41

NEOPLASMS OF THE
NASOPHARYNX
Frank G. Ondrey, MD, PhD
Simon K. Wright, MD

NASOPHARYNGEAL CARCINOMA
Epidemiology
Nasopharyngeal carcinoma (NPC) is unique among squa-
mous cell carcinomas of the head and neck (SCCHN) in its
geographic epidemiologic profile. Although it is a rare tumor
in most parts of the world, in regions of southeastern Asia, its
incidence soars to 27.3 in 100,000. The highest incidence
occurs in Taiwan, where 98% of the population is Chinese,
90% of whom originate from the Guangdong province. There
is a decrease in incidence in northern China, falling to 3 in
100,000 in northern provinces. The Japanese, who trace their
origins to the Mongoloid region, have an incidence of just
1 in 100,000 for both men and women. In Europe and North
America, the incidence is 1 in 100,000. In China, the disease
rate rises after age 20 and falls after age 60; the mean age is
40 to 50 years. The male-to-female ratio is 3 to 1.

Dietary Associations
Because of the strikingly high incidence of NPC among the
“boat people” of southern China (54.7/100,000), specula-
tion about their unique environmental exposures led to the
examination of salted fish as a risk factor. Salted fish has
been shown to contain strong carcinogens and mutagens.
Animal studies support the association, demonstrating a
484
 Neoplasms of the Nasopharynx 485

dose-dependent relationship between salted fish intake and

tumor development in rats.

Epstein-Barr Virus Associations

Epstein-Barr virus (EBV) is a double-stranded deoxyribo-
nucleic acid (DNA) virus that, in addition to being the cause
of infectious mononucleosis, is implicated in a variety of lym-
phoid neoplasms: endemic Burkitt’s lymphoma, post-trans-
plantation lymphoproliferative disorders, subsets of Hodgkin’s
disease, and nasal T-cell lymphoma. The connection between
EBV and NPC was first made in the late 1960s, when sero-
logic studies demonstrated elevated titers of immunoglobin
(Ig)A and IgG titers against viral antigens. Two major lines of
evidence for the role of EBV have been elucidated: serologic
studies and nucleic acid studies.

Serologic Studies
Elevated levels of IgA and IgG antibodies directed against
viral capsid antigen and early antigen in patients with NPC
have been documented by many studies. Immunoglobulin A
can be detected in 80 to 85% of patients with NPC. Response
to treatment yields a corresponding decrease in levels;
increasing titers are associated with progression of disease.
Anti-EBV nuclear antigen 1 IgA has also proven to be a sen-
sitive indicator of the presence of NPC.

Nucleic Acid Studies

Direct evidence for the role of EBV in the pathogenesis
comes from studies of EBV ribonucleic acid (RNA) in NPC
cells, the presence of which indicates infection with the virus.

Biomarkers
Vascular endothelial growth factor, a potent angiogenic
growth factor, has been shown to be elevated in patients with
metastatic NPC but not in patients with nonmetastatic NPC.
486 Otorhinolaryngology

Histology
The World Health Organization (WHO) has classified NPC
into three histopathologic groups. WHO type I is a keratiniz-
ing squamous cell carcinoma similar to others of the head
and neck. It exhibits abundant keratin formation with inter-
cellular bridges and various degrees of differentiation. It can
be subdivided into well-differentiated (G1), moderately dif-
ferentiated (G2), or poorly differentiated (G3) grades. WHO
type II is a nonkeratinizing form with greater pleomorphism,
scant keratin formation, and a variety of patterns. It exhibits
a pavemented or stratified pattern with clear cell margins.
WHO type III is an undifferentiated tumor, characterized by
greater heterogeneity of cell size, indistinct cell borders, and
prominent nucleoli. Types II and III both typically demon-
strate lymphocytic infiltration; these are endemic forms of
NPC and are classically associated with EBV. The clinical
implications of the differential types are considerable. In a
National Cancer Data Base study of 5,069 patients diagnosed
with NPC in the United States between 1985 and 1989, there
were substantial differences between 5-year survival of ker-
atinizing (37%) versus nonkeratinizing (65%) and undiffer-
entiated (64%) NPC.

Staging Systems
The epidemiologic idiosyncrasies of NPC are reflected in the
controversies surrounding the staging of this disease. All stag-
ing of NPC begins with a thorough physical examination
including endoscopy. Imaging studies, including computed
tomography (CT) and magnetic resonance imaging (MRI),
are performed to define soft tissue and bony extension. Ho
developed a staging system based on his extensive experi-
ence treating NPC in endemic areas of southeastern Asia. His
system divides all disease into three T categories that do not
account for nasopharyngeal subsite involvement. Ho’s stag-
ing system divides the neck into three zones, with increasing
 Neoplasms of the Nasopharynx 487

N status from superior to inferior. The fourth edition of the

American Joint Committee on Cancer (AJCC) staging was
developed and applied in the United States, where NPC is
nonendemic. It divides all disease into four T categories,
including T2 accounting for multiple nasopharyngeal subsite
involvement. The neck is treated similarly to other head and
neck cancers. The fifth edition of the AJCC staging system
sought to combine the value of each staging system by
including components of the Ho and AJCC, producing a sys-
tem simplifying the nasopharyngeal subsites and preserving
the vertical stratification of lymph node involvement.

Clincical Presentation
Poor access and confounding early symptoms account for the
high proportion of advanced disease at the time of diagnosis.
Generally, symptoms fall into one of four general areas of
complaint: aural, nasal, neck, and miscellaneous accounted
for by cranial nerve (CN) involvement, the most common
being CN VI. The classic presentation is a neck mass, partic-
ularly in the superior part of the posterior cervical triangle,
and conductive hearing loss, often with bloody drainage.
Nasopharyngeal carcinoma often arises from the lateral wall
of the nasopharynx, near the fossa of Rosenmüller, inducing
a serous otitis media as it enlarges and obstructs the
eustachian tube.
Nodal involvement is extremely common in NPC, occur-
ring in 75 to 90% of WHO type II and III histologies at the
time of diagnosis. In type III, nodal involvement is bilateral in
60% of cases. Distant dissemination is reported by most major
series to be between 5 and 11% at the time of presentation.

Diagnosis
The diagnosis of NPC begins with an accurate history and
complete physical examination, including endoscopic visu-
alization of the nasopharynx. This is followed by endoscopic
488 Otorhinolaryngology

examination of the nasopharynx under general anesthesia for

the purposes of tumor staging. Patients who present with neck
metastases with unknown primaries should have NPC ruled
out by direct biopsy. Imaging studies are done for staging.
Magnetic resonance imaging is useful for evaluation of mus-
cle, nerve, or intracranial invasion, whereas CT demonstrates
bony involvement more reliably. Chest roentgenogram, bone
scan, complete blood count, serum chemistries, and liver
function tests are recommended.

Treatment
Radiotherapy
Historically, external beam radiotherapy (XRT) has been
the standard of treatment for locoregionally confined NPC.
In such patients, it is administered with the intent to cure.
The location of primary disease with respect to vital struc-
tures and the propensity toward bilateral lymphatic metas-
tasis pattern along with the inherent radiosensitivity of NPC
have made XRT the primary treatment modality. The entire
nasopharynx and bilateral retropharyngeal, jugulodigastric,
low neck, posterior chain, and supraclavicular lymph nodes
are included in the initial XRT target. At least 45 to 50 Gy
at 1.8 to 2.0 Gy per fraction (day) are delivered. The dose to
the primary tumor is usually boosted to 66 to 70 Gy based
on tumor stage. Because NPC is generally more radiosen-
sitive than other SCCHN, moderate-dose XRT followed by
neck dissection is not recommended. However, proven
residual disease after full-course XRT should be addressed
with neck dissection 6 to 8 weeks following completion of
XRT. The M. D. Anderson Cancer Center has reported sur-
vival on a consecutive series of 378 patients. Respective
actuarial survival rates at 5-, 10-, and 20-year follow-up
were 48%, 34%, and 18%. Local control rates with radiation
alone for T1, T2, T3, and T4 tumors are 85 to 95%, 80 to
90%, 60 to 75%, and 40 to 60% respectively.
 Neoplasms of the Nasopharynx 489

Treatment of the N0 neck is guided by two principles.

First, the high probability of neck involvement is unrelated to
stage of the primary disease, and bilateral involvement is fre-
quent. Thus, it is not possible to predict reliably a side of dis-
ease or which patients may have subclinical local metastases.
Second, although salvage surgery of the untreated neck is
effective in 80 to 90% of patients, the appearance of disease
in the untreated neck is strongly associated with distant
metastasis. Because patients without subclinical metastases
cannot be distinguished from those with subclinical metas-
tases, coupled with the fact that close surveillance and sal-
vage surgery are associated with adverse outcomes, the
elective treatment of the necks of all patients is warranted,
even though, inevitably, some patients will be receiving treat-
ment unnecessarily. Regional control rates with radiation
alone are good: reported 5-year regional control rates for N0,
N1 and 2, and N3 categories are 90 to 100%, 80 to 90%, and
60 to 80%, respectively. It is unclear whether local recurrence
increases the risk of distant metastasis.
The ability to achieve focal exposure and relative ease of
access to the nasopharynx have generated interest in endo-
cavitary radiotherapy (brachytherapy) as a means of boosting
the dose to the primary tumor site following external beam
radiotherapy. No phase III studies have been performed to
evaluate this modality, and definite indications for endocavi-
tary radiotherapy await further clinical trials.
Predictors of Radiotherapy Failure. The ability to pre-
dict which patients are at greatest risk of failure would make
it possible to focus more aggressive or adjuvant therapy on
those who have the worst prognosis, while sparing those with
a favorable outlook the morbidity of aggressive treatment. As
expected, T category and N category are well-established pre-
dictors of survival. Interestingly, T category is unrelated to
risk of distant metastasis; its impact on survival can be attrib-
uted to increasing risk of local failure. Conversely, N category
490 Otorhinolaryngology

exerts its influence on survival through increasing risk of dis-

tant metastasis, recognizing that, overall, the risk of neck fail-
ure is low. Other strong predictors of failure include more
differentiated tumors (WHO type I) and CN involvement.
Complications of Radiotherapy. In modern clinical trials,
mucositis is the most frequent radiotherapy acute toxicity,
occurring in 18 to 84%. Grade 3 mucositis (< 50%) occurs in
20 to 28% of patients. Long-term complications of radiother-
apy include skin and subcutaneous fibrosis, osteoradionecro-
sis, myelitis, brain necrosis, temporomandibular joint
ankylosis, hypopituitarism, sensorineural hearing loss, and
bone atrophy
Chemotherapy and Radiotherapy. Because NPC is con-
sidered both radiosensitive and chemosensitive, it stands to
reason that treatment with chemotherapy and radiotherapy
protocols would be tried. Problems with overlapping toxici-
ties had precluded such treatments in the past. However, with
advances in XRT delivery, chemotherapeutic agents, and sup-
portive care, chemoradiotherapy protocols have been made
possible. Although radiotherapy has been effective for treat-
ing early-stage disease, patients with bulky lymphadenopathy
or supraclavicular metastases are at greater risk of distant
metastases and experience a 5-year survival rate of 10 to 40%
with radiotherapy alone. The high incidence of distant metas-
tases combined with the chemosensitivity of NPC make this
malignancy an ideal candidate for the addition of chemother-
apy to the treatment regimen.
The goal of chemoradiotherapy is to enhance local control
of tumor and to address distant metastases that are not
included in the field of radiation. To obtain optimal local con-
trol results, the two modalities should be delivered as close in
time as possible to achieve a synergistic effect. Toxicity
becomes the limiting factor in this setting, and drugs with
minimal overlapping toxicities with XRT and each other are
favored. As for control of distant metastases, there is no syn-
 Neoplasms of the Nasopharynx 491

ergistic effect, and the timing of administration is unrelated to

XRT. The earlier the treatment, however, the smaller will be
the micrometastatic tumor deposits.
Neoadjuvant Chemoradiotherapy. Radiation for stage I
and II NPC generally does well. For patients with locore-
gionally advanced NPC with bulky lymph node metastases,
in whom local failure and distant metastasis rates are high, the
5-year survival rate ranges from 10 to 40%. Knowing that
NPC is chemosensitive, it is logical to add chemotherapy
to the treatment regimen in this patient population. Early
studies of neoadjuvant chemotherapy using three cycles of
cisplatin-containing regimens yielded encouraging results
with acceptable toxicities.
Clinical trials using either neoadjuvant or combined
neoadjuvant and adjuvant chemoradiotherapy have shown at
best an improvement in occurrence of distant metastasis. In
one study, the incidence of treatment-related deaths was
excessive. Thus, although neoadjuvant and adjuvant chemo-
radiotherapy may alter the natural history of locoregionally
advanced NPC by prolonging disease-free survival, no ran-
domized trials offer evidence of improving overall or disease-
specific survival.
Concurrent Chemoradiotherapy. Cisplatin is a good can-
didate for concomitant treatment because its toxicities do not
overlap with those of XRT: myelosuppression is uncommon.
Cisplatin was used in a pilot concurrent chemoradiotherapy
study with encouraging results. Based on this, a Head and
Neck Intergroup study for patients with stage III/IV NPC was
initiated; it randomized patients to a standard radiotherapy
control arm (2 Gy/fraction to 70 Gy over 7 weeks) or to a
concurrent cisplatin and adjuvant cisplatin and 5-fluorouracil
group (5-FU) in which cisplatin was given every 3 weeks,
totaling three doses during radiotherapy. This was followed
by cisplatin and 5-FU for three cycles. After the first planned
interim analysis with 138 evaluable patients, the trial was
492 Otorhinolaryngology

closed. About 25% of patients had type I histologies. At a

mean follow-up of 2.7 years, 3-year overall survival rates
were 78% and 47% for the chemoradiotherapy and radio-
therapy arms. The median progression-free survival was
13 months in the radiotherapy arm compared with 52 months
in the chemoradiotherapy arm. No fatal toxicity events related
to planned treatment occurred; however, grade 3 to 4 toxicity
occurred more frequently in the chemoradiotherapy arm (76
versus 50%). Both progression-free survival and 2-year over-
all survival were statistically significant in favor of concurrent
chemoradiotherapy followed by adjuvant chemotherapy.
Because of the rarity of this disease, all stage III and IV
patients were included, thus representing a heterogeneous
group with respect to T and N classification. Forty-four per-
cent of patients in the radiotherapy arm and 45% of patients
in the chemoradiotherapy arm exhibited type III histologies.
The applicability of this heterogeneous study population to
treatment of patients in endemic areas where up to 90% of
histologies can be expected to be type III is unknown. Type I
and types II and III differ in their association with EBV as
well as in their reported response to radiotherapy, which con-
founds the applicability of this study to populations from
endemic areas. A further limitation of this study is the com-
bination of concomitant cisplatin and adjuvant cisplatin and
5-FU. The contribution of concurrent and adjuvant chemo-
therapy treatment cannot be separated in this study.

JUVENILE NASOPHARYNGEAL
ANGIOFIBROMA
A clinical presentation of epistaxis and nasal obstruction in an
adolescent male patient classically represents a juvenile
nasopharyngeal angiofibroma (JNA) until proven otherwise.
This is a relatively rare sporadic neoplasm that represents
approximately 0.05% of all head and neck neoplasms.
 Neoplasms of the Nasopharynx 493

Clinically, this tumor may be locally invasive, even eroding

adjacent skull base bone. This tumor is nonencapsulated and
is highly vascular but has not been shown to be metastatic.
Incomplete excision of JNA may result in its recurrence, but
often microscopic disease is left after excision, and in the
majority of individuals, the neoplasms do not recur.
Spontaneous regression of the neoplasm has been identified
after incomplete gross excision, but untreated angiofibromas
have not been shown to regress spontaneously. Several
hypotheses regarding the source of this mass have been
advanced, but the origin of this tumor as an aberrance of
embryology or as part of a genetic syndrome has never been
substantiated. The anatomic site of origin in nearly all cases
appears to be in the nasopharynx at the superior aspect of the
sphenopalatine foramen. The tumor develops and remains
submucosal in a complicated anatomic compartment that
defies simple surgical extirpation with generous margins.

Differential Diagnosis
The differential diagnosis of lesions within the nasopharynx in
the age group affected by JNA includes both benign and malig-
nant processes. Other benign conditions associated with nasal
obstruction include adenoid and turbinate hypertrophy, nasal
polyposis, antral choanal polyps, and nasopharyngeal cysts.
Other benign neoplasms of the nasopharynx include chordo-
mas, angiomatous polyps, teratomas (eg, dermoids), fibromas,
hemangiomas, gliomas, fibrous dysplasia, chondromas, and
rhabdomyomas. Soft tissue malignancies in the differential
diagnosis include rhabdomyosarcomas, NPCs, and lymphomas.

Clinical Presentation
The average and median ages for the presentation of JNA are
12.5 and 14 years, respectively. Early lesions will present
with epistaxis and nasal obstruction. Symptoms and signs
have predictive value for the anatomic extent of the disease.
494 Otorhinolaryngology

For example, lateral extension may cause serous otitis media,

conductive hearing loss, facial deformity including a cheek
mass, and proptosis. Cranial nerve findings are rare but may
exist and be attributable to involvement of CN I to VI.

Diagnostic Workup
Once the clinical presentation suggests a possible differential
diagnosis, a radiologic workup is performed. The MRI is par-
ticularly helpful in identifying soft tissue characteristics of
the lesion that would increasingly suggest that it is a JNA as
opposed to another neoplasm. The lesion will demonstrate
contrast enhancement on CT scans and MRI, and any vascu-
lar flow voids within the lesion will be identified on MRI.
The usual, nearly uniform enhancement of this lesion radi-
ographically distinguishes it from other vascular entities such
as arteriovenous malformations. Additionally, other accom-
panying features of soft tissue, including reactive inflamma-
tion of the sinus or nasal mucosa or postobstructive sinusitis,
will be well delineated on MRI.
Because of the characteristic clinical presentation and radio-
graphic appearance, few clinicians would feel compelled to
obtain tumor biopsies as part of the workup. Clearly, a biopsy
of this lesion could lead to massive hemorrhage and is dis-
couraged. Lesions currently undergo preoperative emboliza-
tion with carotid angiography at many major centers. This
technique allows for a decrease in blood loss during surgery
by 60 to 80%. Typically, embolization agents are directed via
the external carotid circulation through the internal maxillary
artery, but significant blood supply can be derived directly
from the internal carotid artery and ethmoidal arteries.

Treatment
Surgery
Because JNAs can involve multiple anatomic sites at the skull
base, surgical treatment options can be applied on a stage-
 Neoplasms of the Nasopharynx 495

specific basis. Additionally, the experience and surgical pref-

erence of the otolaryngologist or skull base team may affect
which approach is chosen for a particular tumor. Endoscopic
approaches have been suggested for small tumors, at least for
the smallest stage I tumors, and this has become a preferred
approach for selected tumors at some institutions. Trans-
palatal approaches have been used to remove JNA from the
nasopharynx when there is limited lateral extent of the
tumors. Other surgeons approach lesions of limited extent
transfacially through a lateral rhinotomy and medial maxil-
lectomy approach. Midfacial degloving techniques may
also be used. Lesions with extension into areas outside the
nasopharynx will often require a combination of skull base
approaches to gain adequate exposure. Clearly, lateral
approaches to the infratemporal fossa are required in resect-
ing lesions with lateral extensions to that region.

Other Modalities
Juvenile nasopharyngeal angiofibromas are known to have
recurrence rates up to 25%, and extension of disease into
extranasopharyngeal sites correlates with increased rates of
recurrence. For these reasons, several investigators have con-
sidered additional modalities of treatment for extensive JNA.
Some institutions will employ radiation therapy as standard
care for intracranial disease extension. Typically, 30 to 40 Gy
are used in standard fractions to gain lesion control. Signi-
ficant further growth of tumor is not noted, but lesions do
not completely regress after treatment. Because these tumors
are associated with puberty in young males, considerable
effort has been expended in hormonal therapies as primary
or adjunctive treatment for these tumors. Hormonal thera-
pies for this lesion have included the use of diethylstilbestrol
and flutamide.