Juvenile nasopharyngeal angiofibroma (JNA) represents a rare, complex clinical entity whose vascular
characteristics and propensity for local extension require aggressive surgical excision within the
complex anatomic environment of the sinonasal tract, nasopharynx, and skull base. The tumour
usually arises from the lateral wall of the posterior nasal cavity close to the sphenopalatine foramen
and the pterygoid base. Due to its early submucosal expansion towards the nasopharynx, it has
frequently been termed ‘nasopharyngeal angiofibroma’.
Initially described in 1906 by Chaveau, JNAs are histologically benign and almost exclusively affect
males in the second decade of life. These highly vascular tumors represent 0.05% to 0.5% of upper
aerodigestive tract tumors with recent population studies indicating an overall incidence of 0.4 cases
per million inhabitants per year.
JNAs histologically demonstrate a connective tissue stroma with mesenchymal matrix harboring a
complex array of blood vessels ranging widely in size from small capillaries to large vascular
channels.It is this dense vascular network that results in the tumor’s propensity to bleed often
resulting in spontaneous epistaxis. Moreover, in-office biopsy is contraindicated when this entity is
suspected given its vascular nature. JNAs are characterized on gross pathology as well-defined,
mucosalized, red to purple masses found in the nasal cavity and Nasopharynx.
Symptoms:
The most common presenting symptoms of patients with JNA are unilateral nasal obstruction
occurring in 91% and epistaxis occurring in 63% of patients. Other related symptoms include nasal
discharge; pain; sinusitis; facial deformity; otologic symptoms, such as hearing impairment and otitis
media; and ocular symptoms of proptosis and diplopia. Symptoms are generally present for 6 months
to a year before the patient is diagnosed. JNAs are typically found in the male population between
the ages of 10 and 24 years, with a median age at diagnosis of 15 years.
IMAGING:Computed tomography(CT) and MRI are both critical to proper evaluation of
angiofibromas. CT better delineates bony details of the skull base, including bony erosion, in
particular, the depth of invasion into the bone of the sphenoid sinus, a main predictor of recurrence.
The extent of invasion into the cancellous bone of sphenoid is difficult to determine intraoperatively,
and this leads to a high likelihood of residual tumor and recurrence. CT scans are also commonly
used for intraoperative stereotactic surgical navigation systems to confirm the extent and resection
of tumor. On the other hand, MRI is crucial for highlighting of tissue elements of the tumor and
assesses the relation of the tumor to critical structures such as the internal carotid artery, cavernous sinus, and pituitary gland. Recurrence and residual tumors are best appreciated on MRI. The
pathognomonic radiologic feature of JNAs is the anterior bowing of the posterior maxillary wall,
termed the Holman-Miller sign. Other radiologic features include a mass originating at the
sphenopalatine foramen and erosion of the mass into the pterygomaxillary fossa, sphenoid sinus,
and infratemporal fossa. Further confirmation of the JNA diagnosis is usually provided by
angiography, which also doubles as treatment with embolization. Angiography provides information
on the specific blood supply of the tumor. Distal branches of the internal maxillary artery, a branch of
the external carotid, provide the major blood supply for most JNAs, but, as tumors grow, they may
also develop vascular supply from branches of the ipsilateral internal carotid artery and contralateral
external carotid artery.9,10 Fig. 4 shows the extensive vascular network of a JNA as seen in
reconstructed images from angiography and CT angiography.
The 4 most prevalent staging systems are those of Andrews’ (modified Fisch), Chandler’s, and
Radkowski’s (modification of Sessions’ classification), UPMC staging. JNAs are classified depending on
the extension of tumor and amount of intracranial extension. At present, there is no single
universally adopted classification system.
Modified Fisch/Andrews Classification
Tumor limited to the nasal cavity and nasopharynx
Tumor extension into the pterygopalatine fossa, maxillary, sphenoid, or ethmoid sinuses
Extension into orbit or infratemporal fossa without intracranial extension
Stage IIIa with small extradural intracranial (parasellar) involvement
Large extradural intracranial or intradural extension
Extension into cavernous sinus, pituitary, or optic chiasm
Chandler’s classification of JNAs
Confined to nasopharynx
Extends into nasal cavity and/or sphenoid
Extends to 1 or several of the following: antrum, ethmoids, pterygomaxillary and infratemporal fossa, orbit, and/or cheek
Extends into cranial cavity
Radkowski’s classification (modification of Sessions’ classification) of JNAs
Limited to nose and nasopharyngeal area
Extension into 1 or more sinuses
Minimal extension into pterygopalatine fossa
Occupation of the pterygopalatine fossa with or without orbital erosion
Infratemporal fossa extension with or without cheek or pterygoid plate involvement
Erosion of the skull base (middle cranial fossa or pterygoids)
Erosion of skull base with intracranial extension with or without cavernous sinus involvement
University of Pittsburgh Medical Center (UPMC) staging system for angiofibroma
Nasal cavity, medial pterygopalatine fossa
Paranasal sinuses, lateral pterygopalatine fossa; no residual vascularity
Skull base erosion, orbit, infratemporal fossa; no residual vascularity
Skull base erosion, orbit, infratemporal fossa; residual vascularity
Intracranial extension, residual vascularity; M, medial extension; L, lateral extension
TREATMENT OPTIONS FOR JNA
Surgical resection is widely accepted as the treatment modality of choice for JNAs. Multiple surgical
approaches have been proposed and are often based on tumor size, location, and extent. Recently,
endoscopic approaches have been adopted, secondary to the likelihood of decreased morbidity.
Adjunctive radiation, hormone therapy, and chemotherapy have all been explored, with hormone
therapy and chemotherapy nearly abandoned because of ineffectiveness and significant side effects.
However, radiation therapy is still widely used, although primarily saved for advanced tumors that
would have a high morbidity with attempted resection or residual/recurrent disease in critical
anatomic areas. To complicate the issue of treatment, JNAs may spontaneously regress without any
treatment once the patient completes adolescence.
Radiation Therapy for JNA
Recent studies using radiation therapy as the definitive treatment of advanced JNAs have shown
impressive local control rates of 85% to 91%.
Complications
Malignant transformation of the tumor with increasing radiation doses has also occurred in a small
number of cases.Other complications of radiation therapy include pan-hypopituitarism, growth
retardation, cataracts, radiation keratopathy, temporal lobe necrosis, and delayed transient central
nervous system syndrome. Newer radiation techniques, such as intensity-modulated radiation
therapy, may provide the same local control rates with less morbidity but are still under investigation
for the treatment of JNAs.
ENDOSCOPIC RESECTION: SURGICAL CONSIDERATIONS
Endoscopic resection of JNA follows tumour management principles by keeping the specific
characteristics of this unique tumour in mind. Basically, the strategy of endoscopic resection takes
the following considerations into account:
1. Opening of the maxillary sinus and exposure of its posterior wall are performed early
during surgery. The size of the tumour dictates the size of the medial maxillectomy. The bony
posterior wall of the maxillary sinus is removed with ‘through cutting’ punches or drills avoiding
trauma to the periosteum in the pterygopalatine fossa before resection of the bone is completed.
Following incision of the periosteum, the sphenopalatine and maxillary arteries are identified and
clipped or coagulated. Early control of the main feeding vessel is of great value to assist further
tumour resection. An alternative in early JNAs is to push the tumour gently in a medial direction out
of the pterygopalatine and infratemporal fossae and to identify the main feeding vessel by this
manoeuvre. In cases where an extended access to the maxillary sinus does not allow exposure of
the lateral tumour border within the infratemporal fossa in advanced JNAs, the tumour can be
pushed medially with a finger placed externally at the lateral border of the maxillary sinus below the
jaw.
2. Resection of the posterior nasal septum is advised to widen the access in endoscopic tumour
removal and to define tumour margins at the nasal septum.
3. The anterior sphenoid sinus wall is removed in order to expose the tumour within the sphenoid
sinus. For this purpose, a bilateral opening of the sphenoid sinus is usually necessary.
4. Finally, the tumour is dissected directly off the pterygoid base and pterygoid canal regions and the
clivus. Troublesome venous bleeding from bone can be managed at this stage with drilling,
chemical haemostatic agents or fine endosurgical diathermy.
5. It is of utmost importance to drill at pterygoid base and clivus at end of surgery in order to avoid
residual tumour.
6. Endoscopic dissection should always follow pseudocapsule in order to avoid injury of the tumour
at the surface. Finger-like extensions of the tumour can be gently pulled out along pseudocapsule.
Immediate Postoperative Care
Following JNA Resection once tumor is completely resected, warm water irrigation (110 0F) is
copiously performed throughout the cavity. Any residual bleeding is controlled with bipolar cautery
or pressure. Floseal is usually packed into the areas of the PPF and infratemporal fossa compounds.
Gelfoam is then routinely laid over the Floseal, and pressure is applied using a Foley balloon for 24
hours. In cases of a small tumor with minimal blood loss, the patient can be monitored in a standard
floor bed; however, if the patient experiences significant blood loss or for larger JNAs, it is advisable
to monitor the patient in the intensive care unit (ICU) while the Foley is in place. The Foley is
removed on postoperative day 1. The patient is then started on nasal saline sprays for 1 week and is
transitioned to nasal saline irrigations thereafter. Routinely, the patient is discharged home on this
irrigation regimen with instructions to refrain from nose blowing and strenuous activity, including
instructions regarding bowel regimens in the setting of constipation. Any events of arterial bleeding
should necessitate an endoscopy and possible repeated surgical intervention. If patients present with
a bleed in the outpatient setting, they should be instructed to report immediately to the emergency
room.
Postoperative Follow-Up
In the postoperative setting, patients undergo sinonasal endoscopy with debridements in the clinical
setting at approximately 2 weeks and again at 4 to 6 weeks. The postoperative cavity is usually well
mucosalized by 6 to 12 weeks after surgery. Multidisciplinary follow-up may be necessary in certain
cases. If the patient has significant orbital involvement, postoperative follow-up with ophthalmologic
examination for transient double vision may be warranted. If an aggressive Denker’s medial
maxillectomy was performed and then as al lacrimal duct was transected sharply, postoperative
transient epiphora may be expected. Follow-up with neurosurgical examinations may be necessary if
there was significant intracranial extension or a substantial CSF leak. Follow-up in the first year is
usually every 3 months. It has becomeourtendencyroutinely to obtain a postoperative MRI with
contrast in the first 3 months if we believe we achieved a total resection, so that we have baseline
imaging for future comparison to detect recurrence. If portions of the tumor might need to be
reresected or staged, we obtain an early MRI during the immediate postoperative hospitalization for
planning.
Steroid Hormones and Nuclear Receptors
Steroid hormones have been implicated in the development of many human tumors. Breast and
prostate carcinomas have hormonally-based treatments that improve overall survival and have
significant tumor response rates. JNA’s sex predilection and age presentation, around puberty,
suggest that its development is hormone dependent. Initial studies focused on hormone imbalances,
whereas others have investigated the presence of sex hormone receptors in JNA tissue.Farag and
colleagues evaluated serum levels of dihydrotestosterone, testosterone, and 17b-estradiol in a small
series (N 5 7) of patients with JNA. The influence and mechanism of action of hormones on JNA
remain controversial; however, the antiandrogen drug flutamide has shown promise with significant
partial response rates. Advanced-staged JNAs were administered flutamide orally for 6 weeks before
surgical excision. In this study, pretreatment and posttreatment tumor volumes and responses were
measured by MRI. The study yielded interesting results: prepubertal and postpubertal patients
responded differently to hormonal therapy. Prepubertal cases had inconsistent and minimal
responses, whereas 13 of 15 (87%) postpubertal cases demonstrated a partial radiographic response
(mean, 16.5%; maximum, 40%). Two cases with symptomatic vision loss and optic nerve compression
had visual improvement. Presurgical volume reduction correlated significantly with both serum
testosterone level and postpubertal status. There were minimal side effects from this treatment. Of
note, this study did not compare the histologic effects of treatment or surgical outcomes with those
in a control group. The findings suggest, however, that flutamide treatment might be considered for
presurgical volume reduction, symptomatic tumor compression, or advanced tumor stages. However,
because no complete responses to the drug were noted, complete surgical removal remains the
definitive treatment option.
Growth Factors
Angiogenesis is essential to the growth of solid tumors. The most predominant and well-studied
proangiogenic growth factor in tumor biology is vascular endothelial growth factor (VEGF). In a study
by Brieger and colleagues, immune-histochemical examination of 10 JNAs revealed the frequent
expression of VEGF(80%) in both stromal cells and vessels. Furthermore, VEGF expression was
associated with proliferation and increased vessel density, suggesting that it might promote
vascularization in JNA. Increased levels of other angiogenic factors, including basic fibroblast growth
factor, transforming growth factor b1, and VEGF receptor 2, have also been recently associated with
high vessel densities in JNA. However, the clinical and etiologic relevance of such elevations are
unclear. Although many angiogenic growth factors are present in JNAs at levels that are statistically
significant, it is not known if this is a causative factor or an incidental finding. In the setting of a
vascular tumor, elevated vascular growth factor levels and a higher density of angiogenic proteins
might be expected. Insulin-like growth factors (IGFs)–polypeptides with a variety of functions,
including stimulation of cell growth, cell division, and regulation of apoptosis–have also been
implicated. Although immunohistochemical studies have revealed no expression of IGF-1 receptor in
JNA tissue, Nagai and colleagues reported the expression of IGF-2 in 53% of JNAs, suggesting that
IGF-2 may mediate growth of these tumors via a mechanism not directly involving the IGF-1 receptor.
Although several studies have associated various growth factors with JNA, a potential target in the
treatment of JNA has yet to be clearly identified. Chromosomal Abnormalities Molecular genetic
techniques and genomic analysis have begun to show preliminary evidence of amplified oncogenes
and/or deleted tumor suppressor genes in JNA. There has been a preponderance of evidence that
the location of genetic alterations or chromosomal loss may be directly related to the sex
chromosomes (X and Y). The presence of abnormalities on specific chromosome locations in patients
with JNA, including loss of the Y chromosome, may be of great importance in revealing the
pathogenesis of this disease. However, a direct causal effect of a single gene loss or overexpression is
not suggested by the genetic studies. As with the potential vascular targets, there are no genetically
targeted therapies for JNA currently available.