Sinonasal fungus ball is the most common form of fungal rhinosinusitis that usually occurs in adults with a normal immune system [1-3]; the most commonly involved site is a solitary maxillary sinus [2]. Although the pathogenesis is still unclear, previous studies indicate the role of sex and age as sinonasal fungus ball is predominant in women and those of older age [2-4]. Patients with sinonasal fungus ball usually present with nasal obstruction, facial pain, postnasal drip and purulent rhinorrhea; however, they are sometimes asymptomatic [1,3]. Fungus ball may lead to obstruction of the natural ostium and can cause secondary chronic rhinosinusitis (CRS). The initial treatment of choice for CRS is medical therapy, whereas for the fungus ball, surgical intervention would be preferred [2]. Although it is difficult to differentiate CRS from fungus ball, especially if it is unilateral and without polyposis, it is important for determination of the optimal treatment. Previous studies have reported well verified maxillary sinus fungus ball (MFB) computed tomography (CT) features including intralesional hyperdensity (presence of calcified lesions), irregular surface of the material, complete opacification in sinus with or without expansion sinus and absence of air fluid level [1,5-7]. Among them, presence of intralesional hyperdensity is known to be a highly predictive radiological parameter for fungus ball. The diagnostic criteria based on CT findings have been clearly defined by deShazo et al. [5] and are highly specific (99%) [8]. Previous studies found that 50%–83% of fungus balls present with intralesional hyperdensity on CT imaging; hence, the sensitivity was found to be only about 62% [1,3,9,10]. A significant proportion of patients may not present with these lesions; in such patients, diagnosis is difficult. The purpose of this study was to evaluate the clinical characteristics of MFB and to increase the preoperative diagnostic accuracy based on these characteristics.

This study was approved by the Institutional Review Board of Seoul National University Bundang Hospital (IRB No. B-1903-528-103).

First, 728 patients who underwent unilateral ESS were reviewed. After exclusion; lesions primarily located in sinuses other than maxillary sinus (n=72), CRS combined with other pathologies (n=403), CMS presumably associated with odontogenic causes (n=6), 247 patients were analyzed finally (Fig. 2).

Fungus ball in paranasal sinuses, once considered to be a rare disease, is recently gaining clinical attention because of the dramatic increase in its incidence over the past two decades in Korea [4,13]. With regard to treatment, it should be surgically removed with adequate drainage of the involved sinuses. However, in cases of unilateral CRS from other causes, medical therapy could be initiated as a first-line treatment. Further, there is always possibility of the fungus ball progressing to an invasive form, which has a significant worse disease course even after optimal treatment [14]. Therefore, early diagnosis and proper treatment of sinonasal fungus ball is of utmost importance. However, a definitive diagnosis, which is the pathologic confirmation of the fungal hyphae or mycotic colonization [3], can only be made after surgery.

Among the current available diagnostic tools, CT is the optimum for detecting fungus ball preoperatively, and the most significant finding on the CT scan is the presence of intralesional hyperdensity [5]. According to previous studies, the prevalence of intralesional hyperdensity lesion on the CT scan was 50%– 83% [1,3,9,10]. In the current study, despite the high specificity (1.0), the sensitivity for intralesional hyperdensity in MFB was rather low (0.749), suggesting that with only intralesional hyperdensity, there is a considerable risk of false negative results. Therefore, this study aimed to find other clinical factors that may increase the overall diagnostic accuracy.

Presence of intralesional hyperdensity detected on a CT scan suggests the presence of metal metabolites from the fungal organism [15]. Aspergillus, which comprises most of the organism related to paranasal sinus fungus ball [16], stores metal ions such as zinc in the intracellular vacuole storage system to keep the homeostasis of the zinc ion which is known to be an essential nutrient for the organism [17]. However, in cases of zinc deprivation, down regulation of the genes related to the storage of zinc occurs [18] and under these conditions, zinc concentration in the vacuole decreases and therefore may be reflected by the absence of intralesional hyperdensity on the CT scan.

Our study demonstrated the importance of radiological features, apart from intralesional hyperdensity, in the diagnosis of MFB. Among other radiological features, fuzzy appearance and maxillary sinus full haziness with mass effect were associated with the presence of MFB. When performing a surgery for patients with MFB, fungus ball has a characteristic gritty, matted gross appearance to the surgeon, which corresponds to the fuzzy appearance on the CT scan. From the chronic disease process, bone erosion is possible as one study had shown that disease duration was longer in patients presenting with bone erosion compared to those without bone erosion [19]. Therefore, even in the absence of intralesional hyperdensity, one should clinically suspect MFB when such radiologic features are present.

Among demographic data, age was the only clue to a fungus ball. Endodontic treatment is known as one of the possible risk factors for development of a paranasal fungus ball. Zinc in the root canal fillings may stimulate fungal growth within the maxillary sinus [10]. Despite the lack of evidence, history of endodontic treatment among the older or decreased mucociliary function in the elderly are thought to be associated with fungus ball [3]. Interestingly, our decision tree demonstrated that young patients under age 33 years having fuzzy appearance without any intralesional hyperdensity favored MFB. One possible explanation is the genetic susceptibility in these patients. A recent study discovered an association of single nucleotide polymorphism (rs7203904 [C>G]) to sinonasal fungal ball. This SNP has been reported to be associated with epithelial E-cadherin expression [20]. Therefore pathogenesis of MFB in young age needs to be further evaluated.

In our study, there was no significant difference in multivariate analysis and regression tree model for female predominance. Therefore, radiological characteristics and age may have affected more than the gender difference. However, as was noticed in the previous studies [1,10,14], and from the univariate analysis, there seems to be a female predominance. The reason for gender predominance is still unclear.

It is known that fungus ball is also associated with the presence of marginally immunocompromised patients [2,14,21-23]. Despite the fact that comorbid DM was not significantly associated with the fungus ball in our study, other studies have reported DM as a frequent comorbid disease in patients with fungus ball [2]. Therefore, more studies should be analyzed.

Old age and other characteristic non-intralesional hyperdensity lesions had been already demonstrated to be associated with MFB in the previous studies [2,3,7]. However, as far as we know, no study had represented that these clinical features may increase the preoperative diagnostic accuracy. This study demonstrated a decision tree to determine the optimal algorithm in the diagnosis of sinonasal fungus ball from the preoperative clinical parameters. Although through multivariate logistic regression, significant clinical features associated with MFB were identified, it is difficult to develop a diagnostic algorithm from these features since we cannot estimate the optimal hierarchy of these clinical variables solely based on the calculated OR. However, through the regression tree analysis, it became clearer. As independent variables were added through models 1 to 3, tentative age criteria became precise, and the overall diagnostic accuracy became higher.

Presence of mucosal thickening was more commonly associated with CMS; however, this was not selected as a feature in the regression tree analysis. This is a mixture of heterogenous radiological characteristics, such as mucosal thickening, air-fluid level, and therefore more detailed categorization of such radiological features may increase the overall accuracy.

There are several limitations in this study. Previous study reported unilateral CRS being the most common etiology in unilateral sinus disease [24]; however, in our series, MFB was more common than CMS. In our study, we have excluded patients having a periapical lucency or bony dehiscence as these patients were regarded to have CMS due to odontogenic causes. However, not all CMS with periapical lucency or bony dehiscence are caused by odontogenic factors. Also, patients with remaining disease despite medical therapy tend to have ESS which may explain the higher incidence of MFB (which is resistant to medical therapy). Therefore, this study entails a selection bias that subjects who are less likely to enter the study may have been under-represented. However, at the same time, inclusion of all these patients may increase an overall type I error. In addition, some studies demonstrated a correlation between odontogenic factors and MFB [25,26]. However, these factors had not been evaluated in current study. This is a single center study with a relatively small number of patients that geographical and ethnic factors may have affected. Therefore, further studies are required on a larger scale and additional radiological parameters in the future.

Intralesional hyperdensity in the maxillary sinus suggested a fungus ball in patients with unilateral maxillary sinusitis. However, in the absence of intralesional hyperdensity, old age and other radiological features such as presence of lobulated protruding lesion may also suggest a fungus ball. Physicians should be aware of such findings in the management of patients presenting with unilateral maxillary sinusitis.