------------------------------------------------------------------------------- TITLE: JUVENILE NASOPOHARYNGEAL ANGIOFIBROMA SOURCE: Dept. of Otolaryngology, UTMB, Grand Rounds DATE: May 5, 1993 RESIDENT PHYSICIAN: Ramtin Kassir, M.D. FACULTY: Amy Coffee, M.D. DATABASE ADMINISTRATOR: Melinda McCracken, M.S. ------------------------------------------------------------------------------- "This material was prepared by resident physicians in partial fulfillment of educational requirements established for 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 should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion." I.Introduction A.General Juvenile nasopharyngeal angiofibroma is a rare, histologically benign tumor found almost exclusively in adolescent males. It is highly vascular, aggressive and locally invasive. This tumor has a high potential to cause serious illness from severe epistaxis, involvement of intracranial structures and high rate of recurrence. B.Incidence JNA accounts for 0.05% of all neoplasms of the head and neck. Its incidence is relatively higher in India and Egypt than in the United States and Europe. Reported incidence in the United States varies from 1:6000 to 1:16000 of ear, nose and throat cases. The variability in the reported incidence of JNA might be attributed to inaccurate pathologic diagnosis, as this lesion can be confused with pyogenic granuloma and angiomatous polyp. The rare occurrence of this tumor is one reason for the varying opinions regarding its origin and treatment. In one of the largest series at the Mayo Clinic with 120 patients, age at diagnosis was 9 to 29 years old with a median of 15 years old. All patients were male. While JNA occurs predominantly in males, there have been reports of its occurence in females. Some authorities believe that it occurs only in the male and that if a female is involved, chromosomal studies and a reassessment of the histologic structure are necessary. Brooker et. al. reviewed the pathology of seventeen cases of purported JNA in Ireland, finding seven patients (5 female, one 36 year old male) that required change of diagnosis. C.Natural History The age of actual occurrence is not known. Because the tumor is rarely seen in young adults, spontaneous regression is believed to occur. Recently Jacobsson et.al. presented radiographic evidence of a case of JNA with large intracranial extension that became involuted. More recently Lawrence et.al. described the spontaneous regression of biopsy-proved JNA over a 12 year period in which the patient did not receive any therapy. These reports support the theory of hormonal influence on this group of tumors and the possibility of spontaneous involution. D. Tumor Location Early tumors are localized to the posterior nares. With growth the lesion simultaneously expands anteriorly in the nasal cavity and posteriorly and superiorly in the nasopharynx. Posterior erosion can invade the sphenoid sinus and sella turcica. As it expands it tends to extend through the sphenopalatine foramen to involve the pterygopalatine fossa; there it exerts pressure on the surrounding bone. This behavior accounts for the radiologic finding of anterior bowing of the posterior wall of the maxillary sinus ( Holman - Miller sign ), as well as for the distortion and posterior displacement of the pterygoid plates. It is important to highlight the fact that maxillary sinus invasion, when it does occur, does so via this route and rarely if ever from the nasal cavity outward laterally. As the lesion continues to expand, it does so by escaping further laterally via the pterygomaxillary fissure into the temporal and infratemporal fossae. The latter will present as an obvious cheek mass of the face, or as intraoral buccal mass. By the time a mass appears above the zygoma, the lesion has invariably invaded the inferior orbital fissure from which it expands into the lower end of the superior orbital fissure, where these two join at the posteriosuperior end of the pterygopalatine fossa. This is manifest clinically as proptosis. The lesion can extend intracranially by one of two routes. The most common is via a continuation of growth through the expanded orbital fissures; from which it comes to lie lateral to the cavernous sinus. On occasion, the lesion has been reported to expand intracranially via the sphenoid sinus through the sella turcica. The reported incidence of intracranial invasion varies from 10-20%. E.Origin The origin of JNA remains uncertain. Many theories have been presented, but most feel that the angiofibroma is a connective tissue response of the nasopharyngeal periosteum to a hamartomatous ectopic nidus of vascular tissue, most likely from the inferior turbinate. The tumor appears to arise in the posterolateral wall of the roof of the nasal cavity at the sphenopalatine foramen, where the sphenoid process of the palatine bone meets the horizontal ala of the vomer and the root of the pterygoid process of the sphenoid. Histologic serial sections of fetal heads have confirmed the presence of large endothelial lined spaces in the region of the sphenopalatine foramen and base of the pterygoid plates in both males and females. Because of the development of this tumor in males near puberty a hormonal response by the tumor is presumed. Receptor studies in the past have revealed no estrogen or progesterone receptors in tumor specimens. Bretani, et al. studied receptors in 12 JNA and found estrogen receptors in 25%, progesterone receptors in 58%, and androgen receptors in 25%. Thus, there appears to be considerable variability in the measurement of sex steroid receptors in JNA. Circulating levels of gonadotropins in involved males have all been normal. II.Histopathology A.Gross Appearance JNA appears as an irregular, smooth reddish purple mass. It has a firm, nodular texture with a sessile base. It is nonencapsulated and may attach to invaded structures. B.Microscopic Appearance JNA consists of a vascular component in a fibrous stroma. In the most actively growing tumors the vascular component predominates. Vessel walls generally consist of a single endothelial lining directly against the fibrous stroma. This contributes to the capacity for massive bleeding. Deep vessels may have a muscular layer. The stroma is made of fine and coarse collagenous fibrils with characteristic stellate connective tissue cells interspersed. The angiomatous tissue tends to regress with time. Since the characteristic histologic appearance is seen internally, surface biopsies can be misleading. III.Diagnosis A.Signs and Symptoms Presenting signs and symptoms are determined by the location, size, and extension of the tumor. The initial complaint is progressive nasal obstruction with rhinorrhea. The patient then develops recurrent epistaxis which is usually the reason for seeking medical advice. Eustachian tube obstruction can produce a conductive hearing loss. Extension of the tumor into surrounding areas can produce facial swelling and sinusitis. Further extension into the orbit and intracranial fossae may produce cranial nerve deficits. Patients are frequently followed with an initial diagnosis of sinusitis, rhinitis or antral choanal polyps before the correct diagnosis is obtained. The duration of symptoms before treatment has declined from 20 months in the past two decades to 6 months presently. This is attributed to the increased availability of CT. B.Ancillary Studies 1.Computed Axial Tomography The diagnosis can usually be made from history and physical examination. Additional studies are to confirm the diagnosis and determine the best method of treatment. The first diagnostic study following a complete history and physical is a CT scan with contrast in both axial and coronal planes. The location, pattern of spread and enhancement allow for the accurate diagnosis of JNA. Two findings on CT considered by many to be pathognomonic are: 1) anterior bowing of the posterior wall of the maxillary sinus and 2) a dense homogeneous enhancement with contrast. Other frequent findings include erosion of the sphenoid bone, erosion of the hard palate, erosion of the medial wall of the maxillary sinus and displacement of the nasal septum. 2. Magnetic Resonance Imaging Since 1987, in some institutions, MRI has replaced CT with contrast as the diagnostic procedure of choice in JNA. The advantages of MRI include multiplanar imaging and enhanced three dimensional assessment of the tumor, improved definition at the cribiform plate and cavernous sinus, improved differentiation of tumor from inflamed mucosa and fluid in the paranasal sinuses, and avoidance of diagnostic radiation in young patients who require serial follow-up studies. 3. Angiography In the past carotid angiography was considered essential for the diagnosis and in determining the extent of the tumor, especially intracranial invasion. Now this can be done effectively with CT/MRI. Angiography is used primarily for preoperative embolization and in assisting in determining a surgical approach. The complete blood supply of the tumor is demarcated and feeding vessels from the external carotid arteries are identified and embolized in one procedure. Angiography may also assist in differentiation of scar from recurrent tumor when suspicious areas are noted on follow-up MRI/CT. Bilateral selective internal and external carotid arteriography and simultaneous embolization with Polyvinyl alcohol particles or Gelfoam pledgets should be performed about 24 to 48 hours prior to surgery. If more than 2-3 weeks elapse between embolization and surgery, recanalization of the occluded vessels or neovascularization of the tumor may create technical difficulty from bleeding during the operation. Intraoperative blood loss is reported to drop from an average of 1800cc without embolization to 650cc with embolization without significant side effects. Blood supply to the tumor is predominantly from the ipsilateral internal maxillary artery with a rich collateral supply. This artery is displaced anteriorly as the tumor expands. As the tumor invades the orbit or middle cranial fossa supply from the internal carotid artery system develops. The advent of the detachable balloon catheter has permitted safe occlusion of the internal carotid artery in patients with extensive tumor involvement in the proximity of this vessel or directly supplied by this vessel. C.Staging Following the diagnostic workup the tumor can then be staged. This allows accurate treatment planning and evaluation of end results. In the past end results have often been considered independently of tumor location and extension producing a wide variability in cure and recurrence rates. Presently several different staging classifications exist; one of the most recent by Fisch is presented below: STAGING Ia Tumor limited to nasopharynx and nasal cavity. Bone destruction negligible or limited to the sphenopalatine foramen. II Tumor invading the pterygopalatine fossa or the maxillary, ethmoid or sphenoid sinus with bone destruction. IIIa Tumor invading the infratemporal fossa or orbital region without intracranial involvement. IIIb Tumor invading the infratemporal fossa or orbit with intracranial extradural ( parasellar ) involvement. IVa Intracranial intradural tumor without infiltration of the cavernous sinus, pituitary fossa or optic chiasm. IVb Intracranial intradural tumor with infiltration of the cavernous sinus, pituitary fossa or optic chiasm. IV.Management A.Hormonal Therapy 1. Estrogen Because of the presumed hormonal dependency of JNA many investigators have attempted to alter the tumor with hormonol therapy. Although many authors have reported a reduction in tumor size and intraoperative blood loss with estrogen therapy, the results have not always been consistent. Most studies of JNA hormonal receptors have demonstrated the presence of cytosolic androgen receptors but the absence of estrogen or progesterone receptors, suggesting that the action of estrogen on these tumors is indirect, possibly through hypothalamic suppression and reduction in the secretion of luteinizing hormone and subsequently in the secretion of testosterone. Currently, preoperative estrogen therapy is not used routinely because of 1. the variable effect of estrogen upon the tumor's growth; 2. the delay in carrying out definitive removal; 3. the undesirable feminizing side effects and the risk of cardiovascular complications; and 4. the widespread availability of angiographic embolization for vascular control. 2. Flutamide Extensive investigation regarding the hormonal dependence of JNA has been unable to settle this issue in patients owing, in part, to the rarity of these tumors. Recently JNA tumor models established in nude mice and in vitro did not respond to androgen supplementation. This study suggests that factors other than androgens are at least complementary, if not essential, in promoting the growth of JNA in tumor models, and androgens are not, in and of themselves, sufficient growth stimuli. Recently, however, Gates et al. in a pilot study demonstrated hormonal pharmacoreduction of JNA using Flutamide ( Eulexin ), a potent nonsteroidal androgen blocker which interferes with binding of testosterone in animals and man. The reduction in measured volume over the six weeks of therapy averaged 29% for all 5 patients in the study. Excluding one patient in whom the tumor grew, the average reduction was 44%. These data indicate an effect from flutamide that is clinically significant; however, it has uncovered an obstacle to overcome, namely, the need to obtain sufficient tissue for receptor analysis before instituting hormonal therapy. B. Embolization Preoperative embolization has been found to significantly decrease intraoperative bleeding. It needs to be performed within 48 hours of surgery to prevent the development of collateral flow. Some oppose its use stating that blood loss can be controlled with ligation and adequate exposure and that tissue shrinkage following embolization allows undetected tissue to remain increasing the likelihood of recurrence. C.Radiotherapy JNA has been shown to respond to low dose radiation. Primary control of up to 80% has been reported, although most studies report about 70%. The recommended dose is 3500 rads in 14 to 16 fractional treatments over 3 weeks. Others advocate dosages greater than 3,600 cGy but therapy needs to be individualized. A 30 - 50% regression is evident during the course of radiation, but complete regression by CT scan usually does not occur for months to years. A second course can be used for recurrence. Symptoms, however, may persist during the delayed period of regression. Long term risks include skin cancer, bone and soft tissue sarcomas, thyroid cancer, atrophic rhinitis and alteration of the growth plates in the facial bones. Surgery provides better control of stage I and II tumors without the associated risks of radiation. Therefore, radiation is reserved for recurrences and tumors determined to be unresectable. D. Chemotherapy Chemotherapy as been advocated in recurrences with intracranial extension. Tumor disappearance has been demonstrated after 6 months with doxorubicin and decarbazine. E. Surgery The choice of the best surgical approach is the most critical decision in the care of a patient with a nasopharyngeal angiofibroma. Type I or II tumors are approached through a transpalatal or lateral rhinotomy procedure. The transpalatal procedure is used for the smaller of the lesions. It avoids a facial incision but the exposure provided is more limited. The lateral rhinotomy approach provides good exposure of the nasal cavity, paranasal sinuses, and pterygopalatine fossa. Exposure beyond these regions is limited and direct visualization on the internal carotid artery cannot be maintained during all stages of the resection. The major controversy in the management of JNA is how best to treat those lesions with intracranial extension. Operative complications, tumor recurrence, and mortality are all closely linked to intracranial extension. Complete surgical excision, if necessary via combined neurosurgic-otolaryngologic approaches, is advocated by many as safe and effective. In a review of combined approaches, the authors noted a 31% recurrence for patients so treated, with no complications attributable to craniotomy per se. Close et al. reported success with combined procedure for JNA with involvement of the cavernous sinus. Fisch advocates an infratemporal fossa approach for resection of especially large JNAs. Still others favor an external transphenoehtmoidectomy, with or without medial maxillectomy. Neurosurgical access is afforded by means of bicoronal frontal craniotomy. Still others believe that JNA with intracranial, and specifically cavernous sinus, involvement should be treated solely with radiation therapy. Primary surgical cure rates for extracranial JNA are near 100%. Intracranial surgical cure rates vary but approach 70%. For recurrences (inadequate resection) there is a 90% cure rate with the second treatment. Fisch advocates surgery for all tumors except those with IVb lesions with tumor remnant infiltrating the cavernous sinus. -------------------------------------------------------------------------- BIBLIOGRAPHY 1. Harrison, D.F., The Natural History, Pathogenesis and Treatment of Juvenile Angiofibroma, Arch Oto Head Neck Surg, vol 113, Sept 1987, pp. 936-942. 2. Jacobsson, B., et al, Juvenile Nasopharyngeal Angiofibroma, A Report of Eighteen Cases, Acta Oto (Stockh), vol. 105, 1988, pp. 132-139. 3. Economou, T.S., et al, Juvenile Nasopharyngeal Angiofibroma: An Update of the UCLA Experience, Laryngoscope, vol. 98, Feb 1988, pp. 170-175. 4. Bremer, J.W., et al, Angiofibroma: Treatment Trends in 150 Patients During 40 Years, Laryngoscope, vol. 96, Dec 1986, pp. 1321-1329. 5. Antonelli, A.R., et al, Diagnosis, Staging and Treatment of Juvenile Nasopharyngeal Angiofibroma, Laryngoscope, vol. 97, Nov 1987, pp. 1319-1325. 6. Micheals, L., Non-epithelial Neoplasms, Ear, Nose and Throat Histopathology, 1987, chap. 25, pp. 253-256. 7. Patterson, C.N., Juvenile Nasopharyngeal Angiofibroma, Otolaryngology, English, vol. 5, chap. 13. 8. DeSanto, L.W., Neoplasms, Otolaryngology, Head and Neck Surgery, Cummings, vol. 1, chap. 35, pp. 646-649. 9. Gullane, P.J., et al, Nasopharyngeal Angiofibroma, Current Therapy in Otolaryngology- Head and Neck Surgery, Gates, ed. 3, 1987, pp. 178-181. 10. Arndt, J.D. et al, Juvenile Nasopharyngeal Angiofibroma: Diagnosis and treatment. Otolaryngol Head Neck Surg, 1987; 97: 534-40. 11. Close, L.G. et al., Surgical Management of Nasopharyngeal Angiofibroma. Arch Otolaryngol Head Neck Surg, 1989; 115: 1091-1095. 12. Deschler, D.G., Treatment of Large Juvenile Nasopharyngeal Angiofibroma. Otolaryngol Head Neck Surg, 1992; 106:278-84. 13. Brooker, D.S. et al. Juvenile Nasopharyngeal Angiofibroma in a Static Population: the Implications of Misdiagnosis. Clin Otolaryngol 1989; 14:497-502. 14. Andrews, J.C. et al. The Surgical Management of Extensive Nasopharyngeal Angiofibromas with the Infratemporal Fossa Approach. Laryngoscope 99: April 1989, pp. 429-37. 15. Schiff, M. et al. Juvenile Nasopharyngeal Angiofibroma Contain an Angiogenic Growth Factor: Basic FGF. Laryngoscope 102: August 1992, pp. 940-45. 16. Gates, G.A. et al. Flutamide-Induced Regression of Angiofibroma. Laryngoscope 102: June 1992, pp. 641-644. 17. Bretani, M.M. et al.: Multiple Steroid Receptors in Nasopharyngeal Angiofibromas. Laryngoscope, 99:398-401, 1989. 18. Shikani, A.H. et al.: Juvenile Nasopharyngeal Angiofibroma Tumor Models. Arch Otolaryngol Head Neck Surg. 1992; 118: 256-59. 19. Weprin, L.S. et al.: Spontaneous Regression of Juvenile Nasopharyngeal Angiofibroma. Arch Otolarygol Head Neck Surg. 1991; 117: 796-99. 20. Jacobsson, M. et al.: Involution of Juvenile Nasopharyngeal Angiofibroma With Intracranial Extension. Arch Otolaryngol Head Neck Surg 1989; 115: 238-9. 21. Blitzer, A. et al.: Juvenile Angiofibroma. Surgery of the Paranasal Sinuses. 1991, Chap. 24, pp. 363-76. 22. Williams, Wayne R. Juvenile Nasopharyngeal Angiofibroma. Grand Rounds Presentation, January 4, 1989. -------------------------------END--------------------------------------------