Allergic fungal rhinosinusitis infiltrating anterior skull base and clivus.

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Allergic

fungal

rhinosinusitis

inﬁltrating

skull

base

and

clivus

Giuseppe

Meccariello

a

,

Alberto

Deganello

a

,

Giuditta

Mannelli

a

,

Giacomo

Bianco

a

,

Franco

Ammannati

b

,

Christos

Georgalas

c

,

Oreste

Gallo

a,

*

a

AcademicClinicofOtolaryngology-HeadandNeckSurgery,UniversityofFlorence,Italy

b

NeurosurgeryUnit,AziendaOspedialiero-UniversitariaCareggi,Florence,Italy

c

EndoscopicSkullBase,AmsterdamMedicalCenter,Amsterdam,TheNetherlands

1. Introduction

A bone-eroding mass in the nasal cavity and/or paranasal

sinuses should be always investigated in order to exclude a

malignancy.Itisimportanttonotehoweverthatachronic,

non-tissueinvasive,inﬂammatoryprocessofthenoseandparanasal

sinuses,thesocalledallergicfungalrhinosinusitis(AFRS),could

mimicneoplastic features.Itrepresentsanimmune

hypersensi-tivity to extramucosal fungal antigens, which leads to the

productionandaccumulationofallergicmucin.Thepresentation

ofAFRSisusuallysubtle,consistingofgraduallyincreasingnasal

obstruction, nasal crusting, viscous rhinorrea, and hyposmia.

Unlikebacterialrhinosinusitis,facialordentalpainandheadaches

are less common [1,2]. Conversely, multiple nasal polyps are

virtuallyidentiﬁedinallAFRSpatients,withunilateraldistribution

morecommon than bilateral[2–4].Theclassic and still widely

accepteddiagnosticcriteriaforAFRSweredescribedbyBentand

Kuhn[3],whoproposed thefollowing:type 1hypersensitivity;

nasalpolyposis;characteristic computed tomography (CT)scan

ﬁndings;eosinophilic mucuswithoutfungalinvasion intosinus

tissue;andapositivefungalstainofevacuatedsinuscontents.The

disease’scourseistypicallyindolentandnon-aggressive;however,

asallergicmucinaccumulateswithintheparanasalsinuses,itmay

form a mucocele and mimic an invasive process. In 6–56% of

patientswithAFRS,theexpandingmassleadstobonyerosionand

involvement of adjacent structures [5]. However, investigators

soonnotedthatinsomecases,theallergicmucinevacuatedfrom

the sinuses did not have identiﬁable fungal elements; these

patients were labeled as having an ‘‘AFRS-like syndrome’’ [6].

Additionally,Ferguson[4]proposedtheterm‘‘eosinophilicmucin

rhinosinusitis’’(EMRS)todescribecasesinwhichfunguswasnot

identiﬁed histologically. Moreover, she demonstrated that

al-thoughAFRSandEMRShadidenticalphysicalﬁndings,therewere

clinical differencessuchas acetylsalicylic acid(ASA) sensitivity

wasmorecommoninEMRScasesaswellasthesinusdiseasewas

exclusivelybilateralandasthmawaspresentinnearlyallEMRS

patients.

The primary management for both clinical entities was

representedbysurgery.Thegoalsofthesurgeryare:

1.toclearouttheedematousmucosa,

2.tocreatepatentsinusostialargeenoughtofacilitateadequate

drainageandventilation,

3.tomarsupializeinvolvedsinuses.

Althougheffectiveatremovinglarge portionsof thedisease,

surgeryisinsufﬁcientineradicatingtherelentlessinﬂammationof

AFRS.Intheabsenceofmedicaladjuvanttherapy,recurrencerates

AurisNasusLarynxxxx(2012)xxx–xxx

*Correspondingauthorat:AcademicClinicofOtolaryngology-HeadandNeck Surgery,UniversityofFlorence,viaLargoBrambilla,3-50134Firenze,Italy. Tel.:+390557947988;fax:+390557947939.

E-mailaddress:o.gallo@med.uniﬁ.it(O.Gallo). ARTICLE INFO Articlehistory: Received3February2012 Accepted29June2012 Availableonlinexxx Keywords: AFRS Boneerosion Skullbase Clivus Eosinophil Rhinosinusitis ABSTRACT

Boneerosionandskullbaseinvasionareoftensuggestiveofamalignantmassinparanasalandnasal cavities.Nevertheless,formsofchronicrhinosinusitis,suchasallergicfungalrhinosinusitis(AFRS),could mimicmalignantfeatures.Here,wereportAFRSpatientwithorbital,anteriorcranialfossa,Turkish saddleandclivuserosion.A48-year-oldCaucasianfemalewithhistoryofdrug-resistantheadache,nasal obstructionandanosmiawasreferredtoourinstitution.Imagingshowedhyperdensefeaturelesstissue withsignsofmedialorbitalwall,cribiformlaminaandclivuserosionsandencasementofrightinternal carotidartery.Massiveamountsofthickandgrayishmucoidmaterialwereevacuatedduringsurgery.In caseofbonyerosion,malignancyshouldalwaysbeexcluded.Oftenthecorrectdiagnosiswillbeobtained onlybyoperativespecimens. AFRScould usuallybe managed endoscopically. Appropriatemedical managementoftheAFRSshouldbeadministeredinordertopreventrelapses.

ß2012ElsevierIrelandLtd.Allrightsreserved.

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Pleasecitethisarticleinpressas:MeccarielloG,etal.Allergicfungalrhinosinusitisinﬁltratinganteriorskullbaseandclivus.Auris

NasusLarynx(2012),http://dx.doi.org/10.1016/j.anl.2012.06.005

ContentslistsavailableatSciVerseScienceDirect

Auris

Nasus

Larynx

j our na l ho me p a ge : w ww . e l se v i e r . com / l oc a te / a n l

0385-8146/$–seefrontmatterß2012ElsevierIrelandLtd.Allrightsreserved.

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ofupto100%havebeenreported[2,7].Here,wereportacaseofan

AFRSwithanteriorskullbaseandclivusinvolvementtreatedby

functionalendoscopicsinussurgery(FESS).

2. Casereport

A48-year-oldCaucasianfemalereferredtoourinstitutionwith

amonthhistoryofdrug-resistantheadache,nasalobstructionand

anosmia. Her past medical history was signiﬁcant for ASA

sensitivityandasthma.Sinonasalendoscopyrevealedmanylarge

polyps,occludingthenasalcavities,nomuco-purulentdischarge

norpostnasaldrippingaswellasnoneckmassesnorpathologic

lymphnodeswerefound.ThepatientunderwentaCTscanthat

showed hyperdense formless tissue involving all paranasal

sinuseswithsignsof medialorbitalwall erosion,reduction of

ethmoidalcellsthickness,massiveencasementofrightinternal

carotidarteryinsphenoidsinus,erosionofthecribiformlamina

and clivus (Fig. 1). A contrast-enhanced magnetic resonance

imaging(MRI)wasperformedinordertoclarifytheextensionof

the mass and to visualize any hypervascularization. This

heterogeneous mass did not appear to invade the dura, the

pituitarygland,thecarotidandbasilararteries;furthermore,a

peripheralcontrast-enhancementwasnoted(Fig.2).Thepatient

underwentanendoscopicdrainage,withtheneurosurgicalteam

onstandbyincaseanopenneurosurgicalapproachwasrequired.

As ﬁrst step biopsies of nasal polyps were obtained and

intraoperatively examined.Inﬂammatory tissue wasshown in

all specimens, therefore we performed wide openings of all

paranasal sinuses removing a dense and grayish mucin that

revealedanintactparanasalmucosa.Theintraoperative

exami-nationofthemucindemonstratedfeweosinophiliccellswithout

any fungal hyphae. This tenaceous material fulﬁlled each

paranasalsinusesinvolvingthemedialorbitalwallatbothsides;

after its complete removal in sphenoid sinus, a right internal

carotidandopticnervedehiscenceswerefound.Further,frontal

diseasewascleared.Theoperationwasfreeofcomplicationsand

openapproacheswerenot required.Thesubsequentpathology

report(Fig.3)indicatedthatnofungalelementswerevisualized

withinthe tissue; the mucinwas described as an amorphous

mucoid material with an extensive collection of eosinophils

and neutrophils, Charcot–Leyden crystals were not identiﬁed

and fungal staining and cultures were negative. Serum levels

of immunoglobulins showed low IgE (238mg/dL) and a IgG

deﬁciency (523mg/dL) especially for IgG1 (317mg/dL). The

patient was discharged with topic corticosteroid therapy and

saline irrigations. At the 3-month follow-up, the patient

had healed completely, the paranasal sinus ostia were well

opened with excellent functional results and no mucin was

present.Allofherrhinosinusitis-symptomshadresolved.

3. Discussion

InAFRS-sufferingpatients,multiplenasalpolypsareidentiﬁed

withunilateral distributionmore common than bilateral[2–4].

Further,in6–56%ofAFRSpatients,theexpandingmassleadsto

bonyerosionandinvolvementofadjacentstructures[5].Although

the erosion may beextensive, it is important tonote that the

diseaseprocessitselfdoesnotinvadetissues.Somepostulatethat

the expanding mucin exerts pressure on neighboring mucosal

bloodvessels,thuscompromisingbloodsupplytotheunderlying

bone.Ischemiaensues,weakeningbonystructures,whichbecome

increasinglysusceptibletomechanicalstressandnecrosis[8].The

locationofthedisease,aswellasthepathofleastresistance,will

determinewhereexpansionoccurs.Owingtoitsinnateweakness,

the lamina papyracea is the most common location for bony

destruction and the orbit is the most common location for

extrasinusdiseasespread.Whenallergicmucinextendsintothe

orbit,thepatientoftenpresentswithocularsignsrangingfrom

proptosistovisualﬁeldloss[5].Inadvancedpresentations,lesions

mayerodetheskullbase,leadingtointracranialpresenceofmucin.

Fig.1.CTscanshowshyperdenseformlesstissueinvolvingallparanasalsinuses,medialorbitalwallerosion,reductionofethmoidalcellsthickness,massiveencasementof rightinternalcarotidarteryinsphenoidsinus,erosionofthecribiformlaminaandclivus.

G.Meccarielloetal./AurisNasusLarynxxxx(2012)xxx–xxx 2

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Intracranialextensionmaybecomecomplicatedwithheadaches,

frontallobecompression,facialdeformity,orevenanintracranial

abscess [8]. Initial AFRS management planning includes

radio-graphicimaging.NoncontrastparanasalsinusCTisthepreferred

modality, which demonstrates irregular, hyperdense masses

involving multiple sinuses. The most commonly involved are

theethmoidsinus,followedbythemaxillary,frontal,andsphenoid

sinuses. The opaciﬁed sinuses often exhibit small areas of

heterogeneoushyperattenuation,whichappearasdotsorstreaks

in soft tissue windows. These areas of hyperattenuation are

believedtorepresentaccumulatedcalciumandheavymetalsalts

withintheallergicmucin.Itispossiblethatfungalelementsactas

anidusforprecipitationofthesalts.WhenCTfailstoconﬁrma

clinical picture of AFRS, MRI may be a useful alternative. MRI

revealsmasseswithdecreasedorvoidintensitiesonT1-and

T2-weighted images, respectively, with sinus mucosa appearing

enhanced[8].AlthoughCTandMRIﬁndingsarecharacteristicof

denseextramucosalmucin,theyarenotspeciﬁctoAFRSandcan

provideonlyapresumptivediagnosis.Foradeﬁnitivediagnosisof

AFRS, samples of mucin and mucosa must be obtained. It is

essentialthatspecimensbeacquiredsurgicallyandnotwithan

‘‘ofﬁceswab,’’whichwillgrowﬂoralfungifromvirtuallyanynose

[9]. Histopathologic preparations show mucus peppered with

Charcot–Leydencrystalsandeosinophilswithvariablenumbersof

fungal elements, which arebest visualized usingfungal stains.

Culturesofthemucinmostlygrowdermatiaceousfungisuchas

Alternaria, Bipolaris, and Curvularia species [3,6,9]. Under the

microscope, sinusmucosalsections demonstratenoevidenceof

necrosis,granulomatosis,orfungalinvasion[2,9].However,lacks

evidenceofafungalpresencehasbeenreported [4,6].Ferguson

conductedaretrospectiveandprospectivereviewof69suchcases

andcoinedtheideaofEMRS[4].ShefoundthatalthoughAFRSand

EMRS had identical physical ﬁndings, there were statistically

signiﬁcantclinical differencesin both groups. Themean ageof

AFRSpatientswasyounger(30.7years)thanthatofEMRSpatients

(48.0years).AsthmawaspresentinnearlyallEMRSpatients(93%)

andabouthalfofAFRSpatients(41%).ASAsensitivitywasmuch

morecommoninEMRScases(54%)thanAFRScases(14%).Sinus

diseasewasunilateralin55%ofAFRScasesbutexclusivelybilateral

in EMRS. Total IgE levels were consistently higher for AFRS

patients, and nasalpolyps werepresentin nearly allAFRS and

EMRSpatients.ThesedifferencessuggestthatAFRSislikelydriven

Fig.3.AmorphousmucoidmaterialwithanextensivecollectionofeosinophilsandneutrophilsinabsenceofCharcot–Leydencrystalsandfungi(hematoxylinandeosin staining;2.5and5).

Fig.2.MRIexcludedinvasionofthedura,thepituitaryglandandthecarotidandbasilararteriesbythedisomogeneousmass;furthermore,aperipheral contrast-enhancementwashighlighted.

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byalocalizedIgE-mediatedreactiontofungalantigens,whereas

EMRS occurs because of systemic immunologic deregulation.

TheideathatEMRSisasystemic entitycouldexplainthehigh

association with lower airway and bilateral paranasal sinus

pathology.NeverthelesswefeelthatdifferencesbetweenAFRS

andEMRSaretoofewtojustifythecodiﬁcationofanewclinical

entity.Ourpatientpresentedsomeclinicalfeaturesthatsatisﬁed

Ferguson’s criteria for EMRS [4]: the patient suffered asthma

with ASA intolerance, was older than 40 years of age and

sierologicanalysisdemonstratedlowlevelsofIgEwithlowlevels

of IgG subclasses, showed small areas of heterogeneous

hyperattenuation at MRI (Fig. 2). Nevertheless only the term

AFRShas beenused in recent reviewof chronicsinusitis,and

furthermorethepresenceofextrasinusdiseaseextensionshown

byourpatientisnot listedwithinFerguson’srequirementsfor

EMRS[10–13].Despitethelackofrandomizedcontrolledtrials,it

isacceptedthatthetreatmentofAFRSandmustincludesurgical

decompression of the sinuses, nasal saline irrigation, and

corticosteroidtherapy,eithersystemicorlocal.Thebestclinical

outcomesmightbe achievedin this way. Inour casesurgical

treatmentwithfunctionalendoscopicsurgeryfollowedbysaline

irrigationsandtopicadministrationofcorticosteroidsprovedto

beadequate.

Althougheffectivein removinglarge portionsofthedisease,

surgeryisinsufﬁcientineradicatingtherelentlessinﬂammationof

AFRS.Intheabsenceofmedicaladjuvanttherapy,recurrencerates

ofupto100%havebeenreported[2,7].Unfortunately,randomized

controlledtrials haveyettodetermineoptimaldoses,duration,

andtimingofcorticosteroidtherapyand whethereitheroralor

inhalantcorticosteroidshavedifferentoutcomes.In addition to

inﬂammation,atopy andantigen exposurehavebeentargetsof

adjuvanttherapy.Todecreaseantigenexposure,twooptionsare

available:irrigationandtopicalantifungals.Nasalsalineirrigation

isverysafeandknowntobeeffectiveinpromotingnasalciliary

clearancereducingintranasalinﬂammatorycytokines;thus,itis

recommendedaspartofAFRStreatmentregimen.SinceBentand

Kuhn [14] demonstrated that fungi, found in AFRS, can be

susceptible to antifungal agents in vitro, antifungal systemic

medications have also been administered in AFRS patients;

however,theirutilityremainsrathercontroversialinextramucosal

fungaldiseasessinceconvincingsupportivedataarestillmissing

[2,15].

Finally, despite AFRS could mimic a malignant tumor of

paranasal sinuses with extensive bony erosion encasing vital

structures,the endoscopicapproach allowsto achieve

reason-able functional results removing all pathologic material and

obtaining full aerated sinuses. It is crucial to exclude any

malignantorinvasivefungaldisease,thereforemucosalsamples

shouldbeintraoperativelyanalyzed.Althoughinthemajorityof

casesthesolelyendoscopicapproachisadequate,a

neurosurgi-calteamshouldbealertedsinceanintraoperativediagnosisof

malignancyorinvasivefungaldiseasecouldrequireaswitchto

a combined endoscopic/open surgical approach in order to

achieveclearresectionmarginsandasuitable reconstruction.

4. Conclusion

A bone erosing nasal/paranasal sinus mass should always

investigated to exclude a malignancy, although a chronic

inﬂammatoryprocesscouldbeassumed.However,thedeﬁnitive

diagnosisofAFRSrestsinintraoperativeanalysis,itisimportantto

recognizetheentityinaclinicalsetting.Patientspresentingwith

rhinosinusitis-likesymptomswhodemonstratepatchesof

hyper-attenuationinabackgroundofmucocelesonCTimagesshouldbe

primesuspectsforAFRS.Onceasuspiciousofchronic

inﬂamma-toryprocessstronglypresumed,theendoscopicsurgicaltreatment

todecompressnasalandparanasalcavitiesshouldbeperformed.

Inrarecases,anintracranialneurosurgicalteamapproachcouldbe

necessary to extirpate mucin and to reconstruct bone defects.

Althoughsurgery is veryeffective,withoutadjuvant treatment,

recurrenceisalmostguaranteed.Bothoralandinhalant

cortico-steroidshaveapivotalrolewhilstantifungaldrugsseemstohave

conﬂictingresults.Thereforefurtherinvestigationwith

random-izedcontroltrialswillbenecessary.

Conﬂictofinterest

Allauthorsdisclose any ﬁnancial andpersonal relationships

withotherpeopleororganizationsthatcouldinﬂuencetheown

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