The nasopharynx is a small, tubular structure above the soft palate that connects the nose to the oropharynx. Cancers that arise from this area are usually squamous cell carcinomas that behave differently than the other head and neck cancers. Most common place of origin is the fossa of Rosenmuller, which is the pharyngeal recess. Virus-related oncogenesis is a common theme in head/neck cancers. Oropharyngeal cancers are associated with human papillomavirus (HPV) infection, and nasopharyngeal cancers (NPC) are associated with Ebstein-Barr virus (EBV). The exact pathogenesis is still unknown. However viral oncogenes LMP-1, LMP-2, and EBNA1 have been known to play an important role. In areas with a high incidence of disease, most cases are related to EBV infection. Although HPV related nasopharyngeal cancers have also been reported, no clear association has been established.
The clinical behavior of nasopharyngeal cancers varies depending on its histological subtype. The World Health Organization (WHO) has classified nasopharyngeal carcinoma into the three subtypes based on histology. Type 1 is keratinizing squamous cell carcinoma which is associated with EBV infection in around 70% to 80% of the cases. Type 2 is differentiated non-keratinizing carcinoma, and type 3 is undifferentiated nonkeratinizing carcinoma and is the most common form of nasopharyngeal cancer. The latter 2 types are also most responsive to treatment. Almost all cases of type 2 and type 3 are related to EBV and occur in the area where EBV is endemic. Nasopharyngeal cancer with basaloid features is a newer, rarer histologic category, known to behave aggressively. Treatment does not vary based on histologic subtypes. In general, mortality related to nasopharyngeal cancers has improved in the last decade owing to early detection and advances in treatment.
The etiology of nasopharyngeal carcinoma is complex and is not yet completely understood. Carcinogenesis is however known to be associated with high titers of EBV. Other risk factors include a diet consisting of preserved foods containing nitrosamines and smoking. In some epidemiologic studies, family history of nasopharyngeal cancer has been established as a predisposing factor as well. In areas where EBV is not endemic, like the United States, smoking and alcohol are found to be risk factors. In some areas of the world, circulating EBV DNA is being used for screening and disease surveillance. Studies have shown that high circulating levels of EBV DNA is associated with poorer response to treatment and higher rates of distant metastasis and mortality.
Although common in parts of the world, nasopharyngeal carcinoma is rare in the United States. Incidence is as high as 21 cases per 100,000 people in some parts of China. Most commonly, the incidence is reported in central, south and southeast Asia, the Arctic, Middle East, and North Africa. In the United States, the incidence is 0.4 cases per 100,000 people with a higher incidence in the population that has immigrated from areas of higher prevalence.
It is believed that the Epstein Barr virus (EBV) nuclear antigen may infect the epithelial lining in the nasopharynx and lead to malignant transformation. In many African patients with nasopharyngeal cancer, EBV has been isolated.
Symptoms of nasopharyngeal cancer depend on the stage of presentation. Earlier symptoms may include epistaxis or unilateral nasal obstruction. The classic triad of symptoms including neck mass due to lymph node metastasis, otitis media, and nasal obstruction is rarely seen. All three, however, are individually very common presenting symptoms of nasopharyngeal cancer. Symptoms are based on the extent of the tumor and the pattern of spread. Cranial nerve involvement may lead to facial numbness, diplopia, or any symptoms related to cranial nerve palsies. The third, fifth, sixth, and 12th cranial nerves are most commonly affected. Dysphagia and odynophagia as seen in other head and neck cancers are rarely seen in early-stage nasopharyngeal cancer since the site of origin is above the oropharynx.
A good history and physical exam of the head and neck are of utmost importance. If there is a suspicion, imaging needs to be ordered for further evaluation and appropriate staging of the malignancy. Which imaging study to order has been somewhat controversial; although, the consensus is that an MRI of the face and neck is the best modality to evaluate the extent of the disease, the T stage. A positive emission tomography (PET) scan is recommended to evaluate for metastatic disease (M stage) given the propensity of nasopharyngeal cancers to metastasize. An appropriate referral should be made to an ear, nose, and throat (ENT) surgeon with expertise for a nasopharyngolaryngoscopy for direct visualization and biopsy. A multidisciplinary evaluation is needed for these patients which includes consultation with medical oncology, radiation oncology, and surgery. Supportive care teams should be involved in care as well. The team should include dental, ophthalmologic, nutritional, speech pathology, and audiology evaluation where needed. EBV testing of the tumor (through in situ hybridization) and blood (PCR) should be considered for tumors with nonkeratinizing and undifferentiated histology.
Treatment types include surgery, radiation therapy, chemotherapy, or a combination of the above modalities depending on the stage of the tumor. The goal of therapy is to control local disease and prevent distant metastasis. Efforts should be made to find a suitable clinical trial for all patients. For stage I disease, radiation therapy (RT) alone is the standard of care. Radiation therapy fields usually involve the nasopharynx only although neck nodes can be included.
Radiation therapy alone used to be the standard treatment for all patients with locally advanced nasopharyngeal cancer until the 1990s. A phase III intergroup study showed that patients with stage III and locally advanced stage IV disease had statistically significant improvement in progression-free survival and overall survival with bimodality treatment of radiation therapy with systemic chemotherapy. This demonstrates that most of the recurrence of nasopharyngeal cancer is in the metastatic setting which was able to be controlled with systemic chemotherapy. In locally advanced disease (stage II, III, IVA, IVB), bimodality treatment with concurrent cisplatin with radiation therapy is recommended. This should be followed by adjuvant chemotherapy with cisplatin and 5-fluorouracil in patients who can tolerate further treatment. Induction chemotherapy before concurrent chemotherapy and radiation treatment has been studied in a few trials and has shown a good response, although data remains insufficient and this is a category three recommendation. If the residual tumor is seen on follow-up imaging after completion of chemotherapy and radiation treatment, resection of residual tumor and/or neck dissection may be warranted.
For metastatic disease (stage IVC), platinum-based combination chemotherapy is recommended. Regimens can include cisplatin/5-FU, cisplatin/paclitaxel, and cisplatin/gemcitabine. Imaging should be repeated within 6 months of completion of treatment to ensure a good response.
The survival of patients with nasopharyngeal cancer depends on the time of diagnosis and extent of local invasion. For those patients with local disease, the prognosis is far. For patients with locally invasive disease, the prognosis is guarded. With the use of radiation alone, there is a 40% survival, but when it is combined with chemotherapy, the survival rates are between 50% to 80%.
The majority of patients develop mucositis as a result of radiation, and many foods irritate the mucosa, resulting in pain and dysphagia. A dietitian consult is needed as these patients may require a soft, bland diet. All acidic and spicy foods should be avoided. In some patients, there may be a need for gastrostomy feeding tube to allow for hydration and adequate calorie intake.
Patients usually are not able to participate in any contact sports. Further, because of the chemotherapy, they remain unusually susceptible to microbial agents.
After patients complete treatment, they should continue to follow up with oncology with routine follow-up imaging. Those who have received head/neck radiation should have good dental follow-up and thyroid function tests every 6 to 12 months. EBV DNA monitoring can be considered for patients who had EBV related NPC.
Unfortunately, despite the development of guidelines in the treatment of nasopharyngeal cancer, some patients appear to be overtreated with chemoradiation therapy, which also results in severe adverse effects and poor quality of life. Given this, an interprofessional approach to the cancer is recommended to ensure that all patients get the appropriate stage dependent treatment.
The treating team should consist of an oncologist, dentist, a dietitian, surgeon, radiation oncologist, otorhinolaryngology (ENT) surgeon, a pharmacist, and a chemotherapy nurse.
The oncology nurse and the pharmacist play a vital role in the education the patient about adverse effects of the drugs and how to relieve them. The nurse should emphasize the importance of a dental follow-up and consult with an endocrinologist for assessing thyroid function. (Level V)
Chemoradiation has led to good outcomes, but the patients also develop a variety of adverse effects. While survival has increased, the overall quality of life remains poor. To improve the quality of life, it is important to closely follow up and refer patients early to the appropriate specialist. (Level V)