Allergic Fungal Sinusitis Report of Three Cases Associated with Dematiaceous Fungi

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CLINICAL MICROBIOLOGY Original Article Report of Three Cases Associated with Dematiaceous Fungi GLEN C. FRIEDMAN, M.D., 1 R. WARREN J. HARTWICK, M.D., F.R.C.P.C., 1 JAE Y. RO, M.D., 1 GEORGE Y.

1 CLINICAL MICROBIOLOGY Original Article Report of Three Cases Associated with Dematiaceous Fungi GLEN C. FRIEDMAN, M.D., 1 R. WARREN J. HARTWICK, M.D., F.R.C.P.C., 1 JAE Y. RO, M.D., 1 GEORGE Y. SALEH, M.D., 1 JEFFREY J. TARRAND, M.D., 2 AND ALBERTO G. AY ALA, M.D. 1 Most reported cases of allergic sinusitis have been attributed to Aspergillus, based on the morphologic features of the organisms in tissue sections. However, in most cases, cultures have not been done. This is a report of three cases of non-aspergillus allergic fungal sinusitis. The patients' ages were 11,16, and 43; two were male and one was female. Histopathologic study disclosed fungal organisms resembling Aspergillus. However, cultures of these patients' nasal secretions grew Drechslera, Exserohilum, and Bipolaris fungal organisms. The non-aspergillus nature of these infections was further supported by positive Fontana-Masson melanin staining. The authors conclude that allergic fungal sinusitis most likely results from non- Aspergillus organisms. For definitive fungal identification, tissue culture is mandatory. When tissue is not cultured or no organisms grow, a Fontana-Masson stain can be a useful adjunct in fungal identification. (Key words: Aspergillus; Drechslera; Exserohilum; Bipolaris; Allergic sinusitis; Fontana-Masson stain) Am J Clin Pathol 1991;96: Fungal infections of the nasal cavity and paranasal sinuses may take four different clinicopathologic forms. 1 " 3 Two of these forms, chronic indolent infections and invasive fulminant infections, are tissue invasive, whereas the other two forms, mycetoma and allergic "Aspergillus" sinusitis, are saprophytic and noninvasive. Allergic Aspergillus sinusitis was described recently by Katzenstein and associates 4 " 6 and is characterized by mucus impaction of sinuses, bone destruction, and a history of asthma. Based on fungal hyphal morphologic characteristics in tissue sections and serologic findings, these authors attributed allergic fungal sinusitis (AFS) to Aspergillus However, of 30 reported cases, only 4 were proven by culture to result from Aspergillus. Furthermore, studies in which fungal cultures were used have documented several different fungi, including Aspergillus, 13,7 Curvularia, 8,9 and the dematiaceous fungi Drechslera, Bipolaris, and Exserohilum. 10 " 14 In this report we will describe the clinical, pathologic, and mycologic features of allergic fungal non-aspergillus From the Departments of 1 Pathology and laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. Received November 1, 1990; received revised manuscript and accepted for publication January 17, Address reprint requests to Dr. Ayala: Department of Pathology, Box 85, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas sinusitis in three patients and review the pertinent literature. Case 1 REPORT OF THREE CASES An 11-year-old boy had a six-month history of nasal obstruction and discharge, right periorbital swelling, and decreased vision in his right eye. During this period, antihistaminic decongestant and antibiotic treatment had been ineffective. The patient had a history of seasonal (winter) bronchial asthma, for which he took theophylline. Examination showedrightproptosis and palpable swelling in the region of the right medial canthus. Also, a mass was observed within the right nasal cavity, extending from the middle meatus. Laboratory investigations showed a normochromic, normocytic anemia with a normal total white blood cell count and normal eosinophil levels. Computed tomographic (CT) scan and magnetic resonance imaging showed a soft-tissue mass occupying the right nasal cavity, maxillary and ethmoid sinuses, and sphenoid sinus. There was evidence of erosion of surrounding bones. The patient underwent a right Caldwell-Luc operation on the nasalantral window plus a right external ethmoidectomy and sphenoidectomy and drainage of the sinuses. Exserohilum grew from culture of sinus tissue. Follow-up at eight months revealed CT evidence of persistent mucosal thickening in the ethmoid, sphenoid, and maxillary sinuses; however, there were no expansile masses in the sinonasal areas. Case 2 A 16-year-old girl presented with nasal discharge, obstruction of the left nasal cavity, and nasal polyposis. A nasal polypectomy plus a nasalantral window were performed. Culture of the sinus contents revealed Cladosporium organisms. Fourteen months later, the patient had recur- 368

2 FRIEDMAN ET AL. 369 rent nasal symptoms and underwent allergic desensitization. Fourteen months after that, she had recurrent symptoms again. CT scan revealed pansinusitis with involvement of the sella turcica. The patient underwent nasal polypectomy, septoplasty, and intranasal ethmoidal debridement. Culture of the sinus contents revealed Drechslera organisms. The patient then was referred to M. D. Anderson Cancer Center and underwent bilateral Caldwell-Luc procedures with drainage of the maxillary, ethmoid, and sphenoid sinuses. At surgery, the right planum sphenoidalis, anterior sella turcica, and clivus were noted to have been destroyed, although the dura was intact. The patient was discharged while being treated with ketoconazole. Follow-up studies at one year showed persistent radiologic opacification of the maxillary and ethmoid sinuses. Case 3 A 43-year-old man had a two-year history of increasing nasal obstruction and a one-month history of diplopia. He had no known allergies. Examination revealed a "fleshy" lesion of the right nasal cavity that extended through the septum into the left nasal cavity. CT scan revealed opacification of the ethmoid and anterior sphenoid sinuses and the nasal cavities, with erosion of the clivus. The patient underwent bilateral external ethmoidectomy, maxillectomy, sphenoidectomy, and frontal sinusotomy. Bipolaris species grew from culture of sinus tissue. MATERIALS AND METHODS Three recent cases at the surgical pathology division of M. D. Anderson Cancer Center were reviewed in our study. Clinical histories were retrieved from the medical record charts, and all formalin-fixed, paraffin-embedded, hematoxylin and eosin (H and E)-stained sections were examined for routine histologic evaluations. Representative sections also were stained with Gomori methenamine-silver (GMS) stain, Gram's stain, and Fontana- Masson stain. All three patients' paranasal sinus contents were submitted for fungal culture at the time of surgery. All three specimens were obtained aseptically, transported in sterile saline-moistened gauze, ground, emulsified, and cultured on mold-inhibitory agar and Sabouraud dextrose agar at 30 C. The molds grew after two weeks and were brown or black with a black, pigmented back surface. The fungi were identified with the use of the microslide culture technique. Finally, the clinical, pathologic, and mycologic findings were correlated with findings from the previously reported cases. Gross Pathology RESULTS The gross pathologic features were similar in the three cases. Specimens consisted of fragments of pink-tan mucosa and thick red-gray to green-brown mucoid material. Histology The histologic features were similar in all three cases. The fragments of mucosa were edematous and contained acute and chronic inflammatory cells. Adjacent to the mucosa, there was thick basophilic mucinous material containing large numbers of inflammatory cells and necrotic debris. The inflammatory cells predominantly were eosinophils and neutrophils, with lesser numbers of plasma cells, histiocytes, and lymphocytes. Basophilic laminations were seen within the necrotic material (Fig. 1). Scattered among the eosinophils were Charcot-Leyden crystals, which stained purple with Gram's stain. In all three cases, isolated fungal hyphae were scattered through the mucus in the GMS- and Fontana-Masson-stained sections (Fig. 2). Because the Fontana-Masson stain showed a clean background, it identified the fungal organisms better than did the GMS stain. Fungi were not aggregated into fungal balls. The fungal hyphae showed dichotomous branching and had moderately irregular contours, giving a geniculate or "toruloid" appearance. The hyphae measured 4-9 j^m in width and contained faint horizontal lines suggesting septation (Fig. 3). At the ends of occasional hyphae, round to oval conidia were identified. Hyphal morphologic characteristics in histologic sections could not differentiate these organisms reliably from comparable cases of aspergillosis. No fungi were seen in the mucosal tissue fragments. Fungal Cultures Material submitted from cases 1-3 grew fungi consistent with Exserohilum, Drechslera, and Bipolaris, respectively. These molds took three days to two weeks to grow. The Exserohilum species demonstrated fusoid conidia with a distinct protruding thickened truncate hilum. The Bipolaris species had more ellipsoidal conidia with less prominent truncate hila. Our Drechslera species isolated in 1983 could not be recovered for reidentification. Identification of Drechslera species was confirmed later by the Centers for Disease Control (CDC) as Drechslera spicifera; however, significant taxonomic changes have occurred since Conidia of Exserohilum, Bipolaris, and Drechslera species are all sympodial in arrangement. Conidia of Drechslera and Bipolaris are very similar morphologically. All species had brown to black colony color from the reverse surface. DISCUSSION In 1976, Safirstein 15 reported a case of allergic bronchopulmonary aspergillosis in association with nasal plugs and sinusitis. The sinus contents grew Aspergillus fumigatus on culture. However, the histologic features of the sinonasal contents were not described. In 1978, Young and associates 14 reported a case of chronic nasal obstruction and sinusitis with sinoorbital bone erosion in which Drechslera hawaiiensis was cultured. In 1983, Katzenstein and colleagues 4,5 described seven patients with nasal pol- Vol. 96 No. 3

3 370 CLINICAL MICROBIOLOGY Original Article» 1.1 / > *. «f- ' '.* 4 'it. AJ.C.P.-September 1991

FRIEDMAN ET AL. 371 FIG. t (upper). A. Basophilic laminations within the necrotic material. Hematoxylin and eosin (X40). B. Mucin contains necrotic debris and many inflammatory cells (predominantly eosinophils).

yps and sinusitis in whom Aspergillus was suspected to be a contributing factor.

4 FRIEDMAN ET AL. 371 FIG. t (upper). A. Basophilic laminations within the necrotic material. Hematoxylin and eosin (X40). B. Mucin contains necrotic debris and many inflammatory cells (predominantly eosinophils). Hematoxylin and eosin (X250). FIG. 2 (lower). Both GMS (A) and Fontana-Masson (B) stains demonstrate scattered fungal hyphae (X250). yps and sinusitis in whom Aspergillus was suspected to be a contributing factor. Fungal hyphae identified in histologic sections of sinus mucin and elevated level of serum total IgE or serum precipitins to A. fumigatus were cited as supporting evidence for their hypothesis. Since then, the allergic form of saprophytic fungal disease affecting the nasal sinuses and lower respiratory tract is referred to most often in the medical literature as allergic Aspergillus sinusitis. However, of 30 reported cases, 2-616,17 only 4 were proven by culture to result from Aspergillus. 1 " 3 The remaining 26 were attributed to Aspergillus on the basis of fungal morphologic characteristics in GMSstained tissue sections and elevated serum levels of IgE and precipitins to A. fumigatus. In recent years, the sinus contents were cultured from a small number of cases that fulfilled the clinical and pathologic criteria for allergic Aspergillus sinusitis. In most of these cases, fungal organisms other than Aspergillus were identified. To date, there are reports of two cases resulting from Bipolaris, 10,11 one from Exserohilum, 10 two from Drechslera, 12 " 14 and three from Curvularia. 8,9 The species of Drechslera, Bipolaris, and Exserohilum all are considered to be dematiaceous fungi. These "darkly pigmented" fungi are so-named because their colonies appear brown, dark green, or black with a black reverse. These organisms have septate hyphae that, in tissue sections, may mimic Aspergillus. In fact, in the above-mentioned non-aspergillus cases, the hyphae were described '% 1 ^ y }J : S FIG. 3. The fungal hyphae show dichotomous branching with occasional septae. Fontana-Masson (X400). V 0 as septate in all but one case. In one case, the hyphae were described as "resembling Mucor." Although positive staining with GMS highlights the presence of fungal organisms, it does not aid in distinguishing dematiaceous fungi from Aspergillus or Zygomycetes. A Fontana-Masson melanin stain, however, can help one distinguish dematiaceous fungi from other classes of septate fungi (except in the case of Aspergillus niger, a pigmented species of Aspergillus). 18 The pigment produced by dematiaceous fungi is similar to melanin and stains positively with the Fontana-Masson melanin stain. The three cases in our study stained with Fontana-Masson, as well as with GMS stain. Moreover, we noticed that the Fontana-Masson stain demonstrated the presence of fungal organisms more clearly than did the GMS stain. This finding resulted from clearer background staining with Fontana-Masson. Therefore, the Fontana-Masson stain is an alternative diagnostic method that may be used in cases of infection by hyphae-forming organisms morphologically suggestive of Aspergillus or Mucor. The morphologic similarity of dematiaceous fungi to each other makes speciation difficult. In fact, many previously reported Drechslera infections actually may have been Bipolaris or Exserohilum infections. 19 Recently, however, virtually all isolates that previously were called Drechslera, and which are associated with human disease, now have been reclassified as Bipolaris or Exserohilum. 20 Although these cases of allergic sinusitis result from several fungal species, including Aspergillus, the clinicopathologic features are very similar in all of the cases reported. To date, at least 44 cases of AFS, including the current cases, have been reported. 1 ' 3 " ,21,22 The patients included 24 women and 19 men; in one case, the patient's sex was not stated. Patient age at diagnosis ranged from 8 to 56 years (mean, 26 years; median, 21 years). Twenty-two (50%) of the patients had a history of allergies, rhinitis, or asthma. In most cases, multiple sinuses were involved, and the maxillary and ethmoid sinuses were affected most often. Clinical or radiographic evidence of sinoorbital bone erosion was seen in approximately onethird of all patients. All six pediatric patients reported by Manning and associates had facial deformity secondary to expansile sinusitis. 17 The characteristic pathologic features of AFS were demonstrated in all of the cases. The material evacuated from the sinuses was thick, inspissated, yellow-green mucus. Histologically, the most characteristic feature was "allergic mucin," described by Katzenstein and associ- Vol. 96 No. 3

5 372 CLINICAL MICROBIOLOGY Article ates. 4,5 The mucin is basophilic or slightly eosinophilic and has a laminated or layered appearance resulting from densely packed bands of inflammatory cells (predominantly eosinophils), sloughed respiratory epithelial cells, cell debris, and Charcot-Leyden crystals alternating with less cellular mucinous material (see Fig. 1). Charcot-Leyden crystals, formed from aggregated eosinophil granules, appear hexagonal in cross-section or rectangular or bipyramidal in longitudinal section. The crystals appear bright purple in gram-stained sections. Fungal hyphae also are present in the mucin but usually are not numerous. Dematiaceous fungi have a branched appearance similar to that of Aspergillus and are well visualized in GMS- and Fontana-Masson-stained sections. The variability in appearance and presence of unusual forms may result from degenerative changes. The three cases in our study showed features that were identical pathologically to those described in the literature, including tenacious mucinous material containing inflammatory cells (predominantly eosinophils), necrotic debris, and occasional scattered fungal hyphae. Surgical treatment of AFS consists of debridement of the fungus and mucus, restoration of mucociliary sinonasal drainage, and sinus ventilation. Adjuvant corticosteroids have been used in a few cases, although a clinical trial has not been conducted. Although antifungal agents have been used in a few reported cases, generally they are not considered necessary when fungus has not invaded the tissue. 123 The pathogenesis of AFS is not known, although a combination of type I (IgE) and type III (immune complex) hyperreactivity to fungal antigens has been proposed.' 23 A similar pathophysiology has been proposed for allergic bronchopulmonary aspergillosis. The lack of bronchopulmonary disease in the reported cases of AFS suggests that other factors may play a role in the pathogenesis of these two conditions. It is suspected that susceptible people become infected more often in warm, humid climates. In conclusion, the allergic noninvasive form of fungal disease in the paranasal sinuses is a distinct clinicopathologic entity caused by diverse fungal organisms. Recognition of the pathologic features is important in distinguishing it from other causes of sinonasal obstruction or radiographic opacification, including invasive fungal infection and neoplasia. Allergic fungal infection of the paranasal sinuses may be caused by several species of fungus. Therefore, we recommend culture as a more definitive means of fungal identification than the subjective evaluation of hyphae in tissue sections. Because Aspergillus is not the only organism to cause allergic sinusitis, we recommend that the entity be referred to as "allergic fungal sinusitis" rather than "allergic Aspergillus sinusitis." Acknowledgments. The authors thank Elsa Ramos for photographic assistance and Bobbie Coleman for typing the manuscript. REFERENCES 1. Goldstein MF, Atkins PC, Cogen FC, Kornstein MJ, Levine RS, Zweiman B. Allergic Aspergillus sinusitis. J Allergy Clin Immunol 1985;76: Hartwick RW, Batsakis JG. Sinus aspergillosis and allergic fungal sinusitis. Ann Otol Rhinol Laryngol (in press). 3. Philip G, Keen CE. Allergic fungal sinusitis. Histopathology 1989; 14: Katzenstein A-LA, Sale SR, Greenberger PA. Allergic Aspergillus sinusitis: a newly recognized form of sinusitis. J Allergy Clin Immunol 1983;72: Katzenstein A-LA, Sale SR, Greenberger PA. Pathologic findings in allergic Aspergillus sinusitis: a newly recognized form of sinusitis. Am J Surg Pathol 1983;7: Waxman JE, Spector JG, Sale SR, Katzenstein A-L. Allergic Aspergillus sinusitis: concepts in diagnosis and treatment of a new clinical entity. Laryngoscope 1987;97: Jonathan D, Lund V, Milroy C. Allergic Aspergillus sinusitis: an overlooked diagnosis? J Laryngol Otol 1989; 103: Brummund W, Kurup VP, Harris GJ, Duncavage JA, Arkins JA. Allergic sino-orbital mycosis: a clinical and immunologic study. JAMA 1986;256: Macmillan RH III, Cooper PH, Body BA, Mills AS. Allergic fungal sinusitis due to Curvularia lunata. Hum Pathol 1987; 18: Adam RD, Paquin ML, Petersen EA, et al. Phaeohyphomycosis caused by fungal genera Bipolaris and Exserohilum: a report of 9 cases and review of the literature. Medicine 1986;65: Robson JMB, Benn RAV, Hogan PG, Gatenby PA. Allergic fungal sinusitis presenting as a paranasal sinus tumour. Aust NZ J Med 1989;19: Rolston KVI, Hopfer RL, Larson DL. Infections caused by Drechslera species: case report and review of the literature. Rev Infect Dis 1985;7: Sobol SM, Love RG, Stutman HR, PysherTJ. Phaeohyphomycosis of the maxilloethmoid sinus caused by Drechslera spicifera: a new fungal pathogen. Laryngoscope 1984;94: Young CN, Swart JG, Ackermann D, Davidge-Pitts K. Nasal obstruction and bone erosion caused by Drechslera hawaiiensis. J Laryngol Otol 1978;92: Safirstein B. Allergic bronchopulmonary aspergillosis with obstruction of the upper respiratory tract. Chest 1976;70: Jackson IT, Schmitt E III, Carpenter HA. Allergic Aspergillus sinusitis. Plast Reconstr Surg 1987;79: Manning SC, Vuitch F, Weinberg AG, Brown OE. Allergic aspergillosis: a newly recognized form of sinusitis in the pediatric population. Laryngoscope 1989;99: Anaissie E, Bodey GP, Kantarjian H, et al. New spectrum of fungal infection in patients with cancer. Rev Infect Dis 1989; 11: McGinnis MR. Human pathogenic species of Exophiala, Phialophora and Wangiella in the black and white yeasts. Scientific publication, no Washington, D.C.: Pan American Health Organization, 1978: McGinnis MR, Rinaldi MG, Winn RE. Emerging agents of phaeohyphomycosis: pathogenic species of Bipolaris and Exserohilum. J Clin Microbiol 1986;24: Milroy CM, Blanshard JD, Lucas S, Michaels L. Aspergillosis of the nose and paranasal sinuses. J Clin Pathol 1989;42: Stammberger H, Jaske R, Beaufort F. Aspergillosis of the paranasal sinuses: X-ray diagnosis, histopathology, and clinical aspects. Ann Otol Rhinol Laryngol 1984;93: Walsh TJ, Dixon DM. Nosocomial aspergillosis: environmental microbiology, hospital epidemiology, diagnosis and treatment. Eur J Epidemiol 1989;5: A.J.C.P.

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