Allergic mucin with and without fungus: a comparative clinicopathologic analysis.
Chronic invasive fungal sinusitis, also known as indolent fungal sinusitis, is often seen in diabetic patients, immunocompetent individuals, and in endemic areas such as The Sudan and Saudi Arabia. The histologic features are usually a collection of organisms with a surrounding granulomatous, foreign body inflammatory response and demonstrable hyphae invading tissue. The designation of invasion rests on both morphologic evidence of tissue invasion and radiographic demonstration of bony erosion. This form of sinusitis distinctly lacks evidence of vascular invasion by fungi, as seen with the acute fulminant type of infection.
The fungal ball (mycetoma) is an extramucosal collection of hyphae, usually in the maxillary antrum, which provokes little or no host response. It is seen in immunocompetent individuals who may have a prior history of sinus disease, trauma, or a foreign body.
Allergic fungal sinusitis affects immunocompetent individuals from the third to fifth decades of life. Allergic fungal sinusitis is usually noninvasive and follows a benign albeit uncomfortable course. Patients present with a history of chronic allergy, asthma, nasal polyps, and sinusitis, which is often refractory to medical therapy. Chest radiographs are often normal, but computed tomographic examinations of nasal sinuses reveal areas of high attenuation and increased density. Bony erosion is rare, but remodeling can occur. The disorder has a tendency to recur after surgical evacuation. Characteristic allergic mucin is seen in histologic specimens and serves as an indication to the surgeon and pathologist to be aware of and look for fungal organisms. Following surgical removal and diagnosis, low-dose corticosteroid therapy and, in some cases, immunotherapy have been used as long-term adjunctive treatments with varying success.
Saprophytic fungal infestation is the finding of fungal spores on mucous crusts of respiratory passages. The incidence is unknown, but investigators generally agree that it is best separated from asymptomatic individuals with positive fungal cultures, the incidence of which may be close to 100%. (2)
In 1983, Katzenstein et al (3) reported the histopathologic findings from nasal resections of 7 patients found to have tenacious eosinophilic/basophilic material within which there were scattered fungal hyphae. They thought this was a previously undescribed form of sinusitis that was histologically similar to mucoid impaction of the bronchus. Katzenstein et al proposed the term allergic aspergillus sinusitis because of the similarity to mucoid impaction of the bronchus, which in turn is commonly associated with acute bronchopulmonary aspergillosis. Acute bronchopulmonary aspergillos is now referred to as acute bronchopulmonary fungal disease. Prior to their report, Saferstein (4) described the case of a woman with acute bronchopulmonary aspergillosis and nasal obstruction, and Millar et al (5) reported 5 cases of sinusitis with histologic features of acute bronchopulmonary aspergillosis. In 1989, Robson et al (6) proposed the term allergic fungal sinusitis, because they identified dematiaceous fungi instead of Aspergillus species in their patient. Since then, there have been other reports describing various saprophytic fungal organisms in cultures from allergic mucin. However, there have also been reports describing allergic mucin without the presence of fungi. (7-12) These reports propose terms such as eosinophilic mucin rhinosinusitis, allergic mucin sinusitis without fungus, and allergic fungal sinusitis-like syndrome. The significance of allergic mucin devoid of fungus is currently unknown and there is a need for comparative clinicopathologic study of patients with allergic fungal sinusitis and an allergic fungal sinusitis-like syndrome.
MATERIALS AND METHODS
Cases with evidence of allergic mucin were accrued from surgical pathology specimens of patients who underwent nasal resection for chronic sinusitis at Saint Barnabas Medical Center, Livingston, NJ, between 1992 and 1998. Allergic mucin was confirmed by hematoxylin-eosin examination. Its microscopic characteristics are of a thick, green to gray, lamellated aggregate of dense inflammatory cells, mostly eosinophils and some neutrophils, in a background of tenacious-appearing gray mucus, serum, and Charcot crystals. Macroscopically, it is chalky gray or sometimes black and gumlike in consistency. These criteria were applied to diagnose allergic mucin.
A total of 25 cases were identified out of 400 nasal surgical resections reviewed. All tissue specimens were totally embedded, and the paraffin sections were reviewed with hematoxylin-eosin stain and further evaluated with Gomori methenamine-silver and periodic acid-Schiff to try and identify fungal organisms. Since this study was retrospective, there was no deliberate intraoperative effort to ensure that all tissue was obtained without suction or not put on absorbent gauze. The material submitted to the pathology department was processed similarly for all tissue specimens used in this study. All specimens were embedded totally for microscopic evaluation.
After histopathologic examination, which included complete microscopic examination with step sections and histochemical stains for fungus on all appropriate tissue submitted, patients were separated into 2 groups, one with identifiable fungi and the other without fungi. Each group was analyzed for amount of material available for examination, including number of. slides per case, number of slides with allergic mucin, extent of allergic mucin per slide (measured by ocular micrometry using a grid pattern of 1 [mm.sup.2] and examined at x2.5 magnification for quantitation), percent of involvement per slide (assessed by quantifying [mm.sup.2] of tissue on each slide relative to the [mm.sup.2] involved by allergic mucin, averaged for each case), and a visual estimation of abundance of fungal hyphae.
All patients' histories, including hospital charts and doctors' office records, were obtained for review. The patients' medical histories, preoperative impressions, intraoperative findings, radiographic studies, and follow-up reports were collated within each group, and the groups were compared. Criteria for exclusion were radiographic evidence of bone erosion and/or demonstration of hyphae invading tissue. Culture results were also documented when performed.
Of the 400 cases reviewed during the 6-year time frame, a total of 25 cases with allergic mucin were identified. This number represents an incidence of 6.25%. Of the 25 cases with allergic mucin, fungal organisms were identified in 10. Fifteen patients did not have fungal organisms in all sections reviewed. This finding was the basis for separation into the 2 groups.
Both groups were compared with respect to past medical history, including history of atopy, asthma, physical findings, prior therapy, and intraoperative findings. There was no difference between the 2 groups, with an equal distribution of a history of atopy in both. Both groups were composed of young to middle-aged, immunocompetent individuals. None of the patients had received prior antifungal or antibiotic therapy for their sinusitis. The average age for the group with fungus was 41 years (age range, 29-54 years) and for the group without fungus, 43 years (age range, 23-66 years). Gender distribution was equal for the group with fungus and showed a slight female predilection for the group without fungus. The clinical presentation in both groups included nasal obstruction and rhinorrhea, with durations ranging from several months to years. There were no clinical signs of invasive disease. Bilaterality was not a dominant finding in one group over the other. White blood cell differentials in both groups of patients were within normal limits. One patient from each group manifested peripheral eosinophilia (16% in a patient without fungus and 8% in a patient with fungus). Physical examinations in both groups of patients outside the head and neck were normal. The preoperative impression was chronic sinusitis or allergic fungal sinusitis equally in both groups.
Computed tomographic scans of the paranasal sinuses revealed identical findings in both groups (Tables 1 and 2). These findings included total opacification, pansinusitis, and polyp formation. All chest studies were normal. There was no clinical evidence of allergic bronchopulmonary fungal disease.
Both groups had similar intraoperative findings, including the identification of gray to black inspissated debris. This finding occasionally prompted the surgeon to send tissue for fungal culture and, in one instance, for frozen section. However, there was no greater frequency for culture request in one group over the other. Patients with fungi had more material submitted to pathology compared to the group without fungus; however, the procedure for obtaining specimens generally was the same in all cases.
Review of the macroscopic specimen descriptions from both groups revealed no distinguishing differences. Occasionally there was mention in the operative report of black or chalky gray material macroscopically, but this observation was not unique to one group or the other The average number of slides prepared per case was roughly equal for both groups. However, there were more slides that contained allergic mucin in the group with fungus (Figure 1) than in the group without fungus (Figure 2). The difference was 4.3 versus 3.1 slides on average per case. It was also apparent from the hematoxylin-eosinstained sections that the group with fungi had much more allergic mucin on each slide. The surface area of allergic mucin per slide was measured with an ocular micrometer, quantitated, and averaged for each case, then compared between the 2 groups. There was a significant difference between the amount of allergic mucin in both groups. The group with fungus had almost 10 times more allergic mucin in terms of surface area (measured in [mm.sup.2]) than the group without. Furthermore, allergic mucin covered 42.5% of the slide surface area on average in the group with fungus, compared to 25% for the group without (Tables 3 and 4).
Fungi, when present, were seen singly or in small aggregates (Figure 3). Often they were not intact, but fragmented. Usually they were present well within the tenacious allergic mucin. Charcot crystals were seen in both groups.
Allergic mucin in nasal tissue specimens from patients with chronic sinusitis serves as a clue for the otolaryngologist to suspect and the surgical pathologist to look for fungal organisms. Since its description by Saferstein (4) and the histopathologic association of allergic mucin with mucoid impaction of the bronchus and acute bronchopulmonary fungal disease, otolaryngologists and pathologists have come to accept allergic fungal sinusitis as an entity and acknowledge that different species of fungus are associated with this finding. (13-15) These organisms include different Aspergillus species, as well as many common dematiaceous fungi. The most accepted form of therapy is complete surgical exenteration of diseased tissues, followed by low-dose steroids either locally or systemically. (4) While this procedure may be curative in some cases, recurrence requiring repeat surgery is not uncommon. Immunotherapy has been used with some success in limited studies, and while immunotherapy may be the treatment of choice in the future, it is not currently standard practice. (16)
The subsequent identification of allergic mucin without fungus has elicited interest with respect to histogenesis and pathogenesis. Is the absence of fungus indicative of a separate entity, distinct from allergic fungal sinusitis? There is evidence, according to Ferguson, (7) that this is indeed the case. In that report, the author found significant clinical differences between the groups, most notably age, bilaterality, and allergy to aspirin, but no histopathologic difference. We found no such clinical differences, although our study group was smaller and limited to our own cases. We did not evaluate aspirin sensitivity. Furthermore, Ferguson (7) did not describe any histopathologic difference between the 2 groups. Ferguson proposed use of the term eosinophilic mucin rhinosinusitis when the mucin is devoid of identifiable fungus. It is descriptive of the morphology, but the term is noncommittal to the pathophysiology of the disorder, although Ferguson alluded to a form of systemic immunologic dysregulation. The study by Ponikau et al (2) is significant in that the investigators consistently demonstrated fungus in all of their patients with chronic rhinosinusitis, as well as in their control subjects. They proved that fungi can be identified in virtually all patients with chronic rhinosinusitis if meticulous, painstaking efforts are taken to procure samples. This finding then raises the question of what role the fungus plays in the disorder, since one could make the claim that fungal organisms are most likely present in the respiratory passages of all people. They also propose replacement of the term allergic with eosinophilic, although they do not address in detail eosinophilic mucin without fungus as a true entity.
It is plausible that some individuals react more intensely to the same allergens compared to others, eliciting a greater and more volatile response. Therefore, could we be seeing a 2-part response? The first part, common to both groups, an allergic response, elicits an eosinophilic reaction producing the eosinophilic mucin. The second, a response to the antigens of entrapped fungal organisms, promotes a self-amplifying inflammatory response. (17) This scenario could explain the abundance of eosinophilic mucin in one set of patients and scantiness of it in the other The likelihood of sampling is a legitimate thought; however, our study was a retrospective investigation and devoid of bias. No special attention was given to procuring as much sample as possible, and the procedure for obtaining specimens was the same for patients from both groups, since in most cases allergic fungal sinusitis was not a preoperative diagnosis in either group. The tenacity of the mucin may be an issue, allowing more watery mucin to escape into suction and necessitating manual removal of the more tenacious debris-containing fungus. Surgical resection was usually complete and the specimens were always completely embedded, so sampling error in the laboratory is unlikely. In essence, the findings of our study truly reflect the experience in a community practice setting, one without any particular skew.
The incidence of allergic mucin in our study is similar to that reported by others. (3, 11, 14) The fact that, for the most part, studies from different institutions describe similar types of patients in both groups with similar clinical presentations, radiographic findings, and responses to therapy, favors a single pathogenesis in different stages of development and/or with different degrees of response. While some authors have noted a significant difference in age between the 2 groups, (7) the age difference in our series was much less significant. This difference could be due to identification and treatment at a later stage of the disorder.
The immunologic mechanism behind allergic fungal sinusitis has been thought to be a combined type I and type III immune hypersensitivity response, mainly because of the similarity to mucoid impaction of the bronchus and acute bronchopulmonary fungal disease. (11, 15) Recent studies question this thinking, although the original mechanism is still assumed to be of an allergic nature. (2, 18) Type of response notwithstanding, the result elicits an inflammatory reaction with mucosal edema, a copious release of eosinophils, subsequent impaction, and stasis of the reactive material, leading to what pathologists have identified as allergic mucin. It would follow that if untreated, the process would continue to expand, attracting and entrapping more of the allergic mucin. In the process, this expansion could, and most likely does, entrap whatever may find its way through the nasal passages, promoting a self-amplifying inflammatory response. (17) Entrapped material could include saprophytic fungal organisms, such as the dematiaceous fungi, which are normally found in soil and plants. It is easy to surmise that such normally nonpathogenic, low-virulence organisms may accidentally gain access to respiratory passages and become entrapped in the tenacious and proliferating allergic mucin. Therefore, one must consider the possibility that the organism is merely a bystander and not the instigator of the process, which could explain why these organisms are often seen as broken and fragmented hyphae that are scattered sporadically in a vast and copious expanse of allergic mucin and why there does not seem to be a stark difference in response to therapy from patients in either group.
The findings of our study call attention to a striking similarity between both groups and support the findings of other studies. The fact that both groups have similar clinical and radiographic findings and that the group without fungus had significantly less allergic or eosinophilic mucin are otherwise undescribed observations that support the theory that this malady may represent the same disorder either at a different stage or with a different degree of response. The paucity and sporadic distribution of fungal organisms in our cases raise the question of whether the organism is truly of etiologic significance from the start, later as the process escalates, or merely a bystander incorporated into an expansive trap of tenacious and laminated allergic debris. The course of therapy is, as of now, similar for both groups mainly because of the noninvasive nature of the disorder. While the presence or absence of fungal hyphae in allergic mucin does not seem to affect therapy, immunotherapy notwithstanding, it is important for us to realize that we are most likely dealing with an immunologic rather than infectious disorder.(11) The identification of this histologically intriguing mucin is important information for the clinician to help monitor these patients and properly advise them with respect to adjuvant medical therapy, including low-dose steroid treatment, and to make them aware of the possibility of recurrence and need for follow-up. Understanding the nature of the disorder will lead physicians in the correct direction with respect to future therapeutic options.
In summary, we present a comparative clinicopathologic study of 25 patients with allergic/eosinophilic mucin separated into 2 groups, one with and the other without fungus. We found no significant clinical or radiographic differences between the 2 groups and no differences in the appearance of the allergic mucin. There was, however, a significant difference in the amount of allergic mucin between the 2 groups, a finding that to our knowledge has not been described in the literature to date. Because of the retrospective nature of the study, there was no specific effort to try and obtain all resected tissues from patients, which therefore led to similar methods of procurement in both groups. The amount of material obtained in both groups would reflect the type of specimen obtained in routine practice. In spite of not going through painstaking efforts to obtain as much tissue as possible, there was still an overwhelming amount of eosinophilic mucin in the group of patients with identifiable fungal organisms compared to the group without fungi. The fact that all clinical and radiographic findings were essentially the same in both groups leads us to believe that the presence of fungi may not be as important to the initiation of the disorder as once suspected. However, the identification of classic allergic or eosinophilic mucin may be the pathognomonic finding that dictates therapy. Furthermore, the amount of such mucin may be a hint as to whether fungi will be identified histologically and may provide perspective as to the stage and extent of the disorder. A controlled, prospective comparative study is necessary to validate the observations presented in this article. If our observations are correct, the amount of mucin identified at surgery may indicate patient susceptibility and possibly even predisposition to recurrence. Also, the mere presence of allergic/eosinophilic mucin alone may be the sole feature needed to initiate a specific treatment protocol for what is now called fungal sinusitis. In essence, the fungus may not necessarily be the initial cause of the disorder, but merely a later catalyst or an entrapped passenger/victim of an expansive process of proliferating tenacious and lamellated debris eliciting more production of allergic mucin. Following such thought, we agree that consideration should be given to changing the name of the entity from allergic fungal sinusitis to eosinophilic or allergic mucin sinusitis. The relation to mucoid impaction of the bronchus and acute bronchopulmonary fungal disease should also be reevaluated.
Table 1. Allergic Mucin With Fungus: Clinical and Radiographic Findings Case No. Age, y/Sex Clinical Impression 1 47/M Nasal obstruction, polyps, deviated septum 2 40/M Nasal obstruction, polyps 3 41/M Nasal obstruction, polyps, rhinorrhea 4 29/M Anosmia, pain, polyps 5 49/F Nasal obstruction, polyps, mucocele 6 36/F Nasal obstruction, polyps, rhinorrhea 7 29/F Nasal obstruction, polyps, rhinorrhea 8 32/M Nasal obstruction, polyps 9 53/F Nasal obstruction, polyps 10 54/F Polyps, mucocele Case No. Computed Tomographic Scan Results 1 Unavailable 2 Opacification, expansion of sinus walls 3 Sinus changes "consistent with fungal sinusitis" 4 Pansinusitis with opacification 5 Opacification of sinuses and fullness 6 Opacification of sinuses 7 Near total opacification of sinus 8 Pansinusitis, deviated septum 9 Polyps with obstruction and mucocele 10 Opacification with choanal polyp Table 2. Allergic Mucin Without Fungus: Clinical and Radiographic Findings Case No. Age, y/Sex Clinical Impression 1 46/F Nasal obstruction 2 63/F Nasal obstruction 3 47/F Anosmia, pain, rhinorrhea 4 32/F Nasal obstruction 5 35/M Rhinorrhea, pain 6 23/F Asthma exacerbation 7 47/M Nasal obstruction 8 44/F Nasal obstruction 9 41/F Nasal obstruction, rhinorrhea 10 56/M Nasal obstruction, polyps 11 66/F Nasal obstruction, rhinorrhea 12 29/F Nasal obstruction 13 40/M Nasal obstruction, headache 14 30/F Nasal obstruction, polyps 15 48/F Nasal obstruction, polyps Case No. Computed Tomographic Scan Results 1 Opacification of all sinuses 2 Pansinusitis with opacification 3 Occlusion of osteomeatal complex 4 Polyps and opacification 5 Opacification and air fluid levels in sinuses 6 Pansinusitis and polyps 7 Pansinusitis with obstruction and polyps 8 Opacification of all sinuses 9 Unavailable 10 Opacification and possible bone loss or erosion 11 Pansinusitis and opacification 12 Polyps 13 Near complete opacification 14 Pansinusitis, opacification 15 Unavailable Table 3. Allergic Mucin With Fungus: Pathologic Findings No. of With Area, mm % on Case No. Slides Mucin ([mm.sup.2]) Slide 1 10 9 23 x 22 (506) 75 2 12 7 15 x 10 (150) 50 3 5 3 10 x 0.4 (4) 25 4 4 4 4 x 3 (12) 25 5 2 2 17 x 5 (85) 50 6 3 2 19 x 18 (342) 50 7 3 3 10 x 10 (100) 25 8 6 5 20 x 15 (300) 50 9 5 4 12 x 5 (60) 25 10 4 4 2 x 2 (4) 50 Average 5.4 4.3 159.90 42.5 Table 4. Allergic Mucin Without Fungus: Pathologic Findings No. of With Area, mm % on Case No. Slides Mucin ([mm.sup.2]) Slide 1 2 2 8 x 4 (32) 25 2 2 2 0.2 x 0.1 (0.2) 25 3 3 1 7 x 5 (35) 25 4 2 1 1 x 0.9 (0.9) 25 5 2 2 7 x 3 (21) 25 6 1 1 0.95 x 0.92 (0.82) 25 7 8 2 6 x 4 (24) 25 8 2 1 10 x 4 (40) 25 9 4 3 3.4 x 3.1 (10.5) 25 10 4 1 15.4 x 0.9 (15) 25 11 8 7 9 x 5 (45) 25 12 14 2 1.98 x 1.44 (3) 25 13 3 3 4 x 3 (12) 25 14 19 11 0.95 x 0.63 (0.65) 25 15 8 8 0.36 x 0.15 (0.5) 25 Average 5.5 3.1 16.03 25.0
The authors gratefully acknowledge Tracy Murray for photographic assistance and Samantha M. Lara for assistance in the preparation of this study and manuscript.
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Accepted for publication June 28, 2001.
From the Department of Pathology, Saint Barnabas Medical Center, Livingston, NJ.
This work was presented in part at the Annual Meeting of the United States and Canadian Academy of Pathology, New Orleans, La, March 2000.
Reprints: Jonathan F. Lara, MD, Department of Pathology, Saint Barnabas Medical Center, 94 Old Short Hills Rd, Livingston, NJ 07039 (e-mail: firstname.lastname@example.org).
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|Author:||Lara, Jonathan F.; Gomez, J. Daniel|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Nov 1, 2001|
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