Final Diagnosis:

Nasopharyngeal Carcinoma, Non-keratinizing Type

Positive for Epstein-Barr Viral RNA

Discussion

Nasopharyngeal carcinoma (NPC) is relatively uncommon in the United States, accounting for roughly 0.25% of all cancer, however it is exceptionally common in Africa and Asia 1-3. NPC accounts for approximately 18% of all cancer in China, especially in the southern province of Kwantung. NPC is a disease that primarily affects adults, and has a slight male predilection. Most patients usually present in the fifth to sixth decade of life, however geography plays an important role, as roughly 10-20% of cases in North Africa occur in children2.

Most patients will present with nasal obstruction, epistaxis, otitis media and/or a neck mass (usually posterior triangle and asymptomatic). Most NPCs will originate in the lateral nasal wall near the fossa of Rosenmüller, as in this case2. In addition, NPCs will affect both sides of the nasopharynx equally. Most tumors are exophytic on physical exam; however, they can also appear ulcerative and infiltrative. Because of the low incidence in more developed countries, NPCs are often not considered in the differential diagnosis and thus they are often misdiagnosed leading to a more advanced stage at the time of presentation 4. Most NPCs will spread directly from the primary site to the base of skull, pterygoid fossa, paranasal sinuses and oropharynx 1. At the time of diagnosis, 10-15% of patients will demonstrate cranial nerve impairment and 60-85% will have positive cervical lymph nodes (of which 35-45% will be bilateral)2. Distant metastases are rare and are usually only present in about 5% of cases3. Distant metastases will most often affect the cervical nodes and lungs, followed by the skeleton and liver 1-3.

A number of factors come into play when considering the etiology of NPC, especially race, geography, genetics and the Epstein-Barr virus (EBV)2,3 4. As mentioned previously, the incidence of NPC is highest among native Chinese, however this number decreases among the same populations when successive generations move to western countries like the United States 2. American Indians, Eskimos and Aleuts also demonstrate increased incidences of NPC. Human Leukocyte antigens (HLA) are also important etiologic and prognostic factors for individuals of Chinese ancestry 2. No correlation between HLA type and incidence in the United States has been identified. The role of environmental carcinogens has been implicated, especially the high levels of nitrosamines in salted fish, a staple of the Chinese diet 2. Smoking, chemical exposure and alcohol have also been implicated. EBV also has a strong association with NPC 2-5. Most patients with NPC will demonstrate high EBV titers, regardless of geography.

In 1971, The World Health Organization classified NPC according to the following three categories: keratinizing squamous cell carcinoma, nonkeratinizing carcinoma and undifferentiated carcinoma 2-4. In 1991, this was changed to squamous cell carcinoma and nonkeratinizing carcinoma (NKCa) with dedifferentiated NKCa and undifferentiated carcinoma being subtypes of the latter. Some NPCs will show a combination of histologic subtypes. In fact, the distinction is most often not well defined. In such cases, the tumor is defined by the prominent component. In addition, all NPCs will demonstrate lymphocytes to some degree; however, they are more common in the undifferentiated variant 3. Because of these lymphocytes, malignant lymphoma is always in the differential, especially in patients of Asian and South American decent, where malignant lymphomas are associated with EBV 1. Metastatic squamous cell carcinoma would also have to be considered in the differential, especially if the lesion showed squamous differentiation and keratinization.

When in-situ hybridization or polymerase chain reaction is employed, NPCs will demonstrate the EBV genome in 75-100% of cases. However, the keratinizing variant will be most likely not to demonstrate EBV. Human papilloma virus has also been recently implicated in the pathogenesis of NPC, particularly the EBV-negative squamous cell variants. This, however, is still the subject of debate and more extensive research is needed2,6.

As far as treatment is concerned, radiotherapy is the gold standard 2-4. Location dictates that complete surgical excision is difficult, if not impossible. Due to recent advances in skull bases surgery, some cases that are non-responsive to radiation (especially the keratinizing variant) are now being considered for surgical excision. Local recurrence following radiation therapy is a nuisance and ranges from 30-45%. Recent advances in chemotherapeutic drugs have also shown promise in treating NPC 7-9, although they do not prove that chemotherapeutic intervention significantly decreases recurrence rates 10.

As stated previously, the incidence of cervical metastases at the time of presentation is high, while the incidence of distant metastases is not. Most distant metastases are detected within three years of diagnosis. The keratinizing or squamous cell variant carries a much worse prognosis and traditionally shows poor responsiveness to radiotherapy. In general, the overall 5-year survival rate for patients in the United States with NPC is between 40-50% 2. Specifically, the 5-year survival rate for keratinizing NPC is 20-40%, and 65% for nonkeratinizing NPC. Size and location of positive cervical lymph nodes has a significant impact on prognosis, as patients with positive nodes in the lower neck have a much poorer prognosis2,3. Younger patients tend to fair much better than older patients.

References

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