Juvenile Nasopharyngeal Angiofibroma December 2012

TITLE: Juvenile Nasopharyngeal Angiofibrom= a: Evaluation and Treatment
SOURCE: Grand Rounds Presentation, Department of Otolaryngology
The University of Texas Medical Branch (UTMB Health) <= /span>
DATE: December 19, 2012
RESIDENT PHYSICIAN: Viet Pham, MD
FACULTY PHYSICIAN: Shraddha Mukerji , MD
SERIES EDITOR: Francis B. Quinn, Jr., MD
ARCHIVIST: Melinda Stoner Quinn, MSICS

"This material was prepared by resident physicians in partial fulfillment of educational requirements established f= or the Postgraduate Training Program of the UTMB Department of Otolaryngology/= Head and Neck Surgery and was not intended for clinical use in its present form.= It was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express or implied, are made with respect to= its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and sho= uld not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion." =

INTRODUCTION

A rare tumor that comprises only 0.5% of neoplasm= s in the head and neck (Herman 1999, Tewfik 1999), juvenile nasopharyngeal angiofibroma (JNA) is pathognomonically characterized as a benign vascular tumor located in the posterior nasopharynx of adolescent males. Although not a malignant process, = JNA is known for its locally invasive spread with progressive growth that can attribute to a significant degree of morbidity commonly related to either intracranial extension or massive hemorrhage.

JNA was first described in conjunction with nasal polyps by Hippocrates in the 5^th century BC (Babyn 2005), but it= was Chelius who distinguished it as one associated with puberty in 1847. Initially regarded as a fibrous na= sal polyp at that time, the term “angiofibroma” was not coined until Friedberg did so in 1940 (Gullane 1992).

DEMOGRAPHICS

There is a strong predilection for JNA to affect teenage males, typically between 14-15 years of age, although the reported = age range spans between 10-25 years of age (Ardehali 2010). It exhibits a generally indolent c= ourse with symptoms commonly lasting for 6-12 months prior to diagnosis, with approximately 70% of individuals already demonstrating at least a stage II clinical presentation upon diagnosis (Radkowski 1996).

ORIGIN

The internal maxillary artery is the most common vascular source from which JNAs arise.&nbs= p; Other known vessels include the ascending pharyngeal artery as well = as the external, internal, and common carotid arteries. While not a frequent occurrence, J= NAs have also been known to develop from blood supply contralateral to the side they form. The exact site tha= t JNA originates from remains controversial although most accept the assertion th= at it involves the posterolateral nasal wall at the sphenopalatine foramen. However, there is a minority that believes JNA is related more to the vidian canal.

Similarly, the pathophysiology to JNA formation r= emains hotly contested. Given its ty= pical location near the superior margin of the sphenopalatine foramen, there has = been some postulation that the underlying mechanism derives from the embryologic chondrocartilage of the skull bones (Schiff 1959), particularly at the trifurcation of the palatine bone, horizontal ala of the vomer, and the roo= t of the pterygoid process (Neel 1973, Bremer 1986).

Given its essential exclusivity to adolescent mal= es, there has been some belief that JNA development is related to the pituitary androgen-estrogen axis (Schiff 1959), especially with the observation of androgen and estrogen receptors noted on some JNA cells (Montag 2006). While plausible, there has been no endocrinologic abnormality identified among individuals with JNA (Neel 1973, Sessions 1981, Shikani 1992). Other theories suggest a role for vascular endothelial growth factor receptor-2, transforming growth factor beta 1, or insulin-like growth factor 2 (Coutinho-Camillo 2008), while other ideas suspect that JNA is more of a vascular hamartoma (Girgis 1973) or inflammatory reaction.

HISTOLOGY

Histologically, JNA exhibits cells of myofibrobla= st origin surrounded by a fibrous pseudocapsule. There are multiple vascular channe= ls dispersed within the neoplasm composed of abundant endothelial cells embedd= ed in a collagenous tissue network. An important hallmark is the lack of a true muscular layer, and this absence precludes any form of vasoconstriction and is felt to contribute to the tumor’s high propensity for hemorrhage (Liu 2002).

PRESENTATION

The manner JNA conventionally declares itself is = with unilateral nasal obstruction or recurrent epistaxis in an adolescent male.<= span style=3D'mso-spacerun:yes'> Physical examination will commonly= reveal a smooth and lobulated, compressible purplish or reddish nasal mass. Surrounding structures in the nasopharynx may result in atypical symptoms including middle ear effusions = and conductive hearing loss with blockage of the Eustachian tubes, rhinolalia, palatal deformity, hyposmia, or anosmia.&n= bsp;

With more advanced tumors, anterior extension may impede the nasolacrimal duct and result in dacrocystitis. Further progression may manifest w= ith a facial swelling or proptosis while encroachment toward the intracranial vau= lt will lead to headaches or cranial neuropathies. Massive hemorrhage is typically affiliated with a large tumor burden.

NATURAL HISTORY

The key element of JNA behavior is submucosal ext= ension toward the pterygomaxillary fossa, infratemporal fossa, or the superior orb= ital fissure (Radkowski 1996, Enepekides 2004).= Involvement of the superior orbital fissure facilitates invasion of = the cavernous sinus or orbit. Intracranial extension occurs in 20-36% (Close 1989, Wiatrak 1993), typically with either the anterior or middle cranial fossae or the pituitary parasellar region. Despite the morbidity associated with intracranial spread in general, actual dural penetration is rare with JNA and is one reason some surgeons do not indiscriminately regard all such cases as unresectable.

Complete surgical extrication is vital to definit= ive treatment of JNA as an incomplete resection is the leading etiology for recurrence, estimated to occur in up to 46% depending on surgical technique (Fagan 1997). The risk is hig= her for tumor extension to the sphenoid sinus, pterygoid base, and the clivus. Interestingly, spontaneous regress= ion has been described in some cases, particularly in individuals older than 25 years of age leading to speculation that this phenomenon is related to post-pubertal hormonal changes (Tosun 2008). Others have contested this with the observation that regression is only possible for residual tumors that had undergone prior treatment (Neel 1973, Stansbie 1986, Mishra 1989).

DIFFERENTIAL DIAGNOSIS

A myriad of other neoplasms can masquerade with a similar appearance as JNA, which is an important consideration given its overall rarity. Pyogenic gran= ulomas and hemangiopericytomas can present in the nasal passages and also be affiliated with a certain degree of epistaxis. Nasal polyps are other masses more commonly encountered in the nasal cavity, albeit with a lower propensity for hemorrhage. Other tumors invo= lving the skull base can emulate a locally advanced JNA such as a craniopharyngio= ma, chordoma, chondrosarcoma, nasopharyngeal carcinoma, olfactory neuroblastoma= , or rhabdomyosarcoma.

STAGING

The first classification scheme employed to better define JNA was introduced by Sessions in 1981, and there have been multiple modifications since then including those described by Fisch (1983), Chandler (1984), = and Andrews (1989). The staging s= ystem introduced by Radkowski constitutes the most recent adaptation and focuses = more on the tendency for JNA to extend posteriorly toward the pterygoid plates a= nd also distinguishes the degree of skull base erosion present (Radkowski 1996= ). Table 1 presents this scheme below= . Ultimately, however, no classifica= tion system has been universally accepted, and it is not uncommon for various articles to discuss their results using different systems.

Table 1. Radkowski JNA Classification System

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RADIOLOGY

JNA exhibits a characteristic appearance on roent= genology that often makes obtaining a biopsy redundant. Such a diagnostic approach is favo= rable given the potentially high risk for significant hemorrhage from such neoplasms. Key features to su= pport a diagnosis of JNA include the presence of a vascular mass with an epicente= r at the posterior nasal cavity near the medial pterygopalatine fossa, the prese= nce of bony modeling—but not destruction—with tumor growth, and the lack of regional or distant metastasis (Amdur 2011). For atypical extension or unexpect= ed rapid growth, a biopsy should be considered to assess for other neoplasms a= side from JNA.

JNA will demonstrate an intense homogenous contra= st enhancement on computed tomography (CT). = An important advantage of CT imaging is its superiority in evaluating bony det= ails compared to magnetic resonance imaging (MRI), and this is best exemplified = with an anterior bowing to the posterior maxillary sinus wall that JNA is common= ly associated with known as the Holman-Miller sign. Widening of the sphenopalatine for= amen may also be observed.

Diffuse intense contrast enhancement is also note= d with JNA on both T1- and T2-weighted MRI. The utility of MRI is demonstrated with its improved soft tissue differentiation compared to CT, as it is able to delineate mucosal inflamma= tion versus sinus fluid and assist with accurate tumor staging. MRI is also crucial in assessing t= he degree of intracranial extension, and flow voids within the numerous tumor vessels have been described on MRI scans (John 2006).

ANGIOGRAPHY

JNA’s dependence on the carotid arterial sy= stem has understandably directed attention to evaluate the potential benefit of angiography. In addition to identifying the source vessel, angiography may serve as a vector for embolization prior to surgical excision.&n= bsp; Furthermore, a balloon occlusion test of the carotid may be conducte= d to facilitate appropriate preoperative counseling (Danesi 2008). Despite its utility in managing JN= A, angiography is not a required diagnostic endeavor and surgical excision may still be performed in the absence of it (Ahmad 2008).

Preoperative embolization is generally undertaken= 24-72 hours prior to resection and often employs either gelfoam or polyvinyl alco= hol foam. Gelfoam generally lasts= for approximately two weeks while polyvinyl alcohol foam is more permanent. The rationale is that occluding the responsible artery from which the JNA originates will decrease intraoperati= ve blood loss and even decrease the tumor size to augment resectability. Complications associated with embolization include the potential for cerebrovascular accident if one of t= he carotids is affected, blindness if the ophthalmic artery is embolized, and necrosis of skin and soft tissue depending on which vascular supply has been compromised. Facial paralysis= has also been reported, but this was in conjunction with a preauricular approach for surgical excision and it is plausible that the facial palsy may be attr= ibuted more to the surgical excision as opposed to the embolization.

A number of studies support the role of embolizat= ion in reducing intraoperative blood loss (Moulin 1995, Li 1998, Liu 2002). However, Moulin reported statistic= al significance of this occurrence only for larger staged tumors while Liu not= ed similar findings only for smaller ones limited to the nasal cavity or nasopharynx. Liu also compared embolization with carotid ligation and did not appreciate a difference betw= een the two in regards to hemorrhage.

SURGERY

The primary treatment modality is surgical excisi= on (Marshall 2006), and it remains a viable option in cases of intracranial extension (Bales 2002). While preoperative embolization is regarded as a beneficial adjuvant therapy, it = can obscure tumor borders and complicate resection (Andrade 2007). Recurrence is highly related to incomplete removal, with most reports estimating that this occurs in 6-37.5= % of surgeries (Fagan 1997, Hosseini 2005, Cansiz 2006, Hyun 2011) within six mo= nths postoperatively (Tyagi 2006). However, the surgical plan needs to consider that a more extensive resection in an attempt to prevent recurrence is inherently associated with= a higher degree of morbidity. A= reas of most concern include the pterygoid fossa, clivus, basisphenoid, sphenoid diploe, cavernous sinus, and intracranial vault.

A transpalatal approach involves splitting and retracting the soft palate to expose the hard palate. A portion of the palatine bone and inferior pterygoid plate is then removed to facilitate access to the nasopharynx from which the JNA can be removed. In general, the transpalatal appro= ach is ideal for tumors limited to the sphenoid sinus as there tends to be limited lateral exposure, but Le Fort I osteotomies may permit access to the parana= sal sinuses, pterygopalatine fossa, and infratemporal fossa (Yiotakis 2008). The major risks associated with th= is approach include palatal dehiscence and the formation of an oroantral fistu= la.

Creating a lateral rhinotomy incision provides an external approach to access more of the nasal cavities and nasopharynx, allowing for resection of larger tumors.&n= bsp; A number of variations of this have been introduced that revolve aro= und making a Weber-Fergusson incision with various extensions to customize the exposure necessary to remove a JNA. This includes combinations with a Lynch extension, lateral subciliary extension, and subciliary and supraciliary extensions. While exposure is greatly enhanced compared to a transpalatal approach, it comes with the caveat that a potentially unsightly scar may develop.

The midfacial degloving technique attempts to rec= reate the superior exposure afforded by a lateral rhinotomy but without the associated external incisions. In general, this involves creating a gingivobuccal incision coupled with intercartilagneous and transfixion incisions similar to those made in an external rhinoplasty. This is= to essentially translocate the soft tissue of the midface off the bony midface= of the skull, and access into the nasal passages is provided via Le Fort I osteotomies.

While cosmetically favorable, midfacial degloving= is affiliated with a number of potential sequelae with nasal crusting being the most common. Others include epistaxis, nasal vestibular stenosis, nasolacrimal duct obstruction, facial paresthesia, and facial nerve palsy. An oroantral fistula could still arise, and carotid artery rupture i= s a rare but previously reported complication.

Historically, locally advanced JNAs were addresse= d with a large, extensive infratemporal fossa approach with possible craniotomy. As surgical techniques have progressively been refined, anterior access is now felt to be sufficient for most intracranially invading tumors and use of a craniotomy is less common. A transfacial, transm= axillary approach is generally utilized for such situations (Elsharkawy 2010), and a medial maxillectomy is often believed to be required to access the medial infratemporal fossa, cavernous sinus, sphenoid sinus, or anterior skull base (Fagan 1997). There is growing sentiment that endoscopic access is feasible in select cases (Danesi 2008),= and others have advocated a combined endoscopic and external approach (Douglas 2006).

Much interest has been invested in endoscopic res= ection of JNA given its generally positive results with avoidance of incisions. The general approach involves crea= ting a middle meatus antrostomy with a middle turbinectomy as needed for exposure. With a large enough antrostomy, the posterior maxillary sinus wall can then be removed to allow ligation of the sphenopalatine artery and any other vascular contributions = in the area. Tumor resection fro= m the pterygopalatine fossa can then proceed.&nb= sp; Some disadvantages with endoscopic removal include the difficulty in employing simultaneous instrumentation (Wormald 2003), limited tumor mobilization inside the nasal cavity (Douglas 2006), and significantly impa= ired visualization with brisk hemorrhage (Yiotakis 2008).

One of the more common complications related to endoscopic tumor resection includes nasal synechia. Given the various neurovascular structures nearby, other possibilities include lacrimal duct stenosis, cheek paresthesia with damage to the maxillary nerve, and vision changes if crani= al nerves III or IV are impacted. Sphenoid mucocele formation has been reported in addition to few accounts of cavernous sinus injury.

Acknowledging variations among institutions, stag= e I and II tumors have been felt to be best addressed with either transpalatal = or endoscopic methods while a lateral rhinotomy or midfacial degloving was reserved for stage III tumors (Hosseini 2005). Others have generally followed sui= t, but there has been a shift favoring endoscopic removal of JNA (Mann 2004). The endoscopic approach was observ= ed to manifest with less intraoperative blood loss, a shorter operative time, and= a brief hospitalization as compared to either the transpalatal and midfacial degloving techniques for stage I and II tumors (Yiotakis 2008). Endoscopic removal has been deemed feasible for even stage IIIA tumors (Wormald 2003), and this is further augmented with decreased intraoperative and postoperative hemorrhage and a shorter hospitalization when combined with preoperative embolization (Ardeh= ali 2010).

RADIATION

Originally reserved for unresectable or life-threatening tumors, radiotherapy (XRT) is an alternative treatment modality in managing JNA. Therapeutic results were appreciated with dose ranges between 30-46Gy (McAfee 2006, Chakraborty 2011), and primary XRT has been demonstrated to be just as effective as surgery with a 15% recurrence rate (Reddy 2001). The associated complication rate i= s low but more notable ones include temporal lobe necrosis (Lee 2002), cataracts (Amdur 2011), arrest of craniofacial growth, induction of future malignanci= es (Witt 1983) such as a fibrosacoma (Makek 1989), hypopituitarism, and osteoradionecrosis (Witt 1983).

XRT has historically been regarded to attain tumor control rates between 80-85% (Briant 1978, Cummings 1984, Reddy 2001), alth= ough Amdur reported control rates up to 90% and concluded that neoadjuvant XRT p= rior to a planned subtotal resection and adjuvant XRT for microscopically positi= ve surgical margins were of minimal benefit.&= nbsp; Furthermore, elective nodal irradiation was deemed unnecessary, and = most recurrences after XRT would manifest by two years after treatment. The diagnosis of JNA should be questioned if there was a size decrease of less than 50% by one year post-t= reatment, and while there was no evidence to support the notion, there was concern th= at tumor hypoxia from preoperative embolization might impart radioresistance (Amdur 2011).

MEDICAL AND OTHER THERAPY

Chemotherapy has been investigated as treatment o= ptions in cases of JNA that had recurred after surgery and XRT, but a low therapeu= tic benefit coupled with poorly tolerated side effects has made this a rarely u= sed endeavor (Lee 2002).

Given its sole demographic of adolescent males, hormonal therapy was hypothesized to decrease the size and vascularity to J= NAs via estrogens or antiandrogens. The theory was that the reduced vascularity would support decreased intraoperat= ive blood loss during surgical resection, and it was hoped that the antiandroge= nic push would promote tumor regression. However, the physical and psychological side effects from such medications are understandably poorly tolerated in such young patients and serve as a significant impediment to their use, especially given the lack of efficacy with flutamide (Labra 2004).

Other treatment modalities that have been reporte= dly implemented to address JNA include coblation (Ruiz 2012), cryotherapy (Witt= 1983, Spector 1988), electrocoagulation (Schiff 1959), gamma knife (Dare 2003, Pa= rk 2006), harmonic scalpel (Chen 2006), interstitial brachytherapy (Reddy 2001= ), KTP-laser embolization (Hazarika 2002), and sclerotherapy (Schiff 1959). However, further studies are warra= nted to further elucidate their role in the mainstay treatment of JNAs.

CONCLUSION

JNA is a rare vascular neoplasm localized to the posterolateral nasopharynx of adolescent males that typically presents with either nasal obstruction or recurrent epistaxis. Surgery and XRT constitute the pri= mary treatment options, but given the rarity by which JNA occurs, it is importan= t to evaluate for other neoplasms that may also manifest in the nasal cavity.

REFERENCES

Ahmad R, Ishlah W, Azilah N, Rahman JA. Surgical management of juvenile nasopharyngeal angiofibroma without angiographic embolization. Asian J Surg 2008; 31(4):174-178.

Andrade NA, Pinto JA, N&oacu= te;brega Mde O, et al. Exclusively endoscopic surgery for juvenile nasopharyn= geal angiofibroma. Otolaryngol Head Neck= Surg 2007; 137(3):492-496.

Andrews= JC, Fisch U, Valavanis A, et al. The surgical management of extensive nasopharyngeal angiofibromas with the infratemporal fossa approach. Laryngoscope 1989; 99(4):429-437.<= /p>

Babyn P= S. Case 18: Juvenile Nasopharyngeal Angiofibroma. In: Babyn PS, ed. Teaching Atlas = of Pediatric Imaging. New York: Thieme Medical Publishers; 2005: 89.

Bales C, Kotapka M, Loevner LA, et al. Craniofacial resection of advanced juvenile nasopharyngeal angiofibroma. Arch Otolaryngol Head Neck Surg 2002;128(9):1071-1078.

Booth C= L, McMains KC. Pediatric Epistaxis. In Mitchell RB, Pereira KD, eds. Pediatric Otolaryng= ology for the Clinician. Humana Press: New York, 2009. pp 101.

Bremer = JW, Neel HB 3rd, DeSanto LW, Jones GC. Angiofibroma: treatment trends in 150 patients during 40 years. Laryngoscope 1= 986; 96(12):1321-1329.

Briant = TD, Fitzpatrick PJ, Berman J. Nasopharyngeal angiofibroma: a twenty year study.= Laryngoscope 1978; 88(8 Pt 1):1247= -1251.

Cansiz = H, Güvenç MG, Sekercioğlu N. Surgical approaches to juvenile nasopharyngeal angiofibroma. J Craniomaxillofac Surg 2006; 34(1):3-8.

Chakrab= orty S, Ghoshal S, Patil VM, et al. Conformal radiotherapy in the treatment of adva= nced juvenile nasopharyngeal angiofibroma with intracranial extension: an institutional experience. Int J Rad= iat Oncol Biol Phys 2011; 80(5):1398-1404.

Chandle= r JR, Goulding R, Moskowitz L, Quencer RM. Nasopharyngeal angiofibromas: staging = and management. Ann Otol Rhinol Laryngo= l 1984; 93(4 Pt 1):322-329.

Chelius= JM. System of Surgery. Vol. 2. Lon= don: Henry Renshaw, 1847.

Chen MK= , Tsai YL, Lee KW, Chang CC. Strictly endoscopic and harmonic scalpel-assisted sur= gery of nasopharyngeal angiofibromas: eligible for advanced stage tumors. Acta Otolaryngol 2006; 126(12):132= 1-1325.

Close L= G, Schaefer SD, Mickey BE, Manning SC. Surgical management of nasopharyngeal angiofibroma involving the cavernous sinus. Arch Otolaryngol Head Neck Surg 1989; 115(9):1091-1095.

Coutinh= o-Camillo CM, Brentani MM, Nagai MA. Genetic alterations in juvenile nasopharyngeal angiofibromas. Head Neck 2008; = 30(3):390-400.

Cumming= s BJ, Blend R, Keane T, et al. Primary radiation therapy for juvenile nasopharyng= eal angiofibroma. Laryngoscope 1984= ; 94(12 Pt 1):1599-1605.

Danesi = G, Panciera DT, Harvey RJ, Agostinis C. Juvenile nasopharyngeal angiofibroma: evaluation and surgical management of advanced disease. Otolaryngol Head Neck Surg 2008; 138(5):581-586.

Dare AO, Gibbons KJ, Proulx GM, Fenstermaker RA. Resection followed by radiosurgery = for advanced juvenile nasopharyngeal angiofibroma: report of two cases. Neurosurgery 2003; 52(5):1207-1211= .

Douglas= R, Wormald PJ. Endoscopic surgery for juvenile nasopharyngeal angiofibroma: wh= ere are the limits? Curr Opin Otolaryng= ol Head Neck Surg 2006; 14(1):1-5.

Elshark= awy AA, Kamal EM, Tawfik A, et al. Juvenile nasopharyngeal angiofibroma with intracranial extension: analysis of 23 Egyptian patients. Int J Pediatr Otorhinolaryngol 2010; 74(7):755-759.

Enepeki= des DJ. Recent advances in the treatment of juvenile angiofibroma. Curr Opin Otolaryngol Head Neck Surg 2004; 12(6):495-499.

Fagan J= J, Snyderman CH, Carrau RL, Janecka IP. Nasopharyngeal angiofibromas: selectin= g a surgical approach. Head Neck 19= 97; 19(5):391-399.

Fisch U. The infratemporal approach for nasopharyngeal tumours. Laryngoscope 1983; 93(1):36-44.

Girgis = IH, Fahmy SA. Nasopharyngeal fibroma: its histo-pathological nature. J Laryngol Otol 1973; 87(11):1107-= 1123.

Gullane= PJ, Davidson J, O'Dwyer T, Forte V. Juvenile angiofibroma: a review of the literature and a case series report. Laryngoscope 1992; 102(8):928-933.

Hartley= B. Head and Neck Masses. In Graham JM, Scadding GK, Bull PD, eds. Pediatric ENT<= /u>. Springer: New York, 2007. pp 121.

Hauptma= n G, Ulualp S. Juvenile Nasopharyngeal Angiofibroma. UTMB Department of Otolaryngology Grand Rounds, 3 January 2007. http://www.utmb.edu/otoref/grn= ds/Angiofibroma-Juv-NP-070103/Angiofibroma-Juv-NP_070103.mht <Accessed 2 December, 2012>.

Hazarik= a P, Nayak DR, Balakrishnan R, et al. Endoscopic and KTP laser-assisted surgery = for juvenile nasopharyngeal angiofibroma. Am J Otolaryngol 2002; 23(5):282-186.

Herman = P, Lot G, Chapot R, et al. Long-term followup of juvenile nasopharyngeal angiofibromas: analysis of recurrences. Laryngoscope 1999; 109(1):140–147.

Hosseini SM, Borghei P, Borghei SH, et al. <= /span>Angiofibroma: an outcome review of conventional surgical approaches. Eur Arch Otorhinolaryngol 2005; 262(10):807-812.

Hyun DW= , Ryu JH, Kim YS, et al. Treatment outcomes of juvenile nasopharyngeal angiofibro= ma according to surgical approach. Int= J Pediatr Otorhinolaryngol 2011; 75(1):69-73.

John SD, Hernandez JA, Swischuk LE. Airway imaging in children. In Bailey BJ, Johnso= n, JT, Newlands SD, eds. Head and Neck Surgery – Otolaryngology, 4th = Ed. Philadelphia: Lippincott, 2006. pp 1075-1076.

Labra A, Chavolla-Magaña R, Lopez-Ugalde A, et al. Flutamide as a preoperative treatment in juvenile angiofibroma (JA) with intracranial invasion: report = of 7 cases. Otolaryngol Head Neck Surg 2004; 130(4):466-469.

Lee JT,= Chen P, Safa A, et al. The role of radiation in the treatment of advanced juvenile angiofibroma. Laryngoscope 2002= ;112(7 Pt 1):1213-1220.

Li JR, = Qian J, Shan XZ, Wang L. Evaluation of the effectiveness of preoperative embolizati= on in surgery for nasopharyngeal angiofibroma. Eur Arch Otorhinolaryngol 1998; 255(8):430-432.

Liu L, = Wang R, Huang D, et al. Analysis of intra-operative bleeding and recurrence of juve= nile nasopharyngeal angiofibromas. Clin Otolaryngol Allied Sci 2002; 27(6):536-40.

Makek M= S, Andrews JC, Fisch U. Malignant transformation of a nasopharyngeal angiofibr= oma. Laryngoscope 1989; 99(10 Pt 1):= 1088-1092.

Mann WJ= , Jecker P, Amedee RG. Juvenile angiofibromas: changing surgical concept over the la= st 20 years. Laryngoscope 2004; 11= 4(2): 291-293.

Marshall AH, Bradl= ey PJ. Management dilemmas in the treatment and follow-up of advanced juvenile nasopharyngeal angiofibroma. ORL J Otorhinolaryngol Relat Spec 2006; 68(5):273-278.

McAfee = WJ, Morris CG, Amdur RJ, et al. Definitive radiotherapy for juvenile nasopharyn= geal angiofibroma. Am J Clin Oncol 2= 006;29(2):168-170.

Mishra SC, Shukla GK, Bhatia N, Pant MC. A rational classification of angiofibromas of the post nasal space. J Laryngol Otol 1989;103(10):912-9= 16.

Montag = AG, Tretiakova M, Richardson M. Steroid hormone receptor expression in nasopharyngeal angiofibromas. Consistent expression of estrogen receptor be= ta. Am J Clin Pathol 2006; 125(6):832-= 837.

Moulin = G, Chagnaud C, Gras R, et al. Juvenile nasopharyngeal angiofibroma: comparison= of blood loss during removal in embolized group versus nonembolized group. Cardiovasc Intervent Radiol 1995; = 18(3):158-161.

Neel HB= 3rd, Whicker JH, Devine KD, Weiland LH. Juvenile angiofibroma. Review of 120 cas= es. Am J Surg 1973; 126(4):547-556.

Park CK= , Kim DG, Paek SH, et al. Recurrent juvenile nasopharyngeal angiofibroma treated = with gamma knife surgery. J Korean Med S= ci 2006; 21(4):773-777.

Radkows= ki D, McGill T, Healy GB, et al. Angiofibroma. Arch Otolaryngol Head Neck Surg 1996; 122(2):122-129.

Reddy K= A, Mendenhall WM, Amdur RJ, et al. Long-term results of radiation therapy for juvenile nasopharyngeal angiofibroma. Am J Otolaryngol 2001; 22(3):172-175.

Rha KS<= /st1:State>, Byun SN, Kim TH, Kim YM. Bilateral juvenile nasopharyngeal angiofibroma. Otolaryngol Head Neck Surg 2003; 1= 28(6):891-893.

Ruiz JW, Saint-Victor S, Tessema B, et al. Coblation assisted endoscopic juvenile nasopharyngeal angiofibroma resection. Int J Pediatr Otorhinolaryngol 2012; 76(3):439-442.

Schiff = M. Juvenile nasopharyngeal angiofibroma: a theory of pathogenesis. Laryngoscope 1959; 69:981-1016.

Session= s RB, Bryan RN, Naclerio RM, Alford BR. Radiographic staging of juvenile angiofibroma. Head Neck Surg 19= 81; 3(4):279-283.

Shikani= AH, Richtsmeier WJ. Juvenile nasopharyngeal angiofibroma tumor models. Failure = of androgens to stimulate growth in nude mice and in vitro. Arch Otolaryngol Head Neck Surg 1992;118(3):256-259.

Stansbi= e JM, Phelps PD. Involution of residual juvenile nasopharyngeal angiofibroma (a c= ase report). J Laryngol Otol 1986;1= 00(5):599-603.

Spector= JG. Management of juvenile angiofibromata. Laryngo= scope 1988; 98(9):1016-1026.

Tewfik = TL, Tan AK, al Noury K, et al. Juvenile nasopharyngeal angiofibroma. J Otolaryngol 1999; 28(3):145-151.=

Tosun F= , Onerci M, Durmaz A, Ugurel S. Spontaneous involution of nasopharyngeal angiofibrom= a. J Craniofac Surg 2008; 19(6):1686-= 1689.

Tyagi I= , Syal R, Goyal A. Staging and surgical approaches in large juvenile angiofibroma--study of 95 cases. In= t J Pediatr Otorhinolaryngol 2006; 70(9):1619-1627.

Umamaheswar D, Carrau RL, Ka= ssam AB. Vascular Tumors of the Head and Neck. In Bailey BJ, Johnson, JT, Newlands SD, eds. Head and Neck Surgery – Otolaryngology, 4th Ed. Philadelphia: Lippincott, 2006. pp 1815-1817.

Wiatrak= BJ, Koopmann CF, Turrisi AT. Radiation therapy as an alternative to surgery in = the management of intracranial juvenile nasopharyngeal angiofibroma. Int J Pediatr Otorhinolaryngol 199= 3; 28(1):51-61.

Witt TR= , Shah JP, Sternberg SS. Juvenile nasopharyngeal angiofibroma. A 30 year clinical = review. Am J Surg 1983; 146(4):521-525.
Wormald= PJ, Van Hasselt A. Endoscopic removal of juvenile angiofibromas. Otolaryngol Head Neck Surg 2003; 129(6):684-691.

Yiotaki= s I, Eleftheriadou A, Davilis D, et al. Juvenile nasopharyngeal angiofibroma sta= ges I and II: a comparative study of surgical approaches. Int J Pediatr Otorhinolaryngol 2008; 72(6):793-800.