REVIEW ARTICLE
Sinonasal eosinophilic angiocentric fibrosis: A systematic review Christina H. Fang, BS1 , Leila J. Mady, MD, PhD1 , Neena M. Mirani, MD2 , Soly Baredes, MD, FACS1,3 and Jean Anderson Eloy, MD, FACS1,3,4
Background: Eosinophilic angiocentric fibrosis (EAF) is a benign rare lesion of the upper respiratory mucosa. EAF most commonly presents with an obstructive nasal mass. Due to the rarity of EAF, case reports and case studies have predominated the literature. This systematic review discusses the demographics, clinical presentation, associated findings, management, and outcomes of this uncommon entity. Methods: The PubMed database was searched for all articles describing patients diagnosed with sinonasal EAF. Additional cases were examined from the bibliographies of selected articles. Demographics, clinical presentation, associated findings, radiography, management, and outcome were analyzed. Results: Fiy-two cases were included from 34 articles, including 1 case from our institution. The most common presenting symptom was nasal obstruction (78.8%). Fourteen patients (26.9%) had a previous history of nasal surgery or trauma. Surgical resection alone was the most commonly used primary treatment approach (50.0%), resulting in the
E
osinophilic angiocentric fibrosis (EAF) is a rare lesion of the respiratory mucosa, most commonly found in the sinonasal tract. It was first reported by Holmes and
1 Department
of Otolaryngology–Head and Neck Surgery, Rutgers New Jersey Medical School, Newark, NJ; 2 Department of Pathology, Rutgers New Jersey Medical School, Newark, NJ; 3 Center for Skull Base and Pituitary Surgery, Neurological Institute of New Jersey, Rutgers New Jersey Medical School, Newark, NJ; 4 Department of Neurological Surgery, Rutgers New Jersey Medical School, Newark, NJ
Correspondence to: Jean Anderson Eloy, MD, FACS, Rhinology and Sinus Surgery, Endoscopic Skull Base Surgery Program, Department of Otolaryngology–Head and Neck Surgery, Rutgers New Jersey Medical School, 90 Bergen St., Suite 8100, Newark, NJ 07103; e-mail: [email protected] Potential conflict of interest: None provided. Presented at the American Rhinologic Society (ARS) section of the 117th of Combined Otolaryngology Spring Meetings (COSM), May 14-18, 2014, Las Vegas, NV. Received: 28 February 2014; Revised: 11 April 2014; Accepted: 24 April 2014 DOI: 10.1002/alr.21347 View this article online at wileyonlinelibrary.com.
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greatest proportion of disease-free patients (55.6%) over a median follow-up period of 36 months. A combination of surgery and corticosteroids was the second-most-common treatment modality, used in 28.8% of cases. Of the 40 cases reporting patient outcomes, 100% of patients were alive at follow-up independent of treatment modality. Conclusion: To date, this review contains the largest number of patients with sinonasal EAF. Aggressive surgical resection alone constitutes the most common treatment modality and may be most effective at eradicating disease. C 2014 ARS-AAOA, LLC.
Key Words: eosinophilic angiocentric fibrosis; sinonasal mass; sinus; angiocentric fibrosis; nasal eosinophilic angiocentric fibrosis; sinus eosinophilic angiocentric fibrosis How to Cite this Article: Fang CH, Mady LJ, Mirani NM, Baredes S, Eloy JA. Sinonasal eosinophilic angiocentric fibrosis: a systematic review. Int Forum Allergy Rhinol. 2014;4:745–752.
Panje in 1983 as “intranasal granuloma faciale” and the name was coined by Roberts and McCann in 1985.1 To our knowledge, less than 60 cases of sinonasal EAF have been reported in the literature to date. EAF has a benign, slowly progressing course that leads to local destructive growth in the nasal cavity and surrounding structures. The nasal septum is most commonly involved; however, involvement of the lateral nasal walls, orbit, maxillary sinuses, and ethmoid sinuses is not a rare occurrence. Reports of EAF originating in the orbit, larynx, and lower respiratory tract have also been described.2–8 Patients often present with nonspecific symptoms of nasal obstruction, epistaxis, nasal deformities, facial pain, and epiphora, causing difficulty and delay of diagnosis. Clinically, EAF presents as submucosal thickening or a firm fibrotic mass (Fig. 1).9, 10 EAF predominantly affects those 50 to 60 years of age with no predilection for either gender.7 Though a relationship between EAF and allergies, atopy, or trauma has been reported,11–19 the etiology remains unclear. The diagnosis of EAF is made based on characteristic histologic findings
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FIGURE 1. Coronal CT scan (A) and endoscopic view (B) of a patient with eosinophilic angiocentric fibrosis (EAF) involving the right nasal cavity.
(Fig. 2). Early lesions are marked by a rich inflammatory infiltrate of lymphocytes, neutrophils, plasma cells, and a predominance of eosinophils. Late lesions are characterized by concentric perivascular “onion-skin” fibrosis with fewer inflammatory cells. Both early and late lesions coexist in the same biopsy sample, which suggests that there is an ongoing progression of this disease.9, 14–17, 20–24 Treatment of EAF presents a challenge because of the likelihood of persistent or recurrence of disease. Most cases have been treated with surgical resection; however, local recurrence remains an issue with such treatment modality.11, 12, 14, 20, 25, 26 Use of corticosteroids and immunosuppressants such as dapsone and azathioprine have not provided satisfactory resolution of symptoms.14, 19, 23, 27 In some cases, opting for no treatment has not been associated with increased morbidity.15, 17 Due to the rarity of this lesion, the clinical characteristics and optimal treatment strategy of EAF has not been well-established. Here, we present a systematic review of the demographics, presentation, treatment modalities, and outcomes associated with this uncommon sinonasal entity.
cles were further reviewed to identify additional cases not found in the original search.
Selection criteria The articles were grouped by title and duplicates were excluded. Inclusion criteria included English-language studies that provided individual patient data with specific treatment defined. Foreign-language studies and studies with no individual patient data were excluded. Articles and specific cases from articles with insufficient data, as well as cases of EAF in anatomic locations outside the sinonasal tract were also excluded.
Data extraction and analysis Two independent reviewers (C.H.F. and L.J.M.) extracted data from the selected studies. Disagreement regarding inclusion of a study was resolved following discussion. Extracted data included patient demographics, tumor location, presenting symptoms, associated findings, radiographic imaging, primary treatment modality, recurrence, follow-up, and outcome. Microsoft Excel (Microsoft Corp., Redmond, WA) was used for data aggregation and analysis.
Materials and methods A systematic review of the published literature on cases of EAF of the sinonasal tract was performed. This study qualified as “nonhuman subject research” as per protocol of the Institutional Review Board of Rutgers New Jersey Medical School, Newark, New Jersey, and thus did not require approval.
Literature search strategy The PubMed database was searched for all studies published through December 2013 using the keywords: “eosinophilic angiocentric fibrosis,” “nasal eosinophilic angiocentric fibrosis,” “sinus eosinophilic angiocentric fibrosis,” and “intranasal granuloma faciale.” First, abstracts were reviewed to identify the studies that appeared to involve sinonasal EAF. Full-text versions of these articles were then obtained. These were examined for compliance of studies with eligibility criteria discussed in the next section. The bibliographies of the included arti-
Results The initial PubMed search yielded 92 studies. Duplicate articles were excluded (48). Additional studies eliminated from our study included articles that did not provide individual patient data (4), foreign-language studies (3), cases involving anatomic sites outside of the sinonasal tract (3), unobtainable articles (2), and unrelated articles (1). Review of references from initially included articles yielded 3 additional articles. After applying the aforementioned criteria, 34 studies describing 51 cases were used to conduct data analysis (Fig. 3). These studies are detailed in Table 1. With the addition of 1 case from our institution, a total of 52 patients were analyzed in this systematic review.
Demographics and tumor specifics Demographics, symptoms, and anatomic location were reported in all cases. The average age of patients was 47 years old, ranging from 16 to 79 years. The male to female
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FIGURE 3. Flow diagram of included and excluded studies.
360 months. Information on tumor size was seldom reported, and therefore, not included in the analysis. Fourteen patients (26.9%) had undergone prior nasal surgery or had a history of trauma. Nine patients (17.3%) had allergies and 11 patients (21.2%) had granuloma faciale (GF). Further demographic information is listed in Table 2.
Radiography
FIGURE 2. Hematoxylin-eosin stain of eosinophilic angiocentric fibrosis. (A) There is dense fibrosis entrapping blood vessels. (B) At higher magnification, inflammatory cells in addition to fibrosis can be seen surrounding the small blood vessels. (C) This chronic background inflammation consists of numerous eosinophils.
Imaging was reported in 41 studies. The most commonly used imaging technique was computed tomography (CT) in 37 cases, followed by magnetic resonance imaging (MRI) used in 10 cases, and X-ray used in 3 cases. Of the 37 cases that used CT, 22 cases (54.1%) showed EAF appearing as a soft-tissue swelling or mass. Sinus opacification and thinning of surrounding bone were noted in 12 (32.4%) and 10 cases (27.0%), respectively. EAF appeared isodense on non-enhanced CT in 8 cases (21.6%). Of the 10 cases that used MRI, EAF appeared isointense to gray matter on T1-weighted imaging and hypointense on T2-weighted images in 5 cases (50.0%). All 3 cases that used sinus X-rays showed sinus opacification.
Treatment and patient outcome ratio was 1:1. The most common presenting symptoms was nasal obstruction (78.8%) followed by nasal swelling or nasal deformity (25.0%). EAF was most commonly found in the nasal cavity/nasal septum (90.4%). Orbit involvement was present in 19.2% of cases. Twenty-nine cases reported an average time between onset of symptoms and diagnosis of 70 months in duration, ranging from 1.5 to
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Treatment approach was reported in all cases and included surgery, corticosteroids, immunosuppressive therapy, or a combination of these modalities (Table 3). Surgical treatment included endoscopic sinus surgery, lateral rhinotomy, open rhinoplasty, septoplasty, curettage, and lesion excision and debulking. Corticosteroid therapy included systemic, intralesional, or a combination of both. Immunosuppressive therapy comprised of azathioprine, dapsone,
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TABLE 1. Studies meeting criteria for systematic review
TABLE 2. Summary of individual cases Characteristic
Author
Year
Study type
Cases (n)
Burns et al.35
2001
Case report
1
Subjects, n Demographics
Chinelli et al.29
2004
Case report
1
Clauser et al.20
2006
Case report
1
Deshpande et al.11
2011
Case report
1
Goldman26
2003
Case report
1
Holme et al.27
2005
Case report
1
Holmes and Panje37
1983
Case report
1
Holsinger et al.25
2008
Case report
1
Jain et al.12
2008
Case series
4
Karligkiotis et al.4
2013
Case report
Kim et al.5
2013
Kiratli et al.6
Totals
52
Age, years, mean (range)
47 (16–79)
Sex, male/female (ratio)
26/26 (1:1)
Presenting symptoms, n (%)
52 (100)
Nasal obstruction
41 (78.8)
Nasal swelling/deformity
13 (25.0)
Epistaxis
9 (17.3)
Nasal mass
8 (15.4)
Epiphora
7 (13.5)
1
Pain
6 (11.5)
Case report
1
Eye symptoms (diplopia, periorbital edema, proptosis)
6 (11.5)
2008
Case report
1
Nasal congestion
5 (9.6)
2008
Case series
3
Rhinorrhea
5 (9.6)
Leibovitch et al.
2006
Case report
1
Headache
2 (3.8)
13
2013
Case report
1
Dyspnea
2 (3.8) 1 (1.9)
Kosarac et al.
21 7
Li et al.
18
2002
Case report
1
Cough, postnasal drip, hyponasal speech, decreased
22
2001
Case report
1
taste, dysphagia
Narayan and Douglas-Jones9
2005
Case report
1
Nguyen et al.10
2004
Case report
1
Loane et al. Matai et al.
Anatomic site, n (%)
52 (100)
Nasal cavity (+ septum)
47 (90.4) a
Nigar et al.15
2007
Case report
1
Onder and Sungur28
2004
Case report
1
Owa et al.30
2002
Case report
1
Orbit (+ lacrimal gland, lamina papyracea)
10 (19.2)
Maxillary sinus
7 (13.5)
Ethmoid sinus
4 (7.7)
Sphenoid sinus
1 (1.9)
Paranasal sinus
1 (1.9)
Nasopharynx
1 (1.9)
Paun et al.14
2005
Case series
4
Pereira et al.16
2002
Case report
1
Roberts and McCann1
1985
Case series
2
Slovik et al.17
2006
Case report
1
History of nasal surgery or trauma
14 (26.9)
Sunde et al.31
2010
Case report
1
Granuloma faciale
11 (21.2)
Tabaee et al.32
2003
Case report
1
Allergies (allergic rhinitis, occupational, medication)
9 (17.3)
Thompson and Heffner23
2001
Case series
3
Chronic sinusitis
3 (5.8)
Valenzuela et al.38
2006
Case report
1
Wegener’s granulomatosis, rheumatic fever, chronic
1 (1.9)
Watanabe and Moriwaki39
2006
Case report
1
inflammatory bowel disease, psoriasis, asthma
Yang et al.33
2011
Case series
6
Outcome
40 (100)
Yavuzer et al.24
2000
Case report
1
AWD
27 (67.5)
Yung et al.19
2005
Case series
2
ANED
13 (32.5)
DOD
0 (0.0)
DOC
0 (0.0)
clofazimine, tacrolimus, or hydrochloroquine. The most common primary treatment modality was surgical resection alone, used in 26 cases (50.0%). Corticosteroids in combination with surgery was the second-most-common treatment modality, used in 15 cases (28.8%). Two
Associated findings
Follow-up, n (%) Length, months, mean (range)
33 (100) 51 (0–240)
a
Orbit was involved in addition to the sinonasal tract. ANED = alive with no evidence of disease; AWD = alive with disease; DOC = dead of other cause; DOD, dead of disease.
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TABLE 3. Frequency and treatment outcomes of various
TABLE 4. Treatment outcomes of patients who had total vs
treatment modalities in sinonasal eosinophilic angiocentric fibrosis
subtotal surgical resection of sinonasal EAF
Treatment
Surgery alone
Total
Cases per treatment
cases % (n)
modality (%)
Cases that underwent subtotal resection, n (%)
All treatment modalities
50.0 (26)
ANED
55.6
ANED
11 (84.6)
AWD
44.4
AWD
2 (15.4)
Surgery and steroids
0 (0) 9 (100)
Surgery alone
28.8 (15)
ANED
23.1
ANED
10 (83.3)
AWD
76.9
AWD
2 (16.7)
2 (100)
No treatment
0 (0)
Surgery and steroids
9.6 (5)
ANED
0
ANED
1 (100)
0 (0)
AWD
100
AWD
0 (0)
5 (100)
Immunosuppressant alone
Surgery, steroids, and immunosuppressant
3.8 (2)
ANED
0
ANED
0 (0)
0 (0)
AWD
100
AWD
0 (0)
2 (100)
Surgery, steroids, and immunosuppressant
3.8 (2)
ANED = alive with no evidence of disease; AWD = alive with disease; EAF = eosinophilic angiocentric fibrosis.
ANED
0
AWD
100
Steroids alone
1.9 (1)
ANED
0
AWD
100
Steroids and immunosuppressant
1.9 (1)
ANED
0
AWD
100
Surgery and immunosuppressant
0 (0)
ANED
n/a
AWD
n/a
Total number of cases, n = 52. ANED = alive with no evidence of disease; AWD = alive with disease; n/a = data not available.
patients (3.8%) were treated with immunosuppressive therapy alone, and 2 patients (3.8%) received a combination of surgery, chemotherapy, and immunosuppressive therapy as primary treatment. Five patients (9.6%) did not receive any treatment. Of the 43 cases treated with surgery, either alone or in combination with chemotherapy or immunosuppressive therapy, 22 distinguished between total and subtotal resection. Thirteen patients (59.1%) had total or grosstotal resection of the lesion, whereas 9 patients (40.9%) were reported to have had subtotal resection (Table 4). Patient outcome was reported in 40 cases and was classified as alive with no evidence of disease (ANED), alive
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Cases that underwent total resection, n (%)
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with disease (AWD), dead of disease (DOD), or died of other causes (DOC). All patients (100%) were alive after a median follow-up of 36 months. Twenty-seven patients (67.5%) were AWD while 13 patients (32.5%) were ANED. Table 3 also illustrates patient outcome based on treatment modality. Eighteen cases receiving surgical therapy alone reported patient outcome, of which 11 patients (55.6%) were free of disease at follow-up. Of the 13 cases treated with surgery and corticosteroids in studies reporting patient outcome, 3 patients (23.1%) were disease-free at follow-up. All of the patients treated with corticosteroids alone; immunosuppressive therapy alone; a combination of steroids and immunosuppressants; or a combination of surgery, corticosteroids, and immunosuppressants were AWD at follow-up. Of the 13 patients who had total resection of EAF, 11 (84.6%) were classified as ANED at followup. In contrast, all 9 patients who underwent subtotal resection were AWD at follow-up (Table 4). A large majority of patients (92.3%) who had total surgical resection were treated with surgery alone. Of these patients, 10 (83.3%) were ANED at follow-up. Of the 9 patients who underwent subtotal resection, 5 patients (55.6%) were treated with a combination of surgery and steroids. All of these patients were AWD at follow-up (Table 4).
Discussion Eosinophilic angiocentric fibrosis is a rare fibrotic condition most commonly affecting the respiratory mucosa of the sinonasal tract. Due to its rarity, prospective studies
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involving sinonasal EAF have not been conducted. This study is the first systematic review of sinonasal EAF and aims to provide insight into this rare entity.
Demographics There is no predilection of EAF for either sex, in line with previous reports.4, 13 Of the 52 patients analyzed, 26 were male and 26 were female. The average age of this patient cohort is consistent with previously described data. The mean age was 47 years, ranging from 16 to 81 years of age.
Clinical information The nasal cavity was involved in almost all cases (90.4%). Some studies specifically reported the mass arising from the nasal septum or the lateral wall. Historically, EAF most commonly involves the nasal septum.14, 28 However, not all studies made this distinction; thus, we cannot deduce with absolute certainty which area of the nasal cavity gives rise to the majority of EAF cases. Three cases described primary orbital lesions extending into the ethmoid sinus and middle turbinate.4, 6, 7 Submucosal thickening and nasal septum deviation were commonly seen on physical examination.1, 13, 18, 23, 26, 29–33 Tumor size was not adequately reported. The presenting symptoms of EAF are often nonspecific and closely related to the involved anatomic location. The most common presenting symptom is a progressive obstructing nasal mass.13 Our analysis also found that nasal obstruction was the most common presenting symptom of EAF, noted in 78.8% of symptoms. Other presenting symptoms of EAF reported included nasal swelling, nasal deformity, epistaxis, epiphora, pain (facial, nasal), congestion, rhinorrhea, and headache (Table 2). Due to anatomic intricacy of the sinonasal tract, expansion of the lesion may lead to changes in surrounding vascular and osseous structures. There is often a delay in diagnosis with an average time from onset of symptoms to diagnosis of 5 to 6 years.23, 32 Our study found a similar duration to diagnosis with a mean of 70 months. Given this long period of time, the natural course of EAF is generally thought of as slowly progressive, with most patients recalling a history of chronic symptoms.
Etiology and differential diagnoses The etiology of EAF remains unclear. Commonly cited predisposing factors include allergy, trauma, and history of sinonasal surgery.13, 17 This analysis found that sinonasal EAF was most commonly associated with a prior history of sinonasal surgery or trauma. EAF may be thought of as an inappropriate fibrotic response to a proinflammatory stimulant such as surgery.32 However, whether the relationship between previous sinonasal surgery and sinonasal EAF is causative cannot be determined because few studies report a preoperative biopsy ruling out EAF. Differential diagnoses of EAF include granulomatous, inflammatory, and neoplastic disease processes, including but
not limited to Wegener’s granulomatosis, Churg-Strauss syndrome, sarcoidosis, and GF. On histologic examination, EAF does not involve granuloma formation found in Wegener’s and sarcoidosis or systemic vasculitis found in Churg-Strauss. EAF also lacks systemic manifestations such as fever and fatigue, which are common in these conditions. GF is a rare vasculitic disease of the dermis that manifests as chronic, slowly progressive reddish-brown plaques mostly localized to the face.1 Histologically, GF is characterized by a dense infiltrate of neutrophils, lymphocytes, histiocytes, and eosinophils in the lower dermis with accompanying perivascular inflammation.34 Eleven cases of EAF with GF have been reported. The development of GF varies with respect to EAF; GF has been diagnosed prior to, concurrent with or following the diagnosis of EAF. Because EAF shares similar histologic findings with GF, EAF is considered by some to be the “mucosal variant” of GF.9, 19, 21, 35 However, it has been noted that the skin lesions of GF respond to therapy independently of the response of EAF lesions.32
Radiology Imaging findings of EAF are nonspecific and should be correlated with the patient’s history and physical examination. EAF generally appears as an isodense soft-tissue density with possible sinus opacification on non-enhanced CT. As the lesion progresses, adjacent focal destruction of surrounding bony tissues, thinning, and sclerosis can be visualized. EAF appears isointense compared to gray matter on T1-weighted images with moderate contrast enhancement. On T2-weighted images, EAF generally appears hypointense. This has been attributed to the fibrosis in the late stage.33 Although regarded as a benign disease process, more advanced lesions of EAF can involve adjacent bony or cartilaginous structures. Destruction or erosion of surrounding bone does not appear to be a rare occurrence and was visualized in 27.0% of cases that used CT.
Treatment and patient outcome Due to the rarity of this lesion, consensus has not yet been reached regarding optimal management of EAF. Generally, EAF is regarded as a nonmalignant lesion with no risk of distant metastasis.13 To date, there have been no reports of death caused by EAF. Historically, surgical resection is the treatment of choice for EAF. This review found that surgical resection alone was the most common treatment modality for primary lesions, used in 26 cases (50.0%) (Table 3). Operative management of EAF included open rhinoplasty, lateral rhinotomy, curettage and debridement, total resection, septoplasty, and more recently, endoscopic sinus surgery. The advantages of 1 surgical technique over another or whether endoscopic surgery can accomplish complete removal of the lesion has not been addressed in the literature. Local (intralesional, nasal) and/or systemic corticosteroids have also been used in the attempt to decrease the inflammatory process of EAF. Steroids were used alone in
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only 1.9% of cases and in combination with surgery in 28.8% of cases (Table 3). Steroids were commonly used as the initial treatment approach when used in combination with surgery. Due to inadequate symptomatic relief with corticosteroid therapy alone, subsequent surgical resection was often required for progressive disease.1, 10, 14, 17, 22, 23, 35 Postoperative corticosteroid administration has been reported in 1 case as a mechanism to reduce progression of disease.6 In that study, the patient receiving postoperative steroids had stable disease burden at follow-up. However, whether this outcome is attributable to the combination of corticosteroid therapy and surgery or to the initial surgical resection is unclear. Immunosuppressive therapy is generally not considered first-line treatment of EAF. There are reports of the use of dapsone, clofazimine, tacrolimus, hydrochloroquine, and azathioprine with little success in symptomatic management.14, 19, 27, 29 Dapsone is used to treat GF, a relatively common incidental finding associated with EAF, but has not shown successful results with EAF.36 Three cases were treated with an immunosuppressant and all of these patients were classified as AWD at time of follow-up. Surgical resection is commonly advocated as the primary treatment of EAF.6, 7, 9, 12, 14, 28, 37, 38 Although considered the mainstay of therapy, it has been previously reported that surgical resection alone provides local control in only 30% of cases.31 However, our analysis found a greater proportion of local control with surgical resection. Patients treated with surgical resection alone had the best outcome, with over one-half (55.6%) being ANED at time of follow-up (Table 3). Patients receiving a combination of steroids and surgical resection had the second-best outcome with 23.1% ANED at follow-up. It appears that surgical resection plays an integral role in the control and symptomatic management of EAF. Corticosteroid therapy does not seem to have any added advantage in patient outcome over those treated with surgery alone (Table 3). Of note, of the 6 cases treated with the combination of surgery and corticosteroids that distinguished between total and subtotal resection, 5 underwent subtotal surgical resection (Table 4). Partial resection of the lesion may have decreased the likelihood of disease resolution, independent of corticosteroid use. Complete resolution of disease is notoriously difficult to achieve in EAF, irrespective of treatment modality. The rate of recurrence and persistent disease has been cited to be as high as 70%.31 Recurrence generally occurs in the original anatomic location and is thought to represent disease progression.11, 23 Given the anatomic complexity of the sinonasal tract, total resection of EAF is often difficult.20, 34 Remaining small fragments of the lesion may become a nidus for recurrence. Not all of the studies differentiated between total and subtotal resection of EAF. However, a high percentage (84.6%) of the patients who underwent total resection were disease-free at follow-up. This suggests that the achievement of adequate surgical margins during resection may result in greater local control and prevent persistence of disease.
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If the suspicion for EAF is present, we recommend first ruling out inflammatory or neoplastic processes that may also present with an obstructive nasal mass. Helpful laboratory blood tests include complete blood count (CBC), erythrocyte sedimentation rate (ESR), antineutrophil cytoplasmic antibodies (ANCA), and immunoglobulin E (IgE) titers. These values are usually unremarkable in EAF.1, 14–17, 19, 22, 29, 38, 39 Radiographic imaging including CT and MRI should be done to determine the extent of the lesion. A biopsy and histologic confirmation should be obtained early to prevent delay in diagnosis. This review found no benefits of treating patients with EAF with immunosuppressive therapy. After diagnosis, observation can be considered and does not necessarily result in increased patient morbidity.15, 17 A prior report has suggested considering surgery once symptoms or physical deformities have manifested.12 Although surgical resection of EAF offers the most promising outcomes, resolution of disease is not guaranteed. This, in addition to the possible complications of surgery suggests an individualized approach on a case-bycase basis. Factors to be taken into consideration include tumor size, severity of symptoms, and degree of functional impairment, with the goal of total or gross-total resection of the lesion. Steroid therapy may be considered in conjunction with surgery or if the patient is unable to tolerate or does not desire surgery.
Limitations The limitations of this study include those that are inherent to a systematic review. Allocation bias and selection bias are inherent weaknesses of pooled data. This review is limited by the quality of available studies in the literature. Due to the rarity of EAF, the data analyzed in this study was collected from case reports and small case studies, which precluded us from pursuing a meta-analysis. There are no randomized controlled, multi-institutional, or prospective studies involving sinonasal EAF that are available for analysis. Consequently, the overall quality of analyzed data is judged to be poor. Furthermore, there was a lack of standardized reporting of tumor size, treatment modality, and patient outcome and follow-up, which precludes further formal statistical analysis. Data quality was also inconsistent among the studies included as not all studies reported the aforementioned parameters.
Conclusion Sinonasal EAF is rare lesion of the respiratory mucosa that commonly presents with an obstructing nasal mass. Indolent growth and nonspecific symptoms contribute to the frequent delay in diagnosis. Surgical resection was the most common treatment modality for EAF and resulted in the highest rate of disease-free patients at time of follow-up.
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Roberts PF, McCann BG. Eosinophilic angiocentric fibrosis of the upper respiratory tract: a mucosal variant of granuloma faciale? A report of three cases. Histopathology. 1985;9:1217–1225. Azam M, Husen YA, Hasan SH. Eosinophilic angiocentric fibrosis of orbit. Indian J Pathol Microbiol. 2010;53:850–852. Fageeh NA, Mai KT, Odell PF. Eosinophilic angiocentric fibrosis of the subglottic region of the larynx and upper trachea. J Otolaryngol. 1996;25:276–278. Karligkiotis A, Volpi L, Ferreli F, et al. Primary orbital eosinophilic angiocentric fibrosis with intranasal extension. Head Neck. 2014;36:E8–E11. Kim WJ, Kim YI, Kim JE, et al. Unexplained persistent dyspnea in a young woman with eosinophilic angiocentric fibrosis. Respir Care. 2014;59:e72–e76. Kiratli H, Onder S, Yildiz S, Ozseker H. Eosinophilic angiocentric fibrosis of the orbit. Clin Exp Ophthalmol. 2008;36:274–276. Leibovitch I, James CL, Wormald PJ, Selva D. Orbital eosinophilic angiocentric fibrosis case report and review of the literature. Ophthalmology. 2006;113:148–152. Nogueira A, Lisboa C, Duarte AF, et al. Granuloma faciale with subglottic eosinophilic angiocentric fibrosis: case report and review of the literature. Cutis. 2011;88:77–82. Narayan J, Douglas-Jones AG. Eosinophilic angiocentric fibrosis and granuloma faciale: analysis of cellular infiltrate and review of literature. Ann Otol Rhinol Laryngol. 2005;114(1 Pt 1):35–42. Nguyen DB, Alex JC, Calhoun B. Eosinophilic angiocentric fibrosis in a patient with nasal obstruction. Ear Nose Throat J. 2004;83:183–184, 186. Deshpande V, Khosroshahi A, Nielsen GP, Hamilos DL, Stone JH. Eosinophilic angiocentric fibrosis is a form of IgG4-related systemic disease. Am J Surg Pathol. 2011;35:701–706. Jain R, Robblee JV, O’Sullivan-Mejia E, et al. Sinonasal eosinophilic angiocentric fibrosis: a report of four cases and review of literature. Head Neck Pathol. 2008;2:309–315. Li Y, Liu H, Han D, Zang H, Wang T, Hu B. Eosinophilic angiocentric fibrosis of the nasal septum. Case Rep Otolaryngol. 2013;2013:267285.
14. Paun S, Lund VJ, Gallimore A. Nasal fibrosis: longterm follow up of four cases of eosinophilic angiocentric fibrosis. J Laryngol Otol. 2005;119:119– 124. 15. Nigar E, Dhillon R, Carr E, Matin RN. Eosinophilic angiocentric fibrosis and extrafacial granuloma faciale. Histopathology. 2007;51:729–731. 16. Pereira EM, Millas I, Reis-Filho JS, Maeda SA, Franco M. Eosinophilic angiocentric fibrosis of the sinonasal tract: report on the clinicopathologic features of a case and review of the literature. Head Neck. 2002;24:307–311. 17. Slovik Y, Putterman M, Nash M, Sion-Vardy N. Eosinophilic angiocentric fibrosis of the sinonasal tract in a male patient with chronic bowel inflammation. Am J Rhinol. 2006;20:91–94. 18. Loane J, Jaramillo M, Young HA, Kerr KM. Eosinophilic angiocentric fibrosis and Wegener’s granulomatosis: a case report and literature review. J Clin Pathol. 2001;54:640–641. 19. Yung A, Wachsmuth R, Ramnath R, Merchant W, Myatt AE, Sheehan-Dare R. Eosinophilic angiocentric fibrosis–a rare mucosal variant of granuloma faciale which may present to the dermatologist. Br J Dermatol. 2005;152:574–576. 20. Clauser L, Mandrioli S, Polito J, Marchetti E. Eosinophilic angiocentric fibrosis. J Craniofacl Surg. 2006;17:812–814. 21. Kosarac O, Luna MA, Ro JY, Ayala AG. Eosinophilic angiocentric fibrosis of the sinonasal tract. Ann Diagn Pathol. 2008;12:267–270. 22. Matai V, Baer S, Barnes S, Boxer M. Eosinophilic angiocentric fibrosis. J Laryngol Otol. 2000;114:563– 564. 23. Thompson LD, Heffner DK. Sinonasal tract eosinophilic angiocentric fibrosis. A report of three cases. Am J Clin Pathol. 2001;115:243– 248. 24. Yavuzer R, Pandolfi, PJ, Herschman BR, Jackson IT. An unusual cause of nasal airway obstruction: eosinophilic angiocentric fibrosis. Eur J Plast Surg. 2000;23:49–51. 25. Holsinger JM, Magro C, Allen C, Powell D, Agrawal A. Eosinophilic angiocentric fibrosis. J Otolaryngol Head Neck Surg. 2008;37:E155–E158.
26. Goldman NC. Angiocentric eosinophilic fibrosis. Otolaryngol Head Neck Surg. 2003;128:445–446. 27. Holme SA, Laidler P, Holt PJ. Concurrent granuloma faciale and eosinophilic angiocentric fibrosis. Br J Dermatol. 2005;153:851–853. 28. Onder S, Sungur A. Eosinophilic angiocentric fibrosis: an unusual entity of the sinonasal tract. Arch Pathol Lab Med. 2004;128:90–91. 29. Chinelli PA, Kawashita MY, Sotto MN, Nico M. Granuloma faciale associated with sinonasal tract eosinophilic angiocentric fibrosis. Acta Derm Venereol. 2004;84:486–487. 30. Owa AO, Boyle S, Gallimore AP. Eosinophilic angiocentric fibrosis as a cause of nasal obstruction. Rhinology. 2002;40:41–43. 31. Sunde J, Alexander KA, Reddy VV, Woodworth BA. Intranasal eosinophilic angiocentric fibrosis: a case report and review. Head Neck Pathol. 2010;4:246–248. 32. Tabaee A, Zadeh MH, Proytcheva M, LaBruna A. Eosinophilic angiocentric fibrosis. J Laryngol Otol. 2003;117:410–413. 33. Yang BT, Wang YZ, Wang XY, Wang ZC. Nasal cavity eosinophilic angiocentric fibrosis: CT and MR imaging findings. AJNR Am J Neuroradiol. 2011;32:2149–2153. 34. Teixeira DA, Estrozi B, Ianhez M. Granuloma faciale: a rare disease from a dermoscopy perspective. An Bras Dermatol. 2013;88(6 Suppl 1):97–100. 35. Burns BV, Roberts PF, De Carpentier J, Zarod AP. Eosinophilic angiocentric fibrosis affecting the nasal cavity. A mucosal variant of the skin lesion granuloma faciale. J Laryngol Otol. 2001;115:223–226. 36. Zhu YI, Stiller MJ. Dapsone and sulfones in dermatology: overview and update. J Am Acad Dermatol. 2001;45:420–434. 37. Holmes DK, Panje WR. Intranasal granuloma faciale. Am J Otolaryngol. 1983;4:184–186. 38. Valenzuela AA, Whitehead KJ, Brown I, Sullivan TJ. Eosinophilic angiocentric fibrosis: an unusual entity producing complete lacrimal duct obstruction. Orbit. 2006;25:159–161. 39. Watanabe N, Moriwaki K. Atypical eosinophilic angiocentric fibrosis on nasal septum. Auris Nasus Larynx. 2006;33:355–358.
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Sinonasal eosinophilic angiocentric fibrosis: A systematic review Christina H. Fang, BS1 , Leila J. Mady, MD, PhD1 , Neena M. Mirani, MD2 , Soly Baredes, MD, FACS1,3 and Jean Anderson Eloy, MD, FACS1,3,4
Background: Eosinophilic angiocentric fibrosis (EAF) is a benign rare lesion of the upper respiratory mucosa. EAF most commonly presents with an obstructive nasal mass. Due to the rarity of EAF, case reports and case studies have predominated the literature. This systematic review discusses the demographics, clinical presentation, associated findings, management, and outcomes of this uncommon entity. Methods: The PubMed database was searched for all articles describing patients diagnosed with sinonasal EAF. Additional cases were examined from the bibliographies of selected articles. Demographics, clinical presentation, associated findings, radiography, management, and outcome were analyzed. Results: Fiy-two cases were included from 34 articles, including 1 case from our institution. The most common presenting symptom was nasal obstruction (78.8%). Fourteen patients (26.9%) had a previous history of nasal surgery or trauma. Surgical resection alone was the most commonly used primary treatment approach (50.0%), resulting in the
E
osinophilic angiocentric fibrosis (EAF) is a rare lesion of the respiratory mucosa, most commonly found in the sinonasal tract. It was first reported by Holmes and
1 Department
of Otolaryngology–Head and Neck Surgery, Rutgers New Jersey Medical School, Newark, NJ; 2 Department of Pathology, Rutgers New Jersey Medical School, Newark, NJ; 3 Center for Skull Base and Pituitary Surgery, Neurological Institute of New Jersey, Rutgers New Jersey Medical School, Newark, NJ; 4 Department of Neurological Surgery, Rutgers New Jersey Medical School, Newark, NJ
Correspondence to: Jean Anderson Eloy, MD, FACS, Rhinology and Sinus Surgery, Endoscopic Skull Base Surgery Program, Department of Otolaryngology–Head and Neck Surgery, Rutgers New Jersey Medical School, 90 Bergen St., Suite 8100, Newark, NJ 07103; e-mail: [email protected] Potential conflict of interest: None provided. Presented at the American Rhinologic Society (ARS) section of the 117th of Combined Otolaryngology Spring Meetings (COSM), May 14-18, 2014, Las Vegas, NV. Received: 28 February 2014; Revised: 11 April 2014; Accepted: 24 April 2014 DOI: 10.1002/alr.21347 View this article online at wileyonlinelibrary.com.
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greatest proportion of disease-free patients (55.6%) over a median follow-up period of 36 months. A combination of surgery and corticosteroids was the second-most-common treatment modality, used in 28.8% of cases. Of the 40 cases reporting patient outcomes, 100% of patients were alive at follow-up independent of treatment modality. Conclusion: To date, this review contains the largest number of patients with sinonasal EAF. Aggressive surgical resection alone constitutes the most common treatment modality and may be most effective at eradicating disease. C 2014 ARS-AAOA, LLC.
Key Words: eosinophilic angiocentric fibrosis; sinonasal mass; sinus; angiocentric fibrosis; nasal eosinophilic angiocentric fibrosis; sinus eosinophilic angiocentric fibrosis How to Cite this Article: Fang CH, Mady LJ, Mirani NM, Baredes S, Eloy JA. Sinonasal eosinophilic angiocentric fibrosis: a systematic review. Int Forum Allergy Rhinol. 2014;4:745–752.
Panje in 1983 as “intranasal granuloma faciale” and the name was coined by Roberts and McCann in 1985.1 To our knowledge, less than 60 cases of sinonasal EAF have been reported in the literature to date. EAF has a benign, slowly progressing course that leads to local destructive growth in the nasal cavity and surrounding structures. The nasal septum is most commonly involved; however, involvement of the lateral nasal walls, orbit, maxillary sinuses, and ethmoid sinuses is not a rare occurrence. Reports of EAF originating in the orbit, larynx, and lower respiratory tract have also been described.2–8 Patients often present with nonspecific symptoms of nasal obstruction, epistaxis, nasal deformities, facial pain, and epiphora, causing difficulty and delay of diagnosis. Clinically, EAF presents as submucosal thickening or a firm fibrotic mass (Fig. 1).9, 10 EAF predominantly affects those 50 to 60 years of age with no predilection for either gender.7 Though a relationship between EAF and allergies, atopy, or trauma has been reported,11–19 the etiology remains unclear. The diagnosis of EAF is made based on characteristic histologic findings
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FIGURE 1. Coronal CT scan (A) and endoscopic view (B) of a patient with eosinophilic angiocentric fibrosis (EAF) involving the right nasal cavity.
(Fig. 2). Early lesions are marked by a rich inflammatory infiltrate of lymphocytes, neutrophils, plasma cells, and a predominance of eosinophils. Late lesions are characterized by concentric perivascular “onion-skin” fibrosis with fewer inflammatory cells. Both early and late lesions coexist in the same biopsy sample, which suggests that there is an ongoing progression of this disease.9, 14–17, 20–24 Treatment of EAF presents a challenge because of the likelihood of persistent or recurrence of disease. Most cases have been treated with surgical resection; however, local recurrence remains an issue with such treatment modality.11, 12, 14, 20, 25, 26 Use of corticosteroids and immunosuppressants such as dapsone and azathioprine have not provided satisfactory resolution of symptoms.14, 19, 23, 27 In some cases, opting for no treatment has not been associated with increased morbidity.15, 17 Due to the rarity of this lesion, the clinical characteristics and optimal treatment strategy of EAF has not been well-established. Here, we present a systematic review of the demographics, presentation, treatment modalities, and outcomes associated with this uncommon sinonasal entity.
cles were further reviewed to identify additional cases not found in the original search.
Selection criteria The articles were grouped by title and duplicates were excluded. Inclusion criteria included English-language studies that provided individual patient data with specific treatment defined. Foreign-language studies and studies with no individual patient data were excluded. Articles and specific cases from articles with insufficient data, as well as cases of EAF in anatomic locations outside the sinonasal tract were also excluded.
Data extraction and analysis Two independent reviewers (C.H.F. and L.J.M.) extracted data from the selected studies. Disagreement regarding inclusion of a study was resolved following discussion. Extracted data included patient demographics, tumor location, presenting symptoms, associated findings, radiographic imaging, primary treatment modality, recurrence, follow-up, and outcome. Microsoft Excel (Microsoft Corp., Redmond, WA) was used for data aggregation and analysis.
Materials and methods A systematic review of the published literature on cases of EAF of the sinonasal tract was performed. This study qualified as “nonhuman subject research” as per protocol of the Institutional Review Board of Rutgers New Jersey Medical School, Newark, New Jersey, and thus did not require approval.
Literature search strategy The PubMed database was searched for all studies published through December 2013 using the keywords: “eosinophilic angiocentric fibrosis,” “nasal eosinophilic angiocentric fibrosis,” “sinus eosinophilic angiocentric fibrosis,” and “intranasal granuloma faciale.” First, abstracts were reviewed to identify the studies that appeared to involve sinonasal EAF. Full-text versions of these articles were then obtained. These were examined for compliance of studies with eligibility criteria discussed in the next section. The bibliographies of the included arti-
Results The initial PubMed search yielded 92 studies. Duplicate articles were excluded (48). Additional studies eliminated from our study included articles that did not provide individual patient data (4), foreign-language studies (3), cases involving anatomic sites outside of the sinonasal tract (3), unobtainable articles (2), and unrelated articles (1). Review of references from initially included articles yielded 3 additional articles. After applying the aforementioned criteria, 34 studies describing 51 cases were used to conduct data analysis (Fig. 3). These studies are detailed in Table 1. With the addition of 1 case from our institution, a total of 52 patients were analyzed in this systematic review.
Demographics and tumor specifics Demographics, symptoms, and anatomic location were reported in all cases. The average age of patients was 47 years old, ranging from 16 to 79 years. The male to female
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FIGURE 3. Flow diagram of included and excluded studies.
360 months. Information on tumor size was seldom reported, and therefore, not included in the analysis. Fourteen patients (26.9%) had undergone prior nasal surgery or had a history of trauma. Nine patients (17.3%) had allergies and 11 patients (21.2%) had granuloma faciale (GF). Further demographic information is listed in Table 2.
Radiography
FIGURE 2. Hematoxylin-eosin stain of eosinophilic angiocentric fibrosis. (A) There is dense fibrosis entrapping blood vessels. (B) At higher magnification, inflammatory cells in addition to fibrosis can be seen surrounding the small blood vessels. (C) This chronic background inflammation consists of numerous eosinophils.
Imaging was reported in 41 studies. The most commonly used imaging technique was computed tomography (CT) in 37 cases, followed by magnetic resonance imaging (MRI) used in 10 cases, and X-ray used in 3 cases. Of the 37 cases that used CT, 22 cases (54.1%) showed EAF appearing as a soft-tissue swelling or mass. Sinus opacification and thinning of surrounding bone were noted in 12 (32.4%) and 10 cases (27.0%), respectively. EAF appeared isodense on non-enhanced CT in 8 cases (21.6%). Of the 10 cases that used MRI, EAF appeared isointense to gray matter on T1-weighted imaging and hypointense on T2-weighted images in 5 cases (50.0%). All 3 cases that used sinus X-rays showed sinus opacification.
Treatment and patient outcome ratio was 1:1. The most common presenting symptoms was nasal obstruction (78.8%) followed by nasal swelling or nasal deformity (25.0%). EAF was most commonly found in the nasal cavity/nasal septum (90.4%). Orbit involvement was present in 19.2% of cases. Twenty-nine cases reported an average time between onset of symptoms and diagnosis of 70 months in duration, ranging from 1.5 to
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Treatment approach was reported in all cases and included surgery, corticosteroids, immunosuppressive therapy, or a combination of these modalities (Table 3). Surgical treatment included endoscopic sinus surgery, lateral rhinotomy, open rhinoplasty, septoplasty, curettage, and lesion excision and debulking. Corticosteroid therapy included systemic, intralesional, or a combination of both. Immunosuppressive therapy comprised of azathioprine, dapsone,
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TABLE 1. Studies meeting criteria for systematic review
TABLE 2. Summary of individual cases Characteristic
Author
Year
Study type
Cases (n)
Burns et al.35
2001
Case report
1
Subjects, n Demographics
Chinelli et al.29
2004
Case report
1
Clauser et al.20
2006
Case report
1
Deshpande et al.11
2011
Case report
1
Goldman26
2003
Case report
1
Holme et al.27
2005
Case report
1
Holmes and Panje37
1983
Case report
1
Holsinger et al.25
2008
Case report
1
Jain et al.12
2008
Case series
4
Karligkiotis et al.4
2013
Case report
Kim et al.5
2013
Kiratli et al.6
Totals
52
Age, years, mean (range)
47 (16–79)
Sex, male/female (ratio)
26/26 (1:1)
Presenting symptoms, n (%)
52 (100)
Nasal obstruction
41 (78.8)
Nasal swelling/deformity
13 (25.0)
Epistaxis
9 (17.3)
Nasal mass
8 (15.4)
Epiphora
7 (13.5)
1
Pain
6 (11.5)
Case report
1
Eye symptoms (diplopia, periorbital edema, proptosis)
6 (11.5)
2008
Case report
1
Nasal congestion
5 (9.6)
2008
Case series
3
Rhinorrhea
5 (9.6)
Leibovitch et al.
2006
Case report
1
Headache
2 (3.8)
13
2013
Case report
1
Dyspnea
2 (3.8) 1 (1.9)
Kosarac et al.
21 7
Li et al.
18
2002
Case report
1
Cough, postnasal drip, hyponasal speech, decreased
22
2001
Case report
1
taste, dysphagia
Narayan and Douglas-Jones9
2005
Case report
1
Nguyen et al.10
2004
Case report
1
Loane et al. Matai et al.
Anatomic site, n (%)
52 (100)
Nasal cavity (+ septum)
47 (90.4) a
Nigar et al.15
2007
Case report
1
Onder and Sungur28
2004
Case report
1
Owa et al.30
2002
Case report
1
Orbit (+ lacrimal gland, lamina papyracea)
10 (19.2)
Maxillary sinus
7 (13.5)
Ethmoid sinus
4 (7.7)
Sphenoid sinus
1 (1.9)
Paranasal sinus
1 (1.9)
Nasopharynx
1 (1.9)
Paun et al.14
2005
Case series
4
Pereira et al.16
2002
Case report
1
Roberts and McCann1
1985
Case series
2
Slovik et al.17
2006
Case report
1
History of nasal surgery or trauma
14 (26.9)
Sunde et al.31
2010
Case report
1
Granuloma faciale
11 (21.2)
Tabaee et al.32
2003
Case report
1
Allergies (allergic rhinitis, occupational, medication)
9 (17.3)
Thompson and Heffner23
2001
Case series
3
Chronic sinusitis
3 (5.8)
Valenzuela et al.38
2006
Case report
1
Wegener’s granulomatosis, rheumatic fever, chronic
1 (1.9)
Watanabe and Moriwaki39
2006
Case report
1
inflammatory bowel disease, psoriasis, asthma
Yang et al.33
2011
Case series
6
Outcome
40 (100)
Yavuzer et al.24
2000
Case report
1
AWD
27 (67.5)
Yung et al.19
2005
Case series
2
ANED
13 (32.5)
DOD
0 (0.0)
DOC
0 (0.0)
clofazimine, tacrolimus, or hydrochloroquine. The most common primary treatment modality was surgical resection alone, used in 26 cases (50.0%). Corticosteroids in combination with surgery was the second-most-common treatment modality, used in 15 cases (28.8%). Two
Associated findings
Follow-up, n (%) Length, months, mean (range)
33 (100) 51 (0–240)
a
Orbit was involved in addition to the sinonasal tract. ANED = alive with no evidence of disease; AWD = alive with disease; DOC = dead of other cause; DOD, dead of disease.
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TABLE 3. Frequency and treatment outcomes of various
TABLE 4. Treatment outcomes of patients who had total vs
treatment modalities in sinonasal eosinophilic angiocentric fibrosis
subtotal surgical resection of sinonasal EAF
Treatment
Surgery alone
Total
Cases per treatment
cases % (n)
modality (%)
Cases that underwent subtotal resection, n (%)
All treatment modalities
50.0 (26)
ANED
55.6
ANED
11 (84.6)
AWD
44.4
AWD
2 (15.4)
Surgery and steroids
0 (0) 9 (100)
Surgery alone
28.8 (15)
ANED
23.1
ANED
10 (83.3)
AWD
76.9
AWD
2 (16.7)
2 (100)
No treatment
0 (0)
Surgery and steroids
9.6 (5)
ANED
0
ANED
1 (100)
0 (0)
AWD
100
AWD
0 (0)
5 (100)
Immunosuppressant alone
Surgery, steroids, and immunosuppressant
3.8 (2)
ANED
0
ANED
0 (0)
0 (0)
AWD
100
AWD
0 (0)
2 (100)
Surgery, steroids, and immunosuppressant
3.8 (2)
ANED = alive with no evidence of disease; AWD = alive with disease; EAF = eosinophilic angiocentric fibrosis.
ANED
0
AWD
100
Steroids alone
1.9 (1)
ANED
0
AWD
100
Steroids and immunosuppressant
1.9 (1)
ANED
0
AWD
100
Surgery and immunosuppressant
0 (0)
ANED
n/a
AWD
n/a
Total number of cases, n = 52. ANED = alive with no evidence of disease; AWD = alive with disease; n/a = data not available.
patients (3.8%) were treated with immunosuppressive therapy alone, and 2 patients (3.8%) received a combination of surgery, chemotherapy, and immunosuppressive therapy as primary treatment. Five patients (9.6%) did not receive any treatment. Of the 43 cases treated with surgery, either alone or in combination with chemotherapy or immunosuppressive therapy, 22 distinguished between total and subtotal resection. Thirteen patients (59.1%) had total or grosstotal resection of the lesion, whereas 9 patients (40.9%) were reported to have had subtotal resection (Table 4). Patient outcome was reported in 40 cases and was classified as alive with no evidence of disease (ANED), alive
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Cases that underwent total resection, n (%)
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with disease (AWD), dead of disease (DOD), or died of other causes (DOC). All patients (100%) were alive after a median follow-up of 36 months. Twenty-seven patients (67.5%) were AWD while 13 patients (32.5%) were ANED. Table 3 also illustrates patient outcome based on treatment modality. Eighteen cases receiving surgical therapy alone reported patient outcome, of which 11 patients (55.6%) were free of disease at follow-up. Of the 13 cases treated with surgery and corticosteroids in studies reporting patient outcome, 3 patients (23.1%) were disease-free at follow-up. All of the patients treated with corticosteroids alone; immunosuppressive therapy alone; a combination of steroids and immunosuppressants; or a combination of surgery, corticosteroids, and immunosuppressants were AWD at follow-up. Of the 13 patients who had total resection of EAF, 11 (84.6%) were classified as ANED at followup. In contrast, all 9 patients who underwent subtotal resection were AWD at follow-up (Table 4). A large majority of patients (92.3%) who had total surgical resection were treated with surgery alone. Of these patients, 10 (83.3%) were ANED at follow-up. Of the 9 patients who underwent subtotal resection, 5 patients (55.6%) were treated with a combination of surgery and steroids. All of these patients were AWD at follow-up (Table 4).
Discussion Eosinophilic angiocentric fibrosis is a rare fibrotic condition most commonly affecting the respiratory mucosa of the sinonasal tract. Due to its rarity, prospective studies
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involving sinonasal EAF have not been conducted. This study is the first systematic review of sinonasal EAF and aims to provide insight into this rare entity.
Demographics There is no predilection of EAF for either sex, in line with previous reports.4, 13 Of the 52 patients analyzed, 26 were male and 26 were female. The average age of this patient cohort is consistent with previously described data. The mean age was 47 years, ranging from 16 to 81 years of age.
Clinical information The nasal cavity was involved in almost all cases (90.4%). Some studies specifically reported the mass arising from the nasal septum or the lateral wall. Historically, EAF most commonly involves the nasal septum.14, 28 However, not all studies made this distinction; thus, we cannot deduce with absolute certainty which area of the nasal cavity gives rise to the majority of EAF cases. Three cases described primary orbital lesions extending into the ethmoid sinus and middle turbinate.4, 6, 7 Submucosal thickening and nasal septum deviation were commonly seen on physical examination.1, 13, 18, 23, 26, 29–33 Tumor size was not adequately reported. The presenting symptoms of EAF are often nonspecific and closely related to the involved anatomic location. The most common presenting symptom is a progressive obstructing nasal mass.13 Our analysis also found that nasal obstruction was the most common presenting symptom of EAF, noted in 78.8% of symptoms. Other presenting symptoms of EAF reported included nasal swelling, nasal deformity, epistaxis, epiphora, pain (facial, nasal), congestion, rhinorrhea, and headache (Table 2). Due to anatomic intricacy of the sinonasal tract, expansion of the lesion may lead to changes in surrounding vascular and osseous structures. There is often a delay in diagnosis with an average time from onset of symptoms to diagnosis of 5 to 6 years.23, 32 Our study found a similar duration to diagnosis with a mean of 70 months. Given this long period of time, the natural course of EAF is generally thought of as slowly progressive, with most patients recalling a history of chronic symptoms.
Etiology and differential diagnoses The etiology of EAF remains unclear. Commonly cited predisposing factors include allergy, trauma, and history of sinonasal surgery.13, 17 This analysis found that sinonasal EAF was most commonly associated with a prior history of sinonasal surgery or trauma. EAF may be thought of as an inappropriate fibrotic response to a proinflammatory stimulant such as surgery.32 However, whether the relationship between previous sinonasal surgery and sinonasal EAF is causative cannot be determined because few studies report a preoperative biopsy ruling out EAF. Differential diagnoses of EAF include granulomatous, inflammatory, and neoplastic disease processes, including but
not limited to Wegener’s granulomatosis, Churg-Strauss syndrome, sarcoidosis, and GF. On histologic examination, EAF does not involve granuloma formation found in Wegener’s and sarcoidosis or systemic vasculitis found in Churg-Strauss. EAF also lacks systemic manifestations such as fever and fatigue, which are common in these conditions. GF is a rare vasculitic disease of the dermis that manifests as chronic, slowly progressive reddish-brown plaques mostly localized to the face.1 Histologically, GF is characterized by a dense infiltrate of neutrophils, lymphocytes, histiocytes, and eosinophils in the lower dermis with accompanying perivascular inflammation.34 Eleven cases of EAF with GF have been reported. The development of GF varies with respect to EAF; GF has been diagnosed prior to, concurrent with or following the diagnosis of EAF. Because EAF shares similar histologic findings with GF, EAF is considered by some to be the “mucosal variant” of GF.9, 19, 21, 35 However, it has been noted that the skin lesions of GF respond to therapy independently of the response of EAF lesions.32
Radiology Imaging findings of EAF are nonspecific and should be correlated with the patient’s history and physical examination. EAF generally appears as an isodense soft-tissue density with possible sinus opacification on non-enhanced CT. As the lesion progresses, adjacent focal destruction of surrounding bony tissues, thinning, and sclerosis can be visualized. EAF appears isointense compared to gray matter on T1-weighted images with moderate contrast enhancement. On T2-weighted images, EAF generally appears hypointense. This has been attributed to the fibrosis in the late stage.33 Although regarded as a benign disease process, more advanced lesions of EAF can involve adjacent bony or cartilaginous structures. Destruction or erosion of surrounding bone does not appear to be a rare occurrence and was visualized in 27.0% of cases that used CT.
Treatment and patient outcome Due to the rarity of this lesion, consensus has not yet been reached regarding optimal management of EAF. Generally, EAF is regarded as a nonmalignant lesion with no risk of distant metastasis.13 To date, there have been no reports of death caused by EAF. Historically, surgical resection is the treatment of choice for EAF. This review found that surgical resection alone was the most common treatment modality for primary lesions, used in 26 cases (50.0%) (Table 3). Operative management of EAF included open rhinoplasty, lateral rhinotomy, curettage and debridement, total resection, septoplasty, and more recently, endoscopic sinus surgery. The advantages of 1 surgical technique over another or whether endoscopic surgery can accomplish complete removal of the lesion has not been addressed in the literature. Local (intralesional, nasal) and/or systemic corticosteroids have also been used in the attempt to decrease the inflammatory process of EAF. Steroids were used alone in
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only 1.9% of cases and in combination with surgery in 28.8% of cases (Table 3). Steroids were commonly used as the initial treatment approach when used in combination with surgery. Due to inadequate symptomatic relief with corticosteroid therapy alone, subsequent surgical resection was often required for progressive disease.1, 10, 14, 17, 22, 23, 35 Postoperative corticosteroid administration has been reported in 1 case as a mechanism to reduce progression of disease.6 In that study, the patient receiving postoperative steroids had stable disease burden at follow-up. However, whether this outcome is attributable to the combination of corticosteroid therapy and surgery or to the initial surgical resection is unclear. Immunosuppressive therapy is generally not considered first-line treatment of EAF. There are reports of the use of dapsone, clofazimine, tacrolimus, hydrochloroquine, and azathioprine with little success in symptomatic management.14, 19, 27, 29 Dapsone is used to treat GF, a relatively common incidental finding associated with EAF, but has not shown successful results with EAF.36 Three cases were treated with an immunosuppressant and all of these patients were classified as AWD at time of follow-up. Surgical resection is commonly advocated as the primary treatment of EAF.6, 7, 9, 12, 14, 28, 37, 38 Although considered the mainstay of therapy, it has been previously reported that surgical resection alone provides local control in only 30% of cases.31 However, our analysis found a greater proportion of local control with surgical resection. Patients treated with surgical resection alone had the best outcome, with over one-half (55.6%) being ANED at time of follow-up (Table 3). Patients receiving a combination of steroids and surgical resection had the second-best outcome with 23.1% ANED at follow-up. It appears that surgical resection plays an integral role in the control and symptomatic management of EAF. Corticosteroid therapy does not seem to have any added advantage in patient outcome over those treated with surgery alone (Table 3). Of note, of the 6 cases treated with the combination of surgery and corticosteroids that distinguished between total and subtotal resection, 5 underwent subtotal surgical resection (Table 4). Partial resection of the lesion may have decreased the likelihood of disease resolution, independent of corticosteroid use. Complete resolution of disease is notoriously difficult to achieve in EAF, irrespective of treatment modality. The rate of recurrence and persistent disease has been cited to be as high as 70%.31 Recurrence generally occurs in the original anatomic location and is thought to represent disease progression.11, 23 Given the anatomic complexity of the sinonasal tract, total resection of EAF is often difficult.20, 34 Remaining small fragments of the lesion may become a nidus for recurrence. Not all of the studies differentiated between total and subtotal resection of EAF. However, a high percentage (84.6%) of the patients who underwent total resection were disease-free at follow-up. This suggests that the achievement of adequate surgical margins during resection may result in greater local control and prevent persistence of disease.
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If the suspicion for EAF is present, we recommend first ruling out inflammatory or neoplastic processes that may also present with an obstructive nasal mass. Helpful laboratory blood tests include complete blood count (CBC), erythrocyte sedimentation rate (ESR), antineutrophil cytoplasmic antibodies (ANCA), and immunoglobulin E (IgE) titers. These values are usually unremarkable in EAF.1, 14–17, 19, 22, 29, 38, 39 Radiographic imaging including CT and MRI should be done to determine the extent of the lesion. A biopsy and histologic confirmation should be obtained early to prevent delay in diagnosis. This review found no benefits of treating patients with EAF with immunosuppressive therapy. After diagnosis, observation can be considered and does not necessarily result in increased patient morbidity.15, 17 A prior report has suggested considering surgery once symptoms or physical deformities have manifested.12 Although surgical resection of EAF offers the most promising outcomes, resolution of disease is not guaranteed. This, in addition to the possible complications of surgery suggests an individualized approach on a case-bycase basis. Factors to be taken into consideration include tumor size, severity of symptoms, and degree of functional impairment, with the goal of total or gross-total resection of the lesion. Steroid therapy may be considered in conjunction with surgery or if the patient is unable to tolerate or does not desire surgery.
Limitations The limitations of this study include those that are inherent to a systematic review. Allocation bias and selection bias are inherent weaknesses of pooled data. This review is limited by the quality of available studies in the literature. Due to the rarity of EAF, the data analyzed in this study was collected from case reports and small case studies, which precluded us from pursuing a meta-analysis. There are no randomized controlled, multi-institutional, or prospective studies involving sinonasal EAF that are available for analysis. Consequently, the overall quality of analyzed data is judged to be poor. Furthermore, there was a lack of standardized reporting of tumor size, treatment modality, and patient outcome and follow-up, which precludes further formal statistical analysis. Data quality was also inconsistent among the studies included as not all studies reported the aforementioned parameters.
Conclusion Sinonasal EAF is rare lesion of the respiratory mucosa that commonly presents with an obstructing nasal mass. Indolent growth and nonspecific symptoms contribute to the frequent delay in diagnosis. Surgical resection was the most common treatment modality for EAF and resulted in the highest rate of disease-free patients at time of follow-up.
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