696510
case-report2017
AORXXX10.1177/0003489417696510Annals of Otology, Rhinology & LaryngologyHeft Neal et al
Case Report
A Case Report and Systematic Review of Eosinophilic Angiocentric Fibrosis of the Paranasal Sinuses
Annals of Otology, Rhinology & Laryngology 2017, Vol. 126(5) 415–423 © The Author(s) 2017 Reprints and permissions: sagepub.com/journalsPermissions.nav https://doi.org/10.1177/0003489417696510 DOI: 10.1177/0003489417696510 journals.sagepub.com/home/aor
Molly E. Heft Neal, MD1,2, Nicholas R. Rowan, MD3, Thomas J. Willson, MD3, Eric W. Wang, MD3, and Stella E. Lee, MD3
Abstract Objective: There is a paucity of literature discussing prognostic factors or comparing outcomes in eosinophilic angiocentric fibrosis (EAF). This review aims to analyze tumor and patient characteristics as possible prognostic markers and compare surgical approaches. Methods: Systematic literature review and case report analyzing available cases of EAF located within the paranasal sinuses. Results: The literature search yielded 39 articles meeting criteria for a total of 59 cases (including 1 from our institution). Median patient age was 46 years. The most common presenting symptoms were nasal obstruction (69%, n = 41) and change in external nasal appearance (39%, n = 32). The majority of cases (85%) were treated with surgical resection alone or in combination with medication. Of surgical patients, 62% underwent a complete resection with a recurrence rate of 20%. Median follow-up duration was 2 years. Endoscopic approach showed a significant positive correlation with complete resection (P = .045). Patient sex (P = .6), tumor location (range, P = .32-.98), lateral rhinotomy (P = .26), septoplasty (P = .84), and external rhinoplasty (P = .28) were not significantly correlated with total resection. Insufficient sample size precluded calculation of predictors of recurrence following surgery. Conclusion: This review suggests that an endoscopic approach to EAF tumor is a viable option, frequently yielding complete resection. Keywords eosinophilic angiocentric fibrosis, endoscopic sinus surgery, surgical outcomes, eosinophilic inflammation of nose, nasal mass
Introduction Eosinophilic angiocentric fibrosis (EAF) is a rare fibroinflammatory disease of unknown etiology. Eosinophilic angiocentric fibrosis was originally described by Holmes and Panje1 in 1983, who originally named the disorder “intranasal granuloma faciale” based on the histologic similarities to granuloma faciale (GF). Roberts and McCann2 then coined the term eosinophilic angiocentric fibrosis in 1985 while describing 3 further cases. Eosinophilic angiocentric fibrosis is a slowly progressive condition with varying symptoms depending on site of disease. The nasal mucosa and orbit are the most common locations while rare cases may present in the subglottis.3 The most common presenting symptoms are nasal obstruction followed by swelling of the nasal dorsum or change in external appearance.3 Diagnosis is made based on histological examination and can range from small vessel eosinophilic vasculitis with adjacent inflammatory infiltrate of lymphocytes and plasma cells to the later fibrotic stage,
described as obliterative concentric perivascular fibrosis in an “onion skin” pattern with persistence of eosinophils.2 It is common to have both early and late lesions coexist in the same biopsy specimen, and it is thought that this represents a progressive disease starting with small vessels vasculitis that prompts a fibrotic response.4-11 Numerous treatments have been tried over the years from antihistamines to immunosuppressant medications and steroids, but the only definite 1
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA 2 University of Michigan Department of Otolaryngology, Ann Arbor, Michigan, USA 3 University of Pittsburgh Department of Otolaryngology, Pittsburgh, Pennsylvania, USA Corresponding Author: Molly E. Heft Neal, Department of Otolaryngology, University of Michigan, 1500 E Medical Center Dr, Ann Arbor, MI 48109, USA. Email: [email protected]
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Figure 1. (A) Coronal and (B) axial computed tomography maxillofacial showing disease involvement of bilateral aspects of the nasal septum resulting in marked thickening and inflammation.
Figure 2. Histology. (A) Mixed inflammatory infiltrate. (B) Onion skin fibrosis. Note. Images from University of Pittsburgh, Department of Pathology.
treatment appears to be surgical resection.3 It has now been 30 years since the term eosinophilic angiocentric fibrosis appeared in the literature. This article provides an updated systematic review of the literature on sinonasal cases of EAF over the past 3 decades with a focus on predictors of total resection and risk factors for recurrence with a special consideration of comparing surgical approaches.
Case Report A 45-year-old woman was referred to our institution with a 2-year history of bilateral, left greater than right, nasal obstruction and hyposmia. She had noted progressive swelling of her nasal bridge over the previous 2 years. Her past medical history was significant for allergies to dust, mold, aspirin, and latex and chronic otitis media as a child. She denied history of autoimmune illnesses, past nasal surgery, or trauma. She had previously worked in a sewing factory with exposure to spray cleaners. Her family history was
significant for asthma in her mother and sarcoidosis in her father and paternal uncle. On initial examination, she was found to have a broadened nasal dorsum and a large, firm, submucosal mass located in the midline along the nasal septum with near complete obstruction of the nasal cavities. On imaging, computed tomography (CT) showed thickening of the nasal septum with erosion of the perpendicular plate of the ethmoid bone (Figures 1A and 1B). There was extension to the internal nasal valve on the left side. Bilateral ethmoid and frontal sinuses showed mucosal thickening. Magnetic resonance imaging (MRI) confirmed the presence of a midline enhancing submucosal mass. A biopsy was performed through a left hemitransfixion incision. Histology showed a distinctive perivascular concentric paucicellular fibrosis with rare obliteration of larger vessels. There was an inflammatory background of lymphocytes, plasma cells, and macrophages without eosinophils (Figure 2). While there was no eosinophilia, it was felt that this lesion best
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Figure 3. Intraoperative tumor. (A) Prior to resection. (B) Removal of tumor bulk. (C) Endoscopic view of mucosal invasion. (D) Post endoscopic removal.
fit with a diagnosis of eosinophilic angiocentric fibrosis. Further tissue analysis revealed negative IgG4 stains. Given the patient’s family history of sarcoidosis and the association between EAF and autoimmune vasculitis, the patient underwent rheumatologic evaluation. No features of systemic autoimmune processes were identified. Further workup revealed mildly elevated sedimentation rate at 46 mm (nl 0-20 mm), unremarkable rheumatoid factor (RF), anti-neutrophil cytoplasmic auto-antibody (ANCA), antimyeloperoxidase, anti-proteinase-3, angiotensin converting enzyme (ACE), and antinuclear antibody (ANA) titers. With the diagnosis of EAF, the patient was recommended to undergo surgical excision via a combined open rhinoplasty with an endoscopic endonasal approach (Figure 3). The patient was found to have extensive involvement of the quadrangular cartilage as well as the overlying mucosa, necessitating complete septal resection with a staged reconstruction using cadaveric costal cartilage. All margins were negative. There was excellent remucosalization postoperatively, and the patient was found to be without evidence of recurrence 4 months postoperatively.
Methods Study Design The literature was reviewed systematically using the Preferred Reporting Items of Systematic Reviews and Meta-Analysis (PRISMA) model,12 including the PRISMA flow diagram (Figure 4).
Search Strategy The literature search was done with both PubMed and Ovid. Search terms included angiocentric fibrosis, eosinophilic angiocentric fibrosis, nasal angiocentric fibrosis, sinus angiocentric fibrosis, and orbital angiocentric fibrosis.3 Our search included all articles through December 2015.
Inclusion and Exclusion Criteria Inclusion criteria included all cases of sinonasal pathology with histology consistent with eosinophilic angiocentric
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Figure 4. Systematic review using Preferred Reporting Items of Systematic Reviews and Meta-Analysis (PRISMA).
fibrosis. Lesions were excluded if they involved the glottis, oropharyngeal region, or orbit without extension into the nasal region. Only articles evaluating human subjects and English language were considered (2 articles that had been translated into English were included).
resection, follow-up time, recurrence or residual disease, and histology. Microsoft excel (Microsoft Corporation, Redmond, Washington USA) and R (The R Foundation) were used for data organization and linear regression analysis.
Data Extraction
Results
Each article was reviewed, and the following data were documented: author, year, sex and age of the patient, presenting symptoms, length of symptoms, past medical history (trauma, allergies, autoimmune disease, granuloma faciale), IgG4 counts, imaging modality, location, bony erosion, treatment, surgical approach, complete or partial
Literature Review Both PubMed and Ovid databases were searched, yielding 64 articles. Three additional articles were found in the references of the initial articles (2 were able to be obtained). Screening eliminated articles that did not
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Heft Neal et al Table 1. Patient and Tumor Characteristics. Variables Sex Location of tumor
Presenting symptoms
Past medical history
Histology
Men Women Nasal septum/cavity Maxillary Ethmoid Sphenoid Paranasal Frontal Orbit/eyelid Lacrimal gland Cervical lymph node Nasal obstruction Nasal/septal swelling, change in external appearance Nasal mass Epistaxis Epiphora Congestion Rhinorrhea Pain Headache Eye symptoms (visual loss, proptosis, globe displacement, periorbital edema) Anosmia, hyposmia Otologic symptoms (itchy ears, hearing loss, tinnitus) Rhinolalia Shortness of breath Trauma/Past nasal surgery Atopy/asthma Chronic sinusitis Granuloma faciale Autoimmune disease Early Late
include relevant clinical data (10) and articles that did not specifically focus on EAF (8). The remaining articles (49) were reviewed for eligibility, and of those, only articles describing lesions with consistent histology and in the sinonasal tract were included (39). After eliminating duplicate cases (Rimmer et al. and Paun described 4 of the same cases), there were a total of 58 case reports, plus the additional case from our institution, for a total of 59 cases.1-2,4-11,13-41
Demographics Tumor characteristic and patient demographics are detailed in Table 1. Of the total cases, 46% (27/59) were men, and 54% (32/59) were women, with a median age of 46 years (range, 16-81 years). The most common presenting symptoms were nasal obstruction (41), swelling of the
No. (n = 59)
%
27 32 59 14 7 3 5 2 14 5 1 48 23 11 8 9 3 7 7 2 5
46 54 100 24 12 5 8 3 24 8 2 81 39 19 14 15 5 12 12 3 8
4 1 2 1 6 14 3 12 5 3 19
7 2 3 2 10 24 5 20 8 5 32
nasal dorsum or change in external nasal appearance (23), nasal mass (11), epiphora (9), epistaxis (8), rhinorrhea (7), pain (7), visual symptoms (5), anosmia or hyposmia (4), headache (3), congestion (2), rhinolalia (2), otologic symptoms (1), and shortness of breath (1). The duration of symptoms ranged from 10 months to 20 years, with a median of 3 years. All of the cases reviewed exhibited intranasal involvement. Additional sites of involvement included maxillary sinus (14), orbit/eyelid (14), ethmoid sinus (7), lacrimal gland (5), sphenoid sinus (3), frontal sinus (2), multiple paranasal sinuses (5), and the cervical lymph nodes (1). Of these cases, 24% (14/59) had a history of atopy or asthma, 5% (3/59) had chronic sinusitis, and 10% (6/59) had past trauma or nasal surgery prior to symptom onset. An additional 19% (11/59) had a history of surgery after onset of symptoms but prior to presentation to the case author.
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Treatment
Figure 5. Duration of symptoms by histological stage. There is no significant correlation between duration of symptoms and early versus late histologic characteristics.
Twenty percent (12/59) of patients had granuloma faciale either prior to, during, or after diagnosis of EAF, and an additional 7% (4/59) were diagnosed with other autoimmune illnesses (ie, granulomatosis with polyangiitis [GPA], psoriasis).
Imaging Forty-seven cases had available imaging data. Computed tomography was the most commonly reported, in 79% (37/47) of cases. Magnetic resonance imaging was used less frequently, with 32% (15/47) of cases reporting MRI findings. There were 2 cases (4%) cases that used plain film and 4 cases (9%) that used no imaging. Bony erosion was reported in 18 cases.
Histology/Labs Fifty-three of the total cases reported histological findings, and of those, 6% (3/53) were in the early stages, 36% (19/53) were in the late stages, and 58% (31/53) had characteristics of both early and late stages. Figure 5 depicts the relationship between duration of symptoms and histology. There was no significant correlation between duration of symptoms and histological stage found on biopsy (R2 = 0.0096). Eight of the cases evaluated IgG4 status. Two cases showed increased levels of IgG4 while 2 cases, including the case at this institution, failed to show IgG4 positivity. One case showed intermediate IgG4 staining (5-6 positive cells/HPF). There has also been a report of elevated IgG4 blood levels in 1 case while 3 additional cases measured IgG4 levels and found them to be normal. Three cases reported elevated eosinophil counts, and an additional 1 case had elevated eosinophils in nasal secretions. Nine cases reported normal eosinophil counts. Similarly, there have been 3 reports of elevated IgE levels and 2 cases with positive ANCA without signs of GPA.
Treatment modalities were initially divided into 3 groups: medical management (8), medical and surgical management (19), and surgical management only (25). The remaining 6 cases did not specify a treatment modality. Of the 27 cases where medications were used (either alone or with surgery), 16 used only steroids (systemic, intralesional, topical), 2 used immunosuppressant medications, 6 used both steroids and immunosuppressant medications, and 4 used antihistamines (2 in combination with steroids and 2 as single agent therapy). One case did not specify medication regimen. The surgical resections were broken down by approach: lateral rhinotomy (4), external rhinoplasty (7), septoplasty (9), endoscopic (10), gingivobuccal incision (1), or no stated approach (lesion curettage/dubulking/lysis of adhesions) (19).
Outcomes Thirty cases reported follow-up duration with a range of 1 month to 18 years. The median follow-up time was 2 years. Forty of the surgical cases specified extent of resection. Of those, 62.5% of cases (25/40) were described to have undergone total resection, and 37.5% (15/40) had partial resection. Of the 7 cases described treated with solely medical therapy, all had persistent/stable disease, although 2 cases did note improved symptoms (nasal obstruction and improved tracheobronchial narrowing).14,22,38
Predictors of Total Resection The following variables were studied as predictors of successful total resection: patient sex, tumor location, and surgical approach. In addition, only the cases that reported all of the aforementioned factors were included in the linear regression analysis. See Table 2 for details. When analyzing the 20 cases with complete resection, 50% (10/20) were male, and 50% (10/20) were female. Regarding tumor location, 20% (4/20) were located in the maxillary sinus, 5% (1/20) in the ethmoid sinus, 5% (1/20) in the sphenoid sinus, 15% (3/20) in the paranasal sinuses, 15% (3/20) in the orbit, and 10% (2/20) in the lacrimal gland. Fifteen percent (3/20) used lateral rhinotomy, 20% (4/20) used external rhinoplasty, 15% (3/20) used septoplasty, and 45% (9/20) used an endoscopic approach. Using a regression model, we found that the endoscopic approach was significantly correlated with total resection (P = .045). Patient sex, tumor location, lateral rhinotomy, septoplasty, and external rhinoplasty were not significantly correlated with total resection.
Risk Factors for Recurrence Of the cases reviewed, 5 reported recurrence of disease following complete resection. The same aforementioned factors
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Heft Neal et al Table 2. Predictors of Total Resection.
Table 3. Surgical Approach as a Predictor for Recurrence. Correlation Coefficient
Variable Sex (male vs female) Maxillary sinus Ethmoid sinus Sphenoid sinus Paranasal sinuses Orbit/eyelid Lacrimal gland Lateral rhinotomy External rhinoplasty Septoplasty Endoscopic
(P Value) 0.010 (.606) −0.158 (.590) −0.923 (.318) 1.330 (.493) −0.475 (.613) 0.214 (.792) −0.015 (.977) 0.596 (.257) 0.310 (.276) −0.056 (.844) .512 (.045*)
*P < .05.
(patient sex, tumor location, and surgical approach) were studied as potential risk factors for recurrence. These data are shown in Table 3. Of the 5 recurrences, 60% (3/5) occurred in men and 40% (2/5) in women. Three cases reported tumor confinement to the nasal septum/cavity, 1 reported both orbital and lacrimal gland involvement, and 1 reported maxillary and orbital involvement. Three cases with recurrence specified surgical approach. One patient underwent lateral rhinotomy, 1 patient underwent septoplasty, and 1 underwent endoscopic resection. Two of the 5 cases were treated with only surgical resection, while 3 of the cases had surgery in combination with medical treatment. Two of these patients were treated with steroids and the third with steroids and azathioprine. There were not enough data to run a regression model with all factors. A model was made comparing surgical approaches and showed no significant correlation.
Discussion Demographics Sixty-four percent of the patients were female. This is in line with recent data suggesting both sexes are affected equally.2,3,7,19 Eosinophilic angiocentric fibrosis affects patients of all ages, as seen in these cases. Patient ages ranged from 16 to 80 years and had a median patient age of 46 years.
Correlation Coefficient Surgical Approach
(P Value)
Lateral rhinotomy External rhinoplasty Septoplasty Endoscopic
−0.148 (.609) −0.163 (.486) 0.161 (.541) 0.0748 (.711)
Etiology and Differential Diagnosis There is still no clear etiology for EAF, although recent literature supports the idea that EAF is in the family of IgG4RSD.16,22 Deshpande et al16 showed 4 cases with strong IgG4 positivity and an index case with markedly elevated serum IgG4. Since this publication, Kim et al22 discussed a case with moderate IgG4 positivity. However, there is no consensus on degree of IgG4 positive cells to make a diagnosis of IgG4-RSD.16,22 There have also been multiple other cases, including the case described in this review, that showed no IgG4 positivity, and Rimmer et al31 described 2 cases with normal IgG4 serum levels.2,16,21 Similarities between EAF and IgG4-RSD are most noticeable during early stages of disease.16 Therefore, these lab abnormalities may only be seen at the early stages of EAF pathology. Consistent with this argument, none of the cases that failed to show IgG4 positivity or elevated IgG4 serum levels described only early stage histology. It is possible that given the progression of disease seen in these cases, the IgG4 levels have normalized at the time these patients were tested. Other theories regarding EAF etiology are related to allergic and traumatic causes. Consistent with the literature, the current analysis found 24% of patients had a history of allergy, 10% had a history of trauma/past nasal surgery, and 20% had a history of GF.3 This analysis also noted that an additional 19% of cases had a history of trauma or nasal surgery after the onset of symptoms but prior to presentation, suggesting that trauma/surgery may play a role in potentiation of the disease.7,26 However, given the retrospective nature of these data, it is impossible to ascertain if these factors are causative versus correlative. Differential diagnosis includes but is not limited to granulomatosis with polyangiitis, Kimura disease, Churg-Strauss syndrome, sarcoidosis, and angiolymphoid hyperplasia with eosinophilia. Eosinophilic angiocentric fibrosis can be differentiated from many of these entities by lack of true granulomas, necrosis, or lymphoid aggregates with germinal centers.3,5,8,15,16,42 Eosinophilic angiocentric fibrosis also has the characteristic “onion skin” fibrosis, which is not characteristics of Kimura disease. Many authors argue that GF and EAF
422 are on the same spectrum of disease, and while several of the cases in this analysis had coexisting GF, the fibrinoid necrosis seen in GF is notably absent in EAF histology.6,13,15,26,41 Definitive diagnosis is based on histological findings.
Histology Roberts et al2 described the distinctive stages seen in EAF. This analysis found the majority of cases (53%) showed signs of both early and late stages of histology, while 32% showed only late stage and 5% only early stage histology. Although it is tempting to suggest that the duration of symptoms correlates with stage of fibrosis, this analysis found no association between the 2. One potential explanation is that most cases have both early and late stage histology simultaneously (as is seen in the majority) but during sampling the biopsy specimen only yields either late or early stage pathology. Additionally, this correlation is highly dependent on anatomical location of the disease as duration of symptoms prior to seeking treatment will vary depending on tumor location.
Treatment It is well established that EAF is a surgical disease. In line with this, the majority (85%) of cases in this review underwent surgical resection, with 48% treated exclusively with surgery and the other 37% treated with a combination of surgery and medications. The review by Fang et al3 describes outcomes based on surgical and medication treatments, and the results of this study are in line with their analysis. All 7 patients treated with medical therapy alone (steroids, immunosuppressant, or both) had persistence of disease. Regarding surgical treatment, the most common approach was endoscopic resection followed by septoplasty, external rhinoplasty, and lateral rhinotomy. This review is the first to use regression modeling to assess surgical approach and treatment outcomes. Endoscopic management was the only surgical approach significantly correlated with achievement of a complete resection. Most authors now agree that multiple resections are often required to achieve a disease-free state, and there were 2 cases in this review that describe patients with no evidence of disease after multiple resections.13,26,30-32,36,40,41,43
Annals of Otology, Rhinology & Laryngology 126(5) from case studies. There is a large variation in the quality of data reported, and many of the analyzed parameters were not reported in each case. Additionally, linear regression models are dependent on all variables, and therefore any case without all variables reported was dropped from the analysis, which resulted in a small sample size. As such, the data and analysis in this review should only be applied to clinical practice with caution.
Conclusion Eosinophilic angiocentric fibrosis is a fibroinflammatory disorder. While the disease is uncommon, otolaryngologists should be familiar with both disease presentation and treatment options. Given the rare nature of this disease, it has been difficult to compare treatment modalities and analyze prognostic factors. However, in the past 30 years, increased research in this disease pathophysiology suggests that that it may be related to IgG4-RSD, which may aid in diagnosis if caught while in the earlier stage. In addition, the endoscopic approach appears to be a valid treatment modality often resulting in complete tumor resection. However, more data are needed to confirm these results. Authors’ Note Presented as a poster at the American Rhinologic Society meeting on September 17, 2016.
Acknowledgments Statistical consultation provided by Samuel Heft Neal (Stanford University). Pathology images provided by Dr Raja Seethala and Dr Robert L. Peel (University of Pittsburgh, Department of Pathology).
Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Stella E Lee has a grant from Allakos, Inc and Knopp Biosciences for funding for clinical trials.
Funding
Recurrence Given the small sample size and large number of variables, we were unable to conduct a regression model analyzing risk factors for recurrence after total resection. The regression model using surgical approach yielded no statistically significant results.
Limitations This systemic review is susceptible to selection and allocation bias. In addition, because EAF is a rare disease, available data are limited and depend on information collected
The author(s) received no financial support for the research, authorship, and/or publication of this article.
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Heft Neal et al 4. Altemani AM, Pilch BZ, Sakano E, et al. Eosinophilic angiocentric fibrosis of the nasal cavity. Mod Pathol. 1997;10(4):391-393. 5. 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(4):309-315. 6. Kosarac O, Luna MA, Ro JY, et al. Eosinophilic angiocentric fibrosis of the sinonasal tract. Ann Diagn Pathol. 2008;12(4):267-270. 7. Li Y, Liu H, Han D, et al. Eosinophilic angiocentric fibrosis of the nasal septum. Case Rep Otolaryngol. 2013;2013:267285. 8. Nguyen DB, Alex JC, Calhoun B. Eosinophilic angiocentric fibrosis in a patient with nasal obstruction. Ear Nose Throat J. 2004;83(3):183-184, 186. 9. Sunde J, Alexander KA, Reddy VV, et al. Intranasal eosinophilic angiocentric fibrosis: a case report and review. Head Neck Pathol. 2010;4(3):246-248. 10. Tabaee A, Zadeh MH, Proytcheva M, et al. Eosinophilic angiocentric fibrosis. J Laryngol Otol. 2003;117(5):410-413. 11. Yavuzer R, Pandolfi PJ, Herschman BR, et al. An unusual cause of nasal airway obstruction: eosinophilic angiocentric fibrosis. E J Plastic Surg. 2000;23(1):49-51. 12. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Open Med. 2009;3(3):e123-e130. 13. Burns BV, Roberts PF, De Carpentier J, et al. Eosinophilic angiocentric fibrosis affecting the nasal cavity. A mucosal variant of the skin lesion granuloma faciale. J Laryngol Otol. 2001;115(3):223-226. 14. Chinelli PA, Kawashita MY, Sotto MN, et al. Granuloma faciale associated with sinonasal tract eosinophilic angiocentric fibrosis. Acta Derm Venereol. 2004;84(6):486-487. 15. Clauser L, Mandrioli S, Polito J, et al. Eosinophilic angiocentric fibrosis. J Craniofac Surg. 2006;17(4):812-814. 16. Deshpande V, Khosroshahi A, Nielsen GP, et al. Eosinophilic angiocentric fibrosis is a form of IgG4-related systemic disease. Am J Surg Pathol. 2011;35(5):701-706. 17. Faramarzi M, Dadgarnia MH, Moghimi M, et al. Nasal eosinophilic angiocentric fibrosis with orbital extension. Head Neck Pathol. 2015;9(3):426-429. 18. Goldman NC. Angiocentric eosinophilic fibrosis. Otolaryngol Head Neck Surg. 2003;128(3):445-446. 19. Guerrero-Palma MA, Avila-Espin L, Gonzalez-Perez JM, et al. [Unusual nasal clinical entities]. Acta Otorrinolaringol Esp. 2007;58(10):483-486. 20. Holme SA, Laidler P, Holt PJ. Concurrent granuloma faciale and eosinophilic angiocentric fibrosis. Br J Dermatol. 2005;153(4):851-853. 21. Karligkiotis A, Volpi L, Ferreli F, et al. Primary orbital eosinophilic angiocentric fibrosis with intranasal extension. Head Neck. 2014;36(1):E8-E11. 22. Kim WJ, Kim YI, Kim JE, et al. Unexplained persistent dyspnea in a young woman with eosinophilic angiocentric fibrosis. Respir Care. 2014;59(5):e72-e76. 23. Kiratli H, Onder S, Yildiz S, et al. Eosinophilic angio centric fibrosis of the orbit. Clin Experiment Ophthalmol. 2008;36(3):274-276. 24. Loane J, Jaramillo M, Young HA, et al. Eosinophilic angiocentric fibrosis and Wegener’s granulomatosis: a case report and literature review. J Clin Pathol. 2001;54(8):640-641.
423 25. Matai V, Baer S, Barnes S, et al. Eosinophilic angiocentric fibrosis. J Laryngol Otol. 2000;114(7):563-564. 26. 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. 27. Nigar E, Dhillon R, Carr E, et al. Eosinophilic angiocentric fibrosis and extrafacial granuloma faciale. Histopathology. 2007;51(5):729-731. 28. Onder S, Sungur A. Eosinophilic angiocentric fibrosis: an unusual entity of the sinonasal tract. Arch Pathol Lab Med. 2004;128(1):90-91. 29. Owa AO, Boyle S, Gallimore AP. Eosinophilic angiocentric fibrosis as a cause of nasal obstruction. Rhinology. 2002;40(1):41-43. 30. Paun S, Lund VJ, Gallimore A. Nasal fibrosis: long-term follow up of four cases of eosinophilic angiocentric fibrosis. J Laryngol Otol. 2005;119(2):119-124. 31. Rimmer J, Andrews P, Lund VJ. Eosinophilic angiocen tric fibrosis of the nose and sinuses. J Laryngol Otol. 2004;128(12):1071-1077. 32. Pereira EM, Millas I, Reis-Filho JS, et al. Eosinophilic angiocentric fibrosis of the sinonasal tract: report on the clinicopathologic features of a case and review of the literature. Head Neck. 2002;24(3):307-311. 33. Singh A, Selhi PK, Munjal M, Sood N. Eosinophilic angiocentric fibrosis of sinonasal region: a rare and under reported entity. J Clin Diagn Res. 2015;9(11):ED05-ED06. 34. Slovik Y, Putterman M, Nash M, et al. Eosinophilic angiocentric fibrosis of the sinonasal tract in a male patient with chronic bowel inflammation. Am J Rhinol. 2006;20(1):91-94. 35. Takahashi Y, Takahashi E, Ichinose A, et al. Orbital compartment syndrome in eosinophilic angiocentric fibrosis. Ophthal Plast Reconstr Surg. 2015;31(4):e98-e100. 36. Thompson LD, Heffner DK. Sinonasal tract eosinophilic angiocentric fibrosis. A report of three cases. Am J Clin Pathol. 2001;115(2):243-248. 37. Valenzuela AA, Whitehead KJ, Brown I, et al. Eosinophilic angiocentric fibrosis: an unusual entity producing complete lacrimal duct obstruction. Orbit. 2006;25(2):159-161. 38. Vassallo C, Derlino F, Croci GA, et al. Chronic localized leukocytoclastic vasculitis: clinicopathological spectrum of granuloma faciale with and without extrafacial and mucosal involvement. G Ital Dermatol Venereol. 2015;150(1):87-94. 39. Watanabe N, Moriwaki K. Atypical eosinophilic angiocentric fibrosis on nasal septum. Auris Nasus Larynx. 2006;33(3): 355-358. 40. Yang BT, Wang YZ, Wang XY, et al. Nasal cavity eosinophilic angiocentric fibrosis: CT and MR imaging findings. AJNR Am J Neuroradiol. 2011;32(11):2149-2153. 41. Yung A, Wachsmuth R, Ramnath R, et al. Eosinophilic angiocentric fibrosis—a rare mucosal variant of granuloma faciale which may present to the dermatologist. Br J Dermatol. 2005;152(3):574-576. 42. Fageeh NA, Mai KT, Odell PF. Eosinophilic angiocentric fibrosis of the subglottic region of the larynx and upper trachea. J Otolaryngol. 2006;25(4):276-278. 43. Leibovitch I, James CL, Wormald PJ, et al. Orbital eosinophilic angiocentric fibrosis case report and review of the literature. Ophthalmology. 2006;113(1):148-152.
case-report2017
AORXXX10.1177/0003489417696510Annals of Otology, Rhinology & LaryngologyHeft Neal et al
Case Report
A Case Report and Systematic Review of Eosinophilic Angiocentric Fibrosis of the Paranasal Sinuses
Annals of Otology, Rhinology & Laryngology 2017, Vol. 126(5) 415–423 © The Author(s) 2017 Reprints and permissions: sagepub.com/journalsPermissions.nav https://doi.org/10.1177/0003489417696510 DOI: 10.1177/0003489417696510 journals.sagepub.com/home/aor
Molly E. Heft Neal, MD1,2, Nicholas R. Rowan, MD3, Thomas J. Willson, MD3, Eric W. Wang, MD3, and Stella E. Lee, MD3
Abstract Objective: There is a paucity of literature discussing prognostic factors or comparing outcomes in eosinophilic angiocentric fibrosis (EAF). This review aims to analyze tumor and patient characteristics as possible prognostic markers and compare surgical approaches. Methods: Systematic literature review and case report analyzing available cases of EAF located within the paranasal sinuses. Results: The literature search yielded 39 articles meeting criteria for a total of 59 cases (including 1 from our institution). Median patient age was 46 years. The most common presenting symptoms were nasal obstruction (69%, n = 41) and change in external nasal appearance (39%, n = 32). The majority of cases (85%) were treated with surgical resection alone or in combination with medication. Of surgical patients, 62% underwent a complete resection with a recurrence rate of 20%. Median follow-up duration was 2 years. Endoscopic approach showed a significant positive correlation with complete resection (P = .045). Patient sex (P = .6), tumor location (range, P = .32-.98), lateral rhinotomy (P = .26), septoplasty (P = .84), and external rhinoplasty (P = .28) were not significantly correlated with total resection. Insufficient sample size precluded calculation of predictors of recurrence following surgery. Conclusion: This review suggests that an endoscopic approach to EAF tumor is a viable option, frequently yielding complete resection. Keywords eosinophilic angiocentric fibrosis, endoscopic sinus surgery, surgical outcomes, eosinophilic inflammation of nose, nasal mass
Introduction Eosinophilic angiocentric fibrosis (EAF) is a rare fibroinflammatory disease of unknown etiology. Eosinophilic angiocentric fibrosis was originally described by Holmes and Panje1 in 1983, who originally named the disorder “intranasal granuloma faciale” based on the histologic similarities to granuloma faciale (GF). Roberts and McCann2 then coined the term eosinophilic angiocentric fibrosis in 1985 while describing 3 further cases. Eosinophilic angiocentric fibrosis is a slowly progressive condition with varying symptoms depending on site of disease. The nasal mucosa and orbit are the most common locations while rare cases may present in the subglottis.3 The most common presenting symptoms are nasal obstruction followed by swelling of the nasal dorsum or change in external appearance.3 Diagnosis is made based on histological examination and can range from small vessel eosinophilic vasculitis with adjacent inflammatory infiltrate of lymphocytes and plasma cells to the later fibrotic stage,
described as obliterative concentric perivascular fibrosis in an “onion skin” pattern with persistence of eosinophils.2 It is common to have both early and late lesions coexist in the same biopsy specimen, and it is thought that this represents a progressive disease starting with small vessels vasculitis that prompts a fibrotic response.4-11 Numerous treatments have been tried over the years from antihistamines to immunosuppressant medications and steroids, but the only definite 1
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA 2 University of Michigan Department of Otolaryngology, Ann Arbor, Michigan, USA 3 University of Pittsburgh Department of Otolaryngology, Pittsburgh, Pennsylvania, USA Corresponding Author: Molly E. Heft Neal, Department of Otolaryngology, University of Michigan, 1500 E Medical Center Dr, Ann Arbor, MI 48109, USA. Email: [email protected]
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Figure 1. (A) Coronal and (B) axial computed tomography maxillofacial showing disease involvement of bilateral aspects of the nasal septum resulting in marked thickening and inflammation.
Figure 2. Histology. (A) Mixed inflammatory infiltrate. (B) Onion skin fibrosis. Note. Images from University of Pittsburgh, Department of Pathology.
treatment appears to be surgical resection.3 It has now been 30 years since the term eosinophilic angiocentric fibrosis appeared in the literature. This article provides an updated systematic review of the literature on sinonasal cases of EAF over the past 3 decades with a focus on predictors of total resection and risk factors for recurrence with a special consideration of comparing surgical approaches.
Case Report A 45-year-old woman was referred to our institution with a 2-year history of bilateral, left greater than right, nasal obstruction and hyposmia. She had noted progressive swelling of her nasal bridge over the previous 2 years. Her past medical history was significant for allergies to dust, mold, aspirin, and latex and chronic otitis media as a child. She denied history of autoimmune illnesses, past nasal surgery, or trauma. She had previously worked in a sewing factory with exposure to spray cleaners. Her family history was
significant for asthma in her mother and sarcoidosis in her father and paternal uncle. On initial examination, she was found to have a broadened nasal dorsum and a large, firm, submucosal mass located in the midline along the nasal septum with near complete obstruction of the nasal cavities. On imaging, computed tomography (CT) showed thickening of the nasal septum with erosion of the perpendicular plate of the ethmoid bone (Figures 1A and 1B). There was extension to the internal nasal valve on the left side. Bilateral ethmoid and frontal sinuses showed mucosal thickening. Magnetic resonance imaging (MRI) confirmed the presence of a midline enhancing submucosal mass. A biopsy was performed through a left hemitransfixion incision. Histology showed a distinctive perivascular concentric paucicellular fibrosis with rare obliteration of larger vessels. There was an inflammatory background of lymphocytes, plasma cells, and macrophages without eosinophils (Figure 2). While there was no eosinophilia, it was felt that this lesion best
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Figure 3. Intraoperative tumor. (A) Prior to resection. (B) Removal of tumor bulk. (C) Endoscopic view of mucosal invasion. (D) Post endoscopic removal.
fit with a diagnosis of eosinophilic angiocentric fibrosis. Further tissue analysis revealed negative IgG4 stains. Given the patient’s family history of sarcoidosis and the association between EAF and autoimmune vasculitis, the patient underwent rheumatologic evaluation. No features of systemic autoimmune processes were identified. Further workup revealed mildly elevated sedimentation rate at 46 mm (nl 0-20 mm), unremarkable rheumatoid factor (RF), anti-neutrophil cytoplasmic auto-antibody (ANCA), antimyeloperoxidase, anti-proteinase-3, angiotensin converting enzyme (ACE), and antinuclear antibody (ANA) titers. With the diagnosis of EAF, the patient was recommended to undergo surgical excision via a combined open rhinoplasty with an endoscopic endonasal approach (Figure 3). The patient was found to have extensive involvement of the quadrangular cartilage as well as the overlying mucosa, necessitating complete septal resection with a staged reconstruction using cadaveric costal cartilage. All margins were negative. There was excellent remucosalization postoperatively, and the patient was found to be without evidence of recurrence 4 months postoperatively.
Methods Study Design The literature was reviewed systematically using the Preferred Reporting Items of Systematic Reviews and Meta-Analysis (PRISMA) model,12 including the PRISMA flow diagram (Figure 4).
Search Strategy The literature search was done with both PubMed and Ovid. Search terms included angiocentric fibrosis, eosinophilic angiocentric fibrosis, nasal angiocentric fibrosis, sinus angiocentric fibrosis, and orbital angiocentric fibrosis.3 Our search included all articles through December 2015.
Inclusion and Exclusion Criteria Inclusion criteria included all cases of sinonasal pathology with histology consistent with eosinophilic angiocentric
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Figure 4. Systematic review using Preferred Reporting Items of Systematic Reviews and Meta-Analysis (PRISMA).
fibrosis. Lesions were excluded if they involved the glottis, oropharyngeal region, or orbit without extension into the nasal region. Only articles evaluating human subjects and English language were considered (2 articles that had been translated into English were included).
resection, follow-up time, recurrence or residual disease, and histology. Microsoft excel (Microsoft Corporation, Redmond, Washington USA) and R (The R Foundation) were used for data organization and linear regression analysis.
Data Extraction
Results
Each article was reviewed, and the following data were documented: author, year, sex and age of the patient, presenting symptoms, length of symptoms, past medical history (trauma, allergies, autoimmune disease, granuloma faciale), IgG4 counts, imaging modality, location, bony erosion, treatment, surgical approach, complete or partial
Literature Review Both PubMed and Ovid databases were searched, yielding 64 articles. Three additional articles were found in the references of the initial articles (2 were able to be obtained). Screening eliminated articles that did not
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Heft Neal et al Table 1. Patient and Tumor Characteristics. Variables Sex Location of tumor
Presenting symptoms
Past medical history
Histology
Men Women Nasal septum/cavity Maxillary Ethmoid Sphenoid Paranasal Frontal Orbit/eyelid Lacrimal gland Cervical lymph node Nasal obstruction Nasal/septal swelling, change in external appearance Nasal mass Epistaxis Epiphora Congestion Rhinorrhea Pain Headache Eye symptoms (visual loss, proptosis, globe displacement, periorbital edema) Anosmia, hyposmia Otologic symptoms (itchy ears, hearing loss, tinnitus) Rhinolalia Shortness of breath Trauma/Past nasal surgery Atopy/asthma Chronic sinusitis Granuloma faciale Autoimmune disease Early Late
include relevant clinical data (10) and articles that did not specifically focus on EAF (8). The remaining articles (49) were reviewed for eligibility, and of those, only articles describing lesions with consistent histology and in the sinonasal tract were included (39). After eliminating duplicate cases (Rimmer et al. and Paun described 4 of the same cases), there were a total of 58 case reports, plus the additional case from our institution, for a total of 59 cases.1-2,4-11,13-41
Demographics Tumor characteristic and patient demographics are detailed in Table 1. Of the total cases, 46% (27/59) were men, and 54% (32/59) were women, with a median age of 46 years (range, 16-81 years). The most common presenting symptoms were nasal obstruction (41), swelling of the
No. (n = 59)
%
27 32 59 14 7 3 5 2 14 5 1 48 23 11 8 9 3 7 7 2 5
46 54 100 24 12 5 8 3 24 8 2 81 39 19 14 15 5 12 12 3 8
4 1 2 1 6 14 3 12 5 3 19
7 2 3 2 10 24 5 20 8 5 32
nasal dorsum or change in external nasal appearance (23), nasal mass (11), epiphora (9), epistaxis (8), rhinorrhea (7), pain (7), visual symptoms (5), anosmia or hyposmia (4), headache (3), congestion (2), rhinolalia (2), otologic symptoms (1), and shortness of breath (1). The duration of symptoms ranged from 10 months to 20 years, with a median of 3 years. All of the cases reviewed exhibited intranasal involvement. Additional sites of involvement included maxillary sinus (14), orbit/eyelid (14), ethmoid sinus (7), lacrimal gland (5), sphenoid sinus (3), frontal sinus (2), multiple paranasal sinuses (5), and the cervical lymph nodes (1). Of these cases, 24% (14/59) had a history of atopy or asthma, 5% (3/59) had chronic sinusitis, and 10% (6/59) had past trauma or nasal surgery prior to symptom onset. An additional 19% (11/59) had a history of surgery after onset of symptoms but prior to presentation to the case author.
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Treatment
Figure 5. Duration of symptoms by histological stage. There is no significant correlation between duration of symptoms and early versus late histologic characteristics.
Twenty percent (12/59) of patients had granuloma faciale either prior to, during, or after diagnosis of EAF, and an additional 7% (4/59) were diagnosed with other autoimmune illnesses (ie, granulomatosis with polyangiitis [GPA], psoriasis).
Imaging Forty-seven cases had available imaging data. Computed tomography was the most commonly reported, in 79% (37/47) of cases. Magnetic resonance imaging was used less frequently, with 32% (15/47) of cases reporting MRI findings. There were 2 cases (4%) cases that used plain film and 4 cases (9%) that used no imaging. Bony erosion was reported in 18 cases.
Histology/Labs Fifty-three of the total cases reported histological findings, and of those, 6% (3/53) were in the early stages, 36% (19/53) were in the late stages, and 58% (31/53) had characteristics of both early and late stages. Figure 5 depicts the relationship between duration of symptoms and histology. There was no significant correlation between duration of symptoms and histological stage found on biopsy (R2 = 0.0096). Eight of the cases evaluated IgG4 status. Two cases showed increased levels of IgG4 while 2 cases, including the case at this institution, failed to show IgG4 positivity. One case showed intermediate IgG4 staining (5-6 positive cells/HPF). There has also been a report of elevated IgG4 blood levels in 1 case while 3 additional cases measured IgG4 levels and found them to be normal. Three cases reported elevated eosinophil counts, and an additional 1 case had elevated eosinophils in nasal secretions. Nine cases reported normal eosinophil counts. Similarly, there have been 3 reports of elevated IgE levels and 2 cases with positive ANCA without signs of GPA.
Treatment modalities were initially divided into 3 groups: medical management (8), medical and surgical management (19), and surgical management only (25). The remaining 6 cases did not specify a treatment modality. Of the 27 cases where medications were used (either alone or with surgery), 16 used only steroids (systemic, intralesional, topical), 2 used immunosuppressant medications, 6 used both steroids and immunosuppressant medications, and 4 used antihistamines (2 in combination with steroids and 2 as single agent therapy). One case did not specify medication regimen. The surgical resections were broken down by approach: lateral rhinotomy (4), external rhinoplasty (7), septoplasty (9), endoscopic (10), gingivobuccal incision (1), or no stated approach (lesion curettage/dubulking/lysis of adhesions) (19).
Outcomes Thirty cases reported follow-up duration with a range of 1 month to 18 years. The median follow-up time was 2 years. Forty of the surgical cases specified extent of resection. Of those, 62.5% of cases (25/40) were described to have undergone total resection, and 37.5% (15/40) had partial resection. Of the 7 cases described treated with solely medical therapy, all had persistent/stable disease, although 2 cases did note improved symptoms (nasal obstruction and improved tracheobronchial narrowing).14,22,38
Predictors of Total Resection The following variables were studied as predictors of successful total resection: patient sex, tumor location, and surgical approach. In addition, only the cases that reported all of the aforementioned factors were included in the linear regression analysis. See Table 2 for details. When analyzing the 20 cases with complete resection, 50% (10/20) were male, and 50% (10/20) were female. Regarding tumor location, 20% (4/20) were located in the maxillary sinus, 5% (1/20) in the ethmoid sinus, 5% (1/20) in the sphenoid sinus, 15% (3/20) in the paranasal sinuses, 15% (3/20) in the orbit, and 10% (2/20) in the lacrimal gland. Fifteen percent (3/20) used lateral rhinotomy, 20% (4/20) used external rhinoplasty, 15% (3/20) used septoplasty, and 45% (9/20) used an endoscopic approach. Using a regression model, we found that the endoscopic approach was significantly correlated with total resection (P = .045). Patient sex, tumor location, lateral rhinotomy, septoplasty, and external rhinoplasty were not significantly correlated with total resection.
Risk Factors for Recurrence Of the cases reviewed, 5 reported recurrence of disease following complete resection. The same aforementioned factors
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Heft Neal et al Table 2. Predictors of Total Resection.
Table 3. Surgical Approach as a Predictor for Recurrence. Correlation Coefficient
Variable Sex (male vs female) Maxillary sinus Ethmoid sinus Sphenoid sinus Paranasal sinuses Orbit/eyelid Lacrimal gland Lateral rhinotomy External rhinoplasty Septoplasty Endoscopic
(P Value) 0.010 (.606) −0.158 (.590) −0.923 (.318) 1.330 (.493) −0.475 (.613) 0.214 (.792) −0.015 (.977) 0.596 (.257) 0.310 (.276) −0.056 (.844) .512 (.045*)
*P < .05.
(patient sex, tumor location, and surgical approach) were studied as potential risk factors for recurrence. These data are shown in Table 3. Of the 5 recurrences, 60% (3/5) occurred in men and 40% (2/5) in women. Three cases reported tumor confinement to the nasal septum/cavity, 1 reported both orbital and lacrimal gland involvement, and 1 reported maxillary and orbital involvement. Three cases with recurrence specified surgical approach. One patient underwent lateral rhinotomy, 1 patient underwent septoplasty, and 1 underwent endoscopic resection. Two of the 5 cases were treated with only surgical resection, while 3 of the cases had surgery in combination with medical treatment. Two of these patients were treated with steroids and the third with steroids and azathioprine. There were not enough data to run a regression model with all factors. A model was made comparing surgical approaches and showed no significant correlation.
Discussion Demographics Sixty-four percent of the patients were female. This is in line with recent data suggesting both sexes are affected equally.2,3,7,19 Eosinophilic angiocentric fibrosis affects patients of all ages, as seen in these cases. Patient ages ranged from 16 to 80 years and had a median patient age of 46 years.
Correlation Coefficient Surgical Approach
(P Value)
Lateral rhinotomy External rhinoplasty Septoplasty Endoscopic
−0.148 (.609) −0.163 (.486) 0.161 (.541) 0.0748 (.711)
Etiology and Differential Diagnosis There is still no clear etiology for EAF, although recent literature supports the idea that EAF is in the family of IgG4RSD.16,22 Deshpande et al16 showed 4 cases with strong IgG4 positivity and an index case with markedly elevated serum IgG4. Since this publication, Kim et al22 discussed a case with moderate IgG4 positivity. However, there is no consensus on degree of IgG4 positive cells to make a diagnosis of IgG4-RSD.16,22 There have also been multiple other cases, including the case described in this review, that showed no IgG4 positivity, and Rimmer et al31 described 2 cases with normal IgG4 serum levels.2,16,21 Similarities between EAF and IgG4-RSD are most noticeable during early stages of disease.16 Therefore, these lab abnormalities may only be seen at the early stages of EAF pathology. Consistent with this argument, none of the cases that failed to show IgG4 positivity or elevated IgG4 serum levels described only early stage histology. It is possible that given the progression of disease seen in these cases, the IgG4 levels have normalized at the time these patients were tested. Other theories regarding EAF etiology are related to allergic and traumatic causes. Consistent with the literature, the current analysis found 24% of patients had a history of allergy, 10% had a history of trauma/past nasal surgery, and 20% had a history of GF.3 This analysis also noted that an additional 19% of cases had a history of trauma or nasal surgery after the onset of symptoms but prior to presentation, suggesting that trauma/surgery may play a role in potentiation of the disease.7,26 However, given the retrospective nature of these data, it is impossible to ascertain if these factors are causative versus correlative. Differential diagnosis includes but is not limited to granulomatosis with polyangiitis, Kimura disease, Churg-Strauss syndrome, sarcoidosis, and angiolymphoid hyperplasia with eosinophilia. Eosinophilic angiocentric fibrosis can be differentiated from many of these entities by lack of true granulomas, necrosis, or lymphoid aggregates with germinal centers.3,5,8,15,16,42 Eosinophilic angiocentric fibrosis also has the characteristic “onion skin” fibrosis, which is not characteristics of Kimura disease. Many authors argue that GF and EAF
422 are on the same spectrum of disease, and while several of the cases in this analysis had coexisting GF, the fibrinoid necrosis seen in GF is notably absent in EAF histology.6,13,15,26,41 Definitive diagnosis is based on histological findings.
Histology Roberts et al2 described the distinctive stages seen in EAF. This analysis found the majority of cases (53%) showed signs of both early and late stages of histology, while 32% showed only late stage and 5% only early stage histology. Although it is tempting to suggest that the duration of symptoms correlates with stage of fibrosis, this analysis found no association between the 2. One potential explanation is that most cases have both early and late stage histology simultaneously (as is seen in the majority) but during sampling the biopsy specimen only yields either late or early stage pathology. Additionally, this correlation is highly dependent on anatomical location of the disease as duration of symptoms prior to seeking treatment will vary depending on tumor location.
Treatment It is well established that EAF is a surgical disease. In line with this, the majority (85%) of cases in this review underwent surgical resection, with 48% treated exclusively with surgery and the other 37% treated with a combination of surgery and medications. The review by Fang et al3 describes outcomes based on surgical and medication treatments, and the results of this study are in line with their analysis. All 7 patients treated with medical therapy alone (steroids, immunosuppressant, or both) had persistence of disease. Regarding surgical treatment, the most common approach was endoscopic resection followed by septoplasty, external rhinoplasty, and lateral rhinotomy. This review is the first to use regression modeling to assess surgical approach and treatment outcomes. Endoscopic management was the only surgical approach significantly correlated with achievement of a complete resection. Most authors now agree that multiple resections are often required to achieve a disease-free state, and there were 2 cases in this review that describe patients with no evidence of disease after multiple resections.13,26,30-32,36,40,41,43
Annals of Otology, Rhinology & Laryngology 126(5) from case studies. There is a large variation in the quality of data reported, and many of the analyzed parameters were not reported in each case. Additionally, linear regression models are dependent on all variables, and therefore any case without all variables reported was dropped from the analysis, which resulted in a small sample size. As such, the data and analysis in this review should only be applied to clinical practice with caution.
Conclusion Eosinophilic angiocentric fibrosis is a fibroinflammatory disorder. While the disease is uncommon, otolaryngologists should be familiar with both disease presentation and treatment options. Given the rare nature of this disease, it has been difficult to compare treatment modalities and analyze prognostic factors. However, in the past 30 years, increased research in this disease pathophysiology suggests that that it may be related to IgG4-RSD, which may aid in diagnosis if caught while in the earlier stage. In addition, the endoscopic approach appears to be a valid treatment modality often resulting in complete tumor resection. However, more data are needed to confirm these results. Authors’ Note Presented as a poster at the American Rhinologic Society meeting on September 17, 2016.
Acknowledgments Statistical consultation provided by Samuel Heft Neal (Stanford University). Pathology images provided by Dr Raja Seethala and Dr Robert L. Peel (University of Pittsburgh, Department of Pathology).
Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Stella E Lee has a grant from Allakos, Inc and Knopp Biosciences for funding for clinical trials.
Funding
Recurrence Given the small sample size and large number of variables, we were unable to conduct a regression model analyzing risk factors for recurrence after total resection. The regression model using surgical approach yielded no statistically significant results.
Limitations This systemic review is susceptible to selection and allocation bias. In addition, because EAF is a rare disease, available data are limited and depend on information collected
The author(s) received no financial support for the research, authorship, and/or publication of this article.
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