Juvenile Nasopharyngeal Angiofibroma

Hippocrates described the tumor in the 5th century BC, but Friedberg first used the term angiofibroma in 1940. Other titles (eg, nasopharyngeal fibroma, bleeding fibroma of adolescence, fibroangioma) have also been used.

The image below depicts a coronal CT scan.

Frequency

Juvenile nasopharyngeal angiofibroma (JNA) accounts for 0.05% of all head and neck tumors. A frequency of 1:5,000-1:60,000 in otolaryngology patients has been reported.

Sex

Juvenile nasopharyngeal angiofibroma (JNA) occurs exclusively in males. Females with juvenile nasopharyngeal angiofibroma (JNA) should undergo genetic testing.

Age

Onset is most commonly in the second decade; the range is 7-19 years. Juvenile nasopharyngeal angiofibroma (JNA) is rare in patients older than 25 years.

The lesion originates in close proximity to the posterior attachment of the middle turbinate, near the superior border of the sphenopalatine foramen.

A hormonal theory has been suggested because of the lesion's occurrence in adolescent males. Moreover, a study by Liu et al found that JNAs express higher levels of hormone receptors and vascular endothelial growth factor (VEGF) than does normal nasal mucosa, a possible indication that interaction between the receptors and VEGF is associated with JNA initiation and growth.[4]

Other theories include a desmoplastic response of the nasopharyngeal periosteum or the embryonic fibrocartilage between the basiocciput and the basisphenoid.

Etiology from nonchromaffin paraganglionic cells of the terminal branches of the maxillary artery has also been suggested. Comparative genomic hybridization analysis of these tumors revealed deletions of chromosome 17, including regions for the tumor suppressor gene p53 as well as the Her-2/neu oncogene.

The tumor starts adjacent to the sphenopalatine foramen. Large tumors are frequently bilobed or dumbbell-shaped, with one portion of the tumor filling the nasopharynx and the other portion extending to the pterygopalatine fossa.[5]

Anterior growth occurs under the nasopharyngeal mucous membrane, displacing it anteriorly and inferiorly toward the postnasal space. Eventually, the nasal cavity is filled on one side, and the septum deviates to the other side. Superior growth is directed toward the sphenoid sinus, which may also be eroded. The cavernous sinus may become invaded if the tumor advances further.

Lateral spread is directed toward the pterygopalatine fossa, bowing the posterior wall of the maxillary sinus. Later, the infratemporal fossa is invaded. Occasionally, the greater wing of the sphenoid may be eroded, exposing the middle fossa dura. Proptosis and optic nerve atrophy result if orbital fissures are encroached upon by the tumor. Extranasopharyngeal angiofibroma is extremely rare and tends to occur in older patients, predominately in females, but the tumor is less vascular and less aggressive than juvenile nasopharyngeal angiofibroma (JNA).

Symptoms

See the list below:

• Nasal obstruction (80-90%) - Most frequent symptom, especially in initial stages

• Epistaxis (45-60%) - Mostly unilateral and recurrent; usually severe epistaxis that necessitates medical attention; diagnosis of angiofibroma in adolescent males to be ruled out

• Headache (25%) - Especially if paranasal sinuses are blocked

• Facial swelling (10-18%)

• Other symptoms - Unilateral rhinorrhea, anosmia, hyposmia, rhinolalia, deafness, otalgia, swelling of the palate, deformity of the cheek

Signs

See the list below:

• Nasal mass (80%)

• Orbital mass (15%)

• Proptosis (10-15%)

• Other signs include serous otitis due to eustachian tube blockage, zygomatic swelling, and trismus that denote spread of the tumor to the infratemporal fossa, decreasing vision due to optic nerve tenting (rare)

Differentials

See the list below:

• Other causes of nasal obstruction, (eg, nasal polyps, antrochoanal polyp, teratoma, encephalocele, dermoids, inverting papilloma, rhabdomyosarcoma, squamous cell carcinoma)

• Other causes of epistaxis, systemic or local

• Other causes of proptosis or orbital swellings

Plain radiography views of the sinuses may demonstrate nasopharyngeal polyp. Bowing of the posterior wall of the maxillary sinus and maxillary sinus opacification is very suggestive of juvenile nasopharyngeal angiofibroma (JNA). Newer radiographic modalities have surpassed plain films in usefulness.

CT scan images below demonstrate the extent of the tumor. Extension to the sphenoid sinus, erosion of the greater sphenoidal wing, or invasion of the pterygomaxillary and infratemporal fossae is usually visualized, as in the images below.

Magnetic resonance imaging (MRI) is indicated to delineate and define the extent of the tumor, especially in cases of intracranial involvement. Coronal MRI scan showing extension of the lesion to the cavernous sinus is seen in the image below.

Angiography shows the branches of the external carotid system to be the primary feeders (94%). The main supply comes from the internal maxillary artery, but ascending pharyngeal or vidian arteries may contribute to the blood supply. Unnamed branches from the internal carotid artery contribute to vascularity in rare instances. Bilateral vascular supply may be an underappreciated factor in JNA, and thorough radiographic investigation via angiography of bilateral carotid systems should be routinely performed preoperatively.[3] An angiofibroma before and after embolization can be seen in the images below.

On gross examination, the tumor is usually sessile, lobulated, rubbery, and red-pink to tan-gray in appearance. In rare cases, the tumor is polypoid or pedunculated.

Nasopharyngeal angiofibroma is usually encapsulated and composed of vascular tissue and fibrous stroma with coarse or fine collagen fibers. Vessels are thin-walled, lack elastic fibers, have absent or incomplete smooth muscle, and vary in appearance from stellate or staghorn to barely conspicuous because of stromal compression. Stromal cells have plump nuclei and tend to radiate around the vessels. An abundance of mast cells in the stroma and a lack of other inflammatory cells exist. Localized areas of myxomatous degeneration may be observed in the stroma.

When examined under electron microscope, stromal cells are mostly fibroblasts and show intensive immunostaining for vimentin. However, myofibroblasts may occur focally in connection with fibrotic areas and are characterized by the coexpression of vimentin and smooth muscle actin.

Different staging systems exist for nasopharyngeal angiofibroma. The 2 most commonly used are those of Sessions and Fisch.

• Classification according to Sessions

  • Stage IA - Tumor limited to posterior nares and/or nasopharyngeal vault

  • Stage IB - Tumor involving posterior nares and/or nasopharyngeal vault with involvement of at least 1 paranasal sinus

  • Stage IIA - Minimal lateral extension into pterygomaxillary fossa

  • Stage IIB - Full occupation of pterygomaxillary fossa with or without superior erosion of orbital bones

  • Stage IIIA - Erosion of skull base (ie, middle cranial fossa/pterygoid base); minimal intracranial extension

  • Stage IIIB - Extensive intracranial extension with or without extension into cavernous sinus

• Classification according to Fisch

  • Stage I - Tumors limited to nasal cavity, nasopharynx with no bony destruction

  • Stage II - Tumors invading pterygomaxillary fossa, paranasal sinuses with bony destruction

  • Stage III - Tumors invading infratemporal fossa, orbit and/or parasellar region remaining lateral to cavernous sinus

  • Stage IV - Tumors invading cavernous sinus, optic chiasmal region, and/or pituitary fossa

Hormonal therapy

The testosterone receptor blocker flutamide was reported to reduce stage I and II tumors to 44%. Despite tumor reduction with hormones, this approach is not routinely used. Schuon et al reported on the immunohistochemical analysis of growth mechanisms in juvenile nasopharyngeal angiofibroma.[6] They concluded that juvenile angiofibroma (JNA) growth and vascularization are driven by factors released from stromal fibroblasts. Therefore, inhibition of these factors might be beneficial for the therapy of inoperable juvenile nasopharyngeal angiofibroma (JNA).

Radiotherapy

Some centers have reported 80% cure rates with radiation therapy. However, concerns regarding potential effects of radiation make radiation therapy a nonuseful modality in most cases.

Stereotactic radiotherapy (ie, Gamma Knife) delivers a lower dose of radiation to surrounding tissues. However, most authorities reserve radiotherapy for intracranial disease or recurrent cases.

Conformal radiotherapy in extensive juvenile nasopharyngeal angiofibroma (JNA) or intracranial extension provides a good alternative to conventional radiotherapy regarding disease control and radiation morbidity, even with advanced disease.[7, 8]

Owing to the possibility of massive bleeding, biopsying suspected JNA is contraindicated.

Surgically, a lateral rhinotomy, transpalatal, transmaxillary, or sphenoethmoidal route is used for small tumors (Fisch stage I or II).

The infratemporal fossa approach is used when the tumor has a large lateral extension.

The midfacial degloving approach, with or without a Le Fort osteotomy, improves posterior access to the tumor. (A study by de Mello-Filho et al of 40 patients indicated that JNA can be successfully treated with resection by Le Fort I osteotomy, with the surgery being effective even when the tumor has invaded the central nervous system.[9] )

The facial translocation approach is combined with Weber-Ferguson incision and coronal extension for a frontotemporal craniotomy with midface osteotomies for access.

An extended anterior subcranial approach facilitates en bloc tumor removal, optic nerve decompression, and exposure of the cavernous sinus.

Some authors advocate the use of intranasal endoscopic surgery for lesions with limited extension to the infratemporal fossa. Image-guided, endoscopic, laser-assisted removal has also been used. Hackman et al (2009) reviewed 31 cases of JNA at the University of Pittsburgh Medical Center from 1995 to 2006.[10] Most tumors were completely excised using the expanded endonasal approach (EEA) alone or in combination with minor sublabial incisions, avoiding the morbidity associated with larger open approaches or postoperative radiation therapy.

Radical removal of a large JNA may be difficult because of its extreme vascularity and extension to the cavernous sinus, orbit, middle fossa, and anterior fossa. Nevertheless, most JNAs with intracranial extension can be resected in the first operation with minimal morbidity through a facial degloving and further combination of expanded endoscopic endonasal approaches.[11]

In a retrospective review, Battaglia et al (2014) evaluated the use of endoscopic endonasal surgery in the radical resection of benign or nonmetastatic malignant tumors that have either developed in or extended to the infratemporal fossa or upper parapharyngeal space.[12] According to the investigators, the results, derived from 37 patients, including 20 with JNA, suggested that purely endoscopic endonasal radical resection can be safely used to treat selected tumors involving these spaces.

In a review article, Cloutier et al (2012) reported on 72 patients operated on over a 10-year period.[13] They concluded that the progress in skull-base surgery allowed for expansion of the indications for endoscopic removal of JNA. This approach has a better outcome in terms of blood loss, hospital stay, and complications. Of course, an external approach should be considered only for selected cases due to massive intracranial extension or optic nerve or internal carotid artery entrapment by the tumor.

In a meta-analysis of the endoscopic surgical outcomes of JNA, covering 92 studies and a total of 821 patients, Khoueir et al (2014) calculated that the mean operative blood loss from endoscopic JNA surgery was 564.21 mL. Random effect estimates for recurrence, complications, and residual tumor were 10%, 9.3%, and 7.7%, respectively. The authors stated that endoscopic treatment is currently considered the treatment of choice for JNA but also commented that they could find no randomized, controlled studies for their analysis. They advised that future studies propose a new, endoscopic approach – based classification system.[14]

A study by Overdevest indicated that surgical blood loss in JNAs tends to be greater when the lesions are supplied by the internal carotid artery or have a bilateral arterial supply.[15]

Yi et al (2013) described a simplified classification system and management option for juvenile nasopharyngeal angiofibroma, as follows[16] :

• Type I includes tumor localized in the nasal cavity, paranasal sinus, nasopharynx, or pterygopalatine fossa. The transnasal cavity approach with endoscopic guidance is suitable for this type.

• Type II is if the lesion extends into the infratemporal fossa, cheek region, or orbital cavity, with anterior and/or minimal middle cranial fossa extension but intact dura mater. The transantral-infratemporal fossa-nasal cavity combined approach is reliable for type II.

• Type III is a calabashlike, massive tumor lobe in the middle cranial fossa. For type III tumors, the complete removal is challenging. A combined extracranial and intracranial approach is often needed. Radiotherapy is useful for treating the residual intracranial part.

Preoperative embolization has typically been performed via a transarterial route using a variety of embolic materials. It is accomplished using reabsorbable microparticulate substances (eg, Gelfoam, polyvinyl alcohol, dextran microspheres) or nonabsorbable microparticulates (eg, Ivalon, Terbal). Limiting blood loss during surgery is essential. Endoscopic assistance has been used for direct transnasal tumor puncture and intratumoral embolization using the liquid embolic agent Onyx.[17]

Preoperative angiography and embolization minimize intraoperative blood loss, and the current shift in the treatment to endoscopic excision in selected cases reduces perioperative morbidity.[18] Low-grade consumption coagulopathy may complicate small juvenile nasopharyngeal angiofibroma (JNA) and implies that preoperative coagulation screening may have a role in perioperative hemostasis.

Malignant transformation has been reported in 6 cases; 5 of these patients were treated with radiotherapy, according to a study by Makek et al.[19]

Transient blindness has been reported as a result of embolization, but it is a rare occurrence. Osteoradionecrosis and/or blindness due to optic nerve damage may occur with radiotherapy.

Fistula of the palate at the junction of the soft and hard palate may occur with the transpalatal approach but is prevented by preservation of the greater palatine vessels during flap elevation.

Anesthesia of the cheek is a frequent occurrence with the Weber-Ferguson incision.

A rare case of massive epistaxis from spontaneous rupture of the intracavernous tract of the internal carotid artery 20 days after resection of a giant JNA by midface degloving was recently reported.[20] Coils were selectively used to occlude the vessel and to stop the hemorrhage.

The presence of tumor in the pterygoid fossa and basisphenoid, erosion of the clivus, intracranial extension, feeders from the internal carotid artery, a young age, and a residual tumour are risk factors associated with the recurrence of juvenile nasopharyngeal angiofibroma (JNA).

A retrospective study by Song et al indicated that in patients treated for juvenile nasopharyngeal angiofibroma (JNA), time to recurrence tends to be longer when levels of hypoxia-inducible factor 1-alpha in the endothelial cells are low.[21]

A literature review by Reyes et al indicated that in patients without intracranial compromise, the rate of recurrence after endoscopic surgery for juvenile nasopharyngeal angiofibroma (JNA) is significantly less than that following the open surgical approach (13% vs 28%, respectively). In patients with intracranial compromise, the recurrence rates did not statistically differ.[22]