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
"This material was prepared by
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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
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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.
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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
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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
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9. Yen KL, et al. Salvage neck dissection for cervical
recurrence of nasopharyngeal carcinoma. Arch Otol HNS
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