Nasopharyngeal Carcinoma
Summary
Nasopharyngeal carcinoma (NPC) is common among southern Chinese and is closely associated with the Epstein-Barr virus (EBV). Symptoms and signs are trivial in the early stages, and many patients are diagnosed with advanced-stage disease. Testing EBV DNA is useful in high-risk patients, with the goal to diagnose the disease early. Imaging studies and positron emission tomography (PET) scans provide information on the extent of the disease, with confirmation of the disease through endoscopic examination and biopsy. The primary treatment modality for NPC is radiotherapy for early-stage disease and concomitant chemoradiation for advanced disease. The applications of intensity- modulated radiotherapy (IMRT) have improved control of the disease, along with reduction of long-term side effects. The early detection of residual or recurring tumor in the nasopharynx and the neck has improved the results of salvage treatment. The outcome of salvage with surgery for the disease both in the nasopharynx and in the neck has improved through the choice of appropriate surgical procedures.
Epidemiology
NPC is a squamous cell carcinoma arising from the epithelial lining of the nasopharynx. It is a distinct form of head and neck cancer that differs from other malignancies of the upper aerodigestive tract in etiology, epidemiology, pathology, clinical presentation, and response to treatment. In most countries, NPC is an uncommon neoplasm, with an incidence < 1 per 100,000 outside of endemic areas. In North America, NPC accounts for ~0.2% of all malignancies, with ~1 to 2 cases per 100,000 men and about one-third of that women.
Note
The most common histology of NPC in endemic regions is undifferentiated squamous cell carcinoma.
This malignancy is endemic in southern China, especially the provinces of Guangdong and Guangxi. A particularly high incidence of NPC is observed in Hong Kong, making it the most common type of head and neck cancer. The reported incidence of NPC for 2007 among men and women in Hong Kong was 17.8 per 100,000 and 6.7 per 100,000, respectively.1 There is also a relatively high incidence among inhabitants of northern Africa and the Inuits of Alaska; it is, however, an uncommon disease in most other countries. The incidence of NPC remains high among those Chinese who have emigrated to other parts of the world but is lower among second-generation Chinese who were born in North America.2 This suggests that ethnic, environmental, and genetic factors has some etiologic role in this malignancy. Compared with other head and neck cancers, NPC affects a younger age group, with the peak incidence occurring in the fourth to fifth decades. Over the past decade, a slow but definite decline in the incidence of NPC has been observed in Hong Kong, Taiwan, and Singapore.
Pathology
In the past, there were deliberations on the origin of undifferentiated NPC. Electron microscopy studies have determined that these tumor cells are of squamous origin with varying degrees of differentiation.
In 1978 the World Health Organization (WHO) grouped NPC into three histologic types. Type I is typical keratinizing squamous cell carcinomas, similar to those found in the upper aerodigestive tract. Type II is nonkeratinizing squamous carcinomas, and type III, undifferentiated carcinomas.3 In North America, tumor histology in 25% of patients is type I, 12% type II, and 63% type III. The corresponding histologic distribution in southern Chinese patients is 2, 3, and 95%, respectively. An alternative classification categorized NPC as two histologic types, namely, squamous cell carcinomas (SCCs) and undifferentiated carcinomas of the nasopharyngeal type (UCNTs).4 This second classification has been found to correlate with EBV serology tests. Those patients with SCCs have a lower EBV titer, whereas those with UCNTs have elevated titers. This classification is applicable for epidemiologic research and has been shown to have a prognostic bearing. Undifferentiated carcinomas have a higher local tumor control rate with therapy and a higher incidence of distant metastasis.5
Tips and Tricks
Checking the serum EBV DNA copies is a reliable way to diagnose NPC.
Etiology
NPC is commonly associated with the consumption of salted fish, a type of food that was commonly consumed by southern Chinese in the past. Other factors associated with NPC are cigarette smoke, occupational exposure to dusts, herbal medicine, formaldehyde exposure, and the use of wood as a fuel source in cooking. EBV infection is clearly associated with NPC, and the virus is present in the tumor cells of almost all cases of undifferentiated carcinomas. As a result, EBV DNA can be detected in the plasma of NPC patients, and quantitative assay of EBV DNA can be used to detect recurrence, monitor treatment outcome, and may serve as an independent factor to predict survival. Among southern Chinese, those with human leukocyte antigen (HLA) A2-BW46 and AW19-B17 have a high risk of developing NPC. A family history of NPC is another risk factor, and the estimated risk was 20- to 30-fold higher among the first-degree relatives of patients with NPC. This suggests that genetic, ethnic, and environmental factors may all be responsible in the etiology of this malignancy.
Diagnosis
Clinical
The presenting symptoms of nasopharyngeal cancer can be categorized into four groups ( Table 44.1 ). First are those related to the presence of tumor mass in the nasopharynx; these nasal symptoms include epistaxis, nasal obstruction, and discharge. Second, as the tumor may lead to dysfunction of the eustachian tube, the patient may have otologic symptoms, such as deafness and tinnitus. Third are symptoms related to superior extension of the tumor leading to skull base erosion and affecting the cranial nerve palsies, commonly cranial nerves (CN) V and VI; the patient may experience headache, diplopia, and facial numbness. Fourth, related to metastases to cervical lymph nodes, the patient presents with a painless neck mass that is usually in the upper neck. Other symptoms of malignancy, such as anorexia, malaise, and weight loss, are uncommon, and when present, distant spread should be suspected.6
From a large retrospective analysis of the presenting symptoms of 4768 patients, the most common presenting symptoms were neck mass (75.8%), followed by nasal symptoms (73.4%), ear symptoms (62.4%), headache (34.8%), diplopia (10.7%), facial numbness (7.6%), weight loss (6.9%), and trismus (3%). The most common signs present at diagnosis were enlarged neck node (74.5%) and cranial nerve palsy (20%).7 The presenting symptoms in young patients were similar to those in adults. As many of these symptoms are nonspecific and frequently ignored by the patient, the diagnosis of NPC is made frequently when the disease is in advanced stages.
Where patients present with symptoms suggestive of NPC, they should be examined clinically for physical signs. Imaging studies may be performed to evaluate the nasopharynx and its surrounding tissue. Positive serologic test for EBV or elevated copies of EBV DNA in the serum would justify an endoscopic examination and even a biopsy from the nasopharynx. The nasopharynx can be adequately examined with an endoscope. Both rigid and flexible endoscopes can be used for this purpose. The former gives a better view of the tumor ( Fig. 44.1 ), whereas the latter allows detailed visualization of the whole nasopharynx with the scope inserted once. Some flexible endoscopes have a suction channel through which a biopsy forceps can be inserted and directed to the desired biopsy site.
Serology
Epstein-Barr Virus Titer
Because of the association of NPC with EBV, EBV serology has been used for population screening. In the early 1980s in a study conducted in Wuzhou (Guangxi Province, China), 1136 individuals identified with positive immunoglobulin A (IgA) versus viral capsid antigen (VCA) were followed up regularly for 4 years. During this follow-up period, 35 NPC cases were detected, most of which (91.5%) were diagnosed at an early stage. The annual detection rate of NPC for this group was 31.7 times higher than for the population as a whole.8 The predictive value of EBV serology for NPC was also reported in a recent study. The EBV serology of 9699 study subjects was cross-checked against the cancer and death registries over a 15-year period in Taiwan. It was found that with longer follow-up, a larger difference in the cumulative incidence of NPC between seropositive and seronegative subjects was seen.9
Epstein-Barr Virus DNA
As most NPC harbors the EBV, on cell lysis the EBV DNA is released into the blood. This circulating free EBV DNA can now be detected by polymerase chain reaction (PCR) in patients with NPC.10 During the initial phase of radiotherapy, there was an increased number of copies of EBV DNA found in the blood; this suggests that the viral DNA was released into the circulation after cell death. The detection of EBV DNA has been increasingly used for the diagnosis of NPC. For the detection of distant metastases, the use of serum EBV DNA has been shown to be more sensitive and reliable than other options. The change of quantities of EBV DNA copies detected before and after treatment is significantly related to the overall and disease-free survival rates.11 When EBV DNA was employed together with IgA against VCA of EPV for diagnosis, an increase in the sensitivity of early diagnosis of NPC has been reported.
Imaging Studies
Cross-sectional imaging has revolutionized the management of NPC, as the extent of the disease, especially deep extension, can be accurately determined. This enables radiotherapy treatment to be administered more accurately onto tumor and spare adjacent normal tissues. Thus, the damage of normal structures is reduced, and the tumor control incidence is improved.
Computed tomography (CT) can identify the paranasopharyngeal extension of the tumor, its perineural spread through the skull base to involve the cavernous sinus, and more importantly, its infiltration to surrounding bony structures ( Fig. 44.2 ).
Magnetic resonance imaging (MRI), although limited in its effectiveness for the evaluation of bony involvement, is better than CT for the assessment of soft tissues in the nasopharynx ( Fig. 44.3 ) and for differentiating tumor from inflammation. MRI is more sensitive at evaluating retropharyngeal cervical nodal metastases12 and bone marrow infiltration ( Fig. 44.4 ). It can also demonstrate tissue involvement by tumor extension in both the axial and coronal planes ( Figs. 44.5 and 44.6 ). Usually both MRI and CT have to be performed when the status of the base of the skull needs to be assessed.
The diagnosis of distant metastases with imaging is less rewarding with conventional methods including bone scan. The role of PET in the detection of distant metastases in NPC and other malignancies has been established13 ( Fig. 44.7 ). It is also more sensitive than CT and MRI in detecting residual and recurrent malignant disease in the nasopharynx.
Tips and Tricks
PET is more sensitive than CT or MRI in the diagnosis of residual or recurrent NPC after radiation or chemoradiation.
Staging
The American Joint Cancer Committee/Union for International Cancer Control (AJCC/UICC) system for staging NPC is used in Europe and America, while the Ho system is frequently used in Asia.14 In 1997, a revised AJCC/UICC staging system was published.15 For the latest staging revision, see Table 44.2. This staging system incorporates the experiences of various centers around the world. It takes into account several prognostic factors, such as skull base erosion, involvement of cranial nerves, primary tumor extension to the paranasopharyngeal space,16 and the level and size of the cervical nodes.
The new T3 stage covers tumors that extend to the skull base or other paranasal sinuses. The new T4 stage includes tumors that extend into the infratemporal fossa, orbit, hypopharynx, and cranium or involve the cranial nerves. For cervical nodal staging, N1 under the new system refers to unilateral nodal involvement, N2 bilateral nodal disease includes tumors that have not reached N3 status. N3 refers to lymph nodes > 6 cm (N3a) or nodes that extend to the supraclavicular fossa (N3b).17 The new staging system categorizes patients more precisely and gives a better correlation with survival prediction.
Treatment
Radiotherapy
Radiotherapy is the mainstay of treatment for locoregionally confined NPC. Due the highly aggressive and infiltrative nature of primary tumor and its proximity to many critical structures, early spread to paranasopharyngeal and cervical lymphatics, and good response to radiotherapy, surgery is not used as the primary treatment of NPC. The outcome of patients who received radiotherapy for NPC has improved significantly, from a gloomy 5-year survival rate of 25% in the 1950s, to 50% in the 1970s and 1980s, and to 75% in the 1990s. Factors contributing to improved outcome after radiotherapy include earlier disease at presentation, introduction of new and advanced imaging technique, and improved radiotherapy technique with the use of the megavoltage linear accelerator.
In treating NPC, a large target volume is needed to cover the primary tumor and potential sites of spread. This volume includes not only the nasopharynx but also the paranasopharyngeal space, oropharynx, base of skull, sphenoid sinus, posterior ethmoid sinus, and posterior half of the maxillary antrum. Extension of treatment field to cover the cavernous sinus and cranial fossa may be required in advanced disease. Cervical nodal irradiation is mandatory even in node-negative patients due to the high incidence of nodal involvement. Using high megavoltage radiation, a dose of 65 to 70 Gy is normally given to the primary tumor, 65 to 70 Gy to the involved neck nodes, and 50 to 60 Gy to the node-negative neck ( Fig. 44.8 ).
IMRT is now recommended as the radiation technique of choice for radical treatment of NPC. This is a complicated technique that allows the delivery of highly conformed dose distribution to the target and critical structures through optimization of intensity of multiple beams. The treatment design is based on the computer algorithm to calculate the best result that matches the user-defined parameters in a process called inverse planning. The advantages of IMRT include the ability to deliver highly conformal radiotherapy to irregular targets, such as the generation of concave or U-shaped dose distribution, which is very useful if the target volume wraps around critical structures, such as brainstem and spinal cord, as in NPC. The primary and regional lymphatics can be treated in one volume, delivering a simultaneous integrated boost in the same setting ( Fig. 44.9 ). IMRT has already achieved excellent local control rates for newly diagnosed NPC, with reported local control rates of 92 to 97% at 3 to 4 years. Apart from improvement of tumor control, IMRT may reduce the risk of late complications such as xerostomia in early-stage disease.18
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