Chronic invasive fungal sinusitis: a report of two atypical cases. (Original Article).

Abstract

The purpose of this article is to describe a chronic variant of invasive fungal sinusitis (IFS) and discuss its management. This is a retrospective review of two cases of IFS that were characterized by atypical clinical courses. Patient 1 was a 75-year-old man with noninsulin-dependent diabetes mellitus who came to us with a 5-month history of headache. Computed tomography detected an opacified left sphenoid sinus. After the man failed to respond to medical therapy, he underwent a left endoscopic sphenoidotomy. Pathologic examination revealed that septate, branching fungal hyphae had invaded the soft tissues. The patient was started on oral itraconazole, but later switched to intravenous amphotericin B in response to intracranial extension. The man's disease stabilized, but he died a little more than 1 year later of unrelated causes. Patient 2 was an otherwise healthy 41-year-old woman who came to us with nasal congestion and unilateral nasal polyps. She underwent endoscopic sinus surgery. Pathologic examinat ion identified granulomatous sinusitis and septate, branching fungal hyphae that had invaded the soft tissue of the middle turbinate. The patient was not treated with systemic antifungal medications because of the localized nature of the fungal invasion and the lack of bone invasion or erosion. She has now been symptom-free for 5 years. These two cases demonstrate that IFS can appear in a chronic variant form that is characterized by an indolent course and histologic evidence of tissue invasion by fungal hyphae. The type of treatment is dependent on the extent of the disease on initial examination and the rapidity of its progression.

Introduction

DeShazo et al classified invasive fungal sinusitis (IFS) as one of three types: acute fulminant, chronic, and granulomatous. (1,2) The granulomatous type is believed to be a subcategory of chronic IFS.

Acute fulminant IFS. The acute fulminant form of IFS has been well described in the otolaryngology literature. It mainly occurs in immunocompromised patients, and it is characterized by a rapidly progressive course. The most common causative organisms belong to the families Mucoraceae and Aspergillus. Despite aggressive treatment, which includes wide-field surgical resection and intravenous antifungal medications, the prognosis is poor. (1,3) Mortality has been reported to be as high as 50 to 80% in some series. (4) The incidence of acute fulminant IFS has increased as a result of the widespread use of chemotherapy and corticosteroids. (1,3,5)

Chronic IFS. Chronic IFS is a poorly described entity. It usually appears in immunocompetent hosts, and it is characterized by an indolent clinical course. (3) Most cases have been reported in the Sudan, India, and Pakistan; a few rare cases have appeared in the southeastern United States. It is caused by Aspergillus and dematiaceous fungi. (6) Histopathologic evidence of soft-tissue invasion by fungal hyphae is required to make the diagnosis, which is often delayed. (1) The treatment of chronic IFS is controversial; reported strategies range from local surgical resection only to a combination of aggressive wide-field surgical resection and systemic antifungal medications. (1,3,5)

Granulomatous IFS. Granulomatous IFS differs from chronic IFS with respect to some of its histopathologic characteristics and its clinical course. Yet it is our opinion that these differences are not relevant with respect to choosing a therapy or determining the prognosis. Instead, we believe that treatment and prognosis should be based on the extent of the disease at the initial diagnosis and its subsequent clinical course.

In this article, we describe our management of two patients with long-standing IFS that did not meet the classic definition of either chronic or granulomatous IFS. We also review the clinical and histopathologic characteristics of chronic and granulomatous IFS and discuss their management.

Case reports

Patient 1. A 75-year-old black man came to us with a 5-month history of left-sided headache. His medical history was significant for blindness (glaucoma) and noninsulin-dependent diabetes mellitus. Findings on office endoscopic nasal examination were unremarkable. However, computed tomography (CT) detected a completely opacified left sphenoid sinus without erosion of the sinus walls (figure 1).

The patient was treated with an oral antibiotic and a steroid nasal spray, but he failed to respond. He then underwent a left endoscopic sphenoidotomy. Intraoperatively, the sphenoid sinus was noted to have had a thick, inflamed lining, and it was filled with fungal material (figure 2). The contents of the sinus were debrided, and a wide sphenoidotomy was performed.

On postoperative day 1, the integrity of the sinus walls was confirmed by CT. Histopathologic examination of the sinus contents identified chronic inflammation and noncaseating granulomas with multinucleated giant cells (figure 3). Septate, branching fungal hyphae had invaded the soft tissues but not the blood vessels. The results of a fungal culture of the tissue specimen were negative.

Upon discharge, the patient's headaches had resolved, and he was started on oral itraconazole at a dosage of 200 mg twice daily. However, 3 months later, the headaches returned. Follow-up CT and magnetic resonance imaging (MRI) both showed that the sphenoid opacification had recurred and that there was now evidence of erosion of the sphenoid sinus wall and extension of the disease process toward the middle cranial fossa (figure 4). The patient underwent a revision endoscopic sphenoidotomy with further debridement. During this second procedure, less fungal material was observed grossly in the sinus and on histopathologic evaluation. There was still no blood-vessel invasion. Fungal culture failed to grow any organisms.

The patient was first treated with 15 g of IV liposomal amphotericin B and then switched back to oral itraconazole at 200 mg twice daily. Follow-up CT and MRI showed no progression of the disease. However, the patient died 5 months later of unrelated causes. His family declined a request for an autopsy.

Patient 2. A 41-year-old woman came to us with a chief complaint of a right-sided nasal blockage of 18 months' duration. Other symptoms included intermittent purulent rhinorrhea and right cheek pain. The patient did not respond to medical treatment with an oral antibiotic and a steroid nasal spray. One year earlier, she had undergone a right intranasal polypectomy, which provided temporary relief of her symptoms. The pathology from that operation was unavailable for review. Her medical history was significant for allergic rhinitis.

Our office endoscopic nasal examination revealed the presence of middle meatal polyps and a bulging of the right lateral nasal wall in the region of the uncinate process. CT detected an extensive opacification of the right maxillary, ethmoid, and sphenoid sinuses and heterogenous soft-tissue density in the sinuses (figure 5).

The patient underwent an endoscopic right total ethmoidectomy, middle turbinectomy, middle meatal antrostomy, and sphenoidotomy. The ethmoid cavity was filled with polyps and thick mucopurulent material. The maxillary and sphenoid sinuses had a thickened mucosa and inspissated mucus.

Histopathologic examination of the ethmoid contents revealed the presence of chronic inflammatory cells--predominately lymphocytes and plasma cells--in a sclerotic stroma as well as a noncaseating granulomatous inflammation made up of scattered multinucleated giant cells and histiocytes (figure 6). Septate fungal hyphae, which were best visualized on Gomori methenamine silver staining, were present in the submucosal fibrous stroma and were within and surrounded by multinucleated giant cells (figure 6). Histologic examination of the maxillary and sphenoid contents did not detect any allergic mucin or fungal elements. Fungal culture of a tissue specimen did not grow any organisms.

The patient was diagnosed with chronic IFS, based on the indolent nature of the clinical course and the histopathology. She was not treated with any systemic antifungal medications because of the localized nature of the fungal involvement, the absence of bony erosion, and the lack of blood-vessel invasion on pathologic examination. The patient has now been symptom-free for 5 years and has shown no evidence of recurrent disease.

Discussion

The lack of diagnostic criteria for the different types of fungal sinusitis has contributed to the lack of consensus regarding its classification. Indeed, the same terms are often used to describe different syndromes. Invasive fungal sinusitis was lumped together with allergic fungal sinusitis as recently as the early 1980s. As mentioned, deShazo et al attempted to rectify the situation by classifying the different types of fungal sinusitis as acute fulminant, chronic, and granulomatous. (1,2) They also tried to alleviate some of the confusion by proposing new diagnostic criteria. Accordingly, the diagnosis of IFS is now based on histopathologic evidence of soft-tissue invasion by fungal organisms. IFS is unlike conditions such as allergic fungal sinusitis and fungus ball, in which there is no soft-tissue invasion.

The efforts of deShazo et al notwithstanding, both the classification of the various chronic invasive fungal sinonasal infections and their diagnostic criteria remain controversial. The principal reasons for the uncertainty are the infrequency of these infections, the long follow-up necessary to understand the natural course of the disease process, confusing terminology in the literature, and a lack of important clinicopathologic information in many reported cases. (7)

Diagnosis. Among the histopathologic criteria used to establish a diagnosis of chronic IFS is evidence of hyphal forms in the sinus mucosa, submucosa, blood vessels, or bone. Chronic IFS is characterized by a dense accumulation of hyphae that resembles a fungus ball, vascular invasion by fungal elements, and a scarcity of chronic inflammatory infiltrates. The most common organism is Aspergillus fumigatus. Like acute fulminant IFS, chronic IFS requires aggressive treatment and has a poor prognosis. Chronic IFS is frequently associated with orbital apex syndrome, diabetes mellitus, and corticosteroid treatment.

A diagnosis of granulomatous IFS requires a granulomatous response to the fungus and the presence of multi- nucleated giant cells. Histologic examination reveals (1) a profuse fungal growth with tissue invasion, (2) non-caseating granulomas with multinucleated giant cells, (3) plasma cells, and (4) fibrinoid necrosis. The most common organism is Aspergillus flavus. Treatment is mainly surgical, and oral antifungal therapy might prevent a relapse. Patients with granulomatous IFS are believed to have a better prognosis than do those with chronic IFS, although both conditions can lead to bone erosion of the sinus walls. (1) Granulomatous IFS is often associated with unilateral proptosis.

The two cases described in this article were characterized by an invasion of the sinonasal soft tissue by fungal hyphae and an indolent clinical course, but neither fit the classic description of either chronic or granulomatous IFS. The histopathologic findings in patient 1 were similar to those of granulomatous IFS, but his clinical course was more similar to that of chronic IFS--a slow but steady progression of disease, including extension into the middle cranial fossa. The clinical findings in patient 2, including her CT results, were suggestive of allergic fungal sinusitis, but both hematoxylin and eosin staining and Gomori methenamine silver staining demonstrated fungal hyphae in the sinus submucosal tissue and a granulomatous response directed against the fungal hyphae. Some of the giant cells even contained hyphal fragments intracellularly. Finally, the disease in patient 2 was very localized. Notably, neither case exhibited angioinvasion by fungi.

According to various reports in the literature, different species of Aspergillus are more common in some forms of fungal sinusitis than in others. (1) However, it has been our experience (and that of others) that fungal cultures often do not grow any organisms, even when the specimens have been taken intraoperatively under ideal conditions. (3,5) The hyphae seen in our two patients are most consistent with Aspergillus, but dematiaceous molds--including Bipolaris, Curvularia, and Alternaria spp.--have a similar appearance under light microscopy and cannot be ruled out.

Chronic and granulomatous IFS might be variants of the same disease process and not necessarily two separate clinical entities. The diagnosis of chronic invasive sinonasal fungal infection is based on the slow clinical course of the disease and the demonstration of soft-tissue invasion by fungal elements on microscopic examination. In our opinion, subclassifying such infections as chronic and granulomatous is not necessary for either choosing a therapy or determining the prognosis. Treatment and prognosis can be more accurately based on the extent of the disease and the general health of the patient.

Histopathologic differences between chronic and granulomatous IFS might be a function of the immune status of the host rather than the presence of different subtypes of the disease. Granuloma formation is a reflection of a competent immune system. Blood-vessel invasion indicates a more aggressive disease. Once soft-tissue invasion occurs, the type of infection (i.e., acute vs chronic) is determined by the patient's defense mechanisms. The chronic forms tend to occur more often in immunocompetent patients, while the acute fulminant form is more likely in immunocompromised patients.

Treatment. Most authors agree that acute fulminant IFS should be treated aggressively with wide-field surgical resection and IV antifungal therapy. On the other hand, there is no consensus as to the optimal treatment for chronic invasive fungal sinus infections. The morbidity inherent in surgery and/or systemic antifungal therapy must be weighed against the prognosis. DeShazo et al feel that some patients with chronic IFS have a disease process that mimics acute fulminant IFS, and therefore they should be treated similarly. (1) Others recommend limited surgical debridement, with repeat procedures if necessary, especially for patients who display features of granulomatous IFS. (5) The authors of most case series recommend the use of systemic antifungal therapy for patients with chronic IFS. The drug of choice is amphotericin B, usually at a total dose exceeding 2 g for adults. (5) In a series of seven patients with acute fulminant IFS, Weber and Lopez-Berestein found that liposomal amphotericin B was just as e ffective as and less toxic than standard amphotericin B. (4) Even so, the benefits of liposomal amphotericin B or oral antifungal medications in the treatment of chronic invasive fungal sinonasal infections are not well defined because the condition is so uncommon.

We advocate that treatment be tailored to the extent of the disease at the initial diagnosis and its clinical course thereafter. Although not previously studied, angioinvasion might be an independent variable that predicts a worse prognosis for patients with IFS. Patients with angioinvasion might benefit from a more aggressive therapeutic approach. Conversely, conservative surgery is appropriate for patients without angioinvasion, thus sparing them the morbidity of wide-field resection.

Neither of our patients experienced angioinvasion. Patient 1 was treated initially with endoscopic sphenoidotomy and debridement. Systemic antifungal therapy was added once the pathologic examination led to the diagnosis of IFS. The patient survived more than 1 year with the infection before he died of unrelated causes. Patient 2 was treated with endoscopic sinus surgery alone, including a middle turbinectomy. Systemic antifungal antibiotics were not prescribed because the disease was limited to the ethmoid sinus and there was no bone or blood-vessel invasion. She has been free of disease for more than 5 years.

References

(1.) deShazoRD, Chapin K, Swain RE. Fungal sinusitis. N Engl J Med 1997;337:254-9.

(2.) deShazo RD, O'Brien M, Chapin K, et al. A new classification and diagnostic criteria for invasive fungal sinusitis. Arch Otolaryngol Head Neck Surg 1997;123:1181-8.

(3.) Waitzman AA, Birt BD. Fungal sinusitis. J Otolaryngol 1994; 23:244-9.

(4.) Weber RS, Lopez-Berestein G. Treatment of invasive Aspergillus sinusitis with liposomal-amphotericin B. Laryngoscope 1987; 97:937-41.

(5.) Morpeth JF, Rupp NT, Dolen WK, et al, Fungal sinusitis: An update. Ann Allergy Asthma Immunol 1996;76:128-39.

(6.) Gungor A, Adusumilli V, Corey JP. Fungal sinusitis: Progression of disease in immunosuppression--a case report. EarNose Throat J 1998;77:207-10, 215.

(7.) Washburn RG, Kennedy DW, Begley MG, et al. Chronic fungal sinusitis in apparently normal hosts. Medicine (Baltimore) 1988; 67:231-47.

From the Department of Otolaryngology, Massachusetts Eye and Ear Infirmary (Dr. Busaba, Dr. Colden, and Dr. Salman), the Division of Otolaryngology, VA Healthcare System (Dr. Busaba), the Department of Otology and Laryngology, Harvard Medical School (Dr. Busaba and Dr. Salman), and the Department of Pathology, Massachusetts General Hospital, and Harvard Medical School (Dr. Faquin), Boston.

Reprint requests: Nicolas Busaba, MD, Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, 243 Charles St., Boston, MA 02114. Phone: [phone]; fax: [phone]; e-mail: [e-mail]