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\begin{document}

\title{DESTRUCTIVE NON-INVASIVE INFECTION IN ISOLATED FRONTAL SINUS
ASPERGILLOMA: REVEALING PREVALENCE AND PROPOSITION OF A NEW PATHOGENETIC
MODEL.}



\author[1]{Isabelle Dohin}%
\author[2]{Alessandro Vinciguerra}%
\author[3]{Professor Anshul Sama}%
\author[2]{Benjamin Verillaud}%
\author[2]{philippe herman}%
\affil[1]{Universita degli Studi di Brescia Dipartimento Specialita Medico-Chirurgiche Scienze Radiologiche e Sanita Pubblica}%
\affil[2]{AP-HP}%
\affil[3]{Nottingham University Hospitals NHS Trust}%


\vspace{-1em}



  
  \date{May 15, 2024}


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\selectlanguage{english}
\begin{abstract}
Objectives: The aim of this study is to report our cases of isolated
frontal sinus aspergilloma (FSA), and identify key features and aspects
suggestive of this pathology. Moreover, we have investigated the
pathogenesis of this FSA, which has not been clearly elucidated yet.
Materials and Methods: A retrospective study on cases of isolated FSA
treated at the unit of Otolaryngology of the Hopital Lariboisi\selectlanguage{ngerman}ère in
Paris from 2009 to 2023 was performed. A chart review was done,
Demographic and radiologic data, type of treatment with intraoperative
findings, and follow-up were analyzed. Moreover, a literature review was
carried out on Pubmed and Scopus using the search terms ``frontal sinus
aspergilloma'', ``frontal sinus fungus ball'' and ``frontal sinus
mycetoma''. Non-invasive FSA characteristics, especially the relation
with surrounding bony structures were analyzed. Results: Six patients
were included. The median age of the patients was 58 years old (range
25-69); 2/6 patients were female. The most common symptom was headache.
All the patients underwent exclusive endoscopic sinus surgery. With
regards to literature review, 17 papers have been identified reporting a
total number of 30 cases of FSA. Overall, frontal sinus walls erosion
was described in 47\% of the cases showing a prevalence of erosive
behavior of this pathology. Conclusions: FSA shows a higher incidence of
bone erosion compared to other PSA. The destructive behavior of FSA
could increase the risk of potential intracranial and intraorbital
complications. Recognizing the radiological features of FSA, is crucial
for accurate differential diagnosis with invasive forms of fungal
infections and treatment planning.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


DESTRUCTIVE NON-INVASIVE INFECTION IN ISOLATED FRONTAL SINUS
ASPERGILLOMA: REVEALING PREVALENCE AND PROPOSITION OF A NEW PATHOGENETIC
MODEL.

\textbf{Introduction}

Aspergillosis of the paranasal sinuses (PSA) is a well known entity,
which usually occurs in the maxillary sinus. Frontal sinus is rarely
involved, and usually represents the progression of a mycotic infection
within other sinuses. However, isolated involvement of frontal sinus
even though extremely rare, has been reported, but its pathogenesis
poorly understood {[}1{]}. Computed tomography (CT) and/or magnetic
resonance (MR) imaging are the gold standard in the diagnostic process.
Radiological aspect of frontal sinus aspergilloma (FSA) is similar to
other PSA, except for a high incidence of erosive non-invasive forms
{[}1{]}.

The aim of this study was to report our cases and identify key features
and aspects suggestive of FSA, to enable clinicians to appropriate
diagnosis; moreover, we have investigated the pathogenesis of this
entity which has not been clearly elucidated yet.



\textbf{Methods}

A retrospective study on cases of isolated FSA treated at the unit of
Otolaryngology of the Hopital Lariboisi\selectlanguage{ngerman}ère in Paris from 2009 to 2023
was performed following STROBE guidelines. A chart review was done,
Demographic and radiologic data, type of treatment with intraoperative
findings, and follow-up were analyzed. Moreover, a literature review was
carried out on Pubmed and Scopus using the search terms ``frontal sinus
aspergilloma'', ``frontal sinus fungus ball'' and ``frontal sinus
mycetoma''. All returned items were filtered for relevance and English
language. Relevant clinical information from the literature was
subsequently pulled and tabulated for review with further datasets from
our own case series (\emph{Tab 1-2} ). Geographic distribution of the
cases presented in the literature was reported and the Koppen climate
classification system was used to estimate environmental and climatic
conditions.



\textbf{Results}

Six patients were included. The median age of the patients was 58 years
old (range 25-69); 2/6 patients were female. Among all patients, only
one was immunocompromised due to heart transplantation. The right
frontal sinus was involved in 1/6 patients, one of them reported
bilateral infection. The most common symptom was headache; one patient
was referred to our center for persistence of FSA after two endoscopic
procedures performed in other centers.

All the patients underwent preoperative CT and/or MR imaging.
Non-invasive FSA characteristics, especially the relation with
surrounding bony structures were described (Tab 1). Six patients
underwent exclusive endoscopic sinus surgery with a complete removal of
the material, which was sent for pathologic and microbiologic evaluation
to confirm the presence of fungal hyphae and mycotic colonization in the
culture. A biopsy of the health mucosa of the frontal sinus was also
performed and excluded fungal invasion. In one case (patient n. 5) a
revision surgery was performed for a stenosis of the frontal sinusotomy
which occurred 11 months after the initial surgery (Tab 1). All of them
were followed with endoscopic control with a median of 71 months (range
13-240), no recurrences of FSA have been reported.

With regards to literature review, 17 papers have been identified
reporting a total number of 30 cases of FSA. We analyzed data on
geographic provenance of the patients, symptoms, radiological findings
focusing on the presence of bone damages, surgical treatment and
recurrences (Tab 2).

\emph{}

\textbf{Discussion}

The main finding of the present study is that, in contrast with other
PSA, FSA exhibits a distinctive prevalence of bony wall remodeling. In
particular, it is characterized by a higher incidence of bone erosion
(47\% according to our findings, versus 37.8\% in maxillary sinus
{[}2{]}, 13-52\% in sphenoid sinus {[}3{]} and incidence not established
for ethmoid sinus due to the rarity of the location), suggesting a
potentially higher number of complications in this subsite. Moreover, we
provide a new element to understand the pathogenesis focusing on
temperature variations within sinuses and the impact on spore's
proliferation, which could explain the rarity of frontal sinus
involvement in PSA. To our knowledge, this is one of the largest single
center case series reported and it's the first paper in which a new
hypothesis has been advanced to explain the peculiarity of this entity.

The pathogenesis of PSA poses a unique challenge, with Aspergillus
fumigatus being one of the most common isolated spores and common
component of daily respiratory exposure. Despite inhaling over 100 A.
fumigatus conidia/m³ daily, not all lead to PSA, indicating a
multifactorial origin involving host factors, environmental influences,
and fungal elements. The maxillary sinus is most frequently involved,
followed by sphenoid, while frontal aspergillomas occurrences are rare
{[}2{]}. Different hypotheses attempt to explain varied PSA distribution
within sinuses. Nicolai et al. linked maxillary sinus aspergilloma to
prior endodontic treatments, suggesting that dental sealers and an
anaerobic sinus habitat promote inflammation and fungal growth {[}2{]}.
Conversely, considering the other paranasal sinuses, the only hypothesis
advanced by other authors explaining the occurrence of aspergilloma is
the aerodynamics theory. The latter, especially for the frontal sinus,
conceive that the anatomical complexity and location of the sinus makes
it less accessible for the inhaled spores compared, for example with the
sphenoidal sinus {[}1{]}. However, the peculiar anatomy of the
spheno-ethmoidal recess alone do not explain the higher incidence of
aspergilloma within sphenoid sinus compared to the frontal sinus.
Indeed, attention has been put on the mucociliary drainage pathway,
which is likely to convey spores in remote areas of the sinuses,
justifying the presence of hyphae in these peculiar subsites. This
theory, together with investigations into A. fumigatus optimal growth
conditions have been enquired to justify the difference pattern of
incidence within paranasal sinuses, highlighting temperature and pH as
crucial factors {[}4{]}. It remains unclear whether these elements are
influenced by the climate conditions rather that patient's
microenvironment within paranasal sinuses. However, the ubiquity in the
geographic distribution of the reported cases suggests that paranasal
sinus microenvironment is more reliable in explaining the differences
and the rarity of non-maxillary PSA. In this context, the higher
incidence of sphenoid fungus balls may be due to its central head
position, surrounded by internal carotid arteries and cavernous sinuses,
maintaining a higher temperature. Conversely the frontal sinus shows as
main boundaries the outer surface and the brain, leading to lower
temperatures within the sinus and creating a less favorable environment
for spore proliferation, justifying its sporadic involvement.

Due to the rarity of frontal sinus involvement in PSA, we have
investigated whether this location was not only peculiar in terms of
prevalence and pathogenesis, but mostly in terms of behaviors. General
paranasal sinus aspergilloma is a non-invasive form of paranasal fungal
sinusitis, but cases showing a more aggressive behavior causing bone
erosion without histological evidence of tissue invasion have been
reported {[}5{]}. In these cases, erosion of the sinus walls refer to
the expansion and thinning of the bony wall of the sinus because of the
pressure caused by hyphal proliferation and necrosis. The general
incidence of erosive non-invasive forms of PSA range though 2.2-63\%,
with different incidences between the paranasal sinuses and the
possibility of different complications depending on the proximity of the
adjacent structures {[}2; 6; 7{]}. According to our findings, frontal
sinus walls erosion was described in 47\% of the cases. Only Gupta et
al. specifically commented on the occurrence of bony destruction of the
sinus walls, which involved exclusively the posterior plate and/or the
floor of the sinus {[}8{]}. The consequence and eventual complications
of bony destruction depends on the anatomical structures adjacent to the
sinus. Nevertheless, contrarily to sphenoid sinus aspergilloma, in which
the skull base erosion has been reported to have a clear link with the
occurrence of the intracranial and intraorbital complications, a clear
relation between frontal sinus wall destruction and the occurrence of
complications has not been established {[}3{]}. Uri et al. were the only
authors to compare patients with erosive FSA with patient with
non-erosive FSA, reporting a more violent clinical course for the first
{[}9{]}. Sporadic cases of intracranial or orbital complications such as
orbital cellulitis have been described, and the high incidence of the
destructive bone pattern can explain that proptosis secondary to orbital
erosion is the initial clinical manifestation in 37.5\% of the cases
{[}8; 10{]}. However, these findings were not confirmed in our cohort,
since none of our patients experienced intracranial or intraorbital
complications and the small number of cases in the literature did not
permit to compare the two groups.

When dealing with erosive FSA, differential diagnosis with invasive
forms of chronic fungal sinusitis is mandatory since the bone erosion
could be the manifestation of tissue invasion. On this purpose, biopsy
of the tissue is mandatory to exclude tissue invasion at the
histopathological examination {[}2{]}. Once diagnosis of FSA has been
advanced, surgery is the treatment regardless the presence of symptoms
to avoid potential complications, due to the high incidence of erosive
forms and the relations of the frontal sinus with orbit and the brain.

The main limitation of this study arises from its retrospective
character and the associated bias.

\textbf{Conclusions}

Frontal sinus aspergilloma shows a higher incidence of bone erosion
compared to other PSA. The destructive behavior of FSA could increase
the risk of potential intracranial and intraorbital complications.
Recognizing the radiological features of FSA, is crucial for accurate
differential diagnosis with invasive forms of fungal infections and
treatment planning.



\textbf{References:}

{[}1{]} S. Kodama, M. Moriyama, T. Okamoto, T. Hirano, and M. Suzuki,
Isolated frontal sinus aspergillosis treated by endoscopic modified
Lothrop procedure. Auris Nasus Larynx 36 (2009) 88-91.

{[}2{]} P. Nicolai, D. Lombardi, D. Tomenzoli, A.B. Villaret, M.
Piccioni, M. Mensi, and R. Maroldi, Fungus ball of the paranasal
sinuses: experience in 160 patients treated with endoscopic surgery.
Laryngoscope 119 (2009) 2275-9.

{[}3{]} J.C. Meier, G.A. Scangas, A.K. Remenschneider, P. Sadow, K.
Chambers, M. Dedmon, D.T. Lin, E.H. Holbrook, R. Metson, and S.T. Gray,
Skull base erosion and associated complications in sphenoid sinus fungal
balls. Allergy Rhinol (Providence) 7 (2016) 227-232.

{[}4{]} K.J. Kwon-Chung, and J.A. Sugui, Aspergillus fumigatus--what
makes the species a ubiquitous human fungal pathogen? PLoS Pathog 9
(2013) e1003743.

{[}5{]} J.M. Rowe-Jones, and V. Moore-Gillon, Destructive noninvasive
paranasal sinus aspergillosis: component of a spectrum of disease. J
Otolaryngol 23 (1994) 92-6.

{[}6{]} F. Pagella, E. Matti, F. De Bernardi, L. Semino, C. Cavanna, P.
Marone, C. Farina, and P. Castelnuovo, Paranasal sinus fungus ball:
diagnosis and management. Mycoses 50 (2007) 451-6.

{[}7{]} G.L. Fadda, G. Succo, P. Moretto, A. Veltri, P. Castelnuovo, M.
Bignami, and G. Cavallo, Endoscopic Endonasal Surgery for Sinus Fungus
Balls: Clinical, Radiological, Histopathological, and Microbiological
Analysis of 40 Cases and Review of the Literature. Iran J
Otorhinolaryngol 31 (2019) 35-44.

{[}8{]} R. Gupta, and A.K. Gupta, Isolated primary frontal sinus
aspergillosis: role of endonasal endoscopic approach. J Laryngol Otol
127 (2013) 274-8.

{[}9{]} N. Uri, R. Cohen-Kerem, I. Elmalah, I. Doweck, and E. Greenberg,
Classification of fungal sinusitis in immunocompetent patients.
Otolaryngol Head Neck Surg 129 (2003) 372-8.

{[}10{]} E. Bernardini, A. Karligkiotis, S. Fortunato, P. Castelnuovo,
and I. Dallan, Surgical and pathogenetic considerations of frontal sinus
fungus ball. Eur Arch Otorhinolaryngol 274 (2017) 2493-2497.

\textbf{Tables:}

\textbf{Hosted file}

\verb`image1.emf`  available at \url{https://authorea.com/users/764002/articles/741517-destructive-non-invasive-infection-in-isolated-frontal-sinus-aspergilloma-revealing-prevalence-and-proposition-of-a-new-pathogenetic-model}

\emph{M: male, F: female, CT: Computed Tomography, MRI: Magnetic
Resonance Imaging, FU: Follow UP, NA: non available data}

Table 1. Patients informations

\textbf{Hosted file}

\verb`image2.emf`  available at \url{https://authorea.com/users/764002/articles/741517-destructive-non-invasive-infection-in-isolated-frontal-sinus-aspergilloma-revealing-prevalence-and-proposition-of-a-new-pathogenetic-model}

\emph{RX: Radiography, FNAC: Fine Needle Aspiration Cytology, CT:
Computed Tomography, MRI: Magnetic Resonance Imaging, FU: Follow Up}

Table 2. Review of the literature

\selectlanguage{english}
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\end{document}

