Negative Sinus Biopsy Does Not Rule-Out Orbital Invasive Fungal Sinusitis

Case Report:

Case 1:

An 85-year-old female with poorly controlled diabetes presented with two weeks of right-sided ocular pain, headache, right-sided proptosis, and unilateral hemianopsia. Nasal endoscopy was within normal limits. Laboratory studies were significant for blood glucose level of 304, Hemoglobin A1C of 9.6%, estimated sedimentation rate (ESR) of 45, and a white blood cell (WBC) count of 9.3. CT and MRI showed bony dehiscence at the right lateral sphenoid wall with sphenoid opacification and fat stranding into the orbital apex (Figure 1: A, B). Concern for invasive fungal sinusitis was present. Operative debridement of sinus mucosal tissue was performed; however, the orbital contents were not biopsied. Cultures, stains, and histopathology were all negative for fungal elements and the patient was discharged on antibiotics with a presumed diagnosis of chronic sinusitis.

Figure 1.

A,B: Axial and Coronal CT images of patient 1 at timepoint 1, showing focus of disease in the orbital apex. C,D: Axial and Coronal CT images of Patient 1 at re-presentation (timepoint 2), showing increased burden of disease at the orbital apex and sphenoid sinus. E,F: Axial and Coronal CT images of Patient 2, showing erosion of disease process through the Lamina papyracea.

Eight weeks later, the patient returned with worsening diplopia, retroorbital pain, headaches, right-sided proptosis, periorbital edema, ophthalmoplegia, and hemianopsia.

CT and MRI were repeated, showing enhancement and progression of right sphenoid sinus disease at the orbital apex (Figure 1: C, D). The patient was taken back to the OR for repeat debridement. However, this time, orbital apex contents were biopsied and cultured. The sinus tissue biopsy and cultures were again negative for fungal elements; however, orbital apex contents were positive for invasive aspergillus (Figure 2: A, B). The patient did well postoperatively and was discharged on isavuconazole. At 3-month follow-up, imaging showed signs of stable disease with persistent encasement of the right optic nerve at the orbital apex. The patient refused further surgical intervention. She was hospitalized at 6-month follow-up with urosepsis and persistent altered mental status. In line with her wishes, she was transitioned to hospice care and expired shortly thereafter.

Figure 2.

Tissue Specimens from Orbital Biopsies. A: Necrotic tissue with fungal hyphae (arrows), (H&E, 200x), Patient 1. B: Septate branching hyphae (arrow), (H&E, 400x), Patient 1. C: Necrotic fat with fungal hyphae (arrows), (H&E, 400x), Patient 2. D: Branching fungal hyphae (arrow), (GMS, 400x), Patient 2.

Case 2:

A 59-year-old male with history of uncontrolled diabetes mellitus presented with two weeks of rapidly progressive right-sided vision loss and pain, proptosis, ptosis, and ophthalmoplegia. Laboratory results were notable for hemoglobin A1C 15.9%, WBC 10.4, C-Reactive protein 0.7, ESR 25. Nasal endoscopy was within normal limits. CT and MRI revealed right orbital cellulitis, maxillary and ethmoid sinusitis with thinning of the superior right lamina papyracea (Figure 1: E, F). The patient was taken for operative debridement and orbitotomy. Sinus mucosal tissue was biopsied; cultures and histopathology were negative for fungal elements. The periorbital fat appeared dusky and mucopurulent. This was also biopsied, revealing fat necrosis and invasive mucormycosis. (Figure 2: C, D). Two weeks postoperatively, the patient underwent orbital exenteration. He survived and was discharged on isavuconazole. Imaging at 3-months postoperatively showed effacement of the right intraorbital fat, indeterminate for postsurgical changes versus persistent infectious process. The patient remains on chronic isavuconazole and was doing well as of 14-month follow-up.

Discussion

IFS is an aggressive infection of the sinonasal cavity, presenting most often in immunocompromised hosts or patients with poorly controlled diabetes.¹ Outcomes depend upon timely tissue diagnosis, initiation of empiric antifungal therapy, and endoscopic surgical debridement of involved tissues.^2–4 When involving the orbital structures, IFS can present with vision loss, proptosis, ophthalmoplegia, and may progress to critical structures beyond the orbital apex. Patients at risk for orbital involvement include those with sphenoid or posterior ethmoid sinus involvement, headache, fever, and elevated inflammatory markers.⁵ CT imaging often shows unilateral mucosal soft tissue thickening, with or without erosion of underlying bone, and possible extra-sinus extension of infection, while MRI may show enhancement or a lack thereof depending on tissue viability and progression of infection.^6,7 As illustrated by the two cases presented, IFS may involve the orbit while largely sparing the sinuses. Relying upon sinonasal biopsy alone in the setting of suspected orbital invasive fungal disease may lead to a missed diagnosis with potential for increased morbidity and mortality.

Treatment of orbital IFS is a matter of ongoing study. Universal principles of IFS management are relevant, including timely initiation of antifungal therapy, reduction of immunosuppression, and endoscopic sinonasal tissue debridement. Specific to the orbit, proposed treatment modalities include exenteration, conservative debridement of orbital structures, and retrobulbar amphotericin injection.⁸

Orbital exploration should be considered in patients with a prior negative sinus exploration yet high pretest probability of IFS.

Significance Statement:

Invasive Fungal Sinusitis (IFS) is a rare, aggressive infection of the sinonasal cavity with high associated morbidity and mortality. Diagnosis is determined by histopathology, most often from sinonasal tissue biopsy. However, sometimes sinus tissue biopsy may be insufficient for diagnosis, and may even lead to false-negative diagnosis, particularly when the orbit is involved. Orbital exploration should be considered in patients with a prior negative sinus exploration and high pretest probability of IFS.