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.