Medical Mycology Advance Access published May 30, 2015 Medical Mycology, 2015, 00, 1–7 doi: 10.1093/mmy/myv033 Advance Access Publication Date: 0 2015 Original Article
Original Article
Allergic fungal rhino sinusitis with granulomas: A new entity?
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Rijuneeta Gupta1,∗ , Ashok K. Gupta1 , Sourabha Kumar Patro1 , Jagveer Yadav1 , Arunaloke Chakrabarti2 , Ashim Das3 and Debajyoti Chatterjee3 1
Department of Otolaryngology and Head and Neck Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India, 2 Department of Medical Microbiology and Mycology, Postgraduate Institute of Medical Education and Research, Chandigarh, India and 3 Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India *To whom correspondence should be addressed. Dr. Rijuneeta, Additional Professor, Department of Otolaryngology, Head and Neck Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India 160012. Tel: +09914209762 (m), 01722756762 (o); Fax: +91-172-2744401; E-mail: [email protected] This material has never been published and is not currently under evaluation in any other peer- reviewed publication. Received 10 November 2014; Revised 17 February 2015; Accepted 8 April 2015
Abstract Introduction: Allergic fungal rhino sinusitis (AFS) is classically described as allergic manifestation to the fungal antigen present in sinuses with no evidence of invasion. Granulomas in histopathology, suspicious of invasion, are occasionally observed in AFS and the disease in these patients behaves like invasive fungal sinusitis even without histologic evidence of invasion. We retrospectively studied AFS patients to analyze whether AFS should be continued to be designated as an allergic entity. Material and methods: AFS patients operated from January 2009 to July 2013 were retrospectively reviewed. Of the total 57 cases operated in last 4 years, nine showing presence of granuloma in histology were included in the AFS with granuloma Group (group 1) and the rest 48 were included in the AFS group (group 2). Both the groups were compared in terms of various parameters at presentation, treatment course and rate of recurrence. Results: Group 1 had significantly high rates of orbital erosion (P = .000), with positive association of skull base erosion (P = .092) and high rates of telecanthus (P = .000), diplopia (P = .000), proptosis (P = .161) and facial pain. Recurrent surgery was needed in 8 of 9 patients in the group 1 as compared to 1 of 48 patients group 2. Conclusion: Granulomas suggests a more severe disease with a trend toward the invasive fungal sinusitis and alerts the clinician regarding the nature of progression. AFS seems to be a part of a continuous spectrum of fungal sinusitis rather than an allergic form as a distinct entity. Key words: allergic fungal rhino sinusitis, granulomas, AFS with granulomas, allergic and invasive fungal sinusitis.
C The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.
All rights reserved. For permissions, please e-mail: [email protected]
1
2
Introduction
Materials and methods 57 cases of AFS, diagnosed retrospectively on the basis of clinical examination, radiology, and office based nasal diagnostic nasal endoscopy using Bent and Kuhn’s criteria, attending the Department of Otolaryngology and Head and Neck Surgery at the Postgraduate Institute of Medical Education and Research, Chandigarh, India, over a period of 54 months from January 2009 to July 2013, were included in the study group. All clinical patient charts, treatment details, surgical details, and histological slides done as per the institute protocol, were reviewed. Records mentioning detailed medical history along with clinical examination in-
cluding pictures of preliminary nasal endoscopy taken in the office basis were reviewed in all patients. Other comorbidities were ruled out after diagnosis routinely. Patients having other comorbidities that led to an immune compromised status were excluded from the study. Details of clinical data including computed tomography (CT) of the paranasal sinuses and orbit in the axial and coronal planes, total leukocyte count, differential leukocyte count, and absolute eosinophil count were collected. An eosinophil count more than 500 cells/μl was considered to indicate serum eosinophilia. Any evidence of skull base erosion or intraorbital or extra-sinus extensions on CT scan were analyzed by correlating with histopathological evidences of invasion. All histopathological and microbiological details, reports and records, slides and preserved fungal cultures were reviewed. As a routine practice in fungal sinusitis patients, all surgically excised sinus mucosa and intra-sinus debris (endoscopically removed) were equally divided into two halves. One half was used for histopathologic monitoring, and the other half was used for mycological examination. For histopathologic analysis, the sample was individually fixed in 10% buffered formalin, and 5-pmthick sections were cut from paraffin blocks and stained with hematoxylin-eosin, periodic Acid Schiff, and Gomori’s methanamine silver stains. The histopathologic examination was carried out for the presence (M+) or absence (M−) of extra-mucosal allergic mucin, eosinophil clusters, Charcot-Leyden crystals, fungal hyphae, and possible mucosal invasion by fungal hyphae. Macroscopically, allergic mucin is chalky grey or at times may be brownish green with gum or butter like consistency interspersed with the nasal polyp. Microscopically, it is extracellular, lamellate eosinophilic mucin, which is paler in the center than at the periphery under hematoxylin-eosin staining. On Grocot staining, it appears as green-gray lamellate aggregations. In addition, allergic mucin consists of clumps of eosinophils, Charcot-Leyden crystals, and fungal hyphae. The fungal hyphae are found inside the mucin without evidence of tissue invasion, often seen as broken, fragmented hyphae. The portion of surgically excised specimen used for mycological examination was collected in sterile normal saline (isotonic sodium chloride). Direct microscopy under 10% potassium hydroxide wet mount was performed on homogenized and nonhomogenized tissue to screen for fungal elements (F+ or F−). The homogenized tissue was cultured by inoculation on Sabouraud’s dextrose agar for growth of fungi. The different mycelial isolates were identified by microscopic morphologic analysis and slide culture mount. On the basis of presence or absence of mucosal granuloma in the sinus content, in histopathological examination, patients were categorized into two groups. Group 1 included all patients of AFS with features of
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Allergic fungal sinusitis (AFS) was first reported by Millar and others in the early 1980s as a sinus disease very similar to allergic bronchopulmonary aspergillosis [1,2]. Later on, in 1994 a case series of 15 patients was reported by Bent and Kuhn [3] who made attempts to determine specific diagnostic criteria for the diagnosis of AFS. The following five are the major criteria for diagnosis according to their study: (1) type 1 (immunoglobulin E [lgE]-mediated) hypersensitivity; (2) nasal polyposis; (3) characteristic CT findings; (4) mucin and eosinophilic mucus; (5) positive fungal smear or culture. However, Kuhn added six minor criteria like (1) presence of asthma, (2) unilateral preponderance, (3) radiological bone erosion, (4) fungal culture, (5) Charcot Leyden crystals, and (6) serum eosinophilia to diagnose patients with AFS. Still the pathophysiology of this disease remains controversial in many dimensions. Although currently it is widely accepted that the allergic etiology of AFS is a noninvasive process [4–6], occasionally documented fungal invasions are also reported [7–9]. In some cases, bony erosion is observed, which is explained by the concept of pressure necrosis and remodeling does not adequately account for the extensive destruction seen in some cases. Lack of sufficient biopsies possibly let go the areas of incipient mucosal invasions undetected [6]. Such occult invasion has been reported as a cause of the frequent recurrences of AFS [10]. Allergic fungal rhino sinusitis (AFS) is an increasingly recognized type of chronic rhino sinusitis. It is possibly a nontissue-invasive disease, representing an allergic hypersensitivity response to the presence of extramucosal fungi within the sinus cavity. But we could find occasional cases where we observed evidences of both AFS with chronic invasive granulomatous changes seen in histopathology. We retrospectively reviewed the histopathologic slides and clinical records of all AFS cases diagnosed during a period of January 2009 to July 2013 in the Department of ENT.
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invasion (granuloma formation) consisting of nine patients, and group 2 includes patients of AFS without features of invasion including 48 patients. The clinical, radiologic, and endoscopic details of patients of both the groups were analysed, compared, and correlated with the histology. All these patients are under our routine follow-up.
Results
Figure 1. Fungal granuloma with the presence of plenty of eosinophils, plasma cells, lymphocytes and foreign body giant cells. This Figure is reproduced in color in the online version of Medical Mycology.
Figure 2. High power view of the fungal granuloma seen in a case of AFRS. This Figure is reproduced in color in the online version of Medical Mycology.
Figure 3. CT picture of a patient showing erosion of lamina papyracea who later on had histological evidence of granuloma in the postoperative specimen. This Figure is reproduced in color in the online version of Medical Mycology.
nucleated giant cells in the granuloma which indicates mucosal/tissue invasion by the fungus. These patients consisted the AFS with granuloma group. Computed tomography scanning demonstrating double density signs on CT scan is due to magnesium deposition, showing hyperdense areas on isodense background indicating fungal infestation was seen in most cases. While orbital erosion (Figs 3 and 4) was noted in 19 of 57% of cases out of the whole study population. Erosion of bone between the orbital contents and the paranasal sinuses i.e. erosion of the lamina papyraceae, was taken as orbital erosion. It was present in eight patients in group 1 and 11 patients in group 2 and was significantly associated with AFS with coexisting granuloma (p = 0.000 for orbital erosion). Similarly there was a positive association between intracranial extension
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Fifty-seven cases of proven allergic fungal sinusitis were evaluated, and the retrospectively collected data were compared using chi square test. The majority of patients were in their second or third decade. The age range was 12 to 57 years; however, invasion is seen more in 2nd and 3rd decade. Males comprised 33% of the patients in group 1 and 55% in group 2. Histopathological analysis showed septate hyphae in 37 patients (29 in Group 2 and eight in Group 1). Culture revealed Aspergillus flavus in all of our cases contrary to the world literature showing Aspergillus fumigatus as the most common fungi associated with AFS [11,12]. There was no difference in terms of the type of fungus isolated in terms of the species and culture characteristics in between the groups. In the remaining (20 out of 57, 35.1%) cases, allergic mucin was seen but no fungal spores were identified. Nine (16%) patients demonstrated additional mucosal granulomatous inflammation indicative of fungal tissue invasion in the form of fungal granulomas containing giant cells with fungal elements within the granulomas (Fig. 2) along with the other features of AFRS such as presence of fungal hyphae, allergic mucin and plenty of eosinophils, even in the absence of any histopathological evidence of direct bony or vascular invasion (Figs 1 and 2). Septate and branching fungal hyphae were identified within the multi-
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Table 1. Comparison of parameters between the groups.
No. of patients Age Gender(m:f) h/o atopy Nasal obstruction Nasal polyps Nasal Discharge Post nasal Drip
Group 1 (AFS+ Granuloma)
group 2 (AFS)
9 15 to 32 05:04 6 9 9 8 7
48 12 to 57 16:32 9 48 48 43 44
P Value
0.205 0.003
Clinical features suggestive of aggressive/ invasive disease
and skull base erosion with that of the presence of fungal granuloma in the histopathology in retrospective analysis though it was not statistically significant (P = .092). However, when any form of extra sinus involvement including both intra orbital and intra cranial erosion was compared between both the groups, it was found that extra sinus involvement was present in all the cases in group 1 compared to 12 cases in group 2, and there was a significant difference between both the groups (P = .000). Interestingly, orbital and/or skull base erosion was notably more common in males than in females. Nasal obstruction was the most common clinical feature, being observed in all cases (100%), while nasal discharge (89.58% in AFS group and 88.88% in AFS with granuloma group) and postnasal drip (91.66% in AFS group and 77.77% in AFS with granuloma group) were next in the common findings. Of the extranasal and paranasal sinus symptoms, headache (60.41% in AFS group and 66.66% in AFS with Granuloma group) and telecanthus (33.33% in AFS group and 100% patients in AFS with Granuloma group) were the most common. However, proptosis (31.25% in AFS Group and 55.55% in AFS with Granuloma group) and facial pain (8.33% in AFS Group and 22.22% in AFS with Granuloma Group) were also observed. Presence of telecanthus and diplopia was higher in group 1 compared to group 2 with P values of .000 on comparison. (Table 1) The most common positive laboratory findings were raised eosinophil counts (58.33% in Group 2 and 66% in Group 1). Unilateral involvement of the nose and paranasal sinuses was seen in 59.57% of cases among the whole population comprising both the groups, while nasal polyps and history of atopy and allergic symptoms were present in all cases (100%). All patients were managed surgically using ESS.
6 2 5 9 5
29 4 15 16 4
9 9 9 8 4 9 6
48 39 48 11 9 12 28
0.000 0.092 0.000 0.640
9 9 9
48 48 0
0.000
6 8
27 29
0.561 0.101
0.161 0.000 0.000
Radiology Multiple sinus involvement Bony expansion Hyperdensiy Intraorbital (IO) Intracranial (IC) Extrasinus (IC or IO) Eosinophilia (AEC >500/μl)
0.157
Histology Allergic mucin Fungal hyphae Granuloma Microbiology Fugal smear (+) Culture (+)
All patients were given a short course of two weeks of tapering doses of oral steroids and nasal douching in the postoperative period. In the follow-up period many patients had evidences of polypoidal changes in the nasal cavities and required intermittent short courses of steroids. However, revision ESS was required in 9 out of 57 (15.78%) patients (8 out of 9 patients of group 1 and one out of 48 patients of group 2) who didn’t respond to oral steroids short courses and had frank nasal polyps in nasal endoscopy and multiple sinus involvement in radiology in spite of the routine post-operative therapy. Revision ESS was performed for these recurrent cases with post-operative adjuvant antifungal treatment with Itraconazole for 3 months. Table 1 show various values obtained in the results. All patients were prescribed with long-term topical steroids and alkaline nasal douches. The minimum available follow-up was for five months, with a mean follow-up
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Figure 4. Coronal view of another patient with bony erosion with evidence of granuloma in post op histopathology.
Headache Facial pain Proptosis Telecanthus Diplopia
Gupta et al.
of 10.2 months (5–36 months). All patients who underwent revision surgery with antifungal therapy didn’t show any further evidence of polypoidal changes not responding to steroids.
Discussion
dence supporting either of the hypotheses remains scanty. Clearly, bone erosion has also been described in association with long-standing expansile processes, such as sino nasal polyposis or mucoceles, not related to AFS. Allergic fungal rhino sinusitis usually follows a slow, nonaggressive course. However, the disease may result in massive bone destruction when the process extends outside the confines of the sinuses [22]. Recognition of this possibility is important, because bone erosion can be interpreted as an indication of invasive disease [23]. Orbital erosion was detected in 33.33% of cases in our study. This is comparable to the results of Liu et al. [24], who observed bony erosion in 38.09% of cases. In contrast, Ghegan et al. [25] reported bony skull base or orbital erosion in 56% of cases. Nussenbaum et al. [23] noted bony erosion in 20%, and Kinsella et al. [22] reported skull base erosion in 21.42% cases. Orbital erosion alone was detected in 29.78% of our patients; this result is similar to that of Liu et al. (28.57%) but higher than that of Kinsella et al. (21.42%) [22,24]. Skull base erosion alone was detected in 22.8% of our patients, whereas Liu et al. [24] observed intracranial extension in 38.09% of their patients. Orbital and intracranial involvement seen in clinical and radiological examinations are associated with advanced or long standing disease and these factors are probably associated with tissue invasion. Kinsella et al. [22] suggested that the presence of Bipolaris sp. might be related to cranial base erosion. They proposed a new diagnostic entity, ‘skull base allergic fungal sinusitis’, which incorporates the histological diagnostic criteria of allergic fungal sinusitis with the computed tomography (CT) criteria for bone erosion. The present study clearly shows an association between histological evidence of granulomas and bony erosion which is even statistically significant for orbital erosion. The clinical picture of severe disease like telecanthus, proptosis, and diplopia were more common in group 1 then the other group. An inadequate sampling of histopathological specimen may thus pose problems in proper categorization of cases. Hence, a detailed examination of all the fragments is mandatory to diagnose tissue invasion. Advanced cases with bony erosion may be missed as bony margins are not usually included in resection in endoscopic sinus surgery. Five possible distinct diagnostic categories are recognized based on histopathologic findings [26]. Three types of fungal rhino sinusitis are tissue invasive: acute necrotizing (fulminant), chronic invasive, and granulomatous invasive (indolent). Two types are categorized as noninvasive: fungal ball (sinus mycetoma) and AFS. Fungal sinusitis is considered a potentially progressive continuum, wherein noninvasive disease may convert to or coexist with an invasive form. Such a progression has been previously documented [27,28]. The invasive features noted by us in association
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AFS is possibly a nontissue-invasive disease, representing an allergic hypersensitivity response to the presence of extramucosal fungi within the sinus cavity. Earlier studies estimate the overall incidence of AFS to be 5% to 10% of all patients with CRS who undergo surgery [2,13,14]. In the diagnosis of AFS, the detection of fungi in allergic mucin is considered important, although hyphae are sparse in sinus content. Hence, there may be chances of occurrences of two closely related entities; eosinophilic fungal rhino sinusitis (EFRS) and eosinophilic mucin rhino sinusitis (EMRS) [15,16] as per the alternate hypothesis of Ponikau et al. [17], which proposes a different mechanism of AFS and may also be applied to encompass CRS. Specimens from 93% of patients with CRS showed presence of fungi while type I hypersensitivity was not found to be prevalent in the study group of Ponikau et al. [17]. They hypothesized that CRS is a cell-mediated response to fungal elements and brought into picture the new term, EFRS. The question still remains whether a separate unrecognized form of nonallergic, fungal eosinophilic inflammation exists that leads to a similar clinical presentation. Ferguson [15] claimed that eosinophilic mucin could be present and cause rhino sinusitis without the presence of fungi. The controversy regarding the definition of AFS as noninvasive form became stronger when reports of histologic invasion in possible cases of AFS [8,9] were published. Foci of granulomatous inflammation in patients of AFS with erosion of bone have also been reported [18,19]. In this study, an attempt has been made to identify granulomas in subepithelial tissues in cases of AFS, determinant of invasion. The noninvasive and invasive forms of fungal rhino sinusitis are not necessarily discrete and may coexist in the same patient. Foci of granulomatous inflammation were reported by Klapper et al. [18] in a patient of AFS with orbital apex involvement. Thakar et al. [9] recommended that fungal sinusitis be considered a potentially progressive continuum, wherein noninvasive disease may convert to or coexist with an invasive form. Despite bone destruction associated with AFS, fungal hypersensitivity is considered as prime factor. As reported in earlier studies, pressure atrophy from expansive growth of polyps or mucoceles may play a causative role in AFS related bone erosion [3,20– 22]. Many studies also implicate the inflammatory mediators produced in association with allergic mucin for being responsible for the bone erosion [3,5,20–22]. Direct evi-
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Conclusion In the present study, 16% of AFS cases were associated with histological evidence of fungal tissue invasion. These patients also had significantly increased incidences of clinical evidences of invasive disease like telecanthus, diplopia and proptosis and radiological evidences of extra sinus involvement and intra orbital extension of disease with orbital erosion. These patients had a high incidence of recurrence which eventually required revision surgery and post-operative adjuvant antifungal therapy with Itracona-
zole. Hence, the entity of AFS with coexistent granuloma as described here seems to represent the transition from the allergic and noninvasive form of fungal sinusitis, that is, AFS to the invasive forms in the spectrum of fungal sinus infestations. The coexistence of both kinds of pathologies in the same patients with features of AFS in the sinus nasal mucosa and presence of features of chronic granulomatous fungal sinusitis in the form of granuloma creates a diagnostic dilemma and further warrants the need to reframe the present existing classification of fungal sinusitis with the need of including such cases with evidences of different ends of the spectrum coexisting in the same patient. These findings implicate the role in the management decisions as the patients with features of granuloma need antifungal therapy and cautious use of steroids in the management contrasting the patients of AFS, where antifungals hardly have a role. Clinical involvement of the orbit or radiologic evidence of extrasinus disease should alert the surgeon regarding the possibility of coexisting invasive disease. Specimen should be examined carefully in advanced or longstanding cases. Further studies with larger number of cases and combined effort of otolaryngologists, pathologists and microbiologists would be required for deciding treatment protocol in these cases.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and the writing of the paper.
References 1. Millar JW JA, Lamb D. Allergic aspergillosis of the maxillary sinuses [Abstract]. Thorax 1981; 36. 2. Katzenstein AL, Sale SR, Greenberger PA. Allergic Aspergillus sinusitis: a newly recognized form of sinusitis. J allergy clin immunol 1983; 72(1): 89–93. 3. Bent JP, 3rd, Kuhn FA. Diagnosis of allergic fungal sinusitis. Otolaryngol Head Neck Surg 1994; 111(5): 580–588. 4. Kupferberg SB, Bent JP, 3rd, Kuhn FA. Prognosis for allergic fungal sinusitis. Otolaryngol Head Neck Surg 1997; 117(1): 35– 41. 5. Corey JP, Delsupehe KG, Ferguson BJ. Allergic fungal sinusitis: allergic, infectious, or both? Otolaryngol Head Neck Surg 1995; 113(1): 110–119. 6. Kuhn FA, Javer AR. Allergic fungal rhinosinusitis: perioperative management, prevention of recurrence, and role of steroids and antifungal agents. Otolaryngol Clin North Am 2000; 33(2): 419–433. 7. Schubert MS, Goetz DW. Evaluation and treatment of allergic fungal sinusitis. I. Demographics and diagnosis. J allergy clin immunol 1998; 102(3): 387–394.
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with AFS are similar to the granulomatous variant of invasive fungal sinusitis. Question arises regarding the difference between the courses of treatment in patients of AFS with granuloma from cases of AFS. Kinsella et al. [22] recommended using endoscopic approaches to surgically treat AFS with related skull base erosion. Klapper et al. [18] managed two patients with AFS-related orbital involvement and concluded that aggressive surgery is not necessary. Surgical management of all patients in our series consisted of endoscopic removal of disease. Based on our experience, and also on the cited experience with chronic granulomatous sinusitis, it is probable that many such patients would do well with surgical debridement alone with no adjunctive antifungal therapy but the patients having AFS with coexistence histopathological features of granulomatous fungal sinusitis merit antifungal therapy like itraconazole or voriconazole along with debridement during the course of management suggesting that invasive features like granuloma and features of allergic fungal sinusitis without invasion can be nothing but different stages of the spectrum of the same disease entity. Nevertheless, it does seem prudent to use Itraconazole for all such cases but caution should be taken with steroids. In the present study eight of the nine patients in the AFS with granuloma group showed recurrence in the post-operative period that required revision endoscopic sinus surgery in the absence of antifungal therapy. But when these patients were put on Itraconazole 200 mg BD post revision surgeries for 3 months, they didn’t recur, and the cavity conditions became at par with that of the nonrecurrent patients. Same is the case for one patient of the AFS group, who did show the signs of recurrence and eventually responded to antifungal therapy. All these patients are under our regular follow-up till date. The significantly high recurrence rates observed in these patients with presence of granulomas in histology and requirement of antifungals to prevent recurrence of disease further strengthen the hypothesis that there may be coexisting invasive pathology, and these different forms of disease are part of a continuous spectrum rather than being different and distinct clinical entities.
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19. Klapper SR, Patrinely JR. Orbital involvement in allergic fungal sinusitis. Ophthalmic Plast Rec 2001; 17(2): 149–151. 20. Handley GHVD, Katzenstein AA. Bone erosion in allergic fungal sinusitis. Am J Rhinol & allergy 1990; 4: 4. 21. Torres C, Ro JY, el-Naggar AK et al. Allergic fungal sinusitis: a clinicopathologic study of 16 cases. Human pathology 1996; 27(8): 793–799. 22. Kinsella JB, Rassekh CH, Bradfield JL et al. Allergic fungal sinusitis with cranial base erosion. Head & neck 1996; 18(3): 211–217. 23. Nussenbaum B, Marple BF, Schwade ND. Characteristics of bony erosion in allergic fungal rhinosinusitis. Otolaryngol Head Neck Surg 2001; 124(2): 150–154. 24. Liu JK, Schaefer SD, Moscatello AL et al. Neurosurgical implications of allergic fungal sinusitis. J Neurosurg 2004; 100(5): 883–890. 25. Ghegan MD, Lee FS, Schlosser RJ. Incidence of skull base and orbital erosion in allergic fungal rhinosinusitis (AFRS) and non-AFRS. Otolaryngol Head Neck Surg 2006; 134(4): 592– 595. 26. deShazo RD, Chapin K, Swain RE. Fungal sinusitis. N Eng J Med 1997; 337(4): 254–259. 27. Tsimikas S, Hollingsworth HM, Nash G. Aspergillus brain abscess complicating allergic Aspergillus sinusitis. J allergy clin immunol 1994; 94(2 Pt 1): 264–267. 28. Gungor A, Adusumilli V, Corey JP. Fungal sinusitis: progression of disease in immunosuppression–a case report. Ear Nose Throat J 1998; 77(3): 207–215.
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8. Zieske LA, Kopke RD, Hamill R. Dematiaceous fungal sinusitis. Otolaryngol Head Neck Surg 1991; 105(4): 567–577. 9. Thakar A, Sarkar C, Dhiwakar M et al. Allergic fungal sinusitis: expanding the clinicopathologic spectrum. Otolaryngol Head Neck Surg 2004; 130(2): 209–216. 10. Hartwick RW, Batsakis JG. Sinus aspergillosis and allergic fungal sinusitis. Ann Otol Rhinol Laryngol 1991; 100(5 Pt 1): 427– 430. 11. Schubert MS. Allergic fungal sinusitis. Otolaryngol Clin North Am 2004; 37(2): 301–326. 12. Ryan MW. Allergic fungal rhinosinusitis. Otolaryngol Clin North Am 2011; 44(3): 697–710, ix-x. 13. Ferreiro JA, Carlson BA, Cody DT, 3rd. Paranasal sinus fungus balls. Head & neck 1997; 19(6): 481–486. 14. Collins MM, Nair SB, Wormald PJ. Prevalence of noninvasive fungal sinusitis in South Australia. Am J Rhinol 2003; 17(3): 127–132. 15. Ferguson BJ. Eosinophilic mucin rhinosinusitis: a distinct clinicopathological entity. Laryngoscope 2000; 110(5 Pt 1): 799–813. 16. Thrasher RD, Kingdom TT. Fungal infections of the head and neck: an update. Otolaryngol Clin North Am 2003; 36(4): 577– 594. 17. Ponikau JU, Sherris DA, Kern EB et al. The diagnosis and incidence of allergic fungal sinusitis. Mayo Clin Proc 1999; 74(9): 877–884. 18. Klapper SR, Lee AG, Patrinely JR et al. Orbital involvement in allergic fungal sinusitis. Ophthalmology 1997; 104(12): 2094– 2100.
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Original Article
Allergic fungal rhino sinusitis with granulomas: A new entity?
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Rijuneeta Gupta1,∗ , Ashok K. Gupta1 , Sourabha Kumar Patro1 , Jagveer Yadav1 , Arunaloke Chakrabarti2 , Ashim Das3 and Debajyoti Chatterjee3 1
Department of Otolaryngology and Head and Neck Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India, 2 Department of Medical Microbiology and Mycology, Postgraduate Institute of Medical Education and Research, Chandigarh, India and 3 Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India *To whom correspondence should be addressed. Dr. Rijuneeta, Additional Professor, Department of Otolaryngology, Head and Neck Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India 160012. Tel: +09914209762 (m), 01722756762 (o); Fax: +91-172-2744401; E-mail: [email protected] This material has never been published and is not currently under evaluation in any other peer- reviewed publication. Received 10 November 2014; Revised 17 February 2015; Accepted 8 April 2015
Abstract Introduction: Allergic fungal rhino sinusitis (AFS) is classically described as allergic manifestation to the fungal antigen present in sinuses with no evidence of invasion. Granulomas in histopathology, suspicious of invasion, are occasionally observed in AFS and the disease in these patients behaves like invasive fungal sinusitis even without histologic evidence of invasion. We retrospectively studied AFS patients to analyze whether AFS should be continued to be designated as an allergic entity. Material and methods: AFS patients operated from January 2009 to July 2013 were retrospectively reviewed. Of the total 57 cases operated in last 4 years, nine showing presence of granuloma in histology were included in the AFS with granuloma Group (group 1) and the rest 48 were included in the AFS group (group 2). Both the groups were compared in terms of various parameters at presentation, treatment course and rate of recurrence. Results: Group 1 had significantly high rates of orbital erosion (P = .000), with positive association of skull base erosion (P = .092) and high rates of telecanthus (P = .000), diplopia (P = .000), proptosis (P = .161) and facial pain. Recurrent surgery was needed in 8 of 9 patients in the group 1 as compared to 1 of 48 patients group 2. Conclusion: Granulomas suggests a more severe disease with a trend toward the invasive fungal sinusitis and alerts the clinician regarding the nature of progression. AFS seems to be a part of a continuous spectrum of fungal sinusitis rather than an allergic form as a distinct entity. Key words: allergic fungal rhino sinusitis, granulomas, AFS with granulomas, allergic and invasive fungal sinusitis.
C The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.
All rights reserved. For permissions, please e-mail: [email protected]
1
2
Introduction
Materials and methods 57 cases of AFS, diagnosed retrospectively on the basis of clinical examination, radiology, and office based nasal diagnostic nasal endoscopy using Bent and Kuhn’s criteria, attending the Department of Otolaryngology and Head and Neck Surgery at the Postgraduate Institute of Medical Education and Research, Chandigarh, India, over a period of 54 months from January 2009 to July 2013, were included in the study group. All clinical patient charts, treatment details, surgical details, and histological slides done as per the institute protocol, were reviewed. Records mentioning detailed medical history along with clinical examination in-
cluding pictures of preliminary nasal endoscopy taken in the office basis were reviewed in all patients. Other comorbidities were ruled out after diagnosis routinely. Patients having other comorbidities that led to an immune compromised status were excluded from the study. Details of clinical data including computed tomography (CT) of the paranasal sinuses and orbit in the axial and coronal planes, total leukocyte count, differential leukocyte count, and absolute eosinophil count were collected. An eosinophil count more than 500 cells/μl was considered to indicate serum eosinophilia. Any evidence of skull base erosion or intraorbital or extra-sinus extensions on CT scan were analyzed by correlating with histopathological evidences of invasion. All histopathological and microbiological details, reports and records, slides and preserved fungal cultures were reviewed. As a routine practice in fungal sinusitis patients, all surgically excised sinus mucosa and intra-sinus debris (endoscopically removed) were equally divided into two halves. One half was used for histopathologic monitoring, and the other half was used for mycological examination. For histopathologic analysis, the sample was individually fixed in 10% buffered formalin, and 5-pmthick sections were cut from paraffin blocks and stained with hematoxylin-eosin, periodic Acid Schiff, and Gomori’s methanamine silver stains. The histopathologic examination was carried out for the presence (M+) or absence (M−) of extra-mucosal allergic mucin, eosinophil clusters, Charcot-Leyden crystals, fungal hyphae, and possible mucosal invasion by fungal hyphae. Macroscopically, allergic mucin is chalky grey or at times may be brownish green with gum or butter like consistency interspersed with the nasal polyp. Microscopically, it is extracellular, lamellate eosinophilic mucin, which is paler in the center than at the periphery under hematoxylin-eosin staining. On Grocot staining, it appears as green-gray lamellate aggregations. In addition, allergic mucin consists of clumps of eosinophils, Charcot-Leyden crystals, and fungal hyphae. The fungal hyphae are found inside the mucin without evidence of tissue invasion, often seen as broken, fragmented hyphae. The portion of surgically excised specimen used for mycological examination was collected in sterile normal saline (isotonic sodium chloride). Direct microscopy under 10% potassium hydroxide wet mount was performed on homogenized and nonhomogenized tissue to screen for fungal elements (F+ or F−). The homogenized tissue was cultured by inoculation on Sabouraud’s dextrose agar for growth of fungi. The different mycelial isolates were identified by microscopic morphologic analysis and slide culture mount. On the basis of presence or absence of mucosal granuloma in the sinus content, in histopathological examination, patients were categorized into two groups. Group 1 included all patients of AFS with features of
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Allergic fungal sinusitis (AFS) was first reported by Millar and others in the early 1980s as a sinus disease very similar to allergic bronchopulmonary aspergillosis [1,2]. Later on, in 1994 a case series of 15 patients was reported by Bent and Kuhn [3] who made attempts to determine specific diagnostic criteria for the diagnosis of AFS. The following five are the major criteria for diagnosis according to their study: (1) type 1 (immunoglobulin E [lgE]-mediated) hypersensitivity; (2) nasal polyposis; (3) characteristic CT findings; (4) mucin and eosinophilic mucus; (5) positive fungal smear or culture. However, Kuhn added six minor criteria like (1) presence of asthma, (2) unilateral preponderance, (3) radiological bone erosion, (4) fungal culture, (5) Charcot Leyden crystals, and (6) serum eosinophilia to diagnose patients with AFS. Still the pathophysiology of this disease remains controversial in many dimensions. Although currently it is widely accepted that the allergic etiology of AFS is a noninvasive process [4–6], occasionally documented fungal invasions are also reported [7–9]. In some cases, bony erosion is observed, which is explained by the concept of pressure necrosis and remodeling does not adequately account for the extensive destruction seen in some cases. Lack of sufficient biopsies possibly let go the areas of incipient mucosal invasions undetected [6]. Such occult invasion has been reported as a cause of the frequent recurrences of AFS [10]. Allergic fungal rhino sinusitis (AFS) is an increasingly recognized type of chronic rhino sinusitis. It is possibly a nontissue-invasive disease, representing an allergic hypersensitivity response to the presence of extramucosal fungi within the sinus cavity. But we could find occasional cases where we observed evidences of both AFS with chronic invasive granulomatous changes seen in histopathology. We retrospectively reviewed the histopathologic slides and clinical records of all AFS cases diagnosed during a period of January 2009 to July 2013 in the Department of ENT.
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invasion (granuloma formation) consisting of nine patients, and group 2 includes patients of AFS without features of invasion including 48 patients. The clinical, radiologic, and endoscopic details of patients of both the groups were analysed, compared, and correlated with the histology. All these patients are under our routine follow-up.
Results
Figure 1. Fungal granuloma with the presence of plenty of eosinophils, plasma cells, lymphocytes and foreign body giant cells. This Figure is reproduced in color in the online version of Medical Mycology.
Figure 2. High power view of the fungal granuloma seen in a case of AFRS. This Figure is reproduced in color in the online version of Medical Mycology.
Figure 3. CT picture of a patient showing erosion of lamina papyracea who later on had histological evidence of granuloma in the postoperative specimen. This Figure is reproduced in color in the online version of Medical Mycology.
nucleated giant cells in the granuloma which indicates mucosal/tissue invasion by the fungus. These patients consisted the AFS with granuloma group. Computed tomography scanning demonstrating double density signs on CT scan is due to magnesium deposition, showing hyperdense areas on isodense background indicating fungal infestation was seen in most cases. While orbital erosion (Figs 3 and 4) was noted in 19 of 57% of cases out of the whole study population. Erosion of bone between the orbital contents and the paranasal sinuses i.e. erosion of the lamina papyraceae, was taken as orbital erosion. It was present in eight patients in group 1 and 11 patients in group 2 and was significantly associated with AFS with coexisting granuloma (p = 0.000 for orbital erosion). Similarly there was a positive association between intracranial extension
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Fifty-seven cases of proven allergic fungal sinusitis were evaluated, and the retrospectively collected data were compared using chi square test. The majority of patients were in their second or third decade. The age range was 12 to 57 years; however, invasion is seen more in 2nd and 3rd decade. Males comprised 33% of the patients in group 1 and 55% in group 2. Histopathological analysis showed septate hyphae in 37 patients (29 in Group 2 and eight in Group 1). Culture revealed Aspergillus flavus in all of our cases contrary to the world literature showing Aspergillus fumigatus as the most common fungi associated with AFS [11,12]. There was no difference in terms of the type of fungus isolated in terms of the species and culture characteristics in between the groups. In the remaining (20 out of 57, 35.1%) cases, allergic mucin was seen but no fungal spores were identified. Nine (16%) patients demonstrated additional mucosal granulomatous inflammation indicative of fungal tissue invasion in the form of fungal granulomas containing giant cells with fungal elements within the granulomas (Fig. 2) along with the other features of AFRS such as presence of fungal hyphae, allergic mucin and plenty of eosinophils, even in the absence of any histopathological evidence of direct bony or vascular invasion (Figs 1 and 2). Septate and branching fungal hyphae were identified within the multi-
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Table 1. Comparison of parameters between the groups.
No. of patients Age Gender(m:f) h/o atopy Nasal obstruction Nasal polyps Nasal Discharge Post nasal Drip
Group 1 (AFS+ Granuloma)
group 2 (AFS)
9 15 to 32 05:04 6 9 9 8 7
48 12 to 57 16:32 9 48 48 43 44
P Value
0.205 0.003
Clinical features suggestive of aggressive/ invasive disease
and skull base erosion with that of the presence of fungal granuloma in the histopathology in retrospective analysis though it was not statistically significant (P = .092). However, when any form of extra sinus involvement including both intra orbital and intra cranial erosion was compared between both the groups, it was found that extra sinus involvement was present in all the cases in group 1 compared to 12 cases in group 2, and there was a significant difference between both the groups (P = .000). Interestingly, orbital and/or skull base erosion was notably more common in males than in females. Nasal obstruction was the most common clinical feature, being observed in all cases (100%), while nasal discharge (89.58% in AFS group and 88.88% in AFS with granuloma group) and postnasal drip (91.66% in AFS group and 77.77% in AFS with granuloma group) were next in the common findings. Of the extranasal and paranasal sinus symptoms, headache (60.41% in AFS group and 66.66% in AFS with Granuloma group) and telecanthus (33.33% in AFS group and 100% patients in AFS with Granuloma group) were the most common. However, proptosis (31.25% in AFS Group and 55.55% in AFS with Granuloma group) and facial pain (8.33% in AFS Group and 22.22% in AFS with Granuloma Group) were also observed. Presence of telecanthus and diplopia was higher in group 1 compared to group 2 with P values of .000 on comparison. (Table 1) The most common positive laboratory findings were raised eosinophil counts (58.33% in Group 2 and 66% in Group 1). Unilateral involvement of the nose and paranasal sinuses was seen in 59.57% of cases among the whole population comprising both the groups, while nasal polyps and history of atopy and allergic symptoms were present in all cases (100%). All patients were managed surgically using ESS.
6 2 5 9 5
29 4 15 16 4
9 9 9 8 4 9 6
48 39 48 11 9 12 28
0.000 0.092 0.000 0.640
9 9 9
48 48 0
0.000
6 8
27 29
0.561 0.101
0.161 0.000 0.000
Radiology Multiple sinus involvement Bony expansion Hyperdensiy Intraorbital (IO) Intracranial (IC) Extrasinus (IC or IO) Eosinophilia (AEC >500/μl)
0.157
Histology Allergic mucin Fungal hyphae Granuloma Microbiology Fugal smear (+) Culture (+)
All patients were given a short course of two weeks of tapering doses of oral steroids and nasal douching in the postoperative period. In the follow-up period many patients had evidences of polypoidal changes in the nasal cavities and required intermittent short courses of steroids. However, revision ESS was required in 9 out of 57 (15.78%) patients (8 out of 9 patients of group 1 and one out of 48 patients of group 2) who didn’t respond to oral steroids short courses and had frank nasal polyps in nasal endoscopy and multiple sinus involvement in radiology in spite of the routine post-operative therapy. Revision ESS was performed for these recurrent cases with post-operative adjuvant antifungal treatment with Itraconazole for 3 months. Table 1 show various values obtained in the results. All patients were prescribed with long-term topical steroids and alkaline nasal douches. The minimum available follow-up was for five months, with a mean follow-up
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Figure 4. Coronal view of another patient with bony erosion with evidence of granuloma in post op histopathology.
Headache Facial pain Proptosis Telecanthus Diplopia
Gupta et al.
of 10.2 months (5–36 months). All patients who underwent revision surgery with antifungal therapy didn’t show any further evidence of polypoidal changes not responding to steroids.
Discussion
dence supporting either of the hypotheses remains scanty. Clearly, bone erosion has also been described in association with long-standing expansile processes, such as sino nasal polyposis or mucoceles, not related to AFS. Allergic fungal rhino sinusitis usually follows a slow, nonaggressive course. However, the disease may result in massive bone destruction when the process extends outside the confines of the sinuses [22]. Recognition of this possibility is important, because bone erosion can be interpreted as an indication of invasive disease [23]. Orbital erosion was detected in 33.33% of cases in our study. This is comparable to the results of Liu et al. [24], who observed bony erosion in 38.09% of cases. In contrast, Ghegan et al. [25] reported bony skull base or orbital erosion in 56% of cases. Nussenbaum et al. [23] noted bony erosion in 20%, and Kinsella et al. [22] reported skull base erosion in 21.42% cases. Orbital erosion alone was detected in 29.78% of our patients; this result is similar to that of Liu et al. (28.57%) but higher than that of Kinsella et al. (21.42%) [22,24]. Skull base erosion alone was detected in 22.8% of our patients, whereas Liu et al. [24] observed intracranial extension in 38.09% of their patients. Orbital and intracranial involvement seen in clinical and radiological examinations are associated with advanced or long standing disease and these factors are probably associated with tissue invasion. Kinsella et al. [22] suggested that the presence of Bipolaris sp. might be related to cranial base erosion. They proposed a new diagnostic entity, ‘skull base allergic fungal sinusitis’, which incorporates the histological diagnostic criteria of allergic fungal sinusitis with the computed tomography (CT) criteria for bone erosion. The present study clearly shows an association between histological evidence of granulomas and bony erosion which is even statistically significant for orbital erosion. The clinical picture of severe disease like telecanthus, proptosis, and diplopia were more common in group 1 then the other group. An inadequate sampling of histopathological specimen may thus pose problems in proper categorization of cases. Hence, a detailed examination of all the fragments is mandatory to diagnose tissue invasion. Advanced cases with bony erosion may be missed as bony margins are not usually included in resection in endoscopic sinus surgery. Five possible distinct diagnostic categories are recognized based on histopathologic findings [26]. Three types of fungal rhino sinusitis are tissue invasive: acute necrotizing (fulminant), chronic invasive, and granulomatous invasive (indolent). Two types are categorized as noninvasive: fungal ball (sinus mycetoma) and AFS. Fungal sinusitis is considered a potentially progressive continuum, wherein noninvasive disease may convert to or coexist with an invasive form. Such a progression has been previously documented [27,28]. The invasive features noted by us in association
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AFS is possibly a nontissue-invasive disease, representing an allergic hypersensitivity response to the presence of extramucosal fungi within the sinus cavity. Earlier studies estimate the overall incidence of AFS to be 5% to 10% of all patients with CRS who undergo surgery [2,13,14]. In the diagnosis of AFS, the detection of fungi in allergic mucin is considered important, although hyphae are sparse in sinus content. Hence, there may be chances of occurrences of two closely related entities; eosinophilic fungal rhino sinusitis (EFRS) and eosinophilic mucin rhino sinusitis (EMRS) [15,16] as per the alternate hypothesis of Ponikau et al. [17], which proposes a different mechanism of AFS and may also be applied to encompass CRS. Specimens from 93% of patients with CRS showed presence of fungi while type I hypersensitivity was not found to be prevalent in the study group of Ponikau et al. [17]. They hypothesized that CRS is a cell-mediated response to fungal elements and brought into picture the new term, EFRS. The question still remains whether a separate unrecognized form of nonallergic, fungal eosinophilic inflammation exists that leads to a similar clinical presentation. Ferguson [15] claimed that eosinophilic mucin could be present and cause rhino sinusitis without the presence of fungi. The controversy regarding the definition of AFS as noninvasive form became stronger when reports of histologic invasion in possible cases of AFS [8,9] were published. Foci of granulomatous inflammation in patients of AFS with erosion of bone have also been reported [18,19]. In this study, an attempt has been made to identify granulomas in subepithelial tissues in cases of AFS, determinant of invasion. The noninvasive and invasive forms of fungal rhino sinusitis are not necessarily discrete and may coexist in the same patient. Foci of granulomatous inflammation were reported by Klapper et al. [18] in a patient of AFS with orbital apex involvement. Thakar et al. [9] recommended that fungal sinusitis be considered a potentially progressive continuum, wherein noninvasive disease may convert to or coexist with an invasive form. Despite bone destruction associated with AFS, fungal hypersensitivity is considered as prime factor. As reported in earlier studies, pressure atrophy from expansive growth of polyps or mucoceles may play a causative role in AFS related bone erosion [3,20– 22]. Many studies also implicate the inflammatory mediators produced in association with allergic mucin for being responsible for the bone erosion [3,5,20–22]. Direct evi-
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Conclusion In the present study, 16% of AFS cases were associated with histological evidence of fungal tissue invasion. These patients also had significantly increased incidences of clinical evidences of invasive disease like telecanthus, diplopia and proptosis and radiological evidences of extra sinus involvement and intra orbital extension of disease with orbital erosion. These patients had a high incidence of recurrence which eventually required revision surgery and post-operative adjuvant antifungal therapy with Itracona-
zole. Hence, the entity of AFS with coexistent granuloma as described here seems to represent the transition from the allergic and noninvasive form of fungal sinusitis, that is, AFS to the invasive forms in the spectrum of fungal sinus infestations. The coexistence of both kinds of pathologies in the same patients with features of AFS in the sinus nasal mucosa and presence of features of chronic granulomatous fungal sinusitis in the form of granuloma creates a diagnostic dilemma and further warrants the need to reframe the present existing classification of fungal sinusitis with the need of including such cases with evidences of different ends of the spectrum coexisting in the same patient. These findings implicate the role in the management decisions as the patients with features of granuloma need antifungal therapy and cautious use of steroids in the management contrasting the patients of AFS, where antifungals hardly have a role. Clinical involvement of the orbit or radiologic evidence of extrasinus disease should alert the surgeon regarding the possibility of coexisting invasive disease. Specimen should be examined carefully in advanced or longstanding cases. Further studies with larger number of cases and combined effort of otolaryngologists, pathologists and microbiologists would be required for deciding treatment protocol in these cases.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and the writing of the paper.
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with AFS are similar to the granulomatous variant of invasive fungal sinusitis. Question arises regarding the difference between the courses of treatment in patients of AFS with granuloma from cases of AFS. Kinsella et al. [22] recommended using endoscopic approaches to surgically treat AFS with related skull base erosion. Klapper et al. [18] managed two patients with AFS-related orbital involvement and concluded that aggressive surgery is not necessary. Surgical management of all patients in our series consisted of endoscopic removal of disease. Based on our experience, and also on the cited experience with chronic granulomatous sinusitis, it is probable that many such patients would do well with surgical debridement alone with no adjunctive antifungal therapy but the patients having AFS with coexistence histopathological features of granulomatous fungal sinusitis merit antifungal therapy like itraconazole or voriconazole along with debridement during the course of management suggesting that invasive features like granuloma and features of allergic fungal sinusitis without invasion can be nothing but different stages of the spectrum of the same disease entity. Nevertheless, it does seem prudent to use Itraconazole for all such cases but caution should be taken with steroids. In the present study eight of the nine patients in the AFS with granuloma group showed recurrence in the post-operative period that required revision endoscopic sinus surgery in the absence of antifungal therapy. But when these patients were put on Itraconazole 200 mg BD post revision surgeries for 3 months, they didn’t recur, and the cavity conditions became at par with that of the nonrecurrent patients. Same is the case for one patient of the AFS group, who did show the signs of recurrence and eventually responded to antifungal therapy. All these patients are under our regular follow-up till date. The significantly high recurrence rates observed in these patients with presence of granulomas in histology and requirement of antifungals to prevent recurrence of disease further strengthen the hypothesis that there may be coexisting invasive pathology, and these different forms of disease are part of a continuous spectrum rather than being different and distinct clinical entities.
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