We did an extensive search of MEDLINE and PubMed for English-language articles published between Jan 1, 1990, and Jan 31, 2019. The Cochrane Library was also searched for reviews that had been published between 1990 and 2018. The search terms included: “nasopharyngeal carcinoma”, “nasopharynx cancer”, “epidemiology”, “pathology”, “genetics”, “Epstein-Barr virus”, “staging”, “imaging”, “positron emission tomography”, “radiotherapy”, “chemotherapy”, “combined treatment modality”, “salvage
SeminarNasopharyngeal carcinoma
Introduction
Nasopharyngeal carcinoma is an epithelial carcinoma arising from the nasopharyngeal mucosal lining. In the nasopharynx, the tumour is often observed at the pharyngeal recess (fossa of Rosenmüller). Despite originating from similar cell or tissue lineages, nasopharyngeal carcinoma and other epithelial head and neck tumours are distinctly different.
In comparison with other cancers, nasopharyngeal carcinoma is relatively uncommon. According to the International Agency for Research on Cancer, in 2018, there were about 129 000 new cases of nasopharyngeal carcinoma, accounting for only 0·7% of all cancers diagnosed in 2018.1, 2 Nevertheless, its geographical global distribution is extremely unbalanced; >70% of new cases are in east and southeast Asia, with an age-standardised rate (world) of 3·0 per 100 000 in China to 0·4 per 100 000 in populations that are mainly white (figure 1).1, 2 Over the past decades, nasopharyngeal carcinoma incidence has declined gradually worldwide: substantial reductions have been observed in south and east Asia, north America, and the Nordic countries, with average annual changes of about −1% to −5%.3, 4 In endemic regions, for example, the incidence rate has steadily decreased since the 1980s in Hong Kong, with a total decrease of about 30% over a 20-year period;5 urban Guangzhou has shown average annual changes of about −3% for men and −5% for women in the 2000–11 period.6 Lifestyle and environmental changes may well be the contributory factors.
Nasopharyngeal carcinoma incidence is higher in males than in females, with a ratio of about 2·5 in China in 2015.7 It is noteworthy that the high incidence in people from southern China remains even after they immigrate to non-endemic areas, but reduced incidence has been observed in second-generation migrants. There is also a trend towards decreasing incidence the farther the population has immigrated.8 These findings suggest that a combination of genetic, ethnic, and environmental factors might affect nasopharyngeal carcinoma pathogenesis.
Section snippets
Pathology and risk factors
According to the World Health Organization, there are three pathological subtypes of nasopharyngeal carcinoma: keratinising squamous, non-keratinising, and basaloid squamous. Non-keratinising nasopharyngeal carcinoma can be divided into differentiated and undifferentiated tumours (appendix p 22).9 The keratinising subtype accounts for less than 20% of cases worldwide, and is relatively rare in endemic areas such as southern China; the non-keratinising subtype constitutes most cases in endemic
Population screening
Effective population screening could improve treatment outcomes by identifying early-stage disease in patients, and presents an attractive strategy considering the strained medical resources in endemic areas such as southern China. Although anti-EBV IgA antibody (eg—early antigen [EA-IgA], anti–EBV capsid antigen [VCA-IgA], anti–EBV nuclear antigen 1 [EBNA1-IgA]) serological testing is commonly used to detect incident nasopharyngeal carcinoma, the low sensitivities and specificities impede
Symptoms and diagnosis
The clinical symptoms and signs of nasopharyngeal carcinoma correlate with the involved anatomical regions, and comprehensive head and neck evaluation is indicated in patients with presumed diagnosis of nasopharyngeal carcinoma (see appendix for more detail).
Staging and prognosis
Nasopharyngeal carcinoma is classified according to the International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) TNM (tumour-node-metastasis) staging system. This system was updated to the 8th edition in 2016 (from the 7th edition in 2009), where primary and nodal disease classification, and the stage groups were further refined (table 1).31, 32
As the current anatomy-based staging system is insufficient for predicting prognosis or treatment benefits, many studies have
Imaging studies
MRI, CT, and 18F-fluorodeoxyglucose (18F-FDG)-PET/CT are currently the most commonly used imaging modalities for nasopharyngeal carcinoma staging and radiotherapy. With high soft-tissue resolution, MRI is better for evaluating primary tumour extension and retropharyngeal lymph node metastasis than CT, while they share similar accuracy in detecting cervical lymph node metastasis (appendix p 27).51, 52 18F-FDG-PET/CT performs better than conventional work-up (eg—chest radiography, abdominal
Radiotherapy
Nasopharyngeal carcinoma is highly sensitive to ionising radiation; radiotherapy is the mainstay treatment modality for non-metastatic disease. Over time, photon-based radiotherapy techniques have progressed from conventional two-dimensional (2D) radiotherapy to 3D conformal radiotherapy and then to intensity-modulated radiotherapy (IMRT). Locoregional control and survival have been enhanced by the parallel improved dosimetric properties, and toxicity has been reduced.61, 62, 63, 64, 65
Chemotherapy in non-metastatic nasopharyngeal carcinoma
While early-stage nasopharyngeal carcinoma is treated with only radiotherapy as the main curative treatment, locoregionally advanced disease requires more than radiotherapy. Chemotherapy combined with radiotherapy is a crucial development for treating locoregionally advanced disease. At present, the National Comprehensive Cancer Network (NCCN) Guidelines recommend both concurrent chemoradiotherapy with adjuvant chemotherapy or induction chemotherapy followed by concurrent chemoradiation as
Disease surveillance and toxic effects
Local, regional, and/or distant failure can occur in non-metastatic disease despite aggressive treatment. High-dose radiation or chemoradiotherapy inevitably induces acute and late toxicities, and the latter can emerge months or even years after treatment completion. These issues highlight the importance of close follow-up.
12 weeks after the completion of radiotherapy or chemoradiotherapy is widely considered the appropriate timepoint for initial assessment of residual disease, as by then,
Managing residual or recurrent disease
In the IMRT era, around 10% of patients have residual disease or develop recurrent disease at the primary and/or regional site.66, 117 It is widely acknowledged that neck dissection is the primary choice for patients with isolated regional failure; the 5-year overall survival rate is 41%.118 Radiotherapy or surgery can salvage local nasopharyngeal failure. Commonly, tumours that recur within 1 year are considered radioresistant; surgery is recommended if they are resectable. Recently, a
Management of metastatic disease
Patients with metastatic nasopharyngeal carcinoma (stage IVB) are heterogeneous groups with different outcomes; in some cases, long-term survivorship is possible. For example, in synchronous metastases, which are present in approximately 10% of newly diagnosed patients, prognosis is closely related with the anatomic degree of metastasis lesions; palliative chemotherapy can lead to median overall survival of approximately 10–15 months, which can be greatly increased if the patient is suitable
Immunotherapy for nasopharyngeal carcinoma
Tumour immunotherapy may represent a promising therapeutic approach in nasopharyngeal carcinoma, where the primary strategies include EBV-directed vaccination, adoptive T-cell therapy, and immune checkpoint blockades. EBV-directed vaccination exploits T-cell activation to target nasopharyngeal cancer cells by recognising expressed viral antigens (eg—EBNA1, LMP1, LMP2). For example, vaccination against LMP2 epitopes with dendritic cells or peptides, or adoptive transfer of cytotoxic T
Conclusions and future directions
Nasopharyngeal carcinoma incidence has declined gradually but progressively, accompanied by substantially reduced mortality, which is likely due to lifestyle and environmental changes, enhanced understanding of the pathogenesis and risk factors, population screening, advancements in diagnostic techniques, and individualised comprehensive chemoradiotherapy strategies. However, considering the current lack of reliable evidence, several questions on nasopharyngeal carcinoma pathogenesis and
Search strategy and selection criteria
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