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Tumors of the nasopharynx are classified by the World Health Organization (WHO) into several categories based on histology.1 These include epithelial tumors, soft tissue tumors, bone and cartilage tumors, malignant lymphomas, tumorlike lesions, secondary tumors, and unclassified tumors. This chapter focuses on nasopharyngeal carcinoma (NPC), a malignant epithelial tumor that constitutes 75 to 95% of nasopharyngeal malignancies in low-risk populations and virtually all nasopharyngeal cancers in high-risk populations.²

Nasopharyngeal Carcinoma

NPC is an uncommon tumor in western Europe and North America, occurring sporadically, with an age-adjusted incidence of less than 1 per 100,000 population for both sexes.³ This neoplasm occurs with greater frequency in Southeast Asia, and especially in the Guangdong Province of southern China, where reported incidences range from 15 to 80 per 100,000 population.⁴ Intermediate incidence rates have been reported in North Africa, in the Mediterranean basin, and among the Alaskan Eskimo population.^4–6 Men are affected three times more often than women,⁷ and 80% of these tumors occur in people aged 45 to 85 years.⁸ Although NPC is rare in the pediatric population, a bimodal age distribution has been described specific to low-risk areas,⁹ with the first peak occurring from 15 to 24 years and the second from 65 to 79 years. Globally, the mean age of occurrence in high-risk populations is 40 to 50 years⁵ and this bimodal distribution is not appreciated. Children, therefore, comprise a greater proportion (up to 16%) of the patients with NPC in nonendemic areas than in endemic areas such as China (0.1%).¹⁰

Epidemiology

The pathogenesis of this disease reflects complex interactions between genetic susceptibility, dietary factors, population migration patterns, and environmental exposures (including viral agents such as Epstein-Barr virus [EBV]). This multifactorial etiology is supported by the fact that the incidence of NPC is lower among first-generation Chinese who migrate to low-incidence areas in the West. However, Chinese born in North America still have a seven times higher incidence of NPC than do Caucasians.¹¹ There is also a trend toward decreasing incidence the further the population has immigrated.¹² Within at-risk Asian populations, NPC is more often of the nonkeratinizing or undifferentiated type, tends to present at a more advanced stage, and more likely to appear at an earlier age than in low-incidence populations.^5,6 However, Chinese ethnicity itself is an independent and favorable prognosticator for survival in NPC.¹³

Chromosomal abnormalities in chromosomes 1, 3, 4, 6, 9, 11–17, and X have been described in its pathogenesis.¹⁴ Human leukocyte antigen associations reported in the literature include B17, B18, BW46, and A2. Dietary factors that have been linked to the development of NPC include the consumption of salted fish and preserved vegetables.^2,15,16 Diets lacking in fresh fruits, fiber, and carotene have also been implicated.¹⁶ Increased intake of oranges and tangerines has been shown to cause a reduction in the risk of development of NPC.¹⁵ As yet, no clear association has been established between NPC and tobacco or alcohol use,^17,18 although exposure to domestic wood fires is an independent risk factor for NPC.¹⁹

EBV is a DNA virus from the herpes virus group. The virus is ubiquitous and is usually acquired in early childhood. Once a person is infected with the virus, he or she develops immunity but the virus remains within specific circulating B lymphocytes or is shed through saliva for the rest of the individual’s life.20 EBV is consistently detected in NPC, regardless of geographic region or extent of tumor differentiation. Most individuals infected with the virus do not develop NPC, and so it is believed that EBV is not the initiating event in NPC, but a second event after the initial transformation of epithelial cells of the nasopharynx. The presence of a single form of viral DNA suggests that these tumors are clonal proliferations of a single cell that was initially infected with EBV.²¹

Specific latent viral genes are expressed on NPC cells and in early dysplastic lesions. These genes encode for Epstein-Barr nuclear antigen (EBNA) 1 to 6; latent membrane protein types 1, 2A, and 2B; and EBV-encoded RNA (EBER) 1 and 2. These EBV antigens and EBERs are not expressed by normal nasopharyngeal cells. Their oncogenic products block apoptosis and senescence and alter cellular gene expression and growth to cause rapid proliferation and invasion by tumor cells.²¹

The typical serological profile in NPC consists of an increase in immunoglobulin G (IgG) and immunoglobulin A (IgA) against viral capsid antigen (VCA) and early antigen (EA) and in IgG anti-EBNA.⁵ This profile differs in patients without NPC who are infected with EBV, in whom there are elevated levels of immunoglobulin M and IgG against EA and VCA antigens on EBV (but not IgA).

Anatomy

The nasopharynx extends from the skull base to the level of the soft palate and is continuous with the nasal cavity via the choanae anteriorly. It is a tubular passage with a sloping roof, its posterior wall being formed by the basisphenoid, the basiocciput, and the first cervical vertebra. The Eustachian tube orifices are located in the lateral wall of the nasopharynx, just medial to the medial pterygoid plate. The opening to each forms a comma-shaped elevation known as the torus tubarius. The nasopharynx constitutes part of Waldeyer ring.

The primary tumor generally arises from the lateral nasopharynx, most commonly at the pharyngeal recess (fossa of Rosenmüller) medial to the medial crus of the Eustachian tube, and is characterized by a rich submucosal lymphatic plexus, resulting in the early development of cervical nodal metastases.

Presentation and Diagnosis

The symptoms related to early disease are subtle and nonspecific, and thus many patients with primary NPC are diagnosed once the tumor has progressed to an advanced stage. Almost 80% of nasopharyngeal tumors are T2 or T3 at the initial presentation.⁷ Less than 1% of the patients are diagnosed incidentally and are asymptomatic at the time of diagnosis.

Cervical lymphadenopathy is the most common presenting symptom and is found in up to 90% of the patients,^7,22 with bilateral neck involvement occurring in as many as 50% of the cases.^17,22 Lymphatic involvement of the first echelon nodes, the retropharyngeal nodes, is often detected only radiologically. Occasionally, they may be appreciated as a nodular submucosal swelling in the posterior pharynx on physical examination. Lymphatic spread tends to occur to the jugulodigastric and upper jugular nodes first and then subsequently to the lower jugular and supraclavicular nodal groups. Involvement of that latter group has been shown to have prognostic significance, as reflected in the nodal staging system.

Other presenting symptoms relate to the presence of tumor in the nasopharynx (nasal discharge, obstruction, and epistaxis), Eustachian tube dysfunction (tinnitus and hearing loss), or cranial nerve and skull base involvement with tumor (diplopia, headache, facial pain, and anesthesia). Cranial nerve involvement is present in up to 20% of the patients at diagnosis. The most commonly affected cranial nerve is the fifth, specifically the maxillary division.⁷ Also commonly involved are the sixth, twelfth, and third cranial nerves.^7,22–24 The level of recovery of cranial nerve involvement in response to treatment has been shown to be an independent factor affecting prognosis.²⁵ NPC has a propensity to invade adjacent anatomic regions fairly early, spreading into the nasal cavity (20%) or via the pharyngeal muscles into the oropharynx (15%).²⁶ Parapharyngeal space invasion occurs in more than 80% of the patients.²⁶ Involvement of the skull base occurs in 25 to 35% of the patients,⁵ and intracranial involvement is not uncommon.^26,27 The classic clinical triad of neck mass, nasal obstruction, and serous otitis media or conductive hearing loss is relatively infrequent.⁵

More than 250 cases of paraneoplastic syndrome associated with NPC have been reported in the literature. These syndromes may be divided into six categories: dermatologic, rheumatoid, endocrinologic, hematologic, neurologic, and ocular. Dermatomyositis is the most common cutaneous manifestation; while syndrome of inappropriate antidiuretic hormone secretion and Cushing syndrome are the more common endocrinologic manifestations.²⁸ Other features include clubbing of the fingers and toes, tumor fever, polyneuropathy, and optic neuritis. The paraneoplastic syndrome may appear before the tumor itself manifests. Most often, the paraneoplastic syndrome resolves in parallel with the primary tumor and may prove useful in monitoring for tumor response or recurrence.²⁸

Distant dissemination of NPC is found in approximately 10% of the patients^5,7,26,27,29 at presentation and commonly involves the bones (70 to 80% of the patients with distant disease), lungs, liver, and extra-regional nodes.^5,7 The initial work-up generally includes a chest radiograph, bone scans, and ultrasound of the liver, the objective being to rule out distant disease. Alternatively, computed tomography (CT) of the chest and abdomen may be performed, and, more recently, whole-body positron emission tomography (PET) scans are being used as part of the initial staging work-up.

Definitive diagnosis is made by endoscopic-guided biopsy of the primary nasopharyngeal tumor, usually under local anesthesia. General anesthesia may be indicated after multiple negative biopsies in patients with a strong clinical suspicion of disease or when submucosal disease exists that would require deep biopsies. The mucosa around the fossa of Rosenmüller yields the highest positive biopsy rate when direct examination or imaging does not reveal macroscopic tumor but NPC is strongly suspected.5

CT and magnetic resonance imaging (MRI) are well established as complementary imaging modalities in the initial staging of NPC. CT is useful in assessing cervical lymph node status and skull base invasion, while MRI is more accurate in detecting the primary tumor, the presence of parapharyngeal extension, retropharyngeal lymphadenopathy, and cranial nerve involvement.³⁰ Tumor volume calculated from imaging studies is also a reliable indicator (in addition to the T classification of the tumor) for predicting tumor response to radiotherapy.^31,32

PET is widely used for evaluating squamous cell carcinomas (SCCs) in other sites of the head and neck. Fused PET/CT images provide more accurate interpretations of the overall tumor-node-metastasis (TNM) system stage than standalone PET or CT.^33,34 Studies suggest that PET/CT may be more accurate than conventional imaging in the evaluation of early treatment response and in the detection of recurrent and residual NPC.^35,36 Its role in the initial staging and treatment planning is less clear, and currently, its utility at the time of diagnosis is confined to the detection of distant metastases in patients with advanced locoregional disease and as a baseline study for comparison with future scans used to assess treatment response and detect residual disease after treatment.^35,37 Studies have demonstrated discordance between ¹⁸F-fluorodeoxy-d-glucose PET/CT and MRI when evaluating for invasion into the skull base, cavernous sinus, brain, and orbit, where it is thought that PET may undermap the extent of tumor.³⁵ However, cadaveric studies by Daisne et al reveal that although the volume of primary cancers is smaller on PET (than on CT or MRI), PET provides the most accurate assessment of gross tumor volume.³⁸

Laboratory tests that complement the work-up include complete blood counts, serum chemistries, lactate dehydrogenase level, erythrocyte sedimentation rate, and EBV serological profile. Baseline audiogram is also recommended because hearing is likely to worsen with radiation and with the use of certain ototoxic chemotherapeutic agents, such as cisplatin.

Staging

The stage of disease at the time of diagnosis is the most important prognosticator. The most recent TNM staging system for NPC proposed by the American Joint Committee on Cancer (AJCC) is given in Tables 12.1 and 12.2. Alternative systems that are used more commonly in Asia include Ho’s 1978 system and the 1992 Chinese Staging System.

Pathology

NPC arises from the epithelial cells that line the surface of the nasopharynx. The malignant cells are polygonal, with nuclei that are round or oval with scant chromatin and prominent nucleoli. The cells are frequently intermingled with lymphoid cells in the nasopharynx, giving rise to the term lymphoepithelioma.^21,39 Electron microscopy studies have determined that these tumor cells are of squamous origin and that the undifferentiated type is a form of SCC.²¹

The WHO classification (1978) recognizes three histopathological types: (1) keratinizing SCC (similar to other sites in the upper aerodigestive tract), (2) nonkeratinizing carcinoma, and (3) undifferentiated carcinoma. In the 1991 WHO classification, the keratinizing SCC subtype was retained while the last two subtypes were combined under the category of “nonkeratinizing carcinoma.” This new category was further divided into differentiated and undifferentiated types. Lymphoepithelioma-like carcinoma was considered a variant of undifferentiated carcinoma.⁴⁰ The current WHO classification maintains this terminology with the addition of the category “basaloid SCC” (Table 12.3).

The vast majority of patients in endemic regions display the nonkeratinizing undifferentiated pattern, while the keratinizing SCC is the pattern more commonly seen in low-incidence areas. In general, nonkeratinizing carcinomas have a stronger relationship with EBV and tend to be more radiosensitive, with better locoregional control rates (resulting in improved 5-year survival), despite a higher rate of distant metastases than the keratinizing type.^41–43 The Chinese ethnicity survival advantage is demonstrated among patients with keratinizing nasopharyngeal SCC as well.⁴²

A hypothesis describing the stepwise progression of the histological features that occur as a result of underlying genetic events in the development of NPC has been described.⁴ Patches of dysplasia occur initially and are associated with allelic losses on the short arms of chromosomes 3 and 9,⁴ possibly in response to environmental carcinogens. This in turn causes inactivation of tumor suppressor genes p14, p15, and p16.⁴ It is believed that these initial areas of dysplasia are the sources of the tumor but on their own they are unlikely to progress further. Latent EBV infection is critical in the progression to severe dysplasia. Allelic losses on chromosomes 11q, 13q, and 16q and gains on chromosome 12 eventually lead to invasive carcinoma.⁴⁴ The aberrant expression of cadherins and mutations in p53 contributes to the development of metastases.⁴

Management

Radiation therapy is the mainstay of the treatment of NPC. As a single modality, its use is restricted to small tumors limited to the primary site. Combination with systemic therapy is indicated as soon as early lymph node involvement occurs.30

Table 12.1 TNM Staging of Nasopharyngeal Carcinoma

^aParapharyngeal extension denotes posterolateral infiltration of tumor.

^bMidline nodes are considered ipsilateral nodes.

^cSupraclavicular zone or fossa is relevant to the staging of nasopharyngeal carcinoma and is the triangular region originally described by Ho. It is defined by three points: (1) the superior margin of the sternal end of the clavicle, (2) the superior margin of the lateral end of the clavicle, and (3) the point where the neck meets the shoulder. Note that this would include caudal portions of levels IV and VB. All cases with lymph nodes (whole or part) in the fossa are considered N3b.

This group (stage I disease) comprises the minority of patients with NPC and may be effectively treated with radiation therapy alone to the primary site and elective neck irradiation.45 Clinical trials have demonstrated no survival advantage with the addition of chemotherapy to radiation therapy in this patient population. Patients in this group generally have a favorable outcome, with 5-year local control rates ranging from 80 to 95%.⁴⁵ Although radiation therapy alone was previously thought to be appropriate in addressing patients with T2 (parapharyngeal extension) and N1 disease, it is now known that these patients have a worse outcome with single modality therapy and should be treated with concomitant chemoradiotherapy.⁴⁵

Locally Advanced Disease

The majority of patients with NPC belong to this group (stage II and higher), but despite advances in its delivery techniques, radiation therapy alone has yielded disappointing results.