TITLE: NASOPHARYNGEAL CARCINOMA
SOURCE: Dept. of Otolaryngology, UTMB, Galveston, TX
RESIDENT PHYSICIAN: Carl "Rusty" Stevens, MD
FACULTY PHYSICIAN: Christopher Rassekh, MD
SERIES EDITOR: Francis B. Quinn, Jr., M.D.
DATE: January 21, 1998

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"This material was prepared by physicians in partial fulfillment of educational requirements established for Continuing Postgraduate Medical Education activities and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating group discussion in a interactive computer mediated conference setting. No warranties, either express or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of subscribers or other professionals and should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion."


INTRODUCTION

Although more common in many Asian countries, malignancy of the nasopharynx is a relatively rare disease in the United States. It is often misdiagnosed early because of vague presenting symptoms and the difficulty of examination of the nasopharynx. There are several different types of malignancy known to occur in the nasopharynx including squamous cell carcinoma, lymphoma, salivary gland malignancy, and sarcomas. By far the most common are the squamous cell carcinomas which can be divided into three types and are often collectively called nasopharyngeal carcinoma. These lesions will be the focus of this grand rounds.

ANATOMY

The nasopharynx communicates with the nasal cavity anteriorly at the choanae and with the oropharynx inferiorly at the lower border of the soft palate. Superiorly and posteriorly, important bony landmarks include the skull base and the upper vertebral bodies. The eustachian tubes enter the nasopharynx laterally and are covered superiorly and posteriorly by cartilage known as the torus tubarius. The fossa of Rosenmuller (lateral nasopharyngeal recess) is located superior and posterior to the torus and is the most common location for nasopharyngeal carcinoma. Many of the skull base foramen that carry important neural and vascular structures are located immediately adjacent to the nasopharynx. The nasopharynx is lined by mucosa that is covered with either stratified squamous epithelium or pseudostratified columnar epithelium. It is from this epithelium that nasopharyngeal carcinoma arises. The mucosa also contains other structures including salivary and lymphoid tissue. As mentioned above, these elements can also give rise to malignancy although much less frequently.

EPIDEMIOLOGY

Nasopharyngeal carcinoma may occur at any age and as presented above, occurs much more frequently in the Chinese population (18% verses 0.25% in North America).1 It has been noted that the rate of nasopharyngeal carcinoma rises as Chinese genes are introduced into an area. Also a first generation Chinese-American will have a reduced risk of developing this lesion but it remains higher than the overall U.S. rate. These findings seem to indicate both genetic and environmental etiologies. HLA-A2 and HLA-B-Sin 2 histocompatibility loci have been identified as possible markers for genetic susceptibility.(1) Another important etiology in some types of nasopharyngeal carcinoma is the Epstein-Barr virus. Evidence of the virus has been found in the tumor cells themselves and, as will be discussed later, many patients have anti-EBV antibodies. Other possible etiologies include exposure to nitrosamines, polycyclic hydrocarbons, chronic nasal infection, poor hygiene, and poor ventilation of the nasopharynx.(1)

CLASSIFICATION

The World Health Organization has developed a classification system that divides nasopharyngeal carcinomas into three types based on light microscopy findings. Type I or Squamous cell carcinomas are characterized by moderate to well differentiated cells that produce keratin and have intercellular bridges and other findings similar to typical squamous cell carcinomas. Twenty-five percent of nasopharyngeal carcinomas are of this type. Type II lesions, non-keratinizing carcinomas, have cells that vary from mature to anaplastic in appearance but produce minimal if any keratin. These carcinomas often resemble transitional cell carcinoma of the bladder. Approximately twelve percent of nasopharyngeal carcinomas are of this type. Type III comprises a diverse group of carcinomas often described as undifferentiated carcinomas. Included in this group are lymphoepitheliomas, anaplastic, clear cell, and spindle cell variants. These lesions are often difficult to differentiate from lymphoma and may require special stains and markers to identify their epithelial origin. The tumor cells are often located in a lymphoid stroma and when the density of the stroma is greater than the tumor cells themselves, the lesion is termed a lymphoepithelioma.(2) Sixty percent of all nasopharyngeal carcinomas and nearly all of those found in young patients are of this type.

Although type I lesions are often called squamous cell carcinomas, it must be remembered that all three types arise from nasopharyngeal epithelial cells and can be identified as squamous cell carcinomas by electron microscopy. There are however certain important differences between type I lesions and types II and III. The 5 year survival for type I carcinomas is only 10% whereas types II and III have approximately 50% survival at five years. However, types II and III tend to be more chronic diseases with recurrences sometimes occurring many years after initial treatment. Another important difference is that types II and III are more commonly associated with anti-EBV serologies and EBV DNA in the tumor cells. Human papillomavirus (types 11 and 16) DNA has been identified in WHO type I carcinomas.(3)

CLINICAL COURSE

As mentioned above the symptoms of nasopharyngeal carcinoma are often subtle initially and a high index of suspicion is required for early diagnosis. Unilateral hearing loss from a middle ear effusion is the most common finding and should be considered an indication for nasopharyngeal exam. Unfortunately, another common presenting complaint is a neck mass resulting from regional spread. Large or exophytic lesions may cause nasal obstruction or epistaxis. Also, as the tumor enlarges, adjacent cranial nerves may become involved. Xerophthalmia may result from involvement of the greater superficial petrosal nerve at the foramen lacerum and facial pain may indicate Trigeminal nerve involvement. Diplopia may occur with isolated Abducens nerve injury whereas ophthalmoplegia indicates involvement of cranial nerves III, IV and VI, usually in the cavernous sinus or the superior orbital fissure. Horner's syndrome occurs with injury to the cervical sympathetic chain and more extensive skull base involvement produces deficits of the lower cranial nerves (IX, X, XI, XII).(4)

Examination of the nasopharynx may reveal an exophytic mass or a smooth, mucosal covered mass. The most common initial location for these lesions is in the fossa of Rosenmuller. The nasopharynx may also be essentially normal in appearance with the diagnosis only made after random biopsy for regional spread without a known primary. The nasopharynx has a rich lymphatic network that communicates across the midline making bilateral regional spread a common finding. Distant spread to the lungs, bones or liver is possible but rare in North American patients (< 3% at presentation).(1)

RADIOLOGICAL AND LABORATORY EVALUATION

Contrast CT with bone and soft tissue windows is the imaging tool of choice for determining the extent of spread of nasopharyngeal carcinoma. MRI may also be helpful in the evaluation of soft tissue involvement, especially with recurrent carcinomas. A chest x-ray is usually included in the initial work-up to rule out pulmonary metastasis. Chest CT, including the liver, and bone scans may be indicated if distant spread is suspected.

Routine CBC, chemistry profiles and liver function test are obtained to screen for metastatic disease. Additionally, several anti-EBV serologic test are useful in detecting and determining the prognosis of nasopharyngeal carcinoma, particularly types II and III. Immunofluorescence for IgA antibodies to the viral capsid antigen (VCA) and IgG antibodies to the early antigen (EA) can help identify occult or early disease in many cases. As these tests become more practical and widely available, they may be used to screen for nasopharyngeal carcinoma in high incidence areas. Another serologic test that provides prognostic information is the antibody- dependent cellular cytotoxicity (ADCC) assay. High titers of this antibody are related to better long-term survival.

STAGING

Several staging methods have been developed for nasopharyngeal carcinoma including that of the American Joint Committee for Cancer Staging, International Union Against Cancer, and the Ho system.(1) Unfortunately, many of these systems fail to consider important prognostic indicators peculiar to nasopharyngeal carcinoma and often have a similar prognosis for different stages. Neel and Taylor developed a system based on five important prognostic indicators that provides a clearer separation between stages. This system assigns a numeric value to the presence or absence of the indicator and the stage is determined from the total score. The prognostic indicators considered and the associated value include extensive primary tumor (+0.5), duration of symptoms prior to diagnosis less than 2 months (-0.5), presence of seven or more symptoms (+1), histologic WHO type I (+1), and lower cervical node disease (+1). Stage A is present if the score is less than zero, stage B if 0-0.99, stage C if 1.0-1.99 and stage D if greater than 2.0.5 As mentioned above, the ADCC assay titer is important and may be considered if available.

MANAGEMENT

External beam radiation therapy continues to be the mainstay of treatment for this lesion. Doses of 6500 to 7000 cGy are directed at the primary lesion and the upper echelon lymph nodes. If clinically positive, lower cervical nodes are included in the field. Also, prophylactic treatment of clinically negative lower cervical nodes with 5000 cGy may be considered. Brachytherapy is occasionally used as an adjuvant to external beam radiation or in cases of recurrent/residual tumor. Although improved methods of delivering the radiation have reduced complications, well known side effects do occur. These may be especially problematic when reirradiation is required for residual or recurrent disease. In addition to the common finding of xerostomia, eustachian tube dysfunction often occurs. Early after treatment this manifest as middle ear effusion with associated hearing loss. Over time however, many patients eventually develop patulous eustachian tubes.(6) Endocrine disorders such as hypopituitarism, hypothyroidism, and hypothalamic dysfunction are possible long-term sequelae and periodic endocrine evaluations are appropriate. Trismus and other problems related to soft tissue fibrosis, as well as ophthamologic complications and base of skull necrosis, may occur.

Surgical management is primarily used to obtain tissue for histologic examination and for EBV testing. If an obvious tumor is present in the nasopharynx, biopsy under local anesthesia in the clinic may be practical if the patient is cooperative. Since these lesions are often heterogeneous, the biopsy must be large to ensure appropriate diagnosis and WHO typing. Instruments such as the Takahashi or Blakesley forceps are ideal for obtaining an adequate biopsy.(7) If the tumor is not obvious or if sufficient tissue cannot be obtained in clinic, the patient should be taken to the operative room for formal endoscopy and biopsy under general anesthesia.

Although surgical resection in this region was once considered impossible, modern approaches do allow access for excision. This is rarely indicated as a primary treatment but may be appropriate in certain cases of recurrent disease when additional radiation is not appropriate. The infratemporal fossa and transparotid temporal bone approaches offer access to the pterygomaxillary space and infratemporal fossa but have limited exposure of the nasopharynx, particularly the contralateral side. These lateral approaches also incur significant morbidity. The transpalatal approach is associated with less morbidity but also less lateral exposure. Other authors have reported success using transmaxillary and transmandibular approaches for residual/recurrent nasopharyngeal carcinoma.(8)

A more common therapeutic surgical indication involves a successfully treated primary tumor with regional failure. A radical neck dissection may be an appropriate procedure in this case and has been reported as being more effective at controlling neck disease than additional radiation.(9) Finally, myringotomy with ventilation tube placement may be considered in a patient with persistent, symptomatic middle ear effusion. If indicated this should be performed prior to radiation therapy because the incidence of complications such as otorrhea and persistent otalgia are reduced. If considered after radiation therapy, a period of observation prior to the procedure is usually indicated and amplification may be a better option.(2)

Chemotherapy as an adjuvant to radiation therapy has yet to demonstrate a significant improvement in long-term outcome and therefore continues to be used mainly as a palliative measure. While immunotherapy has also not shown any clear improvement in survival to date, the close association of certain anti-EBV antibodies with an improved prognosis offers the hope of effective immunologically based approach in the future. Also, a vaccine to protect against EBV related disease may one day be reality.

CONCLUSION

Nasopharyngeal carcinoma is a rare disease in North America and has an overall 5 year survival of 40% for all types. It is much more common in people of Chinese ancestry. The presenting signs and symptoms are often subtle requiring a high index of suspicion for early diagnosis. Three WHO classes are described with the first often being described as squamous cell carcinoma and carrying a worse prognosis. It should be remembered that all classes are derived from epithelial cells and can be identified as squamous cell carcinomas by electron microscopy. The second two classes confer better survival and are often associated with anti-EBV antibodies. Treatment is primarily radiation therapy.

REFERENCES

1. Neel HB, Slavit DH. Nasopharyngeal Cancer. In: Bailey BJ ed. Head and Neck Surgery - Otolaryngology. Philadelphia: J.B. Lippincott, 1993:1257-73.

2. Wei WI, Sham JS. Cancer of the Nasopharynx. In: Myers EN, Suen JY eds. Cancer of the Head and Neck. Philadelphia: W.B. Saunders, 1996:277-93.

3. Hording U, Nielsen HW, Daugaard S, Albeck H. Human Papillomavirus types 11 and 16 detected in nasopharyngeal carcinomas by the polymerase chain reaction. Laryngoscope 1994;104:99-102.

4. Gustafson RO, Neel HB. Cysts and Tumors of the Nasopharynx. In: Paparella MM et al. eds. Otolaryngology. Philadelphia: W.B. Saunders, 1991:2189-98.

5. Neel HB, Taylor WF. New staging system for nasopharyngeal carcinoma - long-term outcome. Arch Otol HNS 1989;115:1293-1303.

6. Young YH, Cheng PW, Ko JY. A 10-year longitudinal study of tubal function in patients with nasopharyngeal carcinoma after irradiation. Arch Otol HNS 1997;123:945-8.

7. Hasselt CA, John DG. Diagnosing nasopharyngeal cancer. Laryngoscope 1994;104:103-4.

8. Hsu MM, Ko JY, Sheen TS, Chang YL. Salvage surgery for recurrent nasopharyngeal carcinoma. Arch Otol HNS 1997;123:305-9.

9. Yen KL, et al. Salvage neck dissection for cervical recurrence of nasopharyngeal carcinoma. Arch Otol HNS 1997;123:725-9.