An Emergent Entity: Indolent Mucormycosis ofthe Paranasal Sinuses. A Multicenter StudyErika Celis-Aguilar1 Alan Burgos-Páez1 Nadia Villanueva-Ramos1 José Solórzano-Barrón1
Alma De La Mora-Fernández1 Juan Manjarrez-Velázquez2 Sergio Verdiales-Lugo1
Lucero Escobar-Aispuro1 Perla Becerril3 Ana Valdez-Flores4 Francisco Javier Merino-Ramírez4
Carmen Beatriz Caballero-Rodríguez4
1Department of Otolaryngology, Centro de Investigación y Docenciaen Ciencias de la Salud (CIDOCS) de la Universidad Autónoma deSinaloa, Culiacán, Sinaloa, México
2Department of Otolaryngology, Culiacan General Hospital, Culiacán,Sinaloa, México
3Department of Otolaryngology, General Hospital Regional No. 1“Ignacio García Téllez” del IMSS, Mérida, Yucatán, México
4Department of Pathology, Centro de Investigación y Docencia enCiencias de la Salud (CIDOCS), Universidad Autónoma de Sinaloa,Culiacán, Sinaloa, México
Int Arch Otorhinolaryngol 2019;23:92–100.
Address for correspondence Erika Celis-Aguilar, MD, Blvd. Alfonso G.Calderón No.2193 Poniente, Cons. 603. Desarrollo Urbano Tres Ríos.Zip code 80050. Culiacán, Sinaloa, México(e-mail: [email protected]).
Keywords
► mucormycosis► mucorales► paranasal sinuses► sinusitis► mycoses► chronic
mucormycosis
Abstract Introduction Indolent or chronic mucormycosis is a rare entity that affects bothimmunosuppressed and immunocompetent individuals. Additionally, its clinical evolu-tion is nonspecific and there is no standardized treatment for this condition.Objective To describe the clinical characteristics and management of patients withindolent mucormycosis.Methods In the project of study with chart review in the Interinstitutional secondarycare centers, patients with evidence of indolent mucormycosis, defined as pathologicalconfirmation of nasal/paranasal sinus mucormycosis for more than 1 month, wereincluded. All patients underwent complete laboratory workup, imaging studies,surgical treatment and adequate follow-up. No evidence of disease status was definedwhen patient had subsequent biopsies with no evidence of mucormycosis.Results We included seven patients, three female and four male subjects. The mean agewas 53.14 years. Four patients were immunosuppressed and three immunocompetent.Among the immunosuppressed patients three had diabetes and one had dermatomyositis.The symptomswere nonspecific: facial pain/headache,mucoid discharge and cacosmiawerethe ones most frequently reported. Maxillary sinus involvement was present in all patients.Two immunosuppressed subjects received amphotericin. Posaconazole was the only treat-ment inone immunosuppressedpatient.All immunocompetentpatientshadsingleparanasalsinus disease and received only surgical treatment. All patients are alive and free of disease.Conclusion Indolent mucormycosis is a new and emerging clinical entity in immu-nosuppressed and immunocompetent patients. Single paranasal sinus disease is afrequent presentation and should not be overlooked as a differential diagnosis in thesepatients. Immunocompetent patients should only be treated surgically.
receivedOctober 29, 2017acceptedMay 23, 2018published onlineOctober 24, 2018
DOI https://doi.org/10.1055/s-0038-1667005.ISSN 1809-9777.
Copyright © 2019 by Thieme RevinterPublicações Ltda, Rio de Janeiro, Brazil
Original ResearchTHIEME
92
Introduction
Mucormycosis is commonly a fatal infection caused by fungi ofthe order Mucorales, with Rhizopus being the most commonspecies associatedwith this disease.1Other isolated species areAbsidia, Mucor and Rhizomucor.2,3 Histologically, it presentswith hyphae that are broad-based and non septatedwith rightangles.4,5 Since this is predominantly a fulminant disease, it ispotentially lethal.5 Patients are usually immunosuppressedindividuals, and the clinical hallmark has been vascular inva-sion with tissue necrosis.6 Nonetheless, new cases of indolentmucormycosis are being reported, occurring among immuno-suppressed4,7–9andimmunocompetentpatients.10–15Theclin-ical characteristics are distinguished by its chronic evolution,14
nonspecific symptoms and in some cases absence of frankvascular invasion and necrosis.5 Additionally, single paranasalsinus disease is also a frequent presentation.11 We currentlyaddress this new form of disease with recent evidence. Theobjective of this study is to describe the clinical characteristicsand management of patients with indolent mucormycosis.
Methods
PatientsThe patients were recruited from November 2012 to Novem-ber 2016. This study was a multicenter clinical chart reviewconducted in secondary care centers. Indolent mucormycosiswas defined as pathological evidence of nasal/paranasal sinusmucormycosis for longer than 1 month. The inclusion criteriawere patients with indolent mucormycosis who had patholo-gical confirmation, complete imaging studies and underwentsurgical/medical treatment with adequate follow-up.
This is an interinstitutional study approved by the ethicalcommittees of the hospitals involved and led by Centro deInvestigación y Docencia en Ciencias de la Salud (CIDOCS) dela Universidad Autónoma de Sinaloa, Sinaloa, Mexico. Asigned informed consent was obtained from all patients.
Evaluation and Surgical TechniqueAll patients were evaluated by the otolaryngology and theinfectiology departments. All patients underwent imaging,laboratoryworkup and surgical treatment. The patientswereoperated on by certified interinstitutional otolaryngologists.
The surgical procedures consisted in external maxillaryapproach (modified Caldwell-Luc procedure), endoscopicethmoidectomy and antrostomy. The endoscopic procedureconsisted in the removal of the uncinated process, ethmoidbulla; the resection of anterior and posterior ethmoid cellswas done depending on the extension of disease. The iden-tification of the natural maxillary ostiumwas performed andenlarged with a backbite and a 45° Blakesley forceps.
All surgical specimens were evaluated by two certifiedpathologists.
Statistical AnalysisThe data were gathered by clinical chart review. The statis-tical analysis was performed using the Statistical Package forthe Social Sciences (SPSS) 18.0 (SPSS Inc., Chicago, IL, USA).
The statistical analysis included descriptive statistics (meanand standard deviation).
Results
Demographic DataWe included seven patients, three female and four malesubjects. The mean age was 53.14 years. Four patientswere immunosuppressed and three were immunocompe-tent. Maxillary sinus involvement was present in all patients.
Amongthe immunosuppressedpatients, threehaddiabetesand one had dermatomyositis. The symptoms were nonspe-cific. Facial pain, mucoid discharge and cacosmia were thesymptoms most frequently reported. (See ►Table 1).
The duration of symptoms ranged from 1 to 28 months.Two patients had asymptomatic mucormycosis, found inci-dentally on computed tomography (CT) scan (cases 3 and 5).
Immunosuppressed CasesCase 1 was a 38-year-old female patient who presentedinitially with fulminant mucormycosis disease. Middle turbi-nate resection, modified Caldwell-Luc procedure and endo-scopicethmoidectomywereurgentlyperformed.Necrosiswasseen intraoperatively in themiddle turbinate. In spite ofocularinvolvement (proptosis, pupillary dilation and restriction ofocular movements), we decided on ocular preservation andhospitalization for a period of 1 month, with strict metaboliccontrol, and administration of up to 3g of amphotericin. At theend of the month, she was asymptomatic, and ocular involve-ment was stable. Nonetheless, the magnetic resonance ima-ging (MRI) and CT scan showed progressive orbital apexpathology. An intraconal biopsy was performed, with finalpathology result of mucormycosis. She underwent orbitalexenterationwith confirmation of orbital disease. Subsequentbiopsies of maxillary and ethmoid sinus were negative. Thiscase was included because it shows a patient with persistentdisease that developed chronic symptoms. Once amphotericinwas prescribed for 1 month, the patient had no diseaseprogression and no additional symptoms. The disease wasconfined to the orbital fat. The fulminant course was arrestedand led to an indolent one. See ►Fig. 1.
Case twowasdiagnosedwithdiabetesduringherhospitaliza-tion. Initialnasalendoscopyrevealedonlymiddlemeatusedema.Surgical findingswere compatiblewith fungus ball and necrosisof maxillary mucosa. Pathology study of the mucosa revealedmucormycosis. Two subsequent biopsies were performed, andthe last biopsy showed no evidence of disease. See ►Fig. 2.
Case three was asymptomatic. The patient had diabetesand renal failure and, since he was a candidate for a kidneytransplant, a paranasal sinus CT scan was performed. Sinusoccupation required mandatory surgery, which later led tothe diagnosis of mucormycosis. Subsequent biopsies werenegative. ►Fig. 3 shows histopathological confirmation.
Case four had dermatomyositis. Patient complained of nasalobstruction, facial fullness, chronic rhinorrhea with posteriordischarge and cough. Paranasal sinus CT scan was performedwith leftmaxillarysinusoccupation.See►Table 1 foradditionalsymptoms and treatment. See►Fig. 4 for preoperative CTscan.
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ImmunocompetentAmong the immunocompetent cases (5, 6, and 7), one patienthad cocaine addiction, interrupted 5 years earlier and 2patients had previous septoplasties.
Patient number 5 had right nasal polyp as the only causeof nasal symptoms. Mucormycosis was contralateral and
asymptomatic. See ►Figs. 5, 6 and 7. See ►Table 1 forcomplete description of symptoms and treatments.
TreatmentAll patients underwent surgical treatment, which consistedmainly in an external maxillary approach and endoscopic
Table 1 Demographics and clinical characteristics of the study population
Patientnumber
Sex Age Immunocompetentstatus
Anatomiclocalization
Duration ofsymptoms(mo)
Clinical features Treatment Follow-up
1 F 38 Immunosuppressed Rhino-orbitalLeft maxillaryLeft ethmoidLeft orbit
1 Maxillary pain,proptosis, pupildilation, restriction ofocular movements.Acute facial pain
Antrostromy,Cadwell Luc,ethmoidectomy,orbital exenteration,liposomalamphotericineBwith a total accumulativedose of 3 g,posaconazole 45 days
4 yearsfollow upNED
2 F 61 Immunosuppressed Left maxillarysinus
6 Headache, facial pain,purulent rhinorrhea,halitosis, cacosmia.
Caldwell Luc,endoscopic antrostomy,amphotericin B 750 mg
2.5 yearsfollow up,NED
3 M 54 Immunosuppressed Right maxillarysinus
NA Asymptomatic Caldwell LucPosaconazole
2 yearsfollow up,NED
4 F 46 Immunosuppressed Left maxillarysinus
28 Nasal obstruction,facial fullness, chronicrhinorrhea withposterior dischargeand cough.
Caldwell Luc 2 months
5 M 77 Immunocompetent Left maxillarysinus
NA Contralateral nasalmassRight Nasalobstruction, Left sideasymptomatic.
Resection ofcontralateral massLeft Caldwell Luc andendoscopic antrostomy
1 yearfollow up,NED
6 M 54 Immunocompetent Right maxillarysinus
8 Headache, cacosmia Caldwell Luc and endo-scopicantrostomy (CaldwellLuc a year after,no recurrence)
1.6 years,asymptomatic,NED
7 M 42 Immunocompetent Left maxillarysinus
24 Mucoid discharge,nasal obstruction,headache.
Caldwell Luc,endoscopic antrostomy
1 yearfollow up,NED
Abbreviations: F, female; M, male; mo, months; NA, none available; NED, no evidence of disease.
Fig. 1 Case 1. Chronic orbital mucormycosis. (A-D) Computed tomography scan shows intraorbital density, predominantly on the apex region.(E). Periodic acid-Schiff (PAS) stain showing mucormycosis with 90-degrees non-septated hyphae.
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antrostomy. Regarding medical treatment, one immunosup-pressed subject received only amphotericin, and case onereceived both amphotericin and posaconazole. On the otherhand, posaconazole was the only treatment in one immu-nosuppressed patient. (See ►Table 1)
All immunocompetent patients had unilateral maxillarysinus involvement and received only surgical treatment,with resolution of the disease. The surgical findings in thesepatients were similar: black and abundant debris in themaxillary sinus. Two immunocompetent patients had signsof necrosis in the maxillary mucosa. Interestingly, only caseone had evident necrosis at nasal endoscopy.
Discussion
Mucormycosis refers to any fungal infectionbymembersof theorder mucorales, which is in the class zygomycetes. Mostpathogenic species are members of the family mucoraceae.1,8
It is currently known thatmucormycosis affectsmainly immu-nosuppressed individuals,16 especially uncontrolled diabeticpatientswithacidosis. Deferoxamine therapyand traumahavealso been described as risk factors.1,8,13,17 Furthermore,immunocompetent individuals arealsopronetothisdisease.18
Unfortunately, the previous literature has mainly describedthe fulminant course of this disease.
Chronic or indolent mucormycosis of the paranasalsinuses was described initially in 1964.19 Although thedisease is not universally known, over 30 cases have beendescribed in the literature.15,20 Interestingly, indolentmucormycosis can affect immunocompetent and immuno-suppressed individuals. Although, immunocompetent casesare associated with a less severe disease.7
On the other hand, chronic invasive fungal sinusitis hasgenerally been associated with the aspergillus species,10
reinforcing the concept that mucormycosis develops onlyinto an acute fulminant course. It is the objective of thispaper to describe the chronic presentation of mucormycosisand to show our experience in the treatment of both immu-nocompetent and immunosuppressed patients.
The definition of chronic mucormycosis has been con-troversial, since some authors acknowledge a period of onlyweeks,9,21,22while others consider it necessary the presenceof mucormycosis for at least 1 month.4 All the patients
Fig. 2 Case 2. (A and B) Computed tomography scan shows left maxillary sinus with heterogeneous density and osteitis. (C) Hematoxylin eosinstain (100x) and (D) Periodic acid-Schaff stain (400x) demonstrate respiratory epithelium with thick hyphae; at higher magnification,non-septated hyphae with right angles are confirmed (red arrow).
Fig. 3 Case 3. Pathology specimen shows edematous mucosa withlymphocyte and plasmatic cells infiltration. Abundant irregularhyphae were observed, with 15 to 30µm, broad with thin wall,non septated, with irregular ramifications filling blood vessels.
Fig. 4 Case 4. Computed tomography scan showing osteitis of maxillarywalls and occupation with heterogeneous density of left maxillary sinus.
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An Emergent Entity Celis-Aguilar et al. 95
included in our study had at least 1 month of suggestivemucormycosis infection.
Also, chronic mucormycosis has been associated withinternal carotid artery occlusion,9 although none of ourpatients developed this complication. One common clinical
feature we could find in most of our patients was thepresence of facial pain or headache. This could be a hallmarksymptom when faced with a patient with chronic paranasalsinus disease with evident CT scan sinus occupation. Someauthors5,23,24 also describe this pain frequently in their
Fig. 6 Case 6. (A) Computed tomography scan with total right maxillary sinus heterogeneous occupation. (B) Periodic acid-Schiff stain (400x)shows numerous thick hyphae semi-septated (yellow arrow) with 90-degrees angulation (red arrow) (C) Hematoxylin eosin stain (100x) showsabundant pauci-septated hyphae with right angles and necrosis. (D) Grocott Gomori stain (100X) shows abundant hyphae compatible withzygomycetes.
Fig. 5 Case 5. (A) Computed tomography scan demonstrates left maxillary sinus occupation. (B) Periodic acid-Schaff stain (100x): necrotictissue with mixed inflammatory cells and hyphae with diverse diameters non septated, with some showing 90-degrees angulation, compatiblewith mucor (red arrow). (C, D, E, F) Grocott Gomori stain (40x, 100x, 400x): abundant non-septated hyphae with 90-degree angulation; this stainwas highly positive on hyphae walls.
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patients.6 In our study, only one patient had orbital apexsyndrome. This patient had middle turbinate necrosis, evi-dent at nasal endoscopy. Necrosis was seen in most of ourpatients during modified Caldwell-Luc procedure in max-illary mucosa, but no evidence of necrosis was seen onrhinoscopy or nasal endoscopy. This defies the currentknowledge that necrosis is usually seen at the physicalexploration of these patients. In our study, maxillary sinusdisease was the most common paranasal sinus involved,pointing to a more limited disease. Curiously, other authorshave described a more aggressive course with orbital apexsyndrome, cavernous sinus thrombosis4,21,22 and brainabscess.25 Although, on immunocompetent patients, thedisease has been more localized.5,10,26 Other authors havecorroborated single paranasal sinus disease on immunocom-petent patients.7,11,12,15,16 See ►Table 2 and 3 for a briefreview of the literature.
The CT scan in some of these cases may not have thetypical erosion of sinus wall. Mignogna et al and Ketenci et aldid not find erosion in the CT scans of their patients, onlysinus occupation. Erosion could not be considered a hallmarksign in chronic mucormycosis cases.
Among the immunosuppressed patients, case one beganwith a fulminantmucormycosis disease, only to progress to anindolent orbital course. During the patient’s hospitalization,efforts for orbital preservation led to continued observation inan otherwise stable patient; nonetheless, orbital apex diseaseprogressionwas seen on subsequent CTscans, with additionalmucormycosispathological confirmationultimately leading toorbital exenteration. It is possible that treatment with ampho-tericin B lead in fact to an indolent course in case number 1.only amphotericine treatment on iniatilly invasive mucormy-cosis cases with no surgery could lead to an indolent course.
Careful imaging follow-up is necessary, especially in cases oforbital disease. Also, a chronic orbital case treated with acourse of antifungals could erroneously lead a surgeon to dono further surgery, which, in fact, happened in this case,making it necessary first, an orbital biopsy and later, withthis being positive, an exenteration. Mutilation of a patient(exenteration) is a difficult decision. This article recommendsimmediate orbital exenteration in case of progressive orbitaldisease, only evident on CT scan.
Since this is an infrequent disease, no randomized controltrials are possible, and only case series are reported in theliterature.15 Therefore, there is controversy on the besttreatment available for this pathology. Some authors advo-cate a surgical and amphotericin B treatment,4,7,27,28 whileothers support only the surgical or medical treatment, suchas monotherapy.11,12 These patients, as many authors pointout, have different comorbidities that contraindicate eitherthe use of amphotericin or surgical treatment. Several casereports showed us that monotherapy is a viable treatmentwith good results.19,22 Additionally, many authors describe apersistent disease with a very slow progression that has noimpact on the quality of life of the patient.5,10,27,28
We agree with Tyson et al,5 Seung et al7 Jung H, et al11 andKetenci et al27 that an only surgical treatment in immuno-competent patients is possible. Interestingly, there has been arise in the reported cases of acute and chronic mucormyco-sis.1,2 This could mean an increased interest in publishingthese cases, more awareness of this disease with promptdiagnosis and treatment, or a real increment ofmucormycosiscases due to more diabetic or immunosuppressed patients. Apossible explanation to indolent mucormycosis in Mexico isthe tropicalweather andhigh temperatureof thisgeographicalarea, which could increase the risk of fungal infection. Other
Fig. 7 Case 7. (A) Computed tomography scan with left total maxillary sinus occupation. (B) Periodic acid-Schiff (PAS) stain (400x) showingspores and scant hyphae compatible with mucormycosis. (C) Hematoxylin eosin stain (400 x) showing inflammatory cells, spores and hyphaecompatible with mucor. Figure D and E show non-septated hyphae on PAS stain (100x).
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Table
2Current
literatureon
indo
lent
muc
ormycos
isim
mun
osu
ppressed
patien
ts
Publication
Year
NSe
xAge
DX
Max
Ethm
Sph
OAS
Oth
erTime
(mo)
Clin
ical
features
Surg
sinus
EXAmph
oB
Follo
w-up
Ferstenfeld
25
(197
7)2
F M61 36
DM
DM
Y YY Y
N NN N
Y N1 0.5
Case1:
Feve
r,Pa
in,n
asalco
nge
stion,
exop
htha
lmos
,op
hthalmop
legia,
loss
ofvision
Case2:
Left
temporal
head
ache
andmaxillaryache
.Sw
ellin
gof
theleftside
offace,p
rotrusionleftof
the
left
eye.
Y YY N
Y YCase1:
Reco
verof
func
tiona
lcap
acity.
Case2:
Afebrile
,righ
tarm
wea
knessan
dseizures.
Finn
2
(198
2)2
F M82 58
RA
DM/
Lymph
oma
N YY N
Y NN N
N NCase1:
Periorbital
edem
a,ne
crotic
crust.
Case2:
Prop
tosis,
purulent
nasald
isch
arge
Y YN N
Y NCase1:
36mon
ths.
Nasal
cavity
remaine
dclea
nCase2:
12mon
ths
Norecu
rren
ceof
infection.
Doo
ley2
2
(199
2)1
M45
DM
NY
YY
N1.5
Orbital
Apex
Synd
rome.
YN
Y48
mon
ths.
Improve
doc
ular
mov
emen
t.
Harril,2
1
(199
6)2
F F46 66
DM
DM
Y NY N
Y YY Y
N NCase1:
8Case2:
1.5
Case1:
Ptos
isOphtha
lmop
legia,
intran
asal
mass
Case2:
Facial
pain,op
htha
lmop
legia
Y YN N
Y YCase1:
NED
,21
Months
Case2:
Diedof
unrelatedcause
Ruop
pi16
(200
1)2
F M62 72
Asthm
aDM
Y YN Y
N YN N
N NCase1:
0.6
Case2:
0.1
Case1:
Facial
pain,pu
rulentdischa
rge,
swellin
gin
therigh
tup
perging
ivaan
dpa
late.
Case2:
Facial
pain,co
njun
ctivitis,prop
tosisan
dch
emos
isof
theco
njunc
tiva
Y YN N
Y YCase1:
38mon
ths
Nofung
alinfectionha
soc
curred
.Case2:
37mon
ths.
Nosign
sof
recu
rren
ce.
Rumbo
ldt1
8
(200
2)1
M16
Leuk
emia
NN
YN
IC3
Feve
r,he
adache
,ch
anges
inthemen
talstatus
NN
Y3mon
ths.Only
biopsy.
Thelesion
continu
edto
grow
,an
dthepa
tien
tde
veloped
aninfarction
intheright
middle
cerebral
artery.
WaizelH
aiat
6
(200
3)1
M55
DM
YY
YY
N3
Left
palpeb
ralp
tosiswithincrea
sedvo
lume,
purulent
anterioran
dpo
steriordischa
rge.
YY
Y12
mon
ths.
Nosign
sof
recu
rren
ce.
Bertin
26
(200
3)1
m61
DM
YY
NN
NFacial
cellu
lite
NN
Y6months.
NED
orrecu
rren
ce.
Marin-
Men
dez4
(200
5)
2M M
70 72DM
DM
Y YY Y
Y YY N
N N1
Case1:
wea
kness,
nasalo
bstruction,
rhinorrhea
,OAS
Case2:
ptosis,
nasalo
bstruction,rhino
rrhe
a,OAS
Y YN Y
N YCase1:
Reco
very
ofey
emov
emen
tCase2:
Cav
erno
ussinu
sthrombo
sis,
dece
ased
.
Odessey2
4
(200
8)1
M64
DM
AR
YN
NN
NSe
veral
days
Frontal
head
ache
,righ
tpe
riorbital
pain,diplopia,
numbne
ssan
drigh
tfacial
wea
kness
YN
YNone
spec
ified
.Despite
improv
emen
tin
facial
symmetry
and
ocular
symptom
s.
Kim
7
(201
3)1
F56
DM
YN
NN
NSe
veral
mon
ths
Seve
rena
salo
bstructionwithfacial
tend
erne
ssY
NY
19mon
ths.
Noev
iden
ceof
infectionor
recu
rren
ce
Texeira3
(201
3)1
F46
DM
NY
NY
N24
Right
side
periorbitalan
dde
ficitof
II,III,IV,V
,VIa
ndVIIcran
ialn
erve
s.Y
YY
9years.Asymptom
atican
dwithou
tev
iden
ceof
diseaserecu
rren
ce.
Jung
11
2013
1F
67DM
YN
NN
N36
Foul
odor,po
stna
sald
rip.
YN
N10
mon
ths
Dim
aka8
(201
4)1
M82
DM
YY
YN
N6
Purulent
andod
orou
sna
sald
isch
arge,
epistaxis,
anos
mia
NN
Y42
mon
ths
Still
alivean
drelative
lywell.
Gutierrez-
Delga
do9
(201
6)
1M
47DM
YN
NN
N3
Paresthe
sia,
pain
andsw
ellin
gin
theleft
zygo
matic
bone
YN
Y4months.
NED
orrecu
rren
ce
Abbrev
iation
s:Amph
oB,
ampho
tericinB;
RA,rhe
umatoidarthritis;
DM,d
iabetes
mellitus
;DX,d
iagn
osis;E
thm,e
thmoidsinu
s;EX
,exe
nteration;
F,female;
M,m
ale;
Max,m
axillarysinu
s;MCI,middlece
rebral
infarction
;mo,
mon
ths;
N,no
ne;NED
,no
eviden
ceof
disease;
OAS,
orbitala
pexsynd
rome;
Sph,
sphe
noid
sinu
s;Sinu
ssurg,sinu
ssurgery;
Y,ye
s.
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An Emergent Entity Celis-Aguilar et al.98
Table
3Current
literatureon
indo
lent
muc
ormycos
is:immun
ological
competen
tpa
tien
ts
Public
ation
Year
nSe
xAge
Prev
DX
Max
Ethm
Sph
OAS
Other
Time(m
o)Clin
ical
Features
Sinu
ssu
rgEX
Amph
oB
Follo
w-up
Tyso
n5
(199
2)1
F26
No
YY
NN
N48
Nasal
obstruction,
muc
oiddischa
rge,
left
facial
pain
andpressu
reY
NY
Sheha
sbe
enfree
ofdiseaseformorethan
36mon
thspo
stop
eratively
Del
Valle28
(199
6)1
M54
No
NN
YN
N0.75
days
before
interven
tion.
Seve
releft
temporal
head
ache
,the
patien
twas
healthyun
tilthisacute
episod
e.
YN
Y12
mon
ths.
Exam
inations
andbiopsies
have
show
nto
befree
ofdisease.
Ketenc
i27
(200
5)1
F63
No
NN
YN
N3
Seve
rehe
adache
YN
N6mon
ths
Biopsyan
dCTscan
show
edno
recu
rren
ce.
Virk1
0
(200
7)1
M40
No
YY
YN
N24
Nasal
obstruction,
proptosis,
diplopia.
YN
YNot
spec
ified
Free
ofdiseaseon
regu
laren
dos
copic
follo
w-up.
Migno
gna
(201
1)15
5M
67RP
CY
NY
NN
0.5–
1Case1:
Chron
icbilateralo
rofacial
pain
andfeve
rN
NY
6mon
ths
M46
No
YN
NN
N0.5–
1Case2:
respiratorydistress,feve
rN
NY
24mon
ths
M47
BPH
YN
NN
N0.5–
1Case3:
acutediplopia,
orbital
pain
NN
Y60
mon
ths
M54
No
YN
NN
N0.5–
1Case4:
rhinorrhea
,facial
pain
NN
Y14
mon
ths
F53
No
YN
NN
Y Erosion
oforbit
.5–1
Case5:
rhinorrhea
,he
adac
he,o
rbital
pain
NN
Y20
mon
ths
Jung
11
(201
3)4
F67
No
YN
NN
N5
Case1:
Foul
odor,p
ostna
sald
rip,n
asal
stuffine
ssY
NN
17mon
ths
M60
No
YN
NN
N4
Case2:
Stuffine
ss,po
stna
sald
rip
YN
N24
mon
ths
F68
No
YN
NN
N4
Case3:
Foul
odor,p
ostna
sald
rip,n
asal
stuffine
ssY
NN
12mon
ths
Therewas
norecu
rren
cein
anypa
tien
t.
Jad1
2
(201
5)1
F34
No
YY
YN
N2
Hea
dach
e,bloc
kageof
left
nasal
cavity,ch
ange
sin
voice.
(sim
ilarev
entayear
ago)
NN
N3mon
ths
trea
tmen
twithfluc
onazole.
After
3mon
ths,
theCTscan
was
repea
tedan
dfoun
dto
beno
rmal.
Wolko
w13
(201
7)1
F74
No
YY
YY
N1
Feve
r,ch
ills,
left
facial
pain,a
ndleftpe
riorbitale
rythem
aan
ded
ema.
YN
Y4mon
ths
Lesions
recu
rred
,acco
mpa
nied
byspon
tane
ous
draina
geof
purulent
fluid.
Hem
ashe
ttar
14
(201
1)1
M18
No
NN
NN
Nose
Facial
skin
144
Ulcerativelesion
ontheno
sean
dpa
late
NN
NDeb
ridem
entan
dfluc
onazole.
6mon
thsfollo
w-up.
Thewoun
dhe
aled
butlaterthepa
tien
twas
lost
tofollo
w-up.
Abbrev
iation
s:Amph
oB,
amph
otericin
B;BP
H,b
enignpros
tatichy
pertrophy
;;Ethm
,ethmoidsinu
s;EX
,exenteration;
F,female,
M,m
ale;
Max,m
axillarysinu
s;mo,
mon
ths;N,n
one;
OAS,
orbitalape
xsynd
rome;
Prev
DX,prev
ious
diag
nosis;
RPC
,rhinoph
aryn
geal
canc
er;Sp
h,sphe
noid
sinu
s;Sinu
ssurg,sinu
ssurgery;
Y,ye
s.
International Archives of Otorhinolaryngology Vol. 23 No. 1/2019
An Emergent Entity Celis-Aguilar et al. 99
authorshavehypothesizedthatchronic sinusitis couldbea riskfactor for this fungal infection.15
In contrast to acute fulminant invasive sinusitis, chronicmucormycosis could have better survival. In a recent sys-tematic review,20 only half of the patients with acute fulmi-nant disease survived, with diabetic patients having betterprognosis than patients with other comorbidities. Chronicmucormycosis, at least in our series, had a 100% survival rate.Other authors support this improvement in survival, espe-cially in immunocompetent patients.5,10,11,24,27
Differential diagnosis of this disease should be kept inmind, such as neoplasms, bacterial sinusitis, granulomatousdisorders, cavernous sinus thrombosis, pseudotumors, etc.9
The limitations of this study are mainly the lack ofmucormycosis cultures. Nonetheless, the characteristicbroad non-septated hyphae with right angle branchingusually suffices for diagnosis. Since this is an emerging entity,we are confident that new studies could confirm our resultsand shed new light on this disease.
The strengths of this study are the high number of patientsincluded, in contrast to what has been previously published,the longer follow-up and the fact that it is amulticenter study.
Finally, indolent mucormycosis is a differential diagnosisin patients with facial pain or headache, mucoid discharge,cacosmia with a paranasal sinus occupation on CT scan inimmunosuppressed and immunocompetent individuals.
Conclusion
Indolent mucormycosis is a new and emerging clinical entityin immunosuppressed and immunocompetent patients. Sin-gle paranasal sinus disease is a frequent presentation andshould not be overlooked as a differential diagnosis in thesepatients. Immunocompetent patients should only be treatedsurgically. More studies are needed to confirm our results.
References1 Ibrahim AS, Kontoyiannis DP. Update on mucormycosis patho-
genesis. Curr Opin Infect Dis 2013;26(06):508–5152 FinnDG, Farmer JC Jr. Chronicmucormycosis. Laryngoscope 1982;
92(7 Pt 1):761–7663 Teixeira CA, Medeiros PB, Leushner P, Almeida F . Rhinocerebral
mucormycosis: literature review apropos of a rare entity. BJMCase Rep 2013. Doi: 10.1136/bcr-2013-008552https://www.ncbi.nlm.nih.gov/pubmed/23389725
4 Marin-Mendez H. Monroy- Aguirre D, Rodríguez- Perales M.Caretta-Barradas Sergio. Síndrome de ápex orbitario causadopor mucormicosis orbito cerebral crónica e indolente: reportede dos casos. An Orl Mex 2005;50:64–68
5 Tyson JC, Gittelman PD, Jacobs JB, Holliday R, Press R. Recurrentmucormycosis of the paranasal sinuses in an immunologicallycompetenthost.OtolaryngolHeadNeckSurg1992;107(01):115–119
6 Waizel-Haiat S, Cohn-Zurita F, Vargas-Aguayo AM, Ramírez-Aceves R, Vivar-Acevedo E. Mucormicosis rinocerebral invasoracrónica. Cir Cir 2003;71(02):145–149
7 Kim ST, KimWS, Lee HH, Kim JY. Successful treatment of invasiverhinopulmonary mucormycosis with an indolent presentation by
combined medical and surgical therapy. J Craniofac Surg 2013;24(02):e182–e184
8 Dimaka K, Mallis A, Naxakis SS, et al. Chronic rhinocerebralmucormycosis: a rare case report and review of the literature.Mycoses 2014;57(11):699–702
9 Gutiérrez-Delgado EM, Treviño-González JL, Montemayor-AlatorreA, et al. Chronic rhino-orbito-cerebralmucormycosis: A case reportand review of the literature. Ann Med Surg (Lond) 2016;6:87–91
10 Virk RS, Arora P. Chronic sinonasal aspergillosis with associatedmucormycosis. Ear Nose Throat J 2007;86(01):22
11 Jung H, Park SK. Indolent mucormycosis of the paranasal sinus inimmunocompetentpatients:areantifungaldrugsneeded? JLaryngolOtol 2013;127(09):872–875
12 Jad B, Pottathil S, Raina S, Singh V. Paranasal Sinus Mucormycosisin an Immunocompetent Host: A Case Report. Int J Health Sci Res2015;5:617–620
13 Wolkow N, Jakobiec FA, Stagner AM, et al. Chronic orbital andcalvarial fungal infection with Apophysomyces variabilis in animmunocompetent patient. Surv Ophthalmol 2017;62(01):70–82
14 Hemashettar BM, Patil RN, O’Donnell K, Chaturvedi V, Ren P,Padhye AA. Chronic rhinofacial mucormycosis caused by Mucorirregularis (Rhizomucor variabilis) in India. J Clin Microbiol 2011;49(06):2372–2375
15 Mignogna MD, Fortuna G, Leuci S, et al. Mucormycosis in immu-nocompetent patients: a case-series of patients with maxillarysinus involvement and a critical review of the literature. Int JInfect Dis 2011;15(08):e533–e540
16 Ruoppi P, Dietz A, Nikanne E, Seppa J, Markkanen H, Nuutinen J.Paranasal sinus mucormycosis: a report of two cases. ActaOtolaryngol 2001;121(08):948–952
17 Sun HY, Singh N. Mucormycosis: its contemporary face andmanagement strategies. Lancet Infect Dis 2011;11(04):301–311
18 Rumboldt Z, Castillo M. Indolent intracranial mucormycosis: casereport. AJNR Am J Neuroradiol 2002;23(06):932–934
19 Vignale R, Mackinnon JE, Casella de Vilaboa E, Burgoa F. Chronic,destructive, mucocutaneous phycomycosis in man. Sabouraudia1964;3(02):143–147
20 Turner JH, Soudry E, Nayak JV, Hwang PH. Survival outcomes inacute invasive fungal sinusitis: a systematic review and quanti-tative synthesis of published evidence. Laryngoscope 2013;123(05):1112–1118
21 Harril WC, Stewart MG, Lee AG, Cernoch P. Chronic rhinocerebralmucormycosis. Laryngoscope 1996;106(10):1292–1297
22 Dooley DP, Hollsten DA, Grimes SR, Moss J Jr. Indolent orbital apexsyndrome caused by occult mucormycosis. J Clin Neuroophthal-mol 1992;12(04):245–249
23 Rao SP, Kumar KR, Rokade VR, Khanna V, Pal C. Orbital ApexSyndrome due to mucormycosis caused by Rhizopus micro-sporum. Indian J Otolaryngol Head Neck Surg 2006;58(01):84–87
24 Odessey E, Cohn A, Beaman K, Schechter L. Invasivemucormycosisof the maxillary sinus: extensive destruction with an indolentpresentation. Surg Infect (Larchmt) 2008;9(01):91–98
25 Ferstenfeld JE, Cohen SH, Rose HD, Rytel MW. Chronic rhinocer-ebral phycomycosis in association with diabetes. Postgrad Med J1977;53(620):337–342
26 Bertin H. Mucormicosis rinosinusal. Rev Otorrinolaringol CirCabeza Cuello 2003;63:122–126
27 Ketenci I, Unlü Y, Sentürk M, Tuncer E. Indolent mucormycosis ofthe sphenoid sinus. Otolaryngol Head Neck Surg 2005;132(02):341–342
28 Del Valle Zapico A, Rubio Suárez A, Mellado Encinas P, MoralesAngulo C, Cabrera Pozuelo E. Mucormycosis of the sphenoid sinusin an otherwise healthy patient. Case report and literature review.J Laryngol Otol 1996;110(05):471–473
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