasopharyngeal carcinoma".)

(See "Pathology of head and neck neoplasms".)

EPIDEMIOLOGY — Worldwide, there were over 133,000 new cases and 80,000 deaths due to nasopharyngeal carcinoma [1]. Nasopharyngeal carcinoma displays a distinct racial and geographic distribution, which is reflective of its multifactorial etiology [2].

Geographic and ethnic distribution — The incidence of nasopharyngeal carcinoma demonstrates marked geographic variation. It is rare in the United States and Western Europe, with an incidence of 0.5 to 2 cases per 100,000 [3,4]. By contrast, nasopharyngeal carcinoma is endemic in Southern China, including Hong Kong, where the incidence may reach 25 cases per 100,000 per year. Intermediate-risk regions include Southeast Asia, North Africa and the Middle East, and the Arctic. Populations that migrate from areas of high risk to areas of low risk retain an elevated risk, although this risk typically diminishes in successive generations [4].

Sex and age distribution — The incidence of nasopharyngeal carcinoma is two- to threefold higher in males compared with in females.

In high-risk populations, the incidence peaks around 50 to 59 years of age and declines thereafter. There is also a minor incidence peak observed among adolescents and young adults in Southeast Asia, the Middle East/North Africa, and the United States. In most low-risk populations, nasopharyngeal carcinoma incidence increases with age [3,4].

Secular trend — The incidence of nasopharyngeal carcinoma has declined over the past 30 years in many endemic areas, including Hong Kong, Singapore, and Taiwan [5-7]. The reasons for this decline are unclear, although they are generally attributed to lifestyle changes associated with the rapid economic development that occurred in these areas. As an example, there has been a decrease in the use of salted fish to feed infants and reduced exposure to traditional preserved food. However, the declining incidence may also be due to population shifts as a result of altered immigration patterns.

ETIOLOGY AND RISK FACTORS — The geographic variation of nasopharyngeal carcinoma incidence suggests a multifactorial etiology. In endemic populations, risk appears to be due to an interaction of several factors: Epstein-Barr virus (EBV) infection, environmental factors (such as the high intake of preserved foods and smoking), and genetic predisposition [8]. Furthermore, the increased incidence in younger adults in high- and intermediate-risk areas suggests that exposure to a common agent early in life is a critical factor [3]. In the United States and Europe, nasopharyngeal carcinoma is more commonly associated with alcohol and tobacco use, which are classic risk factors for other head and neck tumors [9].

Epstein-Barr virus — A large body of evidence supports the role of EBV as a primary etiologic agent in the pathogenesis of nasopharyngeal carcinoma [10]. This includes the detection of both EBV deoxyribonucleic acid (DNA) and EBV gene expression in precursor lesions and tumor cells. Nasopharyngeal carcinoma cells express a specific subgroup of EBV-latent proteins, including EBNA1 (Epstein-Barr virus nuclear antigen 1) and two integral membrane proteins, LMP1 (latent membrane protein 1) and LMP2 (latent membrane protein 2), along with the BamHI-A fragment of the EBV genome. Patients with nasopharyngeal carcinoma also demonstrate specific serologic responses to various gene products of EBV, particularly immunoglobulin A antibodies directed against the EBV viral capsid antigen. (See "Virology of Epstein-Barr virus".)

Smoking has also been associated with nasopharyngeal carcinoma and may be involved in the pathogenesis of nasopharyngeal carcinoma by causing EBV reactivation [11,12].

The association of nasopharyngeal carcinoma with EBV infection has been exploited to develop noninvasive diagnostic tests. It is also being used experimentally to treat advanced disease. (See 'Screening based on Epstein-Barr virus testing' below and "Treatment of early and locoregionally advanced nasopharyngeal carcinoma", section on 'Is there a role for EBV DNA in posttreatment surveillance?' and "Treatment of recurrent and metastatic nasopharyngeal carcinoma", section on 'Investigational agents'.)

Human papillomavirus — The role of human papillomavirus (HPV) as an etiologic agent for nasopharyngeal carcinoma is less well defined than that of EBV, and its relative frequency may differ substantially in endemic and nonendemic regions.

In a study of 1328 patients with nonkeratinizing, undifferentiated (type III) nasopharyngeal carcinoma from Hong Kong and Southeast China, EBV RNA was detected in 91.5 percent of cases, while HPV (measured using polymerase chain reaction and p16 immunohistochemistry, with 100 percent concordance) was present in 7.7 percent [13]. Co-infection was rare (less than 1 percent). The prognosis for patients with HPV-associated nasopharyngeal carcinoma was significantly better on a stage-by-stage basis than the prognosis for patients whose disease was associated with EBV.

In nonendemic, low-incidence regions, HPV infection is the same or more common, as a percent of total cases, compared with in endemic areas, with a similar or worse outcome than with EBV-related nasopharyngeal carcinoma. However, HPV-associated nasopharyngeal carcinoma is not well characterized in this setting [14,15].

Diet — Several dietary practices in endemic areas are thought to contribute to the high incidence of nasopharyngeal carcinoma [8,16]:

The cooking of salt-cured food, which releases volatile nitrosamines that are carried by steam and distributed over the nasopharyngeal mucosa.

Early childhood exposure to salted fish, which was traditionally used for weaning.

High consumption of preserved or fermented foods (including meats, eggs, fruits, and vegetables), which contain high levels of nitrosamines as well as bacterial mutagens, direct genotoxins, and EBV-reactivating substances.

The use of Chinese medicinal herbs, which may contribute either by reactivating EBV or through a direct promoting effect on EBV-transformed cells.

The consumption among the Maghrebian population from Tunisia, Algeria, and Morocco of rancid butter and sheep's fat, which contain butyric acid, a potential EBV activator and causative agent for nasopharyngeal carcinoma.

Heredity — Genetic factors may influence the risk of nasopharyngeal carcinoma [8]. One case-control study, for example, suggested that having a first-degree relative with nasopharyngeal carcinoma increased risk sevenfold [17]. With evidence for clustering within families, some have recommended screening for first-degree relatives of patients with nasopharyngeal carcinoma [18]. (See 'Screening based on Epstein-Barr virus testing' below.)

Nasopharyngeal carcinoma has been associated with certain HLA (human leukocyte antigen) haplotypes [19-22]. Nasopharyngeal carcinoma has also been associated with genetic polymorphisms, such as CYP2A6 (cytochrome P450 2A6), which is a polymorphism of a nitrosamine-metabolizing gene [23,24].

Molecular pathogenesis — Development of nasopharyngeal carcinoma involves virologic, genetic, and environmental factors, as shown in the etiologic studies. A collaborative model for nasopharyngeal carcinoma pathogenesis driven by specific genetic alterations and EBV-latent infection has been proposed. Multiple chromosomal abnormalities (eg, copy number changes on chromosomes 3p, 9p, 11q, 12p, and 14q), gene alterations (eg, p16 deletion and LTBR [lymphotoxin-beta receptor] amplification), and epigenetic changes (eg, RASSF1A [Ras association domain family 1 isoform A] and TSLC1 [tumor suppressor in lung cancer 1] methylation) have been identified by various genome-wide approaches. Studies on the precancerous lesions and in vitro immortalized nasopharyngeal epithelial cell models provide important evidence for the involvement of genetic alterations and EBV infection in early development of this cancer, and critical genetic events contribute to the initiation and progression of nasopharyngeal carcinoma [25,26]. (See "Virology of Epstein-Barr virus", section on 'Biology'.)

HISTOLOGY — Nasopharyngeal carcinoma arises from the epithelial lining of the nasopharynx.

The World Health Organization (WHO) classifies nasopharyngeal carcinoma into three histopathologic types [4]:

Keratinizing squamous cell carcinoma – The sporadic form of nasopharyngeal carcinoma is most commonly the keratinizing subtype (WHO type I).

Nonkeratinizing carcinoma – This is subdivided into differentiated (WHO type II) and undifferentiated (WHO type III) forms. The endemic form of nasopharyngeal carcinoma is commonly the undifferentiated, nonkeratinizing subtype (WHO type III); this is strongly associated with Epstein-Barr virus (EBV) and has a more favorable prognosis than other types.

Basaloid squamous cell carcinoma – Basaloid squamous cell carcinoma was added to the WHO classification of head and neck tumors in 2005. There are few reported cases, but they are notable for an aggressive clinical course and poor survival [27].

In North America, the relative frequencies of the different histologic subtypes are 25 percent keratinizing (type I), 12 percent differentiated (type II), and 63 percent undifferentiated (type III). By contrast, the histologic distribution among Southern Chinese patients is 2 percent keratinizing, 3 percent differentiated, and 95 percent undifferentiated [28]. (See "Pathology of head and neck neoplasms".)

CLINICAL PRESENTATION — The most common presenting complaints in patients with nasopharyngeal carcinoma are headache, diplopia, or facial numbness, caused by cranial nerve involvement, and a mass in the neck, due to cervical node metastases [8]. The clinical triad of neck mass, nasal obstruction with epistaxis, and serous otitis media occurs infrequently, although each of these symptoms occurs commonly in patients with nasopharyngeal carcinoma. Otitis media in an adult without a prior history of this condition should raise suspicion for nasopharyngeal carcinoma, especially if the patient is of an ethnicity with a high incidence of this disease.

Nasopharyngeal carcinoma frequently originates from the pharyngeal recess, the fossa of Rosenmüller. Since this is a clinically occult site, patients may remain asymptomatic for a prolonged period. The majority of patients present with locally and/or regionally advanced disease because of this prolonged asymptomatic period or, in some cases, due to a missed diagnosis [8].

The primary tumor may present as a smooth submucosal fullness, a discrete nodule with or without surface ulceration, or an infiltrative fungating mass. Erosion into the skull base is common with or without involvement of cranial nerves [29]. Cranial nerves III, IV, V, and VI are most commonly affected because of paracavernous sinus tumor invasion [30].

Nasopharyngeal carcinoma has a tendency for early metastatic spread [31-33]. Lymph node metastases are present at diagnosis in 75 to 90 percent of cases and are bilateral in over 50 percent. Distant metastases are present at diagnosis in 5 to 11 percent of patients.

The location and extent of lymph node metastases are predictive of distant metastases [34,35]. The most frequent sites of distant metastases are the bone (75 percent), lung, liver, and distant nodes [33]. Multiple paraneoplastic syndromes, including neutrophilia, fever of unknown origin, hypertrophic osteoarthropathy, and dermatomyositis, can occur [33,36].

INITIAL DIAGNOSTIC EVALUATION — A definitive diagnosis is made with endoscope-guided biopsy of the primary tumor. Incisional neck biopsy or nodal dissection should be avoided as this procedure will negatively impact subsequent treatment [37].

Routine evaluation should include a history and physical examination including the cranial nerves, complete blood counts, and serum biochemistry, including liver function tests and alkaline phosphatase. Other studies should include chest radiograph, nasopharyngoscopy, and computed tomography (CT) and magnetic resonance imaging (MRI) of the nasopharynx, skull base, and neck. When ordering an MRI, it is important to specifically request cranial nerve imaging, as a standard brain MRI does not provide adequate detail.

We suggest obtaining pretreatment plasma Epstein-Barr virus (EBV) DNA levels as part of the diagnostic and staging evaluation. Pretreatment plasma EBV DNA levels are prognostic and have been associated with survival outcomes [38-41]. The addition of pretreatment plasma EBV DNA to the eighth edition of the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system has improved its prognostic performance (table 1) [42,43]. (See "Treatment of early and locoregionally advanced nasopharyngeal carcinoma", section on 'Prognosis'.)

Additional imaging is indicated for patients with advanced nodal disease (stage N3 (table 1)), clinical evidence suggesting distant metastases, or an EBV DNA load ≥4000 copies/mL, since these patients are at high risk for distant metastases. Fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging is the preferred modality in this setting [8,44-46]. Because of its superior ability to detect lymph node and bone metastases, we suggest PET scanning if available [8]. (See "Overview of the diagnosis and staging of head and neck cancer".)

STAGING — Nasopharyngeal carcinoma is clinically staged according to the eighth edition (2017) of the Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) system (table 1) [47]. This staging system provides important prognostic information and guidance for choosing the appropriate treatment for patients with nasopharyngeal carcinoma. (See "Treatment of early and locoregionally advanced nasopharyngeal carcinoma", section on 'STAGING'.)

SCREENING BASED ON EPSTEIN-BARR VIRUS TESTING — Given the link between Epstein-Barr virus (EBV) infection and nasopharyngeal carcinoma, and the high cure rate for early-stage nasopharyngeal carcinoma, screening of high-risk populations using EBV testing has been proposed. Nevertheless, routine screening for EBV is not standard practice in most locations, with the exception of a few oncology centers in Southern China, which offer it as early detection to first-degree relatives of patients with nasopharyngeal carcinoma.

The strong etiologic link between EBV infection and nasopharyngeal carcinoma is supported by abnormal anti-EBV antibody profiles, increased circulating EBV DNA levels, and distinct EBV gene expression in tumor cells. Various indicators of EBV infection have been investigated as screening strategies for nasopharyngeal carcinoma; these include EBV-specific antibody-based assays, measurement of circulating EBV DNA levels, and measurement of novel serologic biomarkers, including anti-BNLF2b (P85-Ab).

EBV-specific antibody-based assays – In patients with nasopharyngeal carcinoma, the characteristic anti-EBV serologic profile consists of a sustained rise in antibodies to viral capsid antigen (VCA) and early antigen immunoglobulin A (IgA) [33]. In Southern China, where nasopharyngeal carcinoma is endemic, EBV serology (ie, serum VCA/IgA or IgA/early antigen antibody titers) has been effectively used for population-based screening [48-51]. As an example, a prospective, cluster randomized controlled trial conducted in southern China evaluated the performance of a combined VCA/EBNA1 IgA antibody score to screen for nasopharyngeal carcinoma [51]. This study included over 70,000 subjects in the total screening group (although only approximately 30,000 subjects actually participated in screening) and approximately 50,000 in the control group. At median follow-up of six years, the early diagnostic rates of nasopharyngeal carcinoma were higher in the subjects who participated in screening (79 percent) and the total screening group (46 percent) compared with the control group (21 percent). Although the total screening group demonstrated similar nasopharyngeal carcinoma-specific mortality compared with the control group, nasopharyngeal carcinoma-specific mortality was reduced in subjects who actually participated in the screening program (RR 0.22, 95% CI 0.09-0.49).

EBV DNA measurement – Quantitation of circulating EBV DNA has been studied as a method for nasopharyngeal carcinoma screening in an endemic area [52-56]. In a cohort study of 20,174 participants screened using EBV DNA, with subsequent endoscopic examination and MRI for those with positive results, the sensitivity and specificity for nasopharyngeal cancer were 97 and 99 percent, respectively [56]. Among the 19,865 individuals who initially screened negative for plasma EBV DNA, only one case of nasopharyngeal carcinoma was diagnosed in the year after screening.

A case control study in Taiwan compared EBV antibodies versus plasma EBV DNA levels as screening strategies in 819 newly diagnosed nasopharyngeal carcinoma cases and 1768 controls. Compared with EBV antibody-based testing, EBV DNA load had both a higher sensitivity (93 versus 88 percent) and specificity (98 versus 95 percent) [57].

Novel strategies – A retrospective study used a peptide library of EBV sequences to identify anti-BNLF2b (P85-Ab) as a possible serologic biomarker for nasopharyngeal carcinoma [58]. In a subsequent prospective cohort in almost 25,000 participants in China, including 47 with nasopharyngeal carcinoma, P85-Ab was better than a standard two-antibody based screening method, with higher sensitivity (98 versus 72 percent), specificity (98 versus 97 percent), and positive predictive value (10 versus 4.3 percent) [58]. Using both P85-Ab and the two-antibody method together increased the positive predictive value to 45 percent, with sensitivity of 70 percent.

Monitoring for treatment response and recurrence — Monitoring posttreatment plasma EBV DNA levels may have a role in evaluating treatment response and detecting recurrence [59]. The sensitivity of EBV DNA in the detection of a local recurrence after radiation therapy (RT; ie, tumors regrowing from an irradiated site) is much lower than that in a radiation-naϊve site [60]. (See "Treatment of early and locoregionally advanced nasopharyngeal carcinoma".)

Clinical outcomes are worse among patients with unfavorable plasma EBV DNA responses after induction chemotherapy [61,62], at midcourse of RT [63], and post-RT [39].

Post-RT plasma EBV DNA has been validated as the most significant prognostic biomarker in a prospective biomarker study of 798 patients with nasopharyngeal carcinoma [64]. Post-RT plasma EBV DNA is utilized to select high-risk patients for adjuvant therapy in ongoing clinical trials (NRG-HN001, NCT02135042; NCT02363400) [65].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Head and neck cancer".)

SUMMARY AND RECOMMENDATIONS

Anatomy – Nasopharyngeal carcinoma is an epithelial neoplasm arising in the nasopharynx (figure 1).

Geographic distribution – Although nasopharyngeal carcinoma is rare in most parts of the world, it is endemic in southern China, Southeast Asia, North Africa, and the Arctic, where undifferentiated, nonkeratinizing squamous cell carcinoma is the predominant histology. (See 'Epidemiology' above and 'Histology' above.)

Risk factors – The major etiologic factors for endemic nasopharyngeal carcinoma are genetic susceptibility, early age exposure to chemical carcinogens, and Epstein-Barr virus (EBV) infection. (See 'Etiology and risk factors' above.)

Screening for nasopharyngeal carcinoma using plasma EBV DNA testing – Analysis of EBV DNA in plasma is useful for screening at-risk populations for nasopharyngeal carcinoma. It can detect the cancer at an early stage with a superior treatment outcome compared with the unscreened population. (See 'Screening based on Epstein-Barr virus testing' above.)

Diagnostic evaluation

Biopsy – For the initial diagnostic evaluation of nasopharyngeal carcinoma, we suggest endoscopically guided biopsy of the primary tumor and MRI of the nasopharynx, skull base, and neck to assess locoregional disease extent. (See 'Initial diagnostic evaluation' above.)

Imaging studies – For patients with advanced nodal stage (N3) or clinical or biochemical evidence of distant metastases, we offer additional imaging with positron emission tomography (PET) or integrated PET/CT imaging if available. Otherwise, bone scan and CT of the chest and abdomen may be obtained. (See 'Initial diagnostic evaluation' above.)

Pretreatment plasma EBV DNA testing – We suggest obtaining pretreatment plasma EBV DNA levels for their prognostic significance. There is emerging evidence supporting serial measurement of plasma EBV DNA levels to assess treatment response or monitor for recurrence. (See 'Initial diagnostic evaluation' above and "Treatment of early and locoregionally advanced nasopharyngeal carcinoma".)

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Topic 3404 Version 36.0

References

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