Archives of Pathology and Laboratory Medicine: Vol. 127, No. 11, pp. 14801484.

Growth Factors and Receptors in Juvenile

Nasopharyngeal Angiofibroma and Nasal Polyps:
An Immunohistochemical Study
Paul J. Zhang, MD; Randal Weber, MD; Ho-Hi Liang, MD; Teresa L. Pasha, BS;
Virginia A. LiVolsi, MD
From the Departments of Pathology and Laboratory Medicine (Drs Zhang, Liang, and
LiVolsi and Ms Pasha) and Otorhinolaryngology (Dr Weber), University of Pennsylvania
Medical Center, Philadelphia
Accepted June 25, 2003

Background.Juvenile nasopharyngeal angiofibroma is a rare nasopharyngeal

tumor that occurs exclusively in adolescent boys. It is a histologically benign but
locally persistent growth of stromal and vascular tissue. Although male hormones
and some growth factors, such as transforming growth factor 1 (TGF-1), insulinlike growth factor II (IGF-II), and, lately, the proto-oncogene -catenin, have been
implicated in the histogenesis of the tumor, the biologic signaling pathways that
drive this peculiar fibrovascular proliferation are still nuclear.
Objective.To evaluate immunoexpressions of -catenin, c-Kit, p130Cas, TGF-3,
bone morphogenic protein 4, nerve growth factor (NGF), and the IGF receptor
(IGF-1R) in a series of juvenile nasopharyngeal angiofibromas and to compare to
that of a group of nasal polyps.
Design.A standard immunohistochemical technique was used on paraffin
sections of 12 sporadic juvenile nasopharyngeal angiofibromas and 15 nasal polyps
with microwave or steam antigen retrieval. Immunoreactivity was analyzed
semiquantitatively in stromal cells and endothelial cells of each case.
Results.The expressions of -catenin (nuclear), c-Kit (cytoplasmic), and NGF
(cytoplasmic) were higher and more frequent in stromal cells of juvenile
nasopharyngeal angiofibromas than those of nasal polyps. Both juvenile
nasopharyngeal angiofibromas and nasal polyps showed similarly frequent and
strong immunoreactivity for p130Cas and TGF-3 and weak immunoreactivity for
bone morphogenic protein 4 in both stromal cells and endothelial cells. No IGF-1R
immunoreactivity was detected in any case of either group.
Conclusions.Our results support the role of -catenin in juvenile
nasopharyngeal angiofibromas and suggest a potential involvement of c-Kit and
NGF signaling pathways in the juvenile nasopharyngeal angiofibromas. Although
the biologic significance of c-Kit in juvenile nasopharyngeal angiofibromas has yet

to be defined, the finding of frequent and high c-Kit expression might have
therapeutic importance for patients with juvenile nasopharyngeal angiofibromas.
Juvenile nasopharyngeal angiofibroma (JNA) is a rare nasopharyngeal fibrovascular
tumor that occurs exclusively in the nasopharynx of adolescent boys.13 Histologically, it
is composed of poorly defined but bland stromal cells and an irregular vascular
proliferation.4 Despite its bland histologic features, JNA typically behaves as a locally
aggressive tumor. JNA is currently treated surgically, but local recurrence is common and
has been reported in up to 42% of cases.3,5,6
The histogenesis of JNA is still unclear; however, because of the exclusive male
predilection, sex hormones have been implicated.7,8 Androgen receptor has been detected
in the stromal cells of JNA.911 Antiandrogen hormonal therapy has been used
preoperatively to suppress JNA growth and enhance the resectability of the tumor and
minimize bleeding during surgery.1,12,13
P130Cas, an adapter and docking protein, has been shown to be involved in
intracellular signaling pathways related to cell adhesion, migration, and
transformation.14,15 Recently, high p130Cas levels have been associated with resistance to
first-line tamoxifen treatment in patients with advanced estrogen-dependent breast
cancer.16,17 Its expression has not been evaluated in JNA, which commonly expresses
androgen receptor.
Familial adenomatous polyposis (FAP) results from germline mutations in the
adenomatous polyposis coli (APC) gene that subsequently alters the -catenin signaling
pathway.18 In addition to a high tendency for the development of colorectal neoplasms,
patients with FAP develop JNA 25 times more frequently than an age-matched
population.19,20 A role for the APC-catenin pathway has been suggested in JNA patients
with the APC gene mutation. Recently, activating -catenin mutation without the APC
gene mutation has been reported in sporadic JNA.21,22
Expression of various growth factors, such as transforming growth factor 1 (TGF-1)
and insulin-like growth factor II (IGF-II), has also been detected in JNA.23,24 IGF
functions via the receptor IGF-1R, which has been implicated in tumorigenesis, at least
partly as a result of promoting cell survival in both tissue culture and animal study.25
However, it is unclear whether IGF-1R is expressed in JNA. Bone morphogenic proteins
(BMPs) are members of the TGF- superfamily and have a complex role in regulating
cell growth and differentiation via the BMP-Smad signaling pathway.26 BMP4 has been
shown to regulate steroidogenesis in animal and human gonads.27 Overexpression of
BMP4 has been found in patients with fibrodysplasia ossificans progressiva and in
various bone and soft tissue sarcomas.26,28 Little is known about the potential role of BMP
in the stromal proliferation in JNA.
Proto-oncoproteins c-Kit (CD117) is tyrosine kinase receptor that belongs to the family
of platelet-derived growth factor receptors (PDGFRs).29 Expression of c-Kit and
activation mutation of the gene have been detected in some mesenchymal tumors, such as

gastrointestinal stromal tumors.30,31 Recently, a tyrosine kinase inhibitor specific for the
PDGFR family (STI571) has been reported to have therapeutic effects in tumors that
express either aberrant forms or high quantities of the corresponding target protein.31,32 So
far, c-Kit expression has not been evaluated in JNA.
In addition to its well-known effect to neural tissue, nerve growth factor (NGF), a
member of the neurotrophin family, has been shown to have regulatory effects on mast
cell differentiation and angiogenesis in inflammatory conditions through its receptor
TrkA.33,34 Fibroblasts of the human lower respiratory tract have been shown to secret
NGF.35 The NGF-Trk signaling has also been speculated to play a role in tumorigenesis in
some solid tumors.36 The role of NGF-TrkA signaling has not been evaluated in JNA that
is composed of prominent fibroblastic stromal cells and vascular proliferation of the
upper respiratory tract origin.
Nasal polyps are a benign inflammatory and reactive stromal growth that involve nasal
cavity and paranasal sinuses and are usually associated with underlying allergic
conditions or chronic inflammation.37 Recurrence is common after surgery, which is
sometimes used to relieve the symptoms. However, in contrast to JNA, nasal polyps are
usually nondestructive and self-limited after elimination of the underlying allergens or the
cause of the chronic inflammation.38
To investigate the possible role of these factors in the pathogenesis of JNA, we
examined expression of these factors in a series of JNAs by immunohistochemical
methods. For comparison, a group of benign nasal polyps was also examined. We
compared immunoreactivity of these factors in both the stromal cells and endothelial cells
between JNA and nasal polyps. In this article, we report our results and indicate the
importance of some of these factors and the absence of significant expression of others.
MATERIALS AND METHODS Return to TOC
Records of 12 cases of JNA and 15 cases of nasal polyps were retrieved from the
surgical pathology files at the University of Pennsylvania Medical Center, Philadelphia.
All patients with JNA were male and ranged in age from 11 to 23 years old (average age,
17 years) at the time of the surgery. None of the patients had a history of FAP. Of the 15
patients with nasal polyps, the male-female ratio was 2:3, and patients ranged in age from
21 to 87 years (average age, 58 years). All the patients with nasal polyps had acute and
chronic inflammatory conditions in the nasal and/or sinonasal cavity and 3 (20%) had
recurrences after initial surgery. A representative paraffin block was selected from each
case on histologic review of the hematoxylin-eosinstained slides. Four-micrometer-thick
sections were cut onto probe-on slides (Fisher Scientific, Pittsburgh, Pa) for
immunohistochemical staining. Immunodetection of -catenin, c-Kit, p130Cas, TGF-3,
BMP4, NGF, and IGF-1R was performed using either monoclonal or polyclonal
antibodies with a microwave or steam antigen retrieval method as summarized in Table 1
. Primary antibodies against -catenin, c-Kit, p130Cas, and IGF-1R were incubated at
room temperature for 30 minutes, and the immunostaining was completed on a Dako

autostainer with Envision Plus software (Dako Corporation, Carpinteria, Calif).

Antibodies against TGF-3, NGF, and BMP4 were incubated at 4C overnight, and the
SA-HRP method was used manually for immunodetection. The intensity of the
immunoreactivity and the percentage of positive cells were initially estimated
semiquantitatively under light microscope in stromal cells and endothelial cells of JNA
and nasal polyps in a semiquantitative method as previous described.39,40 The overall
immunoreactivity was then scored in a 4-tier scale system based on the percentage of
positive cells and the intensity of immunoreactivity. Immunoreactivity was scored as
follows: , negative result; +, weak immunoreactivity regardless of the percentage of the
cells being positive; ++, moderate immunoreactivity in less than 75% or strong
immunoreactivity in less than 25% of the cells; and +++, moderate immunoreactivity in
75% or more or strong immunoreactivity in 25% or more of the cells. Only cytoplasmic
reactivity was considered specific for c-Kit, p130Cas, TGF-3, NGF, BMP4, and IGF1R. Either cytoplasmic or nuclear reactivity was considered specific for -catenin. The
final overall scores for the immunoreactivity of each biologic marker were compared
between JNA and nasal polyps, and statistical analysis was performed with the 2-tailed
Mann-Whitney U test for the nonparametric data using GraphPad Prism Version 3.0
software (GraphPad Software Inc, San Diego, Calif).
RESULTS Return to TOC
Results of the immunohistochemical analysis are summarized in Table 2 . When
present, -catenin immunoreactivity was always cytoplasmic and nuclear in the stromal
cells of JNA but only cytoplasmic in stromal cells of nasal polyps and endothelial cells of
both JNA and nasal polyps (Figure 1 ). Immunoreactivity of c-Kit was identified in the
stromal cells only, whereas immunoreactivity of BMP4, NGF, p130Cas, and TGF-3 was
seen in both endothelial and stromal cell components of both JNA and nasal polyps. No
IGF-1R immunoreactivity was identified in any of the JNA and nasal polyp cases.
Except nuclear -catenin expression, none of the markers tested were exclusively
positive in JNA but not in nasal polyps. In general, differences in immunoreactivity for
these biologic markers between JNA and nasal polyps were mainly observed in stromal
cells. There was a significant difference in expression of -catenin (P < .001), c-Kit (P < .
001), and NGF (P = .007) in stromal cells between JNA and nasal polyps (Figures 1
through 3 ). No difference was found in expression of -catenin and NGF in
endothelial cells between JNA and nasal polyps (P = .09 and .07, respectively). The
endothelial cells in both JNA and nasal polyps were negative for c-Kit. No statistically
significant difference was detected in immunoexpression of p130Cas, TGF-3, and
BMP4 in stromal cells or endothelial cells between JNA and nasal polyps (P > .10).
When stromal cells were compared with endothelial cells in the same group, a
statistically significant difference was detected in immunoreactivity of p130Cas in nasal
polyps (P = .007).
COMMENT Return to TOC

In this study, we evaluated the potential roles of -catenin, c-Kit, p130cas, TGF-3,
NGF, IGF-1R, and BMP4 in the growth of JNA by comparing the immunoreactivity of
these biologic markers in JNA to that in nasal polyps. Of the markers tested, -catenin (+
++, 92%), c-Kit (+++, 75%; ++, 25%), p130Cas (+++, 42%; ++, 50%), and TGF-3 (++
+, 92%; +, 8%) were strongly expressed, and BMP4 (++, 25%; +, 67%) and NGF (++,
67%; +, 25%) were moderately expressed in the stromal cells of JNA. However, only the
-catenin, c-Kit, and NGF expressions were significantly higher than that of the nasal
polyps, a benign inflammatory growth. Strong -catenin nuclear expression was
frequently detected in sporadic JNA but not in any of the nasal polyps. These findings
support the role of the -catenin pathway in JNA via activating the -catenin gene
mutation independent of the APC gene mutation as described previously.21
In addition, a higher frequency of stronger c-Kit expression was identified in JNA than
nasal polyps. High levels of c-Kit expression due to activating gene mutation have been
found in other solid tumors, such as the gastrointestinal stromal tumor, and have been
used as a target for treatment with STI571.3133 Little is known about the role of the
PDGFRc-Kit pathway in JNA. Our finding of strong c-Kit expression in JNA, however,
suggests a possible involvement of c-Kit in JNA, which can be the potential target for
treatment with STI571. Traditionally, JNA has been treated mainly with surgery, with a
high incidence of local recurrence. Antiandrogen therapy has been added preoperatively
to enhance the resectability of the tumor and reduce the local recurrence; in fact,
antiandrogen therapy itself has been shown to reduce the size of the tumor without
surgery.10 The finding of frequent strong expression of c-Kit in JNA suggests a potential
application of STI571 in JNA as the treatment of choice in addition to surgery and
antiandrogen therapy to improve the local control of the disease.
Previous studies have shown that fibroblasts in the lower respiratory tract were capable
of secreting NGF.36 In this study, we detected NGF immunoreactivity in the fibroblast
stromal cells and the endothelial cells in both JNA and nasal polyps, suggesting that the
fibroblasts in the upper respiratory tract might also be able to secret NGF in both
inflammatory and neoplastic conditions. However, stromal NGF immunoreactivity was
significantly stronger in JNA than nasal polyps. NGF has been shown to be able to induce
angiogenesis.34,35 This finding indicates a potential role of increased NGF secreted by the
stromal cells in promoting vascular growth in JNA.
Although expression of p130Cas and BMP4 was either strong or moderate in JNA, the
lack of difference in expression of these growth factors between JNA and nasal polyps
suggests an insignificant role of these factors in JNA. Although TGF-1 and IGF-II were
detected in JNA previously,23 the lack of differential expression of TGF-3 between JNA
and nasal polyps and lack of IGF-1R in JNA in our study imply a limited role of these
growth factors in JNA.
Although morphologic analysis of JNA shows that the stromal cells are bland and the
blood vessels appear abnormal, our results indicate that the stromal cells are more likely
the elements involved in the histogenesis of the tumor as previously suggested.21 By
using comparative immunohistochemical methods, nuclear expression of -catenin was

only detected in the stromal cells of JNA, which also expressed a significantly higher
level of c-Kit and NGF than that of their counterparts in nasal polyps. These findings
support the notion that the stromal cells rather than the vascular component are neoplastic
and responsible for the growth of JNA.
In conclusion, we have first shown a significantly high level of c-Kit
immunoexpression in JNA. The role of c-Kit should be further evaluated with molecular
methods, and its strong expression in JNA might be potentially important in offering
STI571 as an alternative treatment for patients with JNA. The strong -catenin expression
found in our study is in agreement with the results of a previous study and further
supports the role of -catenin in JNA.21 Because the nuclear expression of -catenin was
only present in the stromal cells of JNA but not the nasal polyps, detection of nuclear catenin might be helpful in diagnosing small volumes of diseased tissue in the
background of reactive or inflammatory stromal cell proliferation as commonly seen in
cases with residual or recurrent disease. It is possible that the NGF-TrkA signaling is also
involved in JNA because of its strong immunoreactivity in the stromal cells of JNA.
Stromal cells are likely the neoplastic component of the JNA that is probably driven by
multiple signaling pathways, except those involving p130Cas, BMP4, TGF-3, and IGF1R.
References Return to TOC
1. Neel HB, Whicker JH, Devine KD, Weiland LH. Juvenile angiofibroma: review
of 120 cases. Am J Surg 1973;126:547556. [PubMed Citation]
2. McGavran MH, Dorfman RF, Davis DO, Ogura JH. Nasopharyngeal
angiofibroma. Arch Otolaryngol 1969;96:6878.
3. Twefik TL, Tan AKW, Al Noury K. et al. Juvenile nasopharyngeal
angiofibroma. J Otolaryngol 1999;28:145151. [PubMed Citation]
4. Mills SE, Gaffey MJ, Frierson HF Jr. Nasopharyngeal angiofibroma. In: Rosai
J, Sobin LH, eds. Tumors of the Upper Aerodigestive Tract and Ear. Washington,
DC: Armed Forces Institute of Pathology; 2000:252257. Atlas of Tumor
Pathology; 3rd series, fascicle 26.
5. McCombe A, Lund VJ, Howard DJ. Recurrence in juvenile angiofibroma.
Rhinology 1990;28:97102. [PubMed Citation]
6. Hubbard EM. Nasopharyngeal angiofibroma. Arch Otolaryngol 1958;65:192
204.
7. Lee DE, Rao BR, Meyer JS, Prioleau PG, Bauer WC. Hormonal receptor
determination in juvenile nasopharyngeal angiofibroma. Cancer 1980;46:547
551.

8. Schiff M. Juvenile nasopharyngeal angiofibroma. Laryngoscope 1959;69:981

987. [PubMed Citation]
9. Hwang HC, Mills SE, Patterson K, Gown AM. Expression of androgen
receptors in nasopharyngeal angiofibroma: an immunohistochemical study of 24
cases. Mod Pathol 1998;11:11221126. [PubMed Citation]
10. Farag MM, Ghanimah SE, Ragaie A, Saleem TH. Hormonal receptors in
juvenile nasopharyngeal angiofibroma. Laryngoscope 1987;97:208211.
[PubMed Citation]
11. Brentani MM, Butugan O, Oshima CT, Torloni H, Paiva LJ. Multiple steroid
receptors in nasopharyngeal angiofibroma. Laryngoscope 1989;99:398401.
[PubMed Citation]
12. Gates GA, Rice DH, Koopmann DF, Schuller DE. Flutamide-induced
regression of angiofibroma. Laryngoscope 1992;102:641644. [PubMed Citation]
13. Johns ME, Macleod RM, Cantrell RW. Estrogen receptors in nasopharyngeal
angiofibroma. Laryngoscope 1980;90:628634. [PubMed Citation]
14. Panetti TS. Tyrosine phosphorylation of paxillin, FAK, and p130CAS: effects
on cell spreading and migration. Front Biosci 2002;7:143150.
15. Yi J, Kloeker S, Jensen CC. et al. Members of the Zyxin family of LIM
proteins interact with members of the p130 Cas family of signal transducers. J
Bio Chem 2002;277:95809589. [PubMed Citation]
16. van der Flier S, Chan CM, Brinkman A. et al. BCAR/130Cas expression in
untreated and acquired tamoxifen-resistant human breast carcinomas. Int J
Cancer 2000;89:465468. [PubMed Citation]
17. Brinkman A, van der Flier S, Kok EM, Dorssers LC. BCAR1, a human
homologue of the adapter protein p130Cas and antiestrogen resistance in breast
cancer cells. J Natl Cancer Inst 2000;92:112120. [PubMed Citation]
18. Morin PJ. -catenin signaling and cancer. Bioessays 1999;21:10211030.
[PubMed Citation]
19. Giardiello FM, Hamilton SR, Krush AJ, Offerhaus JA, Booker SV, Petersen
GM. Nasopharyngeal angiofibroma in patients with familial adenomatous
polyposis. Gastroenterology 1993;105:15501552. [PubMed Citation]
20. Ferouz AS, Mohr RM, Paul P. Juvenile nasopharyngeal angiofibroma and
familial adenomatous polyposis: an association?. Otolaryngol Head Neck Surg

1995;113:435439. [PubMed Citation]

21. Abraham SC, Montgomery EA, Giardiello FM, Wu TT. Frequent -catenin
mutations in juvenile nasopharyngeal angiofibromas. Am J Pathol
2001;158:10731078. [PubMed Citation]
22. Guertl B, Beham A, Zachner R, Stammberger H, Hoefler G. Nasopharyngeal
angiofibroma: an APC-gene-associated tumor?. Hum Pathol 2000;31:14111413.
[PubMed Citation]
23. Nagai MA, Butugan O, Logullo A, Brentani MM. Expression of growth
factors, proto-oncogenes, and p53 in nasopharyngeal angiofibromas.
Laryngoscope 1996;106:190195. [PubMed Citation]
24. Dillard DG, Cohen C, Muller S. et al. Immunolocalization of activated
transforming growth factor beta 1 in juvenile nasopharyngeal angiofibroma. Head
Neck Surg 2000;126:723725.
25. Mendelsohn J, Baird A, Zhen F, Markowitz SD. Growth factors and their
receptors in epithelial malignancies. In: Mendelsohn AC, Mowley A, Israel SJ,
Liotta L, eds. The Molecular Basis of Cancer. 2nd ed. Philadelphia, Pa: WB
Saunders; 2001:144145.
26. Cohen MM. Bone morphogenetic proteins with some comments on
fibrodysplasia ossificans progressiva and NOGGIN. Am J Med Genet
2002;109:8792. [PubMed Citation]
27. Dooley CA, Attia GR, Rainey WE, Moore DR, Carr BR. Bone morphogenetic
protein inhibits ovarian androgen production. J Clin Endocrinol Metab
2000;85:33313337. [PubMed Citation]
28. Guo W, Gorlick R, Ladanyi M. et al. Expression of bone morphogenetic
proteins and receptors in sarcomas. Clin Orthop 1999;365:175183.
29. Yarden Y, Kuang WS, Yang-Feng T. et al. Human proto-oncogene, c-Kit, a
new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J
1987;6:33413351. [PubMed Citation]
30. Matsuda R, Takahashi T, Nakamura S. et al. Expression of the c-Kit protein in
human solid tumors and in corresponding fetal and adult normal tissues. Am J
Pathol 1993;142:339346. [PubMed Citation]
31. Joensuu H, Roberts PJ, Sarlomo-Rikala M. et al. Effect of the tyrosine kinase
inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N
Engl J Med 2001;344:10521056. [PubMed Citation]

32. Joensuu H, Dimitrijevic S. Tyrosine kinase inhibitor imatinib (STI571) as an

anticancer agent for solid tumours. Ann Med 2001;33:451455. [PubMed
Citation]
33. Sawada J, Itakura A, Tanaka A, Furusaka T, Matsuda H. Nerve growth factor
function as a chemoattractant for mast cells through both mitogen activated
protein kinase and phosphatidylinositol 3-kinase signaling pathways. Blood
2000;95:20522058. [PubMed Citation]
34. Raychaudhuri SK, Raychaudhuri SP, Weltman H, Farber EM. Effect of nerve
growth factor on endothelial cell biology: proliferation and adherence molecule
expression on human dermal microvascular endothelial cells. Arch Dermatol Res
2001;293:291295. [PubMed Citation]
35. Olgart C, Frossard N. Human lung fibroblasts secrete nerve growth factor:
effect of inflammatory cytokines and glucocorticoids. Eur Respir J 2001;18:115
121. [PubMed Citation]
36. Nakagawara A. Trk receptor tyrosine kinases: a bridge between cancer and
neural development. Cancer Lett 2001;169:107114. [PubMed Citation]
37. Mills SE, Gaffey MJ, Frierson HF Jr. Nasopharyngeal angiofibroma. In: Rosai
J, Sobin LH, eds. Tumors of the Upper Aerodigestive Tract and Ear. Washington,
DC: Armed Forces Institute of Pathology; 2000:355357. Atlas of Tumor
Pathology; 3rd series, fascicle 26.
38. Frazer JP. Allergic rhinitis and nasal polyps. Ear Nose Throat J 1984;63:172
176. [PubMed Citation]
39. Scobie JV, Acs G, Bandera CA. et al. C-kit immunoreactivity in endometrial
adenocarcinomas and its clinicopathologic significance. Int J Gynecol Pathol
2003;22:149155. [PubMed Citation]
40. Acs G, Zhang PJ, McGrath CM. et al. Hypoxia-inducible erythropoietin
signaling in squamous dysplasia and squamous cell carcinoma of the uterine
cervix and its potential role in cervical carcinogenesis and tumor progression. Am
J Pathol 2003;162:17891806. [PubMed Citation]

Original Article

COMMON PRESENTING SYMPTOMS DIAGNOSIS

AND MANAGEMENT OF ANGIOFIBROMA
- A study of twenty cases
Gohar MS1, Rashid D2 & Ahmed B3
ABSTRACT
Objective: To determine common presenting symptoms, age, disease extent; and the
efficacy of different surgical approaches in the diagnosis and treatment of Angiofibroma
of nasopharynx.
Design: All prepubertal and adolescent patients presenting with nasal obstruction,
recurrent epistaxis, denasal speech, conductive deafness and anaemic look, reporting to
our dept for consultancy were evaluated.
Setting: Patients were diagnosed on the basis of history, clinical examination, and CT
scan with contrast. Tumour excision was performed through lateral rhinotomy; lateral
Rhinotomy plus Weber, Weber Fergusson and U-shaped trans palatal approaches.
Subjects: Twenty patients with suggestive history, clinical examination and CT scan
findings were operated for excision of tumour.
Main Outcome Measures: CT scan with contrast was found most valuable investigation.
Lateral rhinotomy incision was found useful for angiofibromas with extension into
pterygopalatine fossa, and Weber-Fergusson approach for tumors occupying
infratemporal fossa.
Results: All patients were male, mean age 17.25 years. 80% presented with epistaxis,
10% with denasal speech and conductive deafness. Tumour was excised through lateral
rhinotomy 8 (40%), lateral Rhinotomy plus Weber in 4 (20%). Weber Fergusson 4(20%)
and U-shaped trans palatal 4(20%). Tumor was limited to nasopharynx (4(29%),
retromaxillary space 8(40%), into pterygopalatine fossa 6(30%), and infratemporal fossa
2 (10%). All tumors were excised completely.
Conclusion: Angiofibroma of nasopharynx should be suspected in young adolescent
males presenting with epistaxis or denasal speech. CT scan with contrast is the key
investigation and lateral rhinotomy alone or in combination with Weber is suitable for
tumours of nose, nesopharynx or more widespread.

KEY WORDS: Angiofibroma, Epistaxis, Denasal speech.

1. Major M. Shahid Gohar FCPS
ENT Specialist
Combined Military Hospital, Attock, Pakistan
2. Dr. Danyal Rashid FRCS
Ex-Advisor in ENT
Heart International Hospital, Rawalpindi, Pakistan
3. Dr. Bashir Ahmed FCPS
Consultant Otorhinolaryngologist,
Combined Military Hospital, Quetta, Pakistan
Correspondence
Major M. Shahid Gohar
E-mail: nmjrm@hotmail.com
* Received for publication: February 24, 2004
Revision received:

June 10, 2004

Revision accepted:

July 13, 2004

INTRODUCTION
Angiofibroma is a rare tumour and constitutes less than 0.05% of all those occurring in
head and neck1 but is the common tumour of nasopharynx. Some researchers reported 1
in 5000 incidence of otorhinolaryngology admissions2. The term angiofibroma was
coined by Friedberg3. It is suggested that angiofibroma is similar to most haemangiomas
by nature and is likely a vascular hamartoma4. It has a tendency to grow and extend along
the foramina and fissures. It does not invade dura mater, leaving a useful cleavage plane
for surgeons5.
Investigations are employed mainly to confirm the diagnosis, to determine the extent of
the tumour and to choose the treatment modality. Plain lateral radiographs demonstrate a
variable sized nasopharygeal mass causing anterior bowing of the posterior wall of the
maxillary antrum. Although it is considered pathognomonic for angiofibroma but may be
mimicked by other slow growing non invasive tumours involving this region6. Anterior
bowing sign is positive in 81% of patients7. CT scan with contrast is of extreme value in
assessing the extent of the tumour. The diagnosis by CT is based upon the site of origin of
the lesion in pterygopalatine fossa. There are two constant features i.e. 1 a mass in
posterior nasal cavity and pterygopalatine fossa 2 - erosion of bone behind the
sphenopalatine foramen with extension to the upper medial pterygoid plate.
The introduction of CT scanning has to a large extent preempted the routine use of
arteriography, but useful information is obtained from arteriograms on the size and extent

of the lesion, and the size and location of feeding vessels, some of which arise from
unusual sources as the internal carotid and vertebral arteries8. Generally arteriography is
not used routinely, as it is not readily available, requires skill and carries high
complication rate. Biopsy is generally contraindicated due to risk of uncontrollable
haemorrhage.
We conducted this study with the aim to determine the presenting symptoms, disease
extent and then to determine the efficacy of different surgical
approaches.
PATIENTS AND METHODS
From Jan 1998 to Dec 2000, we included those prepubertal and adolescent patients who
presented with nasal obstruction, recurrent epistaxis, denasal speech, conductive deafness
and anaemic look, in this prospective study.
Patients were diagnosed on the basis of history and clinical examination. Diagnosis was
confirmed by CT scan with contrast and by the histophathological report of the resected
tumour specimen.
Patients with intracranial extension of the tumour, patients with recurrent tumours and
patients treated elsewhere were excluded from the analysis. The medical records of the
patients were evaluated and a statistical assessment of the data was performed. The data
included age, presenting features, preoperative findings, site of origin, type of incision,
amount of blood transfused, stay in hospital and complications. All the tumours were
excised surgically using various surgical approaches and were confirmed on
histopathology.
RESULTS
Eight thousand patients with complaints of nasal obstruction, recurrent epistaxis and
anaemic look, from Jan 1998 to Dec 2000 were received; out of which 20 patients were
included in the study. All were male with age range from 5 to 24 years, with mean age
17.25 years. The presenting symptoms in 90% of patients were nasal obstruction,
recurrent epistaxis and anaemic look. About 10% presented with denasal speech and
conductive deafness. All the tumours were excised in toto. Surgical approaches employed
are shown in table-I. Lateral rhinotomy incision was used for 8 (40%) cases. In 4 (20%)
cases lateral rhinotomy was combined with Webers incision. In 4 (20%) cases Weber
Fergusson approach was used. We used U shaped tranpalatal approach for 4 (20%) cases.
Tumour was limited to the nasopharynx in 4 (20%) cases. Tumour was just spilling into
the retromaxillary space in 8 (40%) cases and extended to pterygopatlatine fossa in 6
(30%) cases. In 2 (10%) cases it reached the infratemporal fossa. In 12 (60%) cases
tumour was from right side and in 8 (40%) cases was from left side. Extent of tumour is
summarized in table-II. The average perioperative blood transfusion was 3.8 pints as
shown in table-III. The means age was 17.25 years. Average stay in hospital was 6.9 days

as shown in table-IV. CT scan with contrast was found the most informative and reliable
investigation for assessment of tumour size, site and extension.
No complication was seen in the perioperative period. Only two (10%) patients reported
after 5 months with recurrence. One recurrence was noted in a patient with ongiofibroma
extending into pterygopalatine fossa, in which Weber Fergusan approach was used.
Second case of recurrence occurred in a patient with angiofibroma just spilling into
retromaxillary space. Lateral rhinotomy approach was used in this case. Revision surgery
was performed in those two cases.

DISCUSSION
Angiofibroma is the most frequent benign tumour of nasopharynx in young males. The
mean age at presentation is 14 years given by Harison DFN9. The entire patients in our
series were males and the mean age at presentation was 17.25 years which is at par with
most published studies10-11. The triad of nasal obstruction recurrent epistaxis and mass
nasopharynx in an adolescent male should be investigated seriously because it might be
angiofibroma which requires early treatment. In our study every patient presented with
nasal obstruction and recurrent epistaxis. In most nasopharyngeal mass was observed
clinically.
Generally investigations are employed to confirm the diagnosis, determine the extent of
the tumour and help plan for suitable mode of treatment. CT scan with contrast is very
informative. We employed this investigation in every case to determine exact site, size
and extension of the lesion into the surrounding regions. Biopsy of the lesion was not
carried out in any case because its need is obviated by the use of radiological
investigaions. The introduction of CT scanning with enhancement and MRI has to a large
extent pre-empted the routine use of arteriography12. Although various modalities of
treatment are available for this disease, such as hormonal therapy, radio therapy and
embolization but the mainstay of treatment is surgery due to its safety and radical
clearance of the disease. We treated all our patients under study, surgically. The patients
with intracranial extension of disease and patients with recurrent disease were excluded
from the study. 100% cure rate has been claimed by Jafec13 and 79% by Brajendra and
SK Kockerk14 employing surgery. Our cure rate is
90%.
We used lateral rhinotomy incision in 8 (40%) cases. We found this approach very useful
to deliver the angiofibroma with extension into the pterygopalatine fossa. Stell and
Maran15 advocate that the use of lateral rhinotomy approach is better for direct and easy
access. For larger tumours occupying infratermporal fossa, Weber Fergusson16 or facial
degloving is usually advocated17. We employed this approach in 4 (20%) cases. Our
experience is that lateral rhinotomy with medial maxillectomy is sufficient for complete
removal of the angiofibroma without intracranial extension.

The recurrence rate varies with different series e.g. 50% with Conley and Williams18. Two
(2%) percent with Chatter Jee and Soni19, and 6.1% in I.H Jaffery and S.H Zaidi20 series.
In our series it is 10%.
CONCLUSION
Angrofibroma is a particularly important disease in otolaryngological practice. The
prognosis for this disease is extremely good if diagnosed well in time and if tumour has
not extended intracranially.
Once the disease is diagnosed and its size and extent is outlined then the key to complete
cure is good exposure and removal of tumour in toto. Lateral rhinotomy approach alone
or in combination with Weber is very suitable for tumours confined to nose and
nasopharynx and also for more extensive spread. We also recommend that radiotherapy
should be considered for intracranial spread or recurrent tumours. Regular follow up is
mandatory to detect any recurrence well in time. For this a radiological work up is
recommended after four months of surgery.
REFERENCES
1.

2.
3.
4.
5.

Ballenger JJ, Snow JB. Otorhinolaryngology Head and Neck Surgery 15th ed. Williams and Wilkins,
New York, 1995: p245-8.
Lee DA & Sessions DG. Juvenile Nasophayngeal Angiofibroma: Diagnosis and Treatment. Surg
Rounds 1980; 3: 38-44.
Nasopharyngeal Angiofibroma. Zhonghua Yi Xue (Taipei) 2001; 64(1): 39-46.
Liang J, Yi Z, Liang P. The nature of juvenile nasopharyngeal angiofibroma; Otolaryngol Head Neck
Surg 2000; 123(4): 475-81
Coley J, Healey WV, et al. Nasopharyngeal angiofibroma in the juvnile. Surg Gynecol Obstet 1968;
126: 825-37.

6.

7.
8.
9.
10.
11.
12.
13.
14.
15.
16.

Diagnostic images in Surgery. Peter Armstrong Matin-L-Waste (eds). Oxford Blackwell Scientific
Publications, London, 1987 p:64.
Text Book of Radiology and Medical Imaging Vol: 2, 5th ed. David Sutton (eds), Elsevier Science
Ltd., London 1992: p1263-64.
Scot Browns Otolaryngology. 6th ed. Butterworth - Heineman, Oxford 1992; 5:12-4.
Harrison DFN: The natural history, Pathogenisis and Treatment of Juvnile Angiofibroma. Arch
Otolaryngol Head and Neck Surg 1987; 113:936.
Martin H, Juvenile nasopharyngeal angiofibroma, Ann Surg 1984; 127:513-36.
J Alam, S Khalid. A Ashrafi nasopharyngeal angiofibroma: Experience at civil hospital Karachi: Pak
J Otolaryngol 1997;13:111-3.
Levine HL, Tucker HN. Diagnosis of nasopharyngeal angiofibroma by computed tomography,
Otolaryngol, Head Neck Surg 1979; 87(16):2476-259.
Jafec SW. Surgical treatment of juvenile nasopharyngeal angiofibroma, Larynogoscope,
1973;83:707-720
Bragendra, Kackerk SK; Extensive Fibroangioma of Nasopharynx. Report of 15 cases with literature
review. Pak J Otolaryngol 1987:3:97.
Stell and Marans; Head and Neck Surgery 4th ed. Butterworth - Heineman, Oxford 2000: p405.
Shaheen OH. Angiofibroma. Scot Browns Otolaryngology 4th ed: 1987;4:330.

17.
18.
19.
20.

Howard DJ, Lund VJ. The mid facial degloving approach to sinonasal disease. J Laryngol Otol
1992;106:1059-62.
Conley J, Healey WV, et al. Nasopharyngeal angiofibroma in juvenile. Surg Gynaecol Obstet
1968;126:825-37.
Chatterji P, Soni NR. A few points in management of JNPA. JLO 1984; 98:489.
Zaidi SH, Jafery IM, JN PAF. Pak J Otolaryngol 1988;4:77.

NASOPHARYNGEAL ANGIOFIBROMA WITH CAVERNOUS SINUS

INVOLVEMENT
An Unusual Presentation
http://www.bhj.org/journal/2000_4204_oct00/case_621.htm
Dinaz K Irani*, Makarand V Damle**,Bachi T Hathiram***, N L Hiranadani****
*Lecturer; **Senior Resident; ***Associate Professor; ****Hon. Professor, Department
of Otorhinolaryngology, TN Medical College and BYL Nair Ch. Hospital, Mumbai 400
008.
INTRODUCTION
Juvenile nasopharyngeal angiofibroma (JNA) is an uncommon benign vascular tumour
occurring almost exclusively in pre-pubescent or pubescent males. The triad of
epistaxis, nasal obstruction and the presence of a nasopharyngeal mass strongly
ind`icates an angiofibroma, especially when seen in an adolescent male. It accounts
for less than 0.05% of head and neck tumours (Waldman et al, 1981). Its incidence
has been stated to be as low as one in 50,000 otolaryngological new patients.[1]
Intracranial extension has been observed in 20-30% patients with JNA.[2,3]
It is a benign tumour and is locally aggressive eroding adjacent bone and growing
through natural foramina and fissures thus gaining an easy access into the cranium
and the infratemporal region. The intracranial extension is either through erosion of
the sphenoid sinus through the sella medial to the carotid artery and lateral to the
pituitary gland or via erosion of the greater wing of sphenoid through the middle
cranial fossa anterior to the foramen lacerum and lateral to the cavernous sinus and
carotid artery.
In this paper we report our experience of an unusual presentation of a huge JNA with
intracranial extension into the middle cranial fossa, which encroached the cavernous
sinus. We treated it surgically by the conventional combined lateral rhinotomy and
transpalatal approaches. The entire tumour including the intracranial extent was
removed without opening the cranium.
CASE REPORT
A 17 year old boy was referred to us with chief complaints of right-sided nasal
obstruction, repeated episodes of epistaxis and a nasal twang since a period of 1
year. The patient was alright 1 year back when he started experiencing a right-sided
nasal obstruction which was gradually increasing. He also complained of repeated
episodes of epistaxis, which increased to 10-15 ml of fresh blood daily. The epistaxis
was controlled by the patient by lying in the supine position. There was no headache,
vomiting, diplopia or any other symptoms suggestive of raised intracranial tension or
involvement of the cavernous sinus. The patient occasionally complained of bleeding
from the mouth.
On general examination, the patient was anaemic. There was widening of the bridge
of the nose. Anterior rhinoscopy showed purulent discharge in the right nasal cavity
and a huge reddish lobulated mass seen extending into the oropharynx behind the
palate for about 2 cm.
Haematological investigations of the patient were as follows

Haemoglobin 6 gm%, PCV 42 gm%, MVC 65 fl., MCH 25 pg., MCHC 25%, BUN 15 mg
%, Serum creatinine 0.5 mg%, Serum Na 133 mEq/L, Serum K 3.5 mEq/L, ESR 9 mm
at the end of the Serum Ca 9 mg%.
On radiographic investigations the X-ray chest was normal. The X-ray paranasal
sinuses Waters and Caldwells view showed haziness in the right nasal cavity and
right maxillary sinus without bony destruction. The X-ray nasopharynx revealed a
mass occupying the entire nasal cavity, nasopharynx and upper part of the
oropharynx.
The contrast CT scan axial and coronal views revealed a large well defined
moderately enhancing nasopharyngeal mass extending into the right nasal cavity
with widening of the pterygopalatine fossa laterally, into the sphenoid sinus, right
optic canal and middle cranial fossa encroaching on the posterior and medial aspect
of the right cavernous sinus superiorly and into the oropharynx inferiorly (Figs
1a,b,c).
The diagnosis of JNA with intracranial extension (Cavernous sinus) was made and the
patient was advised surgery - combined lateral rhinotomy with transpalatal approach.
Pre-operatively 5 units of blood were transfused to the patient to bring the
haemoglobin to 11 gm%; general anaesthesia was given. The right external carotid
artery was ligated. A lateral rhinotomy and transpalatal incisions were taken. The
lateral rhinotomy incision was extended sublabially. The flaps were elevated and the
maxillary antrum was opened and inspected. The medial wall of the maxilla,
especially the anterosuperior part was removed partially to expose the tumour which
was then inspected and it was gently dissected out by finger dissection and gentle
traction from all its anterior and superior attachments including infratemporal,
nasopharyngeal and lastly the intracranial part was removed by guarded traction and
dissection. Brisk bleeding from the venous plexus of the right cavernous sinus ensued
but was controlled with gentle pressure applied over gelatin sponge, reinforced with
moistened cottonoids. After removal of the intracranial part the defect in the
periosteum and medial wall of the right cavernous sinus was seen.

Fig.1a Contrast CT scan axial view showing a large well

defined moderately enhancing mass involving the right
nasal cavity nasopharynx, pterygopalatine fossa and
infratemporal fossa

Fig.1b Contrast CT scan coronal view showing a large well

defined moderately enhancing mass involving the
nasopharynx,infratemporal fossa and extending into the
sphenoid sinus and middle cranial fossa

Fig.1c Contrast CT scan coronal view showing the

enhancing mass involving the right cavernous sinus.

No CSF leak was found. No attempt was made to repair the defect. Simultaneously
through the transpalatal incision removal of the nasopharyngeal attachments of the
tumour was done by finger dissection.
Inspite of ligation of the right external carotid artery, the patient bled profusely and
we had to transfuse 3 pints of blood and 2 pints of fresh frozen plasma
intraoperatively and 2 pints of blood in the immediate post-operative period. Anterior
nasal packing was done and the incisions were sutured. The pack was removed in the
operation theatre after 72 hours under general anaesthesia and we encountered no
active bleeding.
The gross appearances of the tumour was a round, nodular, nonencapsulated pink
mass which measured 8 cm x 4 cm in dimension. Histopathological examination
revealed fibrous connective tissue with endothelium lined/spaces confirming the
diagnosis of angiofibroma (Figs. 2 and 3).
DISCUSSION

Juvenile nasopharyngeal angiofibroma (JNA) is a locally aggressive benign vascular

tumour. It affects mainly adolescent males and the diagnosis is often made at a
relatively late stage, after the patients have had symptoms for several months. The
typical initial symptoms include nasal obstruction, epistaxis, pain, nasal discharge
and hearing impairment.[4]
The diagnosis and assessment of tumour extension are made on the basis of clinical
symptoms and radiographic investigations, including computed tomography (CT) and
angiography.
A staging system similar to that proposed for cancer by the American Joint
Committee has been suggested by the Chandler et al in 1984. According to this
classification, in Stage I tumour is confined to the nasopharynx and in Stage II tumour
extends into the nasal cavity and/or sphenoid sinus. In Stage III tumour extends into
one or more of the followings: maxillary antrum, ethmoid sinus, pterygomaxillary and
infratemporal fossae, orbit and/or cheek. Tumour extension intracranially is stage IV.
Treatment modalities include pre-operative arterial embolization[5] and Surgery.[6] In
cases with intracranial extension of the tumour which occurs in 10% to 20%7
different modalities of treatment have been tried such as irradiation6 or intracranial
surgery.[7]
Tumours invading the cavernous sinus have generally been considered inoperable
because of the high likelihood of bleeding from the cavernous venous plexus, or
potential injury to the internal carotid artery or one of the cranial nerves.[8] In
addition, surgical defects in the dura surrounding the cavernous sinus can be difficult
to repair, leading to the possibility of an uncontrollable cerebrospinal fluid leak.[9]
Based largely on these concerns, most surgeons addressing the treatment of
intracranial angiofibromas have advocated either non-surgical treatment or
incomplete resection of tumour involving this structure.[10,11]
The unusual and interesting finding in our case are that inspite of being a large and
extensive JNA the patient had no symptoms of intracranial and/or cavernous sinus
involvement. Since the tumour is benign, encapsulated and extradural it was
dissected out by gentle traction and finger dissection by combined transpalatal and
lateral rhinotomy approach.
The advantage of this approach is that it is less morbid than intracranial surgery
which involves traction on the cerebrum with risk of anaesthesia and other
complications of intracranial surgery. Therefore we recommend it for JNA with
intracranial extension in selected cases.

Fig2. Gross appearance of the specimen

Fig.3 Microphotograph showing features of angiofibroma ( H

and E ) x 40.

ACKNOWLEDGEMENT
We are grateful to Dean, Dr. (Mrs) NA Kshirsagar for allowing us to publish this paper.
REFERENCES
1. Chandler JR, Goulding R, Moscowitz L, et al. Nasopharyngeal
angiofibromas : Staging and Management. Annals of Otology Rhinology
Laryngology 1984; 93 : 323-20.
2. Jafek BW, Krekorian EA, Kirsch WM, Wood RP. Juvenile nasopharyngeal
angiofibroma : Management of intracranial extension. Otolaryngology
1979; 2 : 119-28.
3. Cummings BJ, Blend R, Keane T, et al. Primary radiation therapy for
juvenile nasopharyngral angiofibroma. Laryngoscope 1984; 94 : 1599605.
4. Jacobsson M, Petruson B, Svendsen P, et al. Juvenile nasopharyngeal
angiofibroma : A report of 18 cases. Acta Otolaryngologica 1988; 105 :
132-39.
5. Bryan RN, Sessions RB, Horowitz BL. Radiographic management of
Juvenile angiofibromas. American Journal of Radiology 1981; 2 : 15766.
6. Ward PH. The evolving management of Juvenile Nasopharyngeal
angiofibroma. Journal of Laryngology Otology 1983; Suppl 8 : 103-4.
7. Jafek BW, Nahum AM, Butler RM, et al. Surgical treatment of Juvenile
Nasopharyngeal Angiofibroma. Laryngoscope 1973; 83 : 707-20.
8. Sekhar LN, Moller AR. Operative management of tumours involving the
cavernous sinus. Journal of Neurosurgery 1986; 64 : 879-89.
9. Mickey B, Close LG, Schaefer SD, Samson D. A combined
frontotemporal and lateral infratemporal fossa approach to the skull
base. Journal of Neurosurgery 1988; 68 : 678-83.
10. Fisch U. The infratemporal fossa approach for nasopharyngeal tumours.
Laryngoscope 1983; 93 : 36-44.
11. Goepfert H, Cangir A, Lee Y. Chemotherapy for aggressive Juvenile
nasopharyngeal angiofibroma. Archives of Otolaryngology and head
neck surgery. 1985; 111 : 285-89.