On endoscopic examination, JNA presents as a rubbery vascular mass protruding into the anterior nasal space and may have excessive bleeding on contact. A CT scan with contrast will show an enhancing soft tissue mass arising from the NP or lateral wall of the nose. Although the pterygopalatine fossa may be widened by the tumor (Fig. 99-1), bone erosion is not present in general. MRI will show a vascular tumor with flow voids within the mass and enhances on gadolinium. MR angiography will be the least invasive form of vascular imaging that will show the feeding vessels arising from the branches of the external carotid system. The authors have found the MRI with contrast to be more useful for follow-up evaluation (Fig. 99-2). The use of ^99mTc-RBC single photon emission computed tomography has been suggested to be accurate in the diagnosis of JNA.⁴ However, final proof of diagnosis is histologic.

Figure 99-1. Computed tomography showing the widening of the left sphenopalatine foramen from a juvenile angiofibroma.

Figure 99-2. Magnetic resonance imaging showing the follow-up of the same JNA patient with no recurrence at 3 years.

In 1984 Chandler and colleagues ⁵ proposed a staging system (Table 99-2) on the basis of clinical and CT assessment. This staging system is logical and easy to understand and it is useful for reporting. Due to the large anatomic region of stage 3, Sessions and Radkowshi have suggested refining stage 3. However, none of the systems has been used extensively for comparing outcomes because published case series have usually been of small numbers.

Table 99-2 The 2002 UICC TNM Staging of Nasopharyngeal Carcinoma

T Classification
Tx	Primary tumor unable to be assessed
T0	No evidence of tumor
T1	Confined to nasopharynx
T2a	Extends to nasal cavity, oropharynx
T2b	Tumor extends to parapharyngeal space
T3	Tumor involves sinuses, orbit, skull base, hypopharynx
T4	Intracranial or infratemporal involvement
N Classification
N0	No nodal involvement
N1	Ipsilateral lymph nodes < 6 cm
N2	Bilateral lymph nodes < 6 cm
N3	Lymph node > 6 cm; supraclavicular node
M Classification
M0	No distant metastasis
M1	Distant metastasis (includes mediastinal nodes)
Stage Classification
Stage I	T1N0M0
Stage II	T1N1M0, T2N0M0, T2N1M0
Stage III	T3N0-2M0, T1-2N2M0
Stage IVa	T4, any NM0
Stage IVb	any TN3M0
Stage IVc	any T, any N, M1

TNM, tumor node metastasis; UICC, Union Internationale Contre Cancre.

Chandler’s Staging of JNA

Stage 1 Tumor confined to nasopharynx

Stage 2 Tumor extends into nasal cavity or sphenoid

Stage 3 Tumor involves the maxillary, ethmoids, infratemporal fossa, orbit, cheek, and cavernous sinus

Stage 4 Tumor is intracranial

Management

The primary treatment is surgical extirpation. Due to the infrequency of the disease, most of the experience for managing this disease is limited to case series based on institutional practice gleaned over a period of time. For the patient diagnosed with histologically proven JNA, the initial relevance would be to assess for fitness for surgery. Although this is usually not an issue with young adult males, intracranial lesions can be associated with long surgeries and comorbidities. With intracranial masses, a team of skull base surgeons (head and neck and neurosurgeon) would be necessary for joint management.

Although the traditional method of surgery has been the open approach, recent interest surrounds the use of the exclusively endoscopic techniques for removal of such vascular tumors. The open approach, however, remains an important method for tumors that may not be fully accessible endoscopically. For small lesions, an intraoral transpalatal approach allows for access to the nasopharynx. This approach will likely be replaced by the endoscopic route. The more commonly employed medial maxillectomy approach can be done via a lateral rhinotomy or preferably a midfacial degloving incision, which affords reasonably good access to the NP and eliminates facial scars.

For extension outside the NP into the paranasal sinuses, a Le Fort type 1 osteotomy will allow an inferior approach to the maxillary and ethmoid sinuses as well as the pterygopalatine canal. For lesions involving the infratemporal fossa or large lesions involving the majority of the sinuses, a facial translocation approach affords a large window of access. The facial translocation involves the rotation of the facial cheek flap as a single osteoplastic unit with the underlying maxilla rotated laterally after osteotomies to the maxillary nasal, orbital maxillary, and zygomatic arches. The senior author has also incorporated the entire nose and cheek as a single rotation based laterally. This allows for excellent access to the infratemporal fossa and hemostatic options in the event of bleeding. A lateral infratemporal fossa approach has been recently used as reported by Tyagi and colleagues.⁶

Endoscopic sinus surgery techniques have advanced significantly over the past 2 decades and have allowed the intranasal access and nasal anatomy to be approached in an extremely competent fashion. Several authors have published their experience of successful endoscopic resection of such tumors. Several reports of endoscopic resection have reasonable follow-up durations (13 patients in 23 months) and low recurrence rates (8%).⁷ Combination approaches of type 3 JNA with open and endoscopic approaches have also reported good success but of shorter-term results.⁸ For larger lesions such as stage 3A disease, Hofmann and colleagues have reported successful endoscopic resection with long-term results (52 months) in a series of 21 patients and have reported that extension to the medial aspect of infratemporal fossa and retromaxillary space was not a contraindication to an endonasal endoscopic approach.

Preoperative embolization of the tumor mass is used by some to reduce intraoperative bleeding. However, the risk of recurrence has been highlighted with the use of preoperative embolization.⁹ In extensive tumors where the feeding vessels come from the internal carotid system, a laser-assisted extracranial-intracranial bypass has been used before the definite surgery in order to prevent neurologic deficits.¹⁰

Recurrence rates have been reported to be as high as 35% depending on the length of follow-up. For patients with recurrent disease, the options remain for observation alone, revision surgery, or radiation. Radiation has been used for treatment of JNA, especially those that recur after surgery and those with intracranial extension where clearance of margins may be difficult. Cummings and colleagues ¹¹ reported a series of 56 patients treated with 3000 cGY. However, issues of impact on growth centers, cataract formation, and osteoradionecrosis have been reported, as have cases of malignant transformation.¹² For these various reasons, observation, sometimes followed by involution with aging or repeat surgery, is an option in the presence of recurrence. In patients who cannot undergo surgery, recalcitrant cases of tumor recurrence despite several repeat resections and inaccessible recurrences may be considered for radiation therapy with full disclosure of possible long-term, late effects (e.g., radiation-induced malignancy, carotid artery damage). Park¹³ recently reported using the gamma knife with good success for a case of recurrent intraorbital JNA.

Chordoma

Chordoma is a locally aggressive malignancy that may arise from bone of the basisphenoid and erode through the bony skull base to appear through the sphenoid and into the nasopharynx. These tumors arise from notochord remnants and can present with cranial nerve deficits including hoarseness, swallowing difficulties, or diplopia. They may also present in asymptomatic patients when identified incidentally by CT or MRI of the head and neck. The definitive diagnosis of these tumors may be accomplished by transnasal endoscopic biopsy, but it is also frequently made at the time of surgery, which will require a team effort including a neurosurgeon and skull base surgeon. An anterior midline subfrontal approach, or more recently an expanded endonasal approach, may be employed for exposure. Cranial nerve deficits and even long tract deficits may ensue after surgery due to the need to work around the brainstem and vertebrobasilar system of vessels on the dorsal extent of these tumors. The use of postoperative radiotherapy is necessary in patients who do not have complete removal of these lesions due to the complicated anatomy and risk of neurologic or vascular trauma. Proton beam therapy is recommended.

Adenoid Cystic Carcinoma of the Nasopharynx

Adenocystic carcinoma of the sinonasal tract constitutes 20% of all adenoid cystic carcinomas of the head and neck. They, along with other tumors of salivary gland origin, arise from the minor salivary glands in this region. Those of the NP are not common but can be insidious and slow growing.¹⁴ The lesion can extend from the nasopharynx into the anterior skull base and can present as bilateral nasal lesions. In the latter, there is a need to differentiate this from simple bilateral nasal polyps. Patients with either condition may present with simple nasal obstruction with hyposmia. Other accompanying symptoms do not usually occur, unless palpable neck metastasis is detectable at presentation. Otitis media with effusion may exist if the eustachian tube is involved. These tumors have the propensity for perineural spread and thus MR imaging is important in the pretreatment evaluation. The primary treatment of such lesions is surgical resection. However, proximity of the nasopharynx to the sphenoid, and, hence, the internal carotid arteries and intracranial structures, plus their propensity for centrifugal spread along nerves, may preclude complete removal. Postoperative radiotherapy is important in local control of such lesions.

Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is unique in its epidemiologic pattern. It is common in certain ethnic groups, with the highest incidence in southern China, Hong Kong, and southeast Asia. The majority of patients with NPC are diagnosed with advanced disease. However, over the past 20 years, the survivals of these patients have improved.¹⁵ This has been attributed to the combined use of chemotherapy and radiation to treat the patients with advanced disease.¹⁶ Furthermore, with the advent of improved techniques in radiation, the side effects, which plagued long-term survivors in the past, may be reduced.^17,¹⁸ The strategy in the management of NPC is to find novel methods of early detection and develop improved techniques of effective primary treatment with the focus on reducing morbidity from the treatment. In this chapter we describe the epidemiology, etiology, pathology, clinical features, staging, treatment, and prognosis of NPC.

Epidemiology

The highest incidence of NPC is recorded in Guangzhou, China, where the age-adjusted incidence rate is reported to be more than 30 per 100,000.¹⁹ Hong Kong has a rate of 20.2 per 100,000 in males and 7.8 per 100,000 in females.¹⁵ Patients who are affected by NPC are ethnic Chinese with an ancestry from the southern part of China. In southern China the two main ethnic subgroups are the Cantonese and the Fujians. In Hong Kong the vast majority of the population is Cantonese. In Singapore the overall incidence in males from 1998 to 2002 was 10.8 per 100,000.²⁰ This lower rate may be in part accounted for by the demographics of Singapore, which unlike China, Hong Kong, and Taiwan, has a more heterogeneous population. The population in Singapore is approximately 70% Chinese, with the remaining major ethnic groups being Malays and Indians. The majority of the NPC patients in Singapore are Chinese (Fujians and Cantonese).²¹ The incidence of NPC in Singaporean male Chinese is 12.5 per 100,000. These incidence rates in southern China, Hong Kong, and southeast Asia are among the highest in the world and have remained stable for many years. However, in the most recent review of the latest trend in the incidence of NPC, both Singapore and Hong Kong have reported a significant decrease for the first time after many years of stable rates.¹⁵ Why there was a fall in incidence is unclear, but one theory advanced to account for this is the change in dietary habits.^22,²³ Other ethnic groups, with rates that are reported to be intermediate to high, include the Eskimos,^24,²⁵ Polynesians, and indigenous Mediterranean population.²⁶ NPC is not common in whites. In North America the highest incidences are seen in the ethnic Chinese who are first-generation immigrants.²³ Subsequent-generation immigrants have a lower incidence, although it is still higher than the other ethnic groups. Overall, these incidence rates are lower than those in southern China and southeast Asia. This pattern of decreasing incidence rates seen in emigrant Chinese is a well-known phenomenon. It is likely that with migration, there is over time a greater variation in the gene pool arising from factors such as intermarriage, although the adoption of different dietary habits cannot be discounted. The epidemiologic pattern indicates that NPC occurs commonly in Chinese. This will suggest the possibility of a genetic link or a shared habit such as dietary intake.

Etiology

Three main factors are believed to be associated with the development of NPC.²⁷ These are genetic and environmental factors, as well as EBV. The knowledge relating to these factors that are associated with NPC has been advanced over the past 20 years. However, we are still unable to assimilate the information in an orderly fashion to translate the knowledge into prevention, early detection, or markedly improved survivals. Nevertheless, the current school of thought among those involved in NPC research believes that this cancer is probably a result of interaction among the three main factors.

Genetic Factors and Nasopharyngeal Carcinoma

A large body of evidence indicates that genetic factors play a significant role in NPC. Family clusters with NPC are not uncommon. Ung and colleagues ²⁸ had reported that the risk of NPC in a first-degree family member could be as high as eight times. Reports from Hong Kong and Guangzhou have also estimated this risk to be as high as 20 times when compared with the general population. We had reported that 15.5% of all NPC patients have had a first-degree relative with NPC.²⁹ The majority of first-degree family members who are affected are usually siblings (70%) rather than parents and children (30%).²⁹ The mean duration between two siblings who are affected within a family is 5.3 years, whereas that between a parent and child is 25 years.²⁹ Experts also believe that the risk for a first-degree relative also developing NPC is higher if the index NPC patient is diagnosed at age younger than 40 years.³⁰ The presence of such family clusters may indeed be due to common genetic factors, but it can also be argued that shared environmental factors may play a role.

The association of HLA alleles with NPC was established in 1975.³¹ These alleles are the HLA class I alleles belonging to the HLA A, B, and D groups in chromosome 6. HLA A2, Bw46, B 17, Bw58, DR3, and DR9 have been consistently found to be significantly more prevalent in NPC patients in contrast to the general population.³¹^–³⁵ These haplotypes are associated with increased risks for NPC. Further refinements in establishing these haplotypes have been reported with the highest risks established consistently for patients with the haplotypes A2 and B46.^34,³⁶ It has also been found that multiple alleles confer protective effects. The evidence suggests it is likely that the tumor susceptibility gene has a recessive mode of inheritance because an NPC-linked gene with a dominant mode will not be associated with such wide allelic variations in protective effects.³⁷ It has also been established that most Chinese patients with NPC have the HLA-A0207 haplotype in contrast to the HLA-A0201 found in whites.³⁸ Microsatellite instability in the nearby region of the HLA loci has been described, suggesting the possibility of tumor susceptibility factors.³⁹ NPC patients may have alleles in these loci that may contain genes that contribute to the oncogenesis of normal nasopharynx cells. However, linkage analysis has shown that the tumor susceptibility gene is not likely to be at the position of the high-risk A2 B46 haplotypes.

Chromosome changes that have been described include deletions in chromosomes 3, 9, and 11.⁴⁰^–⁴³ The significance of these chromosomal changes is the implied loss of function of known specific factors: for example, chromosome 9p21 region codes for known cell cycle regulators such as p15 and p16. The protein p16 has been reported to be inactivated in NPC patients.^44,⁴⁵ Other chromosomal changes have been sporadically reported. Each of these genetic deletions has also been associated with an implied tumor suppressor gene. Novel markers have also been reported to suggest the possibility of other tumor suppressor gene candidates.⁴⁶ Despite this wealth of information, it is difficult to determine if these changes are downstream events rather than early changes. What will be helpful will be genome-wide scans of NPC tumor samples and normal tissues, as well as using techniques such as comparative genomic hybridization to narrow in on the true early changes.

Environmental Factors and Nasopharyngeal Carcinoma

The most common environmental factor associated with NPC is diet. It has been suggested that certain diets high in preservatives are associated with NPC. These include salted fish, eggs, and vegetables.⁴⁷^–⁵¹ The origin of these associations is traced to the epidemiologic studies performed on a group of high-incidence NPC patients, the “boat people” of Hong Kong. These people had originated from a common region in China many years ago and had settled into a life based largely on living in boats. The diets are necessarily based on preserving the food from the sea (e.g., salted fish). Subsequently large epidemiologic studies have suggested similar findings, too.⁵² It is believed that the risk is associated with early exposure or during weaning period.^50,⁵³ The carcinogen believed to be the inciting factor is nitrosamines. Other environmental causes that have been thought to be associated include chemical fumes and wood dust.⁵⁴ Smoking is not an associated factor unlike squamous cell carcinoma of the aerodigestive tract. However, it is always difficult to attribute food alone as the factor that leads to oncogenesis because many confounding factors are also often present.

Epstein-Barr Virus and Nasopharyngeal Carcinoma

EBV is a ubiquitous virus. The vast majority of the population in the world have been infected with EBV. It is a herpes virus, with a central core of DNA and an envelope known as the capsid. Infection with the virus occurs in early childhood or as young adolescents. Those infected in early childhood tend to be asymptomatic, whereas young adolescents will be symptomatic, often resulting in a clinical syndrome that is consistent with infectious mononucleosis. Once a person is infected with EBV, he or she develops immunity. However, EBV is present for the remaining life of the person within specific circulating B lymphocytes or shed through saliva. The latter route is believed to account for the horizontal transmission typical of this infection.

The IgM and IgG class of antibodies to antigens on the EBV are raised in acute and convalescent phases of infection. The antigens on the EBV are either the nuclear core early antigen (Ea) or the viral capsid antigen (VCA). Hence in the majority of any population, the IgG VCA and Ea will be raised. In NPC, however, the IgA VCA and Ea are raised.⁵⁵ This is used as a marker, with laboratories using immunofluorescence to detect these antibodies. The sensitivity and specificity of these two antibodies are high.

EBV antigens are also found on NPC cells. EBV expresses both lytic and nuclear antigens. Lytic antigens include latent membrane proteins 1, 2, and 3 (LMP-1, -2, -3). Nuclear antigens include the Epstein-Barr nuclear antigens 1 to 6 (EBNA-1 to 6). In NPC, EBNA-1 is always expressed, whereas LMP-1 is consistently expressed in significant levels. Both of these are latent proteins. EBNA-1 is believed to be responsible for maintaining the viral episomes in the tumor cells. LMP-1 has been shown to induce cellular growth by inducing epithelial hyperplasia and altered keratin gene expression.^56,⁵⁷ It reduces cytokeratin expression and inhibits squamous cell differentiation. It has been shown to up-regulate epidermal growth factor receptors. NPC also expresses Epstein-Barr encoded ribonucleic acids (EBERs) within the cytoplasm. These EBV antigens and EBERs are not present in normal nasopharynx cells.

The vast majority of the people infected with EBV do not develop NPC. In addition, the expression of latent proteins EBNA-1 and LMP-1 are not seen in normal nasopharynx cells. Therefore it is believed that EBV is not the initiating event in NPC and that its role in the development of NPC is a result of latent infection of the genetically susceptible and environmentally transformed epithelial cells of the nasopharynx.

Clinical Presentation

Virtually all NPC patients are symptomatic at the time of diagnosis. Less than 1% of NPC patients are asymptomatic and diagnosed incidentally. This may occur because of imaging performed for some other indications or an abnormal EBV serology is detected because of health screening. Three quarters of NPC patients are males. More than 80% are diagnosed between 30 and 60 years of age with more than 50% diagnosed between 30 and 50 years. The proportion of NPC patients diagnosed at a relatively young age has a significant socioeconomic impact on these patients and their families. Approximately 15% to 20% of NPC patients will also report a first-degree relative who was similarly affected.²⁹

The most common presentation in NPC is the presence of a neck lump (Fig. 99-3). About 60% of our patients presented with a neck lump. These neck lumps are due to metastatic disease in the cervical lymph nodes. It is not uncommon for the enlarged nodes to be matted. The nodal metastasis is usually located in the superior aspect of the neck (Fig. 99-4), corresponding to high level V and level II. The first echelon of nodal metastasis is in the retropharyngeal nodes. These retropharyngeal nodes may be so bulky that they can be visualized on physical examination as nodular swellings in the posterior pharyngeal wall. Occasionally NPC patients may present with enlarged level III nodes (Fig. 99-5) and less commonly level IV. Enlarged submental lymph nodes at the time of diagnosis are rare and not encountered in our series. Some patients may present with a parotid swelling due to metastatic parotid lymph nodes, although these are also uncommon. Metastatic NPC nodes are usually firm. If left for a significant duration of time, a node may enlarge to such an extent that central necrosis occurs, followed by abscess formation. In endemic regions such as China, Hong Kong, and Singapore, a Chinese adult male presenting with large bulky bilateral nodes is usually either NPC or lymphoma. Although 60% of NPC patients present with a neck lump due to nodal metastasis, at least 80% of NPC will be classified as N1. This is because even in the NPC patients without palpable nodes, imaging will show metastatic nodes in at least another 20%.

Figure 99-3. Clinical presentation of nasopharyngeal carcinoma patients.

Figure 99-4. Bulky bilateral cervical lymph nodes in levels II, III, IV, and V.

Figure 99-5. Right level III nodes in nasopharyngeal carcinoma.

The next most common presenting symptom or sign is that of blood-stained saliva or sputum (41.3%). The patient usually reports a persistent production of blood in the saliva without any other symptom. Epistaxis is not common in NPC because the tumor is located in the postnasal space. The natural tendency is for blood from the tumor to gravitate and hence mix with saliva or sputum. Indeed, epistaxis was reported in only 23.1% of our patients. Frank epistaxis, however, is not typical of NPC. Deafness was more commonly reported (30.2%). This is due to otitis media with effusion, which is believed to be secondary to eustachian tube dysfunction. The hearing loss is therefore conductive in nature and impedance tympanometry corresponds to the type b pattern. Other presenting complaints include nasal obstruction and unilateral tinnitus. Persistent headaches are also common in patients with intracranial extension or clival erosion. Cranial nerve palsies are encountered in about 10% of the patients. The most common nerves affected in descending order of frequency are the sixth, fifth, twelfth, and ninth/tenth nerves. In the endemic regions, isolated sixth nerve palsy, caused by cephalad extension through the foramen lacerum, is an indication to have the nasopharynx examined and the skull base imaged for possible NPC. Some of these patients with cranial nerve palsies at the time of diagnosis may show resolution following treatment with radiation. The most likely explanation for this is that the tumor had caused surrounding edema near the cranial nerves, resulting in deficits such as diplopia. Also, some syndromes are associated with NPC. Patients with dermatomyositis are at high risk for developing this cancer and should be screened regularly because approximately 10% of these patients can be at risk for developing the cancer.

Examination of the nasopharynx in NPC patients usually reveals an exophytic mass that may occupy the whole postnasal space (Fig. 99-6). This may be ulcerated and contact bleeding is usually encountered. However, in about 10% of NPC patients the lesion is submucosal. In these cases the mucosal surface of the nasopharynx is normal in appearance. Occasionally, only a slight irregular mucosa is detected. This may consist of a small area of heaped-up mucosa or just an erythematous change, both of which could be passed off as normal. The significance of submucosal NPC in a patient is unclear, although a review of our patients suggested that this group might have more aggressive disease.

Figure 99-6. Nasopharyngeal mass occupying the whole of the post-nasal space.

In the endemic regions the axioms are that a Chinese adult male presenting with a neck lump needs to be investigated for NPC and that a Chinese adult male presenting with a neck lump, blood-stained sputum, and unilateral deafness has NPC until proven otherwise.

Diagnosis of Nasopharyngeal Carcinoma

The gold standard in the diagnosis of NPC is histologic confirmation by nasopharynx biopsy. This is performed transnasally under local anesthesia using rigid endoscopy. The biopsy of the tumor is thereby performed under direct visualization. In rare instances patients suspected of NPC will have the biopsy performed under general anesthesia. An example of such a situation is when the fine-needle aspirate cytology of a metastatic node confirms undifferentiated carcinoma but the nasopharyngeal biopsies remain negative for malignancy. In these patients a deep nasopharynx biopsy under general anesthesia including Rosenmüller’s fossa and the vault of the nasopharynx is indicated. A nasopharyngeal biopsy may also be performed under general anesthesia if previous biopsies in a patient highly suspected of having NPC were negative and a diagnosis is imperative before treatment is instituted.

The classification of NPC ^58,⁵⁹ is shown in Table 99-3. The vast majority of patients with NPC—at least 90%—in the endemic region have a histologic pattern termed as nonkeratinizing undifferentiated carcinoma (type 2b or type III). Squamous cell carcinoma is uncommon in endemic regions.

Table 99-3 World Health Organization (WHO) Classification of Nasopharyngeal Carcinoma

Type 1 (I)	Squamous cell carcinoma
Type 2a (II)	Keratinizing undifferentiated carcinoma
Type 2b (III)	Nonkeratinizing undifferentiated carcinoma

Types 1, 2a, and 2b correspond to WHO types I, II, and III, respectively, and are used interchangeably.

Staging of Nasopharyngeal Carcinoma

The TNM staging system is shown in Table 99-2. This staging system is based on clinical and radiologic examination. In general, two thirds of NPC patients are classified as stage III or IV at the time of diagnosis. Only about 10% of newly diagnosed NPC patients have stage I disease.

Computed Tomography Scan/Magnetic Resonance Imaging

CT scan had been for many years the essential staging investigation for assessing the primary tumor, as well as regional disease. The soft tissue of the nasopharynx is shown well and CT is particularly useful in delineating clival and skull base erosion.⁶⁰ It has been the cornerstone of radiologic staging of NPC for many years. However, MRI has been used increasingly in many centers. This is because of the superior definition afforded by MRI in detecting soft tissue changes and intracranial involvement. It is not uncommon for MRI to show features consistent with disease that is not shown on a CT scan.⁶¹

Other Staging Investigations

These include chest radiograph, ultrasound of liver, and bone scans. Alternatively, CT scans of the lungs and liver may be performed. The main purpose is to locate distant metastasis. Of these the highest pick-up rate appears to be the bone scan. This is consistent with the skeleton being the most common distant site of metastasis in NPC. In the past 5 years, PET scans have come into more prominent use. Much of the information in the literature on the use of PET CT in NPC is with regard to detecting local and regional recurrences or residual disease, as well as in the detection of distant metastasis.⁶² It is a useful imaging tool for patients with indeterminate CT or MRI abnormalities that may represent local, regional, or distant recurrences. Enhancement will suggest a higher possibility of recurrences in such indeterminate imaging abnormalities. However, caution has to be advised in the interpretation of current data on PET CT, especially as a tool for staging newly diagnosed NPC patients. The main criticisms of these reports have been the lack of a standardized methodology to determine the histopathology of the tissues that have high uptake of agents like 18-fluoro-2-deoxyglucose (FDG). Oftentimes these reports will include any form of enhancement on PET CT to represent metastasis without confirmation of the pathology. Inflammatory reactions and radiation necrosis, without malignancy, can lead to high uptake.⁶³ Literature on the efficacy and cost-effectiveness of using PET CT as a staging tool in newly diagnosed NPC patients to assess the primary tumor and regional metastasis is scant.

Other Investigations

An audiogram and tympanogram are performed to obtain a baseline level. This is crucial as the patient undergoes radiation that might worsen the hearing. Indeed, with increasing use of combined chemotherapy and radiation, certain chemotherapy agents like cisplatin might give rise to idiosyncratic sensorineural hearing loss.

EBV serology titers are performed. These include IgA VCA (viral capsid antigen) and IgA Ea. The former is highly sensitive and the latter specific. The main usefulness of this test is in assisting diagnosis of new NPC patients. In particular, a negative IgA Ea likely will indicate that the patient has no NPC. It has to be emphasized that the diagnosis of NPC is histologic proof on biopsy of the nasopharynx, therefore, these titers are not a substitute for diagnosis.

Treatment of Nasopharyngeal Carcinoma

Pretreatment Planning

The treatment of a newly diagnosed NPC patient is best served by a multidisciplinary team of head and neck surgeon, radiation oncologist, medical oncologist, pathologist, and radiologist. This includes audiological investigations and dental clearance. In addition, if chemotherapy is part of the treatment, hematologic and biochemical investigations are performed including creatinine clearance. Dental clearance involves ensuring that oral hygiene is maintained because the oral cavity will inevitably be in the radiation field. The decaying, unhealthy tooth is extracted to prevent osteomyelitis from setting in during the postradiation period. However, there is no evidence that prophylactic extraction will reduce osteoradionecrosis in patients undergoing radiation of the head and neck.^64,⁶⁵ Allowing such prophylactic extractions will potentially delay treatment and increase costs for the patient.

Treatment

NPC is treated by radiation. In general, patients with stage I and II NPC are treated by radiation only, whereas stage III and stage IV patients are treated by concurrent chemotherapy and radiation. In addition, there is evidence that patients diagnosed with stage IV NPC with locally advanced disease may be better controlled by neoadjuvant cisplatin followed by chemoradiation.⁶⁶ Radiation is administered by linear accelerator, and the dose reaches 60 to 70 Gy in the nasopharynx and both necks. This is given daily at up to 2 Gy in 35 to 40 fractions. The main side effects include mucositis and xerostomia. The former may take up to 3 months after the last day of treatment to heal. Xerostomia affects every patient and can be permanent, although the younger patients show much better improvement with time. Other side effects include sinusitis, crusting, and blood-stained nasal discharge. Otitis media with effusion can develop or be worsened with radiation. Sensorineural hearing loss has been attributed to radiation, although the cochlea is resistant and it has been shown that this may be due to other causes such as infiltration by tumor cells.⁶⁷ Trismus is particularly more severe in those treated for skull base involvement. It may take several years for trismus to develop. Late side effects include cranial nerve palsies, which may give rise to difficulties in distinguishing trismus from recurrent disease. The most common cranial nerve to be affected postradiation, other than the cochlear-vestibular nerve, is the hypoglossal nerve. In the past 5 to 10 years, data have emerged to confirm the efficacy of using intensity-modulated radiation therapy (IMRT) to treat NPC patients. This has resulted in control rates similar to conventional radiation.⁶⁸ It has also resulted in better treatment outcomes, especially xerostomia¹⁷ and skin burns.

The use of concurrent chemotherapy and radiation to effectively treat local and regionally advanced NPC patients was reported by Al-Sarraf.⁶⁹ There is compelling evidence for using concurrent chemotherapy and radiation in advanced stage NPC.⁷⁰ The concurrent chemotherapy regimen includes cisplatin and 5-fluorouracil (5-FU). We had found this to give good local and regional control, but it increases both acute and late toxicities. Two of the significant toxicities associated with cisplatin are idiosyncratic sensorineural hearing loss and peripheral neuropathy. To avoid these toxicities, other agents such as Taxol combined with 5-FU and hydroxyurea are alternatives that can be considered.⁷¹

Surgery is reserved for recurrent local and regional disease. Although recurrent local disease may be treated by brachytherapy, localized recurrent tumor may be considered for resection. The three contraindicating factors are internal carotid artery involvement, skull base erosion, and intracranial involvement. The surgical approaches use either one or a combination of transnasal, transmaxillary, midfacial degloving, or transpalatal approach. Regional disease in general is dealt with by neck dissection. This will usually take the form of a radical neck dissection or a modified neck dissection. Usually the spinal accessory nerve and the sternocleidomastoid muscle are not spared and the internal jugular vein is not commonly preserved. If brachytherapy is considered, a pectoralis major myocutaneous flap is harvested to reduce the likelihood of cutaneous necrosis and to protect the carotid artery. A second course of radiation to treat regional recurrences may be considered, albeit with its attendant risks.

Surgical Treatment of Nasopharyngeal Carcinoma

The indications for surgical treatment of NPC are currently for local and regional recurrences.

Surgical Treatment of Local Recurrences

Approximately 5% to 10% of all newly diagnosed NPC patients will develop local recurrences. Up to 50% of these patients will be amenable to salvage by surgery. The remaining 50% are usually too far advanced for surgical intervention. This may be due to intracranial invasion or carotid artery encasement. In some patients this may be due to concomitant distant metastasis. The surgical treatment of locally recurrent or residual NPC is nasopharyngectomy. In those who can be salvaged surgically, the recurrent T (rT) classification is often rT1 to rT3.⁷² The success of surgical intervention in recurrent NPC is strongly correlated with T classification. The best results are obtained with rT1 patients. Patients with rT3 recurrences are considered by some to be not salvageable. In particular if there is clival erosion, some surgeons consider this to be a situation in which complete tumor extirpation is not possible. Hence careful and diligent follow-up coupled with biopsies of any suspicious areas of the nasopharynx are crucial factors that allow for early detection of recurrences or residual tumor.

The local recurrences may be dealt with by either another course of radiation or by surgery. Treatment by a second dose of radiation will carry with it the risk of complications such as transverse myelitis, leading to weakness and numbness of the limbs. The risks of temporal lobe necrosis, severe trismus, severe sensorineural hearing loss, choanal stenosis, palatal dysfunction, and lower cranial nerve palsies are increased by a second course of radiation. These effects may be reduced by the use of IMRT. Radiation is generally reserved for patients with a large recurrence such as when there is skull base erosion or intracranial extension or when tumor tissue surrounds the carotid arteries.

All patients with local recurrences are assessed with a CT scan or MRI. The thorax, liver, and bones are also assessed for possible metastasis. In the past 3 years, the use of PET scan has been found to be a useful tool for staging recurrent patients. The depth of invasion of the local recurrences can be assessed by a PET CT and allows us to plan our resection approaches.

When faced with a local recurrence that can be salvaged, the head and neck surgeon will have to decide the surgical approach. The factors that govern the chosen approach and access to tumor resection are usually the surgeon’s preference and expertise, as well as the extent of the tumor recurrence. Many surgical approaches have been reported. This is a testament to the difficult access to the nasopharynx. The anterior-posterior distance from the nasal vestibule to the nasopharynx is about 10 cm, and open approaches mean that the surgeon is operating through a narrow and deep window. In addition, the internal carotid artery lies just posterior and lateral to the eustachian tube cushion. These considerations, as well as possible intracranial extension and operating in a previously radiated or chemoradiated field, are the main issues in nasopharyngectomy. All the approaches give adequate visualization.

Endoscopic Approach

This approach is clearly possible for small recurrences.⁷³ It is best limited to recurrences that are centrally placed on the posterior wall of the nasopharynx (Fig. 99-7). Recurrences that extend out to the pterygopalatine fossa, the soft palate, and beyond may be too large for endoscopic nasopharyngectomy, although experienced endoscopic skull base surgeons may not necessarily consider this an absolute contraindication. The success of this approach lies in being able to choose the patients well. Besides proper instruments, the key to being able to have excellent visualization and control of the surgical approach lies in resection of the posterior nasal septum. Depending on the site and size of the recurrences, the medial maxillary wall may have to be resected. It is also important to remember to resect adequately the roof of the nasopharynx and drilling down the vomer. The depth of resection should include at least the prevertebral muscles. Once the resection and frozen sections are completed, the wound in the resected nasopharynx is packed with antiseptic gauze and left for at least 1 week.

Figure 99-7. Magnetic resonance imaging showing a small recurrence on the left side of the nasopharynx.

Lateral Rhinotomy and Medial Maxillectomy Approach

This approach can be used for tumors slightly larger than those indicated for endoscopic approach. It may be used for recurrent or residual tumors limited to the nasopharynx or with extension out to the pterygopalatine fossa. It may also be combined with a transoral approach to resect tumors with oropharyngeal extension. Alternatively it may be extended for tumors that invade the orbit. After completion of the lateral rhinotomy, the medial wall of the maxilla is removed as far out laterally as possible while preserving the infraorbital nerve. The nasolacrimal duct is marsupialized. Resecting the inferior half of the middle turbinate will also help with surgical access. The key to visualizing the entire nasopharynx well is in resecting the posterior nasal septum (Fig. 99-8). The surgical access is adequate but not as wide as the view afforded by the maxillary swing approach. It does not require any palatal split. The wound almost always heals well and cosmetically it is not an issue with the patient. Trismus is uncommon and palatal fistula does not exist. However, postoperatively these patients often complain of headaches, which usually take about a month to settle. The problem is the prolonged period of nasal clearance required to rid the crusts that develop. Exposed bone may lead to localized osteoradionecrosis.

Figure 99-8. Lateral rhinotomy approach with resection of medial maxilla and posterior nasal septum completed, exposing the whole nasopharynx.

Maxillary Swing

This is an elegant operation described by Wei in 1991.⁷⁴ It provides a wide access for resecting nasopharyngeal tumors. The procedure involves a Weber-Ferguson incision. The maxilla is exposed, and osteotomies are made such that the maxilla will be rotated laterally but the skin and subcutaneous tissues continue to provide the blood supply to the maxilla because it is not dissected off the anterior wall of the bone (Fig. 99-9). The medial maxillary wall is removed. This is an approach that provides excellent access to remove tumors that have infiltrated the pterygopalatine space. It is also argued that the internal carotid artery may be controlled should there be tumor extension laterally. It does, however, require a palatal split and this can lead to palatal fistulas.

Figure 99-9. Left maxillary swing approach. The skin, subcutaneous tissue, left maxilla, and hard palate are rotated laterally en bloc to expose the nasopharynx.

Other Surgical Approaches

Lateral infratemporal and Le Fort 1 drop-down approaches have been described. These are not common approaches used to perform nasopharyngectomy for recurrent NPC and are used by surgeons familiar and comfortable with the respective surgical approaches.

Surgical Treatment of Regional Recurrences

Regional recurrences or residual regional disease occur in about 10% of patients. These patients commonly also have local disease or distant metastasis. Which factors are associated with regional recurrences is unclear. It is also difficult to detect regional recurrences because it may be difficult to elicit signs on palpation of the fibrotic neck after radiation. In fact, it is not uncommon to be able to palpate an obvious mass in the neck and yet the fine-needle aspirate cytology to be negative. A CT scan or MRI of the neck is useful. Once regional recurrence is detected, metastatic workup should be performed and the primary site should be cleared before setting off on a treatment plan for the patient.

The treatment of regional recurrence and residual regional disease is by neck dissection (Fig. 99-10). The evidence clearly indicates that a radical neck dissection should be performed.⁷⁵ This is because regional disease is often along the chain of nodes of the upper internal jugular vein, as well as the accessory nerve. Furthermore, the metastatic node, unlike similar nodes in squamous cell carcinoma of the head and neck, tends to have a propensity for extracapsular spread. Hence the internal jugular vein, accessory nerve, and sternocleidomastoid muscle should be sacrificed. In fact, it is not uncommon to perform an extended radical neck dissection involving resection of the skin. Levels I to V nodes are removed. Although retropharyngeal nodes are said to be the first echelon of nodes in NPC, these do not need to be removed because oftentimes the radiation will have encompassed the retropharyngeal nodes. The main problems with performing a radical neck dissection for recurrent NPC are related to bleeding and wound infection, because a good proportion of these patients will have had radiation with or without chemotherapy. The risk of carotid blowout is higher if the wound breaks down and the carotids are exposed. This may be prevented by the use of a pedicled flap such as the pectoralis major (see Fig. 99-10) or latissimus dorsi flap. The effectiveness of the treatment is good, with overall survival after radical neck dissection reaching above 50%.⁷⁶ Regional control is often achieved and further recurrences are often at distant sites.

Figure 99-10. Left radical neck dissection and left myocutaneous pedicled pectoralis major flap to cover skin defect, as well as protect the carotid artery.

Prognosis

The poor prognostic factor in NPC is stage IV disease. In particular, N3 disease is associated with poorer survival and higher rates of distant metastasis. Patients with stage III or IV disease who have had concurrent chemoradiation have a 5-year overall survival rate of about 70%.⁷⁷ Stage I and II NPC patients treated by radiation alone have 5-year overall survival rates of 80% and higher. The use of chemoradiation for stage III and IV patients has seen improvements in local and regional control, but distant metastasis remains the main failure leading to death in NPC patients.⁷⁸

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Benign and Malignant Tumors of the Nasopharynx

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