Nasopharyngeal angiofibroma (NA)


(Juvenile) Nasopharyngeal angiofibroma (JNA) is a rare, highly vascular, histologically benign but locally invasive tumor, affecting predominantly male adolescents.

The earliest known documentation of nasopharyngeal angiofibroma (NA) dates to Hippocrates in the fifth century B.C. Commonly referred to as juvenile nasopharyngeal angiofibroma (JNA), it is also known as juvenile angiofibroma (JAF), or fibromatous or angiofibromatous hamartoma of the nasal cavity.


Etiology

Hormonal factors:

Hormonal influence affecting the proliferation of vascular erectile tissues following repeated microhemorrhages and repair. Predominant adolescent male incidence, as the increase in androgen production in puberty stimulates the growth and vascular expansion of the tumor. Others have shown that tumor growth can occur at any time, even after treatment, from testosterone administration. This concept has support from case reports of nasopharyngeal angiofibroma in older women that have since downregulated their estrogen and progesterone production, suggesting that estrogen has a protective effect; but further confounded by case reports of nasopharyngeal angiofibroma being discovered in pregnant females, suggesting that androgen influence is not important.

Nasopharyngeal angiofibroma represents <1% of all nasopharyngeal tumours. Boys and adolescent to young men are almost exclusively affected, with a peak in the 2nd decade of life. If a female is affected, testicular feminisation has to be excluded. Fair-skinned and red-haired males are more commonly affected. Exact etiology is still unclear.

Other nasopharyngeal angiofibroma associations:

  • Familial adenomatous polyposis (FAP)
  • Gardner syndrome (altered APC gene expression in this subset of nasopharyngeal angiofibroma)
  • Human papillomavirus (HPV) infection: HPV is known to be associated with head and neck squamous cell carcinoma (HNSCC).

Pathophysiology

The tumors are frequently located in the posterolateral wall of the nasal cavity, where the sphenoid process of the palatine bone articulates with the base of the pterygoid process, forming the sphenopalatine foramen. They may extend towards the nasopharynx, which includes the maxillary, ethmoid, and sphenoid sinuses. Laterally, these tumors may extend to and fill the pterygomaxillary fossa, causing the posterior wall of the maxillary sinus to bulge and eroding the pterygoid plate. Tumors that further extend into the infratemporal fossa may progress into the orbit, through the inferior orbital fissure and to the base of the skull through the base of the pterygoid process. From a triangular region formed by the foramen ovale, a round and lacerated tumor may reach the middle fossa, migrating to the parasellar region and remaining generally extradual and lateral to the cavernous sinus. Rarely, the tumor may destroy the posterior sphenoid sinus and invade the cavernous sinus, pituitary, and/or optic chiasm. Tumors may invade the anterior fossa through the ethmoid and sphenoid sinuses, being more frequent in the middle fossa and remaining extradural.

JNA: Gross features
Gross features, a Gross specimen has a firm-elastic consistency, color may vary from yellowish-brown to blackish depending on the grade of intraoperative hemorrhage. Specimens show the shape of the normal anatomical cavities, as shown in the picture, as tumors in general, tend to fill anatomical spaces, before causing bone resorption by secondary pressure. b A cut section of a different specimen showing grayish color and inconspicuous vascular channels, which can eventually be difficult to visualize macroscopically | Sánchez-Romero, C., Carlos, R., Díaz Molina, J. P., Thompson, L., de Almeida, O. P., & Rumayor Piña, A. (2018). Nasopharyngeal Angiofibroma: A Clinical, Histopathological and Immunohistochemical Study of 42 Cases with Emphasis on Stromal Features. Head and neck pathology, 12(1), 52–61. https://doi.org/10.1007/s12105-017-0824-z

Presentation

JA typically affects the male population, most commonly between 9 and 19 years of age.

Classic presentation:

JNA classically presents as a painless, progressive unilateral nasal obstruction. The main clinical presentation of JNA is unilateral nasal obstruction with or without epistaxis.
  • Recurrent spontaneous epistaxis (M/C presentation)
  • Rhinorrhea
  • Pain

Facial deformities:

As this tumor is aggressive and expansile, it invades adjacent structures causing further symptoms.
  • Frog-face deformity: Orbital spread leads to charactreristic facies with porptosis of eyes
14-year-old male with a tumoral mass affecting the nasopharynx and extending into left cheek
14-year-old male with a tumoral mass affecting the nasopharynx and extending into left cheek: a) Clinically the patient shows facial left swelling and asymmetry. This clinical aspect was favored by a previously unsuccessful attempt of surgical removal. b) In a coronal CT section, a large tumoral mass deviating the nasal septa and extending from sinonasal spaces to pterygopalatine fossa, infratemporal fossa and extents into soft tissues of the check. c) Axial CT image of the same tumor shows anterior displacement of posterior wall of left maxillary sinus is evident. Contrast media highlights the prominent vascularity | Sánchez-Romero, C., Carlos, R., Díaz Molina, J. P., Thompson, L., de Almeida, O. P., & Rumayor Piña, A. (2018). Nasopharyngeal Angiofibroma: A Clinical, Histopathological and Immunohistochemical Study of 42 Cases with Emphasis on Stromal Features. Head and neck pathology, 12(1), 52–61. https://doi.org/10.1007/s12105-017-0824-z

Case study:

Javier and his family share their experience at Johns Hopkins Medicine, after seeking treatment following a diagnosis of a Juvenile Nasopharyngeal Angiofibroma (JNA) tumor.

Complications:

Though histologically benign, NA often demonstrates aggressive features with local invasion into the nasal turbinates, nasal septum, and medial pterygoid lamina. It commonly extends into the nasal cavity, nasopharynx, and pterygopalatine fossa, with larger lesions extending into the sphenoid, maxillary, and ethmoid sinuses. They can also demonstrate extension through the inferior orbital fissure, and into the masticator space through the infratemporal fossa. Severe disease is likened to have orbital and intracranial involvement, seen in approximately 10 to 37% of cases.
  • Blood loss (most significant complication): Primarily in the operative/procedural setting, and can be fatal absent proper precautions.
  • Orbital invasion: Exophthalmos, facial/orbital deformity, vision loss, and loss of extraocular movements
  • Vision loss can also be a potential complication of nontarget embolization if there is internal carotid artery branch involvement. Other severe complications of preoperative embolization include arterial vasospasm, facial palsy, infarction, or cranial nerve injury. More self-limiting, less severe complications include facial swelling, pain or abnormal sensation, headache, or nausea/vomiting.

Diagnosis

Nasopharyngeal angiofibroma is both a clinical and imaging diagnosis. There is no beneficial laboratory evaluation for diagnosing JNA.

Nasal endoscopy:

  • Firm, friable, reddish, or reddish-purple mass within nasal cavity
Endoscopic view of the right nasal fossa. Juvenile angiofibroma (JA) obstructing the nasal cavity and protruding between the middle turbinate (MT) and the nasal septum (NS)
Endoscopic view of the right nasal fossa. Juvenile angiofibroma (JA) obstructing the nasal cavity and protruding between the middle turbinate (MT) and the nasal septum (NS) | Abbreviation: IT, inferior turbinate. | Safadi, A., Schreiber, A., Fliss, D. M., & Nicolai, P. (2018). Juvenile Angiofibroma: Current Management Strategies. Journal of neurological surgery. Part B, Skull base, 79(1), 21–30. https://doi.org/10.1055/s-0037-1615810

Imaging:

Imaging evaluation is primarily performed with either computed tomography (CT) or magnetic resonance imaging (MRI)
  • Radiography: Bowing or anterior displacement of posterior wall of maxillary sinus from mass effect
  • Contrast-enhanced CT (CECT): Avidly enhancing soft tissue mass within posterior nasal cavity near sphenopalatine foramen with extension to and/or beyond the nasopharynx, pterygopalatine fossa, and adjacent sinuses.
  • MRI: Superior to CT for detecting soft tissue extension of the tumor intracranially
  • Angiography: Useful adjunct in the diagnosis of vascular tumors
  • Hollman-Miller/Antral sign: Anterior bowing of posterior wall of maxillary sinus

Tissue biopsy:

Contraindicateed as vessels lack contractile component and thus cannot be controlled with adrenaline
  • Proliferative connective tissue stroma interspersed with a thick vascular network
Microscopic appearance of JA (H&E staining (left) and immunohistochemistry for factor VIII (right))
Microscopic appearance of JA (H&E staining (left) and immunohistochemistry for factor VIII (right)): Vessel caliber is extremely variable, the muscular layer of vessels is frequently absent, and stromal cells have usually a spindle-shaped appearance. | Nicolai, P., Schreiber, A., & Bolzoni Villaret, A. (2012). Juvenile angiofibroma: evolution of management. International journal of pediatrics, 2012, 412545. https://doi.org/10.1155/2012/412545

Staging:

Various systems have been proposed for staging and classifying nasopharyngeal angiofibroma to aid in decision making for surgery and adjunctive treatment. The most commonly used today are the Radkowski and Andrews-Fisch staging systems, primarily for their impact on surgical approach and recurrence/outcome. Most recently, the UPMC system was proposed focusing on endoscopic staging, considering current surgical approaches and the nature of the tumor.
Staging system for JNA
Staging system for JNA | Juvenile nasopharyngeal angiofibroma: Current treatment modalities and future considerations – Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Staging-system-for-JNA-11-12_tbl1_232807448 [accessed 26 Nov, 2021]

Differential diagnosis:

  • Olfactory neuroblastoma (esthesioneuroblastoma): Avidly enhancing nasal cavity mass of olfactory neuroepithelium that can have similar presenting symptoms and age of onset. These tumors can have a dumbbell appearance on imaging with intracranial extension and the waist centered at the cribriform plate. They can demonstrate intracranial cysts, restricted diffusion, and areas of necrosis. Olfactory neuroblastoma is much more common in females than is JNA.
  • Rhabdomyosarcoma: Soft tissue sarcoma of the striated muscle. When occurring in the head and neck, the most common site is within the orbit, but also parameningeal sites such as nasopharynx, pterygopalatine fossa, middle ear, paranasal sinuses, or parapharyngeal space have been described. This condition is typically a malignancy of younger patients, with 70% occurring younger than 12 years, and 40% occurring younger than 5 years. They will demonstrate variable, mild to moderate contrast enhancement, with avid enhancement atypical, unlike JNA. They will also typically restrict diffusion, which can be another discriminator.
  • Sinonasal polyp: Inflammatory polyp that can become hypervascular following repeated injury but will have less vascularity relative to JNA. The most common is the antrochoanal polyp, originating from the maxillary sinus and extending through the maxillary ostium into the nasal cavity. Sinonasal polyps can also originate from or extend into the nasopharynx. However, they will typically not extend into the sphenopalatine foramen or pterygopalatine fossa. Osseous remodeling is smooth, not destructive. Polyps will demonstrate peripheral enhancement without central enhancement, unlike nasopharyngeal angiofibroma. Also seen in teens/young adults with nasal obstruction, but rarely results in epistaxis.
  • Encephalocele: Meninges covered outpouching of brain parenchyma and CSF that protrudes through a skull base defect. The nasoethmoidal/nasopharyngeal variant can present as a nasal cavity mass. These are generally more anteriorly positioned than JNA and are nonenhancing.
  • Nasopharyngeal carcinoma (NPC): This is a mucosal tumor that arises in the superolateral aspect of the nasopharynx within the fossa of Rosenmuller. It is a malignancy primarily of adults, with a peak incidence of 40 to 60 years, and rare in the pediatric/adolescent group. It has a strong EBV association. This tumor demonstrates a mild homogeneous enhancement pattern, unlike the avid enhancement of nasopharyngeal angiofibroma. Also a destructive lesion, however unlike nasopharyngeal angiofibroma, it is prone to infiltrating the parapharyngeal fat and other deep facial soft tissues. Often it will demonstrate more extensive osseous destruction, including the clivus and into the cavernous sinus.

Management

Arteriography followed by preoperative embolization and surgical resection is the treatment of choice. JNA being an aggressive tumor may recur posttreatment. Thus, early diagnosis, accurate staging and adequate treatment are essential in the management of this lesion.

Preoperative embolization:

Preoperative embolization is used for all cases of JA except the very small lesions. The most commonly used approach for embolization is transarterial embolization (TAE). This technique most frequently uses particle material (polyvinyl alcohol [PVA], microspheres, etc.) that is introduced by a superselective catheterization of the feeding vessel or vessels. Glue, coils, or more recently ethylene vinyl alcohol copolymer (Onyx) are also used as embolic agents.
JNA: Preoperative interventional neuroradiology embolization
Preoperative interventional neuroradiology embolization: Coronal (1) and sagittal (2) images displaying angiogram pre-embolization (A) illustrating blush of lesion’s vasculature, during embolization (B) illustrating the wire used, and post-embolization (C) showing a decrease in vascular flow. | Stubbs, V. C., Miller, L. E., Parasher, A. K., Glicksman, J. T., Adappa, N. D., & Palmer, J. (2019). Nasopharyngeal Angiofibroma: A Forgotten Entity in Older Patients. Clinical medicine insights. Case reports, 12, 1179547619841062. https://doi.org/10.1177/1179547619841062

Surgical management:

The most commonly used approach for embolization is transarterial embolization (TAE). This technique most frequently uses particle material (polyvinyl alcohol [PVA], microspheres, etc.) that is introduced by a superselective catheterization of the feeding vessel or vessels. Glue, coils, or more recently ethylene vinyl alcohol copolymer (Onyx) are also used as embolic agents.
  • External approaches (previously mainstay of surgical treatment): Transpalatal approach, Le Fort I osteotomies, lateral rhinotomy, midfacial degloving, facial translocation, anterior craniofacial, and lateral infratemporal/subtemporal approaches.
  • Endonasal endoscopic approach (current standard)
JNA excision surgery: Endonasal/endoscopic approach
Axial contrast-enhanced T1-weighted magnetic resonance (MR) ( A ) and endoscopic view ( B, C ) of juvenile angiofibroma (white asterisks) extending along the right vidian canal (white arrowheads). After removal of the vidian portion of the lesion, the endoscopic procedure is completed by extensive drilling of the pterygoid root ( B ) till the foramen lacerum ( C ; dashed white circle). Abbreviations: LR, lateral recess; MSB, middle skull base; NPH, nasopharynx; SPH, sphenoid sinus. | Safadi, A., Schreiber, A., Fliss, D. M., & Nicolai, P. (2018). Juvenile Angiofibroma: Current Management Strategies. Journal of neurological surgery. Part B, Skull base, 79(1), 21–30. https://doi.org/10.1055/s-0037-1615810

Radiotherapy:

Large skull base residual lesions are associated with increased risk for recurrent severe epistaxis and damage to critical neurovascular structures and warrant further intervention. Surgery for such lesions can be hazardous and patients may be referred to radiotherapy. As radiotherapy has the potential to be associated with significant complications in a growing child, it is reserved as last choice for unresectable lesions with a high risk of recurrence.

Treatment complications:

  • Surgical complications can include mass effect complications with the addition of scarring and facial deformity.
  • Hormonal therapy, if employed, can lead to feminization as a complication or at least undesirable side effect in adolescent boys.
  • Recurrence (35% cases)

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