Chronic Invasive Fungal Sinusitis With Negative Histopathology: A Diagnostic Challenge

Introduction

Chronic invasive fungal sinusitis (CIFS) is a rare but potentially life-threatening disease that has demonstrated increasing prevalence over recent years. It can be distinguished from other forms of fungal rhinosinusitis based on a clinical course greater than 12 weeks and fungal invasion of mucosa with characteristic histopathological features. ¹ CIFS is generally found in immunosuppressed patients most often secondary to diabetes but has been reported in the context of AIDS, corticosteroid use, solid organ transplants, intranasal drug use, and renal failure.^1-5 Globally, rates of fungal rhinosinusitis in immunocompetent individuals are uptrending. ⁶

Diagnosis of CIFS is challenging. Symptoms are nonspecific and range from facial pain to vision loss. Computed tomography (CT) may show soft tissue opacification, air-fluid levels, mass lesions, or bony erosions and is often mistaken for a malignant process.^7,8 Involvement of a multidisciplinary team is important in detecting subtle radiographic signs of CIFS. ⁹ Furthermore, because of the insidious nature of CIFS, nasal endoscopy may not reveal the extent of disease. Other times, endoscopy may reveal areas of white lesions and pallorous mucosa, which can be confused with nasal necrosis due to intranasal drug abuse. ⁴ Although patients may demonstrate initial clinical improvement following antibiotic therapy, symptoms recur with increased severity following antibiotic treatment, prompting further workup and biopsy. ¹⁰ Definitive diagnosis of CIFS relies on surgical debridement of tissue and biopsy with identification of fungal forms on histology, which may necessitate repeat biopsies for adequate sampling. Still, often pathology samples and biopsies may be negative for fungal organisms due to the nature of the disease.^1,4

Treatment for CIFS consists of reversal of any underlying immunosuppression, surgical debridement, and systemic antifungal therapy. Although surgical treatment for CIFS has classically involved extensive resection of all infected tissue, a more conservative approach may be appropriate in conjunction with systemic antifungal therapy.^4,11 First-line antifungal agents include amphotericin B and voriconazole. However, as rates of invasive fungal disease rise, rare fungal agents with unique sensitivities have been reported.^12,13

Because of the lack of a definitive diagnostic test and pathology samples sometimes being devoid of fungal organisms, further options are needed to help diagnose these difficult cases. Here, we describe the case of a patient with tissue negative for fungal organisms on histopathology found to have CIFS identified through fungal DNA detection.

Case Report

The patient was a 46-year-old man with medical history significant for type 2 diabetes mellitus and Philadelphia-like B-cell acute lymphoblastic leukemia, who was enrolled in a clinical trial with the monoclonal antibody Inotuzumab at the time of admission. He was admitted to the study institution for neutropenic fever. The general otolaryngology team was initially consulted for epistaxis, at which time the patient required placement of right-sided nasal packing. Packing was removed 5 days later without complication. Later in this admission, the patient developed left-sided periorbital edema with a CT scan demonstrating minimal paranasal sinus mucosal edema. Nasal endoscopy showed no signs of acute bacterial or fungal infection. He improved on antibiotics and was discharged.

Two weeks later, the patient was readmitted for worsening left-sided periorbital edema. A repeat CT scan showed persistent maxillary and ethmoid mucosal edema with no significant changes from his prior scan. Nasal endoscopy again showed sensate mucosa without evidence of infection. The patient again improved with antibiotics and was discharged.

One week after discharge, the patient presented with worsening left-sided orbital and periorbital edema. Computed tomography was unchanged. However, given his persistent symptoms, he was brought to the operating room (OR) for evaluation. Endoscopy showed scattered areas of pale, necrotic tissue concerning for invasive fungal sinusitis, for which the patient underwent left-sided endoscopic sinus surgery with partial septectomy and middle turbinate resection (Figure 1). Intraoperative and final pathology stains were negative for fungal organisms. On hospital day 3, the patient returned to the OR for debridement. Additional tissue was again negative for fungal organisms with no evidence of granulomas or vasculitis. He was treated for presumed invasive fungal sinusitis with amphotericin B, meropenem, letermovir, and acyclovir and discharged on daily intravenous (IV) amphotericin B and meropenem. Because of the high clinical suspicion for fungal infection, tissue was sent to a separate institution for further evaluation. Polymerase chain reaction (PCR) analysis confirmed presence of Aspergillis fumigatus.

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Figure 1.

Intraoperative nasal endoscopy demonstrating tissue necrosis in the (A) ethmoid sinuses, (B) inferior turbinate, and (C) septum.

On outpatient follow-up 6 weeks after discharge, magnetic resonance imaging showed possible residual infection of the sinuses with no evidence of fungal disease in the orbits or brain. The patient was transitioned from IV antifungals to oral antifungals and has been maintained on prophylactic oral antifungals without recurrence of disease. Considering the indolent course of the patient’s disease and evidence of fungal forms on PCR assay, this was consistent with a diagnosis of CIFS.

Discussion

As the incidence of fungal rhinosinusitis rises, it is important to critically assess our current methods of diagnosis. This case demonstrates the pitfalls of histology-dependent diagnosis of CIFS. This patient’s presentation highlights the importance of considering the clinical picture and other methods of diagnosis in detecting difficult cases.

The presentation and onset of disease in this patient lasted greater than 3 months. This illustrates the indolent quality of the disease and helps to define it as a separate disease entity from acute invasvie fungal sinusitis (AIFS). In addition, while the pathology samples did not show fungal organisms, they also did not have evidence of thrombosis or mycotic aneurysms that are indicative of a fast-moving infection such as AIFS. ⁴ Finally, the PCR result of Aspergillus fumigatus is aligned with prior studies showing this to be a primary pathogen in CIFS. ⁴

Early nasal endoscopy and biopsy may prevent delays in diagnosis and treatment of CIFS, which can result in permanent neurological damage and even death. ¹¹ Repeat biopsies are recommended for patients who exhibit negative histology but have a persistent clinical course. However, as seen in our case, histopathologic analysis of tissue may not be sufficient for diagnosis. Histopathology has historically been a mainstay in diagnosis of fungal infection and is currently held as the gold standard in diagnosis of fungal rhinosinusitis. ¹⁴ Negative histopathology results are believed to arise secondary to lack of proper tissue sampling or sparse fungal forms in tissue, a phenomenon seen more often in chronic granulomatous invasive fungal rhinosinusitis. ¹⁵ CIFS typically demonstrates more numerous fungal forms detectable on hematoxylin and eosin stain. Our patient underwent a series of biopsies and extensive surgical debridement with multiple areas biopsied, all of which returned negative for fungal forms on histopathology with both acid-fast bacilli and Groscott’s methenamine silver stains. Thus, it is unlikely that the negative results on histopathology were due to inadequate sampling.

A previous study by Singh et al found PCR to be the most sensitive method in detecting fungal rhinosinusitis, followed by culture, then potassium hydroxide microscopy and histopathology. ¹⁶ Polymerase chain reaction may allow for earlier diagnosis of invasive fungal diseases as well as proper identification of fungal species.^17,18 However, the cost-effectiveness of PCR compared to traditional histology- and culture-based diagnosis is controversial.^19,20 Drawbacks of PCR-based fungal detection techniques include decreased availability relative to histopathology and culture, as well as decreased sensitivity for certain fungal species. ¹⁷ Although a false positive on PCR fungal assay is possible, our patient had a clinical course consistent with CIFS and demonstrated improvement with surgical debridement and empiric systemic antifungal therapy, further confirming the diagnosis. It is important to consider PCR as an important tool to complement histology and microbiology in the diagnostic workup of CIFS.

Conclusion

Our case highlights the importance of maintaining a high degree of clinical suspicion and pursuing complementary methods of diagnosing chronic invasive fungal rhinosinusitis in the appropriate clinical context. Although not available in all facilities, PCR fungal assay may be a more reliable method of detection than histopathology or culture in some cases.