Transformation of a maxillary paranasal sinus fungal ball into a mass-like form of invasive fungal sinusitis in the immunocompromised host

Abstract

Background

Paranasal sinus fungal balls are typically non-invasive and can be managed conservatively in the immunocompetent. In the immunocompromised, life-threatening invasive transformation is possible. The temporal relationship between onset of fungal balls and invasive transformation is poorly understood. We report a patient with lymphoma undergoing chemotherapy, with multiple surveillance scans demonstrating evolution from non-invasive to invasive fungal disease.

Results

A 67-year-old male with multiply relapsed angioimmunoblastic T-cell lymphoma received multiple regimens of systemic chemotherapy over 2 years. During the latest course of romidepsin-azacitidine, he developed right frontotemporal headaches, right V2 numbness, and vertical diplopia. Cross-sectional imaging revealed an erosive soft tissue mass along the right orbital floor and inferior rectus without necrosis, and contiguous hyperdense material within the right maxillary sinus, suggesting superimposed fungal colonisation. Our suspicions were of lymphoma progression, or a second primary neoplasm. Histopathology from intralesional biopsies revealed Aspergillus with tissue invasion without angioinvasion. Retrospective review of multiple surveillance scans performed up to 1 month prior demonstrated presence of a right maxillary sinus fungal ball. He was treated for invasive fungal sinusitis with voriconazole and debridement. He remains well on prophylactic oral voriconazole while on chemotherapy.

Conclusions

Our report describes the timeline of invasive transformation of a paranasal sinus fungal ball in an immunocompromised host. Further studies are needed to understand its chronology. Invasive disease can also appear mass-like without clinically apparent necrosis, mimicking neoplasms. Due to its high mortality, vigilance and surgical removal is strongly advised in patients with paranasal sinus fungal balls planned for immunosuppression, and even immunocompetent or diabetic patients.

Introduction

Fungal sinusitis can be classified into invasive or non-invasive disease. Invasive fungal sinusitis (IFS) is characterised by the presence of fungal hyphae within tissues. ¹ Paranasal sinus fungal balls (PSFB) are a non-invasive form of fungal sinusitis which typically occurs in the immunocompetent, with no clear risk factors, and can be managed conservatively if asymptomatic. ² However, there have been cases of invasive transformation from PSFB to IFS in patients who develop immunocompromise,^3,4 and attempts to characterise the nature of progression.^5,6

We describe in detail a case of an immunocompromised patient with known PSFB, which progressed to IFS, necessitating urgent surgical intervention.

Case report

Patient background

We present a 67-year-old male with multiply relapsed Angioimmunoblastic T-cell Lymphoma (AITL) diagnosed in May 2022. He had undergone chemotherapy regimens with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone), ICE (ifosfamide, carboplatin, etoposide) and romidepsin-ICE, and most recently romidepsin-azacitidine. His disease and treatment timeline are detailed in Figure 1.

Figure 1.

CT findings suggestive of PSFB have been stable since diagnosis of AITL, until 1 month prior to onset of headache. IFS symptoms are described in relation to the course of AITL and chemotherapy regimens.

Patient presentation

He presented in early October 2023 for 3-weeks duration of right frontotemporal headache with daily nausea and vomiting, and poor oral intake. He denied diplopia or neurological deficits. He had no significant symptoms of sinusitis. On examination, he had reduced sensation over the right V2 distribution, and diplopia on upward gaze. Nasoendoscopy revealed mucopus within the right middle meatus.

Investigations and diagnosis

Computed tomography (CT) and magnetic resonance imaging (MRI) scans (Figure 2) showed an erosive soft tissue mass along the right orbital floor, inseparable from the inferior rectus. There was absence of extensive necrosis of adjacent structures. Contiguous hyperdense material (on CT) with low T2W signal (on MRI) was seen within the right maxillary sinus, suggestive of superimposed fungal colonisation. Our initial suspicion was of progression of lymphoma or a second primary neoplasm.

Figure 2.

Preoperative (A) CT scan and (B, C) MRI scans showing maxillary opacification with a soft tissue erosive mass inseparable from the inferior rectus muscle. Biopsies were obtained with image-guidance from the right OF, LP, and EJ. Postoperative (D) MRI at 2 weeks with reduction in disease burden, and (E, F) Axial CT scan sections 14 months after surgery, demonstrating stable resolution of disease at ethmoids and maxillary sinuses respectively Abbreviations: OF, orbital floor; LP, lamina papyracea; EJ, ethmoid junction.

Treatment and follow-up

The patient underwent functional endoscopic sinus surgery where a maxillary antrostomy and anterior ethmoidectomy were performed. Intraoperatively, severe inflammation was noted around the anterior ethmoid and maxillary sinuses. A large maxillary fungal ball filled the entire maxillary sinus. It was removed entirely and mucosa over the orbital floor was stripped. A bony defect was noted over the orbital floor. However, there was no breach seen in the periorbita (Figure 3). Tissue biopsies, confirmed to be intralesional with image-guidance, were taken from the right anterior ethmoid junction, orbital floor, and lamina papyracea.

Figure 3.

(A) Endoscopic photograph taken 1 week postoperatively after initial debridement. (B) Endoscopic photograph of the orbital floor taken 5 months postoperatively.

Fungal culture of the maxillary sinus fungal ball returned positive with Aspergillus fumigatus. Fungal culture of the invasive lesion returned negative, and histology revealed fungi with acute-angle branching and septations seen on staining with GMS, suggestive of Aspergillus spp. There was severe ulceration and hyphae were seen invading mucosa, without angioinvasion. Tissue aerobic cultures, fungal microscopy, and acid-fast bacilli smear and cultures returned negative. Serum galactomannan was negative. Our diagnosis was of chronic IFS.

Retrospective review of Positron Emission Tomography-CT (PET-CT) imaging done for lymphoma surveillance showed previous stable maxillary sinus opacification with hyperdense material within, consistent with PSFB, without evidence of bony erosion. This was present at initial diagnosis of AITL, and stable up to 1 month prior to symptom onset (Figure 1).

The patient was treated with intravenous voriconazole and regular debridement. A repeat MRI 2 weeks postoperatively revealed an indeterminate residual small amount of soft tissue thickening in the right orbit (Figure 2). Clinic nasoendoscopy 5 months postoperatively showed a clean maxillary sinus with a healed right orbital floor (Figure 3), with no evidence of recurrence. His V2 numbness resolved, and has no residual symptoms of sinusitis. He continues to be well on oral voriconazole for secondary prophylaxis while receiving ongoing treatment for AITL with romidepsin and azacitidine. PET-CT imaging for surveillance of AITL also demonstrated sustained resolution of disease (Figure 2).

Discussion

PSFBs are a non-invasive fungal sinusitis, and have been known to transform into invasive disease in the immunocompromised host, classically described as the elderly, those with haematologic diseases or on chemotherapy.^3,5

Our case was notable for a number of reasons.

Firstly, our patient had a number of surveillance scans performed for lymphoma which clearly demonstrated presence of non-invasive PSFB. This strongly suggests it was initially a typical PSFB prior to its flare into IFS. In our case, a negative fungal culture from intralesional tissue is not surprising as only 23% – 50% of fungal cultures return positive. ³ We are drawing an assumption that the Aspergillus species seen on histology is the Aspergillus fumigatus from the maxillary PSFB that has invaded.

There is currently poor understanding of the time course from diagnosis of PSFB to the onset of invasive transformation when immunocompromised. Recent systematic reviews have attempted to evaluate the nature of progression of PSFB to IFS, but few cases report the time between non-invasive to invasive disease.^5,6 Most cases diagnose PSFB and IFS concurrently at presentation, with only Ota et al. describing a CT-diagnosed maxillary PSFB which transformed into IFS after 5 years, in an immunocompetent non-diabetic patient. This patient did not have regular surveillance scans, but only presented 5 years later when symptoms progressed. ⁷

Secondly, although most describe acute IFS as progressive over less than 4 weeks, ⁸ as in our case with supporting PET-CT findings, we cite several reasons for our diagnosis of chronic IFS. One; acute IFS is characterised by rapid necrotizing infection in patients with severe immunodeficiency. ⁹ The lack of extensive necrosis as well as prominent soft tissue component in our patient favoured an aggressive neoplasm rather than an infective/invasive disease. The pathognomonic ‘black turbinate sign’ is also absent in our case, a highly sensitive and specific finding in acute IFS in haematological malignancy. ¹⁰ Two; the mass-like appearance on CT is more suggestive of chronic IFS or malignancy. ¹¹ Three; chronic IFS is almost exclusively due to Aspergillus fumigatus, presumed to be the culprit pathogen in our patient. ⁸

Thirdly, there was radiological presence of mass-like extra-sinonasal infiltration. Such infiltrative extra-sinonasal processes are typically seen in non-fungal processes, such as inflammatory pseudotumour and skull base osteomyelitis. ¹² As such, we had initially entertained the differential of a second primary neoplasm or recurrence of lymphoma. The histological and microbiological testing however later proved this was indeed IFS.

Lastly, it is uncertain why invasive transformation only occurred during treatment with romidepsin and azacitidine, with the PSFB remaining stable on various other courses of chemotherapy. Further research is required in this area.

Though CIFS was likely secondary to the immunocompromise from chemotherapy in our patient, it is important to note that diabetes mellitus (DM) is one of the most common comorbidities in CIFS.^6,13 Additionally, diabetes control does not have to be poor. ⁹ This should be taken into account when counselling patients with PSFB and comorbid DM, which we more frequently encounter in clinical practice with rising incidence of DM. CIFS has also been reported to occur in immunocompetent patients with no comorbities, which raises the question if PSFBs should be routinely surgically removed. ⁷

It is crucial to maintain vigilance among patients with known PSFBs who are treated conservatively, especially those who have planned immunosuppression. This situation is particularly challenging because patients scheduled for immunosuppression typically also have a high anaesthetic risk. Therefore, it is essential to balance these two risks and discuss appropriate treatment options with the patient.

Conclusion

PSFB is known to transform into IFS in the immunosuppressed patient, however its chronology of transformation is not well described. Additionally, as suggested in this case, it can take on a mass-like form without significant clinically apparent necrosis, mimicking a neoplasm. Due to the high mortality of IFS, surgical removal of PSFBs should be strongly considered prior to planned immunosuppression. Elective removal of PSFBs should also be discussed with diabetic patients given its strong association with CIFS.