Tumours of the nasopharynx include adenocarcinomas, lymphomas, and sarcomas, but the predominant tumour is nasopharyngeal carcinoma, which arises from the epithelium of the nasopharynx. The World Health Organization (WHO) recommended a uniform subclassification of nasopharyngeal carcinoma as poorly differentiated or non-keratinizing carcinoma (WHO 2), undifferentiated carcinoma (WHO 3), and the less common well-differentiated squamous cell carcinoma (WHO 1). These are considered to be variants of squamous cell carcinoma because they show features of epithelial differentiation, such as the presence of tonofilaments on electron microscopy. The poorly differentiated and, especially, the undifferentiated carcinoma are the dominant tumour types in areas with a high incidence of nasopharyngeal carcinoma, and are associated more closely with infection by Epstein–Barr virus.

While nasopharyngeal carcinoma affects predominantly southern Chinese and south-east Asians, it is gaining worldwide attention for two reasons. First, the geographical movement of ethnic groups either as travellers or migrants, over the last decades has increased the incidence with which clinicians encounter nasopharyngeal cancer. Second, the strong causal relationship between nasopharyngeal carcinoma and Epstein–Barr virus makes it a valuable model for the study of virus-related tumours.

The incidence of nasopharyngeal carcinoma is highest in southern China, especially in the provinces of Guangdong, Guangxi, Fujian, Hunan, and Jiangxi (average 20/100 000/year), where this tumour accounts for 4 to 14 per cent of all cancer deaths. In the highest risk areas of Guangdong, the incidence of nasopharyngeal carcinoma in males between 45 and 55 years of age reaches 120/100 000/year. The incidence is also high in other areas of south-east Asia heavily populated by southern Chinese (Singapore, Hong Kong, northern Thailand), at 20/100000/year. A similarly high incidence of nasopharyngeal carcinoma has been observed in southern Chinese who have migrated to America and also in native Alaskans. Elsewhere, an intermediate incidence of 1.5 to 9/100 000/year is observed in North Africa (Algeria, Tunisia, Morocco, Sudan), while Europe, the United States of America, Canada and South America have an incidence of only 1/100000/year.

Registry data collected in Guangdong and Singapore suggest that the annual incidence of nasopharyngeal carcinoma during the 1970s has shown little fluctuation.

Nasopharyngeal carcinoma has a male preponderance of 3:1. Although it has been reported in patients ranging from 3 to 86 years of age, it is uncommon under the age of 20 years (<1 per cent). In high-risk areas, there is a sharp rise in incidence after the age of 20 reaching a plateau between 40 and 60 years of age before declining with age thereafter. The age distribution pattern suggests an induction time of 20 years and a plateauing period that is generally 10 years earlier than squamous carcinoma of other head and neck sites, suggesting aetiological factors other than alcohol and smoking may be implicated in nasopharyngeal carcinoma.

Epidemiological surveys have established that southern Chinese are at high risk of developing nasopharyngeal carcinoma, regardless of their domicile. Familial aggregation of the disease has also been reported. In a case-control study carried out in China, 33 of 200 patients had a family history of cancer, including 14 families with nasopharyngeal carcinoma, while 10 of 200 matched controls had family history of cancer with only two cases of nasopharyngeal carcinoma. Nasopharyngeal carcinoma was significantly more common in the siblings of patients with the disease (14.6 per cent) than in the controls (1.8 per cent). Whether the increased risk of developing nasopharyngeal carcinoma observed among siblings of patients represents genetic or environmental influences remains to be elucidated.

Nasopharyngeal carcinoma may be associated with the southern Chinese habit of feeding dried and salted fish to children. Traces of nitrosodimethylamine, found in salted fish, induce paranasal and nasal tumours when fed to weaning rats. Case-control studies carried out in Malaysia and Hong Kong also show a highly significant association between salted fish intake in childhood and nasopharyngeal carcinoma.

The relationship between certain medicinal herbs and nasopharyngeal carcinoma has also been under recent investigation. A Chinese medicinal herb extract (Wikstroemia indica, found in southern China) promoted the induction of nasopharyngeal carcinoma in rats by the actions of dinitrosopiperazine, a nitroso compound with relative predilection for nasopharyngeal epithelium. Chemicals present in the environment may therefore act as strong promoting factors in the development of nasopharyngeal carcinoma.

Epstein-Barr virus is a herpes virus discovered by Epstein in 1964 in a culture derived from a Burkitt lymphoma biopsy. It is a ubiquitous virus with DNA of around 106 × 10&sup6; Da. Latent infection by Epstein-Barr virus is present in many populations around the world, but the age at which primary infection occurs varies. The virus is transmitted horizontally by saliva. Early infection in childhood is associated with Burkitt lymphoma and nasopharyngeal carcinoma in tropical Africa, and with nasopharyngeal carcinoma in southern China. Late infection in adolescence is associated with infectious mononucleosis in North America and Europe.

Regardless of ethnic and geographic origin, sera derived from patients with nasopharyngeal carcinoma exhibit a characteristic pattern of antibodies to Epstein-Barr virus. In 1966, precipitating antibodies to Epstein-Barr virus-related antigen were demonstrated in sera from patients with nasopharyngeal carcinoma. Virus-associated nuclear antigen was demonstrated in tumour cells of patients with nasopharyngeal carcinoma in 1974. By 1976, antibodies to viral capsid antigen and early antigen had been identified in sera and were used clinically for early diagnosis of nasopharyngeal carcinoma. More recently an antibody-dependent cellular cytotoxicity assay for detection of antibodies against Epstein-Barr virus-specific membrane antigen and antibody against viral proteins such as DNase and DNA polymerase have also been under investigation for use as other serological tests for early diagnosis and prognosis. The current and potential clinical applications of selected serological tests for the detection of Epstein-Barr virus-related nasopharyngeal carcinoma is summarized in Table 1 610. The aetiological relationship between virus and nasopharyngeal carcinoma has also been further strengthened by the discovery of viral DNA sequences in epithelial cells of these tumours by in-situ hybridization.

The nasopharynx is the uppermost portion of the aerodigestive tract. It functions as a conduit for air and for nasal and paranasal sinus secretions, and is lined by squamous, respiratory, and transitional epithelium. Cuboidal in shape, it lies above the level of the soft palate and posterior to the nasal septum and the choana (Fig. 1) 2351. The sphenoid sinus, the lower clivus, the atlas of the cervical spine, and prevertebral muscles make up its posterosuperior wall. This is covered by pharyngeal mucosa, superior constrictor muscle, and the tough pharyngobasilar fascia. Laterally, the clinically important lateral wall consists of the eustachian tube opening, the lateral pharyngeal recess (fossa of Rosenmüller), and the cartilagenous medial end of the eustachian tube (torus tubarius) upon which the levator veli palatini muscle attaches. The fossa of Rosenmuller is a cleft-like pouch reaching to the parapharyngeal space through which runs the internal carotid artery, internal jugular vein, cranial nerves IX to XII, and sympathetic nerves.

Common signs and symptoms associated with early nasopharyngeal carcinoma include nasal symptoms (bloodstained anterior or postnasal discharge, epistaxis, obstruction) and aural symptoms (serous otitis media, tinnitus, conductive hearing loss). Because the nasopharynx is not readily visible or accessible, the first sign of nasopharyngeal carcinoma in more than 50 per cent of patients is enlarged metastatic cervical node(s). Due to the proximity of the nasopharynx to the skull base, neurological symptoms such as diplopia, facial numbness and pain, ptosis, and hoarseness due to involvement of single or multiple cranial nerves III to XII and sympathetic nerves may be present in advanced disease. Headaches occur with intracranial disease, and trismus from oropharyngeal extension indicates extensive local disease.

In general, metastasis first occurs by the lymphatics to jugulo-digastric and upper posterior triangle cervical lymph nodes. Bilateral cervical metastasis occurs. Distant metastasis to bone (frequently the spine), liver, and lungs is a sign of late or recurrent disease. Rarely, spread of disease to the axilla and inguinal lymph nodes may mimic lymphoma.

The diagnosis of nasopharyngeal carcinoma must therefore be considered in an adult presenting with any one of cervical lymphadenopathy, bloodstained nasal discharge, and serous otitis media.

Following a history and physical examination with emphasis on the head and neck area, patients suspected of, or at risk of, developing nasopharyngeal carcinoma should undergo flexible fibreoptic nasopharyngoscopic examination as a routine, along with blood tests for IgA antibodies to Epstein-Barr virus capsid antigen and early antigen.

The flexible fibreoptic nasopharyngoscope has made easy the complete examination of the nasopharynx in the doctor's office with minimal discomfort to the patient. Direct visualization of the nasopharynx by this means allows simultaneous biopsy of any tumours seen and close inspection of the nasopharyngeal mucosa for easy bleeding or presence of inflamed, haemorrhagic, granular mucosa, which may be the only subtle abnormalities present in a nasopharynx with submucosal infiltration by early nasopharyngeal carcinoma. Figure 4 2354 shows the endoscopic view of an ulcerative and nodular tumour arising from the right posterolateral wall. As a rule, nasopharyngeal carcinoma is best diagnosed by punch biopsy of the primary tumour. Excisional node biopsy can usually be avoided if the nasopharynx has been thoroughly examined and biopsied.

Symptomatic patients with elevated levels of antibody to viral capsid antigen and/or early antigen and an apparently normal nasopharynx should be admitted for examination under general anaesthesia and multiple endoscopic-guided biopsies of the nasopharynx. IgA to viral capsid antigen is a sensitive screening marker for nasopharyngeal carcinoma (sensitivity better than 90 per cent) (Table 1) 610, but levels may be falsely elevated in patients with no clinical evidence of nasopharyngeal carcinoma or other head and neck cancer. There is a growing belief that reactivation of Epstein-Barr virus infection, indicated by elevated levels of this antibody, is a prerequisite for the development of nasopharyngeal carcinoma. The relative risk of developing this tumour is 50 to 80 times higher for people with an elevated level of IgA against viral capsid antigen than in the average population. These antibody levels can be elevated many months before the onset of clinical symptoms of nasopharyngeal carcinoma: patients with elevated antibody levels but a negative biopsy result should be kept under continuous surveillance. Only 60 per cent of patients with nasopharyngeal carcinoma have elevated levels of IgE to the viral early antigen, but nearly all of those in whom this antibody is present have the disease; hence, symptomatic and asymptomatic patients with increased levels of IgA against the early antigen must undergo extensive biopsy of the nasopharynx to confirm the diagnosis. Measurement of levels of IgA against viral capsid antibody has largely replaced the assay of non-specific IgG antibodies to capsid and early antigens as the most sensitive and reliable serological screening for nasopharyngeal carcinoma. The IgG antibody levels are usually non-specifically elevated in patients with past history of Epstein-Barr virus infection.

When lymph nodes are affected by metastases from an unknown primary tumour and nasopharyngeal carcinoma is suspected, tissue smears from fine needle aspiration smears of the node or from a biopsy can be stained for Epstein-Barr-related nuclear antigen. This confirms the presence of a neoplasm related to this virus when positive (Table 1) 610. Nasopharyngeal carcinoma can be excluded when the stained tissue is negative for this antigen.

When the results of antibody tests become available, usually within a week, sequential diagnostic steps including repeat nasopharyngoscopy whenever necessary, biopsy of the nasopharynx under local or general anaesthesia, and fine needle aspiration biopsy of any enlarged cervical node are undertaken to confirm or to exclude the diagnosis (outlined in Fig. 5 2355).

Plain radiographic examination of the nasopharynx is of historical interest. It has no role in the early diagnosis of nasopharyngeal carcinoma. CT scanning cannot replace direct examination of the nasopharynx by endoscopy for detection of early disease, since mild asymmetry of the nasopharynx is common. Once the histological diagnosis has been made, however, CT scanning is routinely required for clinical staging and planning for radiotherapy. High resolution CT scanning with contrast is valuable in delineating the local extent of the tumour in relation to the parapharyngeal space, the retropharyngeal space, and the skull base. The CT scan appearance of a large, polypoid nasopharyngeal carcinoma extending to the choana is shown in Fig. 6 2356. Both a CT scan and MRI are also useful in detecting recurrent primary disease following radiotherapy. MRI is particularly helpful in distinguishing between fluid and tumour in opaque sinuses and between tumour and muscle. MRI has the additional benefit of providing axial as well as sagittal and coronal images.

External radiotherapy is the primary treatment for biopsy proven nasopharyngeal carcinoma of all stages. Nasopharyngeal carcinoma is more radioresponsive than is squamous carcinoma of other head and neck sites, but a dose of more than 6000 cGy is still required for curative treatment. At the Prince of Wales Hospital in Hong Kong, the entire nasopharynx and adjacent soft tissues and bones are usually treated with 6500 cGy by a three-field technique. Significant parapharyngeal disease receives an extra dose of 2000 cGy. High radiation doses to the spinal cord, pituitary gland, and the temporomandibular joint must be avoided in order to prevent radiation myelitis and trismus. Prophylactic as well as therapeutic radiation of the neck glands is routinely administered. An additional cervical irradiation is delivered with an electron beam to any palpable nodes that remain after external radiotherapy. Persistent localized disease in the nasopharynx is treated with intracavitary iridium-192, afterloaded into pre-placed nylon tubes. Patients with nodes more than 5 cm in size receive adjuvant chemotherapy with cis-platinum and 5-fluorouracil for two to three courses, 3 weeks apart, prior to radiotherapy. In an effort to improve the results of radiotherapy, a multidisciplinary approach to the treatment of nasopharyngeal carcinoma is currently under evaluation (Fig. 7) 2357.

Although radiotherapy is the primary treatment for nasopharyngeal carcinoma of all stages, local, regional, and distant metastases often remain after such therapy: approximately 50 per cent of patients have recurrent disease 5 years after treatment. For early stage disease (T1,2), the 5-year relapse-free survival is 75 per cent; detection and treatment of recurrent disease is therefore important.

Re-irradiation at the primary site renders 10 to 25 per cent of patients disease-free, but is associated with complications, including radiation myelitis, radiation encephalopathy, cranial nerve palsy, otitis media, trismus, and osteoradionecrosis. As an alternative, Fee reported surgical treatment of nine patients with recurrent nasopharyngeal carcinoma, using a transpalatal approach to en bloc nasopharyngectomy with transcervical protection of the internal carotid artery, with good early results.

We have carried out nasopharyngectomy for recurrent nasopharyngeal carcinoma using a transoropalatal approach in which the internal carotid artery in the parapharyngeal space at the lateral limit of resection is protected by transoropharyngeal dissection (Fig. 8) 2358. We prefer to raise the entire soft and hard palate mucoperiosteal flap pedicled on a single greater palatine artery to obtain maximum exposure of the nasopharynx after removal of the posterior two-thirds of the palatal bone (Fig. 9) 2359. In a typical nasopharyngectomy, the entire nasopharyngeal mucosa and the underlying superior constrictor muscle, pharyngobasilar fascia, prevertebral fascia and muscles, and the cartilaginous portion of the eustachian tube are resected en bloc. The resultant defect is skin grafted. Figure 10 2360 shows the CT scan of the nasopharynx of a patient with recurrent nasopharyngeal carcinoma after transoropalatal right nasopharyngectomy.

Parapharyngeal disease and severe trismus may require a combined infratemporal fossa or mandibulotomy approach (mandibular swing), respectively. The presence of simultaneous cervical metastasis requires a combined nasopharyngectomy and radical neck dissection. Curative nasopharyngectomy is not possible in patients with massive parapharyngeal extension, cranial nerve disease, or intracranial extension. Although transoropalatal nasopharyngectomy with carotid artery protection is feasible, the long-term benefits of nasopharyngectomy remain under evaluation. This approach is currently undertaken only in selected patients who fail to respond to conventional radiotherapy.

Regional recurrence after radiotherapy presenting as persistent or recurrent cervical lymphadenopathy is more common in patients with bulky cervical disease. Recurrent cervical disease can be confirmed by fine needle aspiration biopsy or by excisional biopsy of a suspicious cervical node. In the absence of distant metastasis and when biopsy reveals absence of disease at the nasopharynx, radical neck dissection for cure is indicated.

Between 1986 and 1991, we carried out radical neck dissection in 38 patients with nasopharyngeal carcinoma and recurrent cervical metastasis after radiotherapy. There were no in-hospital deaths. Three of 38 patients required a myocutaneous flap for neck coverage. As pectoralis major and latissimus dorsi myocutaneous flaps become commonly available for soft tissue coverage of the neck whenever cervical skin becomes deficient due to surgery or infectious complications, the risk of carotid artery exposure and rupture after radical neck dissection in heavily irradiated necks can be minimized.

Less than a formal radical neck dissection (such as modified radical neck dissection with preservation of the spinal accessory nerve) is not recommended for these patients because of the possible involvement of the spinal accessory chain of lymph nodes and extranodal disease. In our experience, radical neck dissection results in minimal shoulder dysfunction and is well tolerated, even in heavily irradiated patients. Figure 11 2361 shows a patient with well-healed parallel incisions (McFee) after a left radical neck dissection for recurrent cervical metastasis after radiotherapy for nasopharyngeal carcinoma.

The prognosis of nasopharyngeal carcinoma is largely dependent on the extent of the primary tumour (T-stage), and the size and level of cervical node involvement (N-stage), as reflected in the modified Ho and the International Union against Cancer (UICC) staging systems.

Previous series of patients with nasopharyngeal carcinoma from Hong Kong and the United States of America gave the following approximate 5-year survival rates after radiotherapy: stage I, 80 per cent; stage II, 65 per cent; stage III 40 per cent and stage IV, 20 per cent. Since 1985, we have treated 407 patients with radiation as the primary therapy. Preliminary results suggest an apparent improvement in the overall 3-year disease-free survival rate compared to an historical control of 44 per cent to 56 per cent.

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