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Ea , Nose & Th oa Jou nal
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Re iew
In oduc ion
Whi e lesions o he o al mucosa a e commonly encoun-
e ed in daily p ac ice by den is s, o ola yngologis s, and
maxillo acial su geons.1,2 O al leukoplakia is a ely symp-
oma ic, and he impo ance o sc eening and ea ly diagno-
sis is de i ed om i s equen associa ion wi h o al ca i y
squamous cell ca cinoma.3,4 O al leukoplakia cons i u es
85% o all po en ial malignan diso de s occu ing in he
o al ca i y, wi h a desc ibed p e alence o 2.89% o 3.6%,
a highe incidence among men.5-7 The e iology o o al leu-
koplakia is mul i ac o ial.8-12 Consump ion o obacco,
whe he h ough smoking o chewing, appea s o be he
sole di ec isk ac o implica ed in he induc ion o o al
leukoplakia.13-17 The mos commonly desc ibed loca ions
a e ep esen ed by mandibula al eolus (25%-40%), buccal
mucosa (22%-46%), pala e (27%), ongue (26%), and loo
o he mou h (19.3%).18-21 Nega i e p ognos ic isk ac o s
include being o he emale gende , ad anced age, ha ing a
size g ea e han 200 mm², and ha ing a Candida albicans
in ec ion. HPV, o human papilloma i us, plays a signi i-
can ole in de eloping o al leukoplakia.22 Pa icula ly,
high- isk s ains like HPV-16 and HPV-18 a e associa ed
wi h an inc eased likelihood o de eloping o al leukoplakia
and i s p og ession o cance .22 Also, di e en genes
in ol ed in DNA damage esponse and epai pa hways
1245204EARXXX10.1177/01455613241245204Ea , Nose & Th oa Jou nalKhong e al
e iew-a icle2024
Pas , P esen , and Fu u e Diagnos ic
Me hods o he Ea ly Nonin asi e
De ec ion o O al P emalignan Lesions:
A S a e o he A and Sys ema ic Re iew
B endan Khong, MD1, Sal a o e Fe li o, MD, PhD2, S ua Quek, MD3,
Gianluca Con e, MD4, Angelo Ing assia, MD2, Je ome Rene Lechien, MD, PhD5,
Ca los Chiesa-Es omba, MD, PhD6, Miguel Mayo, MD, PhD7,
An onino Maniaci, MD, PhD8, Thomas Radulesco, MD, PhD9,
Jus in Michel, MD, PhD9, Nicolas Fakh y, MD, PhD9,
and Ricca do Polosa, MD, PhD10,11
Abs ac
Objec i es: To p o ide an in-dep h analysis o nonin asi e me hods o he ea ly diagnosis o o al p emalignan lesions,
ocusing on no el bioma ke s and op ical echnologies, and o discuss hei po en ial in imp o ing he p ognosis o
pa ien s wi h o al oncological diseases. Me hods: This s a e-o - he-a e iew examines a ious nonin asi e diagnos ic
echniques, including he u iliza ion o sali a y mic oRNAs and op ical echnologies such as Raman spec oscopy, elas ic
sca e ing spec oscopy, di use e lec ance spec oscopy, na ow-band imaging, au o luo escence imaging, oluidine blue
s aining, and mic oendoscopy. Resul s: Se e al nonin asi e echniques ha e shown a ying deg ees o e ec i eness in
de ec ing o al cance . Au o luo escence imaging exhibi ed sensi i i ies up o 100% bu had a iable speci ici y. oluidine
blue s aining epo ed sensi i i y be ween 77% and 100% o high- isk lesions o cance , wi h speci ici y a ound 45%
o 67%. Spec oscopy echniques achie ed 72% o 100% sensi i i ies and speci ici ies o 75% o 98%. Mic oendoscopy
p esen ed a sensi i i y o 84% o 95% and a speci ici y o 91% o 95%. Conclusion: The e iew highligh s he s eng hs
and limi a ions o each nonin asi e diagnos ic me hod and hei ecen ad ancemen s. Al hough p omising esul s ha e
been demons a ed, he e is a need o u he de elopmen o eliable s a egies o ea ly de ec ion and in e en ion
in o al oncology.
Keywo ds
o al leukoplakia, diagnosis, nonin asi e es , nonin asi e bioma ke s, o al cance , sali a es ing
2 Ea , Nose & Th oa Jou nal 00(0)
ha e been epo ed as candida es o cance suscep ibil-
i y.23,24 O al leukoplakia can p esen ca cinoma in si u in
7% o 7.6% o cases,25-27 wi h nonhomogenous leukoplakia
possessing g ea e malignancy p obabili y (20%-25%).28-31
Visual examina ion ep esen s he i s cos -e ec i e
app oach, comp omised by i s inhe en subjec i i y and he
hea y eliance on he clinician’s expe ience. Toluidine blue
s aining is employed o supplemen isual examina ion,
due o selec i ely s ain a eas o dysplasia o malignancy.32,33
Howe e , diagnos ic accu acy is some imes comp omised
by po en ial alse posi i es and nega i es. As a mo e sensi-
i e app oach, b ush biopsy and cy ology a e o en u i-
lized.34,35 While minimally in asi e, hei sensi i i y and
speci ici y can a y, and mo e se e e o deepe dysplas ic
changes may no be cap u ed. Al hough issue biopsy
emains he de ini i e diagnos ic me hod wi h high diag-
nos ic accu acy, he p ocedu e can p esen isks and po en-
ial discom o o he pa ien . In he ace o eme ging
echnologies, op ical imaging echniques such as Raman
spec oscopy (RS) and na ow-band imaging (NBI) a e
gaining a en ion.31-34 These inno a i e, nonin asi e ech-
niques can pinpoin sub le s uc u al and biochemical issue
changes in eal ime. Howe e , hei success ul implemen-
a ion equi es specialized equipmen and expe ise o
accu a e in e p e a ion.
To e alua e and analyze he di e en diagnos ic indica-
ions, he ad an ages, and limi a ions o each p ocess, we
conduc ed a comp ehensi e e iew o he li e a u e on he
diagnos ic p ocedu es in ol ed in he ea ly de ec ion o
o al leukoplakia.
Me hods
S udy Design
This sys ema ic e iew was conduc ed ollowing he
P e e ed Repo ing I ems o Sys ema ic Re iews and
Me a-Analyses (PRISMA) guidelines, he Coch ane
Handbook o Sys ema ic Re iews o In e en ions,
and he PICOTS amewo k (Popula ion, In e en ion,
Compa ison, Ou comes, Timing, and Se ing).
Sea ch S a egy
The au ho s pe o med a comp ehensi e li e a u e sea ch
in he ollowing elec onic da abases: PubMed/Medline,
Embase, Web o Science, Google Schola , and he
Coch ane Lib a y. The sea ch s a egy included he combi-
na ion o keywo ds and MeSH e ms ela ed o “o al leu-
koplakia,” “o al p ecance ous lesions,” “ea ly diagnosis,”
“ea ly de ec ion,” “neoplas ic lesions,” “o al ca i y,”
“diagnos ic echniques and p ocedu es,” and “bioma k-
e s.” The sea ch was limi ed o English-language publica-
ions wi h no publica ion da e es ic ions.
Inclusion C i e ia
S udies we e conside ed eligible o inclusion i hey me
he ollowing c i e ia:
1. S udy design: C oss-sec ional s udies, case-con ol
s udies, e ospec i e coho s udies, p ospec i e
coho s udies, p ima y science a icles, and epide-
miological s udies.
2. Popula ion: Pa ien s wi h o al leukoplakia.
3. In e en ion: P ocedu es o echniques used o he
ea ly diagnosis o o al leukoplakia.
4. Ou comes: Diagnos ic accu acy, sensi i i y, speci-
ici y, posi i e p edic i e alue, nega i e p edic-
i e alue, and o he ele an measu es.
Exclusion C i e ia
S udies we e excluded i hey:
1. We e no published in English.
2. We e case epo s, case se ies, e iews, commen-
a ies, edi o ials, o le e s o he edi o .
1 Ash o d and S Pe e ’s Hospi als NHS T us , Che sey, UK
2 Depa men o Medical and Su gical Sciences and Ad anced Technologies “GF Ing assia” ENT Sec ion, Uni e si y o Ca ania, Ca ania, Sicilia, I aly
3 Bed o dshi e Hospi als NHS Founda ion T us , Bed o dshi e, UK
4 Depa men o Gene al Su ge y and Medical-Su gical Special ies, Uni e si y o Ca ania, Ca ania, Sicilia, I aly
5 Depa men o Human Ana omy and Expe imen al Oncology, Facul y o Medicine, UMONS Resea ch Ins i u e o Heal h Sciences and
Technology, Uni e si y o Mons (UMons), Mons, Belgium
6 Depa men o O o hinola yngology—Head and Neck Su ge y, Hospi al Uni e si a io Donos ia, San Sebas ian, Spain
7 Depa men o O o hinola yngology—Head and Neck Su ge y, Uni e si y Hospi al Complex o A Co uña, A Co uña, Spain
8 Facul y o Medicine and Su ge y, “Ko e” Uni e si y o Enna, Enna, I aly
9 Depa men o O o hinola yngology—Head and Neck Su ge y, APHM, Aix Ma seille Uni e si y, La Concep ion Uni e si y Hospi al, Ma seille, F ance
10 Cen e o Excellence o he Accele a ion o HA m Reduc ion (CoEHAR), Uni e si y o Ca ania, Ca ania, Sicilia, I aly
11Depa men o Clinical and Expe imen al Medicine, Uni e si y o Ca ania, Ca ania, Sicilia, I aly
Recei ed 15 Oc obe 2023; e ised Ma ch 10 2024; e ised manusc ip accep ed 15 Ma ch 2024
Co esponding Au ho :
An onino Maniaci, MD, PhD, Facul y o Medicine and Su ge y, “Ko e” Uni e si y o Enna, ia San a So ia 78, Enna 95124, I aly.
Email: [email p o ec ed]
Khong e al 3
3. Focused on diagnosing o he o al lesions o condi-
ions wi hou a speci ic ocus on o al leukoplakia.
4. Did no p o ide su icien da a o assess he diagnos-
ic accu acy o o he ele an ou come measu es.
S udy Selec ion and Da a Ex ac ion
Two independen e iewe s sc eened he i les and
abs ac s o he iden i ied a icles. Full- ex a icles we e
ob ained o hose ha appea ed o mee he inclusion c i-
e ia o when he e was unce ain y. Disag eemen s
be ween e iewe s we e esol ed h ough discussion o by
in ol ing a hi d e iewe .
Da a ex ac ion was pe o med using a s anda dized
da a collec ion o m. The ex ac ed da a included s udy
design, popula ion cha ac e is ics, diagnos ic p ocedu es,
ou comes, and ollow-up. In addi ion, he isk o bias and
quali y o he included s udies was assessed using app o-
p ia e ools, such as he Quali y Assessmen o Diagnos ic
Accu acy S udies and he Newcas le-O awa Scale.
Da a Syn hesis
A na a i e syn hesis o he indings was conduc ed, sum-
ma izing he included s udies’ main ea u es, diagnos ic
p ocedu es, ea men modali ies, ou comes, and ollow-
up. The p ima y objec i e o his e iew was o e alua e
he diagnos ic accu acy o a ious me hods o he ea ly
de ec ion o o al leukoplakia. The seconda y objec i e was
o compa e di e en diagnos ic echniques and iden i y
po en ial bioma ke s ha could aid in he ea ly diagnosis
o o al leukoplakia. Due o he expec ed he e ogenei y in
s udy designs and diagnos ic me hods, a o mal s a is ical
analysis was no pe o med. Ins ead, a quali a i e syn he-
sis o he indings was p esen ed, highligh ing he s eng hs
and limi a ions o he included s udies.
Resul s
S udy Design and Pa ien Inclusion
A e assessmen o eligibili y, 16 a icles we e included
o quan i a i e analysis. The sys ema ic p o ocol is sum-
ma ized in Figu e 1. The sample sizes a ied signi ican ly
ac oss he s udies, anging om a minimum o 18 o a
maximum o 184 subjec s. The s udies included pa ien s
wi h a ious o al condi ions, om benign in lamma o y
lesions o po en ially malignan diso de s and o al squa-
mous cell ca cinoma (OSCC).
Me hodologies and Ou comes Repo ed
Se e al di e en diagnos ic me hods we e used ac oss he
s udies. These included sali a y mic oRNA, me hylene
blue s aining, Rose Bengal (RB) s aining, blue oluidine
s aining, Lugol’s iodine s aining, RS, elas ic sca e ing
spec oscopy (ESS), di use e lec ance (DR) spec os-
copy (DRS), au o luo escence, NBI, high- esolu ion
mic oendoscopy (HRME), and pho odynamic diagnosis.
The sensi i i y o he diagnos ic me hods anged om
64.3% o nea ly 100%. The speci ici y o he me hods
anged om a ound 60% o 100%. Se e al s udies epo ed
ins ances o alse posi i es and alse nega i es. The diag-
noses made included no mal issues, dysplasia, po en ially
malignan diso de s (PMDs), and OSCC. Some s udies
epo ed on he abili y o he diagnos ic me hod o es ic
he ma gins o p emalignan lesions o di e en ia e
be ween di e en ypes o o al lesions.
The isk o bias o each included s udy, acco ding
o he Joanna B iggs Ins i u e ool, is summa ized in
Figu e 2.
O al Leukoplakia—Diagnosis
Ea ly de ec ion o o al p emalignan lesions (ie, leukopla-
kia) is essen ial o educe he high mo bidi y and mo ali y
a e associa ed wi h ensuing o al cance .36,37 The di e en
nonin asi e es app oaches a ailable o sc een lesions o
he o al mucosa a e summa ized in Figu e 3.
Du ing o al examina ion, i is impo an o iden i y he
ollowing by isual inspec ion and palpa ion:
•• Loca ion
•• Size
•• I he lesion is aised
•• P esence o ulce s
•• Bo de s o he lesion—whe he i is well-de ined o
i egula
Pa ien s who a e suspec ed o ha e p emalignan dis-
ease will unde go incisional biopsy o his ological exami-
na ion o con i m he diagnosis. Howe e , o al leukoplakia
emains a diagnos ically challenging lesion ha is a po en-
ial hu dle o clinicians.38 I was epo ed ha he 5 yea
su i al a es ha e no imp o ed despi e ad ancemen s in
ea men .39 Gi en he agg essi e na u e o his condi ion,
he high a es o malignan ans o ma ion, and i s p open-
si y o ea ly lympha ic sp ead, ea ly diagnosis is c i ical
in limi ing ea men mo bidi y and maximizing oncologic
con ol.
Nonin asi e Tes s
The new nonin asi e es ha his a icle discusses can be
used o aid he iden i ica ion and diagnosis o o al leuko-
plakia. Di e en diagnos ic me hods o leukoplakia e al-
ua ion a e summa ized in Table I.
4 Ea , Nose & Th oa Jou nal 00(0)
Reco dsiden i ied om*:
Da abases (n =2892)
Regis e s (n =0)
Reco ds emo edbe o e sc eening:
Duplica e eco ds emo ed (n =19)
Reco ds emo ed o o he easons
(e a um, e ac ed publica ion) (n
=18)
Full ex sc eened.
(n =2855)
Reco ds excluded
(n =0)
Repo ssough o e ie al
(n =2855)
Repo sno e ie ed (n =1852)
Re iew (n = 826)
Case epo s(n = 708)
Le e ,Edi o ial,Commen ,
(n=221)
A icle no inEnglish (n =97)
Repo sassessed o eligibili y
(n =1003) Repo sexcluded (n= 993):
1) Pa ial o incomple e da a
2) No adequa e pa ien selec ion
S udies included in e iew o :
Quali a i e analysis (n =16)
Iden i ica ion o s udies ia da abases and egis e s
Iden i ica ion
Sc eening
Included
•
Figu e 1. Flow-diag am desc ibing sys ema ic p o ocol acco ding o PRISMA guidelines. PRISMA, P e e ed Repo ing I ems o
Sys ema ic Re iews and Me a-Analyses.
Sali a y bioma ke s. The echnique in ol es he collec ion
o sali a samples om pa ien s, which is a nonin asi e,
easy- o-pe o m, and s ess- ee p ocedu e. Once he
sali a sample is collec ed, i is p ocessed o ex ac he
mic oRNA. This ex ac ion can be done using a ious
me hods, including comme cial ki s. The le els o speci ic
mic oRNAs associa ed wi h o al leukoplakia a e measu ed
a e he ex ac ion. This is o en done using quan i a i e
Khong e al 5
1. We e heg oups compa able o he han he p esence o diseaseincases o
heabsence o diseaseincon ols?
2. We e casesand con ols ma chedapp op ia ely?
3. We e hesamec i e iaused o iden i ica ion o casesand con ols?
4. Wasexposu e measu ed in as anda d, alid and eliableway?
5. Wasexposu emeasu edin he same way o casesand con ols?
6. We e con ounding ac o siden i ied?
7. We e s a egies o deal wi h con ounding ac o s s a ed?
8. We e ou comes assessed in as anda d, alidand eliableway o cases and
con ols?
9. Was he exposu e pe iod o in e es long enough o be meaning ul?
10.Was app op ia es a is ical analysis used?
C.-J.Chang. e al.,
2005
Ya-Wei Chen e al.,
2006
A. Sha wani e al.,
2006
Ge- ei Du e al., 2007
ManjuMS ephen
e al., 2013
Ke inGuzee al.,
2014
F. Zah an e al., 2015
She eenFa imae al.,
2016
QuangTe al., 2016
BoscoloNa aF.e al.,
2021
NChainani-Wu e al.,
2015
Ono e JB e al.,2001
El e s De al.,2015
Koch FP e al., 2011
Chenxi Li e al., 2022
Mo o e al., 2010
Figu e 2. Risk o bias summa y au ho ’s judgmen s o each included s udy, assessed by he JBI. C i ical app aisal checklis o
case-con ol s udies. JBI, Joanna B iggs Ins i u e.
6 Ea , Nose & Th oa Jou nal 00(0)
Figu e 3. Nonin asi e es subclasses and main ea u es.
eal- ime polyme ase chain eac ion (qRT-PCR), a ech-
nique ha p ecisely measu es he amoun o a speci ic
RNA. The le els o hese mic oRNAs a e hen compa ed
o a con ol g oup o es ablished h esholds o de e mine
whe he hey a e ele a ed o educed. In 2015, he e was
a s udy ha in es iga ed he use o 3 sali a y mic oRNAs
(miRNA-21, miRNA-184, and miRNA-145) as ma ke s
o o al cance s.40 This s udy isola ed RNA om sali a
samples using he mic oRNA Isola ion Ki (Qiagen), and
miRNA exp ession analysis was pe o med using qRT-
PCR (Applied Biosys ems). This s udy showed a highly
signi ican inc ease in sali a y miRNA-21 and miRNA-
184 in OSCC and PMDs. The miRNA-184 was ound o
disc imina e be ween OSCC and PMDs wi h dyspla-
sia. I has also p o ided good diagnos ic alue, wi h a
speci ici y o 75% and sensi i i y o 80%.6 The usage
o sali a y in e leukin-6 (IL-6) has also been in es i-
ga ed. A s udy in ol ing 40 pa ien s showed ha IL-6
le els we e ele a ed in leukoplakia wi h coexis ing
pe iodon i is and pe iodon i is pa ien s compa ed o
heal hy con ols. Wi hin he g oup o pa ien s wi h leu-
koplakia, IL-6 le els also co ela ed wi h he se e i y o
dysplasia.41 Se e al compa a i e s udies ha e collec-
i ely ad anced he unde s anding o o he sali a y bio-
ma ke s in he de ec ion and moni o ing o o al diseases
wi h po en ial malignan ans o ma ions.42-47 Agha-Hosseini
and Mi zaii-Dizgah42 iden i ied inc eased sali a y p53 in
pa ien s wi h plaque-like O al Lichen Planus (OLP), sug-
ges ing a highe malignancy isk compa ed o e osi e
OLP, while Jacob e al43 ound ele a ed sali a y o al
sialic acid (TSA) le els in o al p ecance and OSCC,
indica i e o disease p og ession. Complemen ing hese
indings, Va un e al44 epo ed ha sali a y He 2/neu le -
els we e signi ican ly highe in OSCC han in PMDs and
con ols, unde sco ing i s po en ial as a localized bio-
ma ke o malignancy. The s udy by Jancsik e al45 ein-
o ced he concep ha sali a es ing could be an e ec i e
and eliable me hod o he ea ly de ec ion o OSCC, pa -
icula ly in high- isk popula ions such as hose wi h dia-
be es. A sali a y p o eomic analysis was conduc ed o
iden i y po en ial bioma ke s o OSCC, u ilizing Sodium
Dodecyl Sul a e-Polyac ylamide Gel Elec opho esis
(SDS-PAGE) and Ma ix-Assis ed Lase Deso p ion/Ion-
iza ion Time-o -Fligh /Time-o -Fligh (MALDI TOF/
TOF) mass spec ome y, he esea che s ound ele a ed
le els o annexin A8, pe oxi edoxin-2, and y osine kinase
in he sali a o diabe ic indi iduals, p o eins p e iously
associa ed wi h cance and OSCC in sali a. In he s udy
led by Punyani and Sa hawane,47 he ocus was on e alu-
a ing he sali a y le els o IL-8 in pa ien s wi h o al p e-
cance and OSCC o unde s and i s po en ial as a
bioma ke . The esea ch e ealed ha sali a y IL-8 con-
cen a ions we e signi ican ly highe in OSCC pa ien s
compa ed o bo h he p ecance g oup and heal hy
7
Table 1. Sys ema ic Table o Di e en Diagnos ic Me hods o Leukoplakia Assessmen .
Au ho s, yea S udy design
Sample
size Type o es s Resul s Sensi i i y/speci ici y Ad an ages Disad an ages
Zah an e al,
2015
P ospec i e
con olled
100 Sali a y
mic oRNA
Highly signi ican inc ease in sali a y
miRNA-21 and miRNA-184 in
OSCC and PMDs.
A 4- old inc ease in
miRNA-21 was associa ed
wi h a speci ici y and
sensi i i y o 65%.
A dec ease o 0.6 in
miRNA-145 esul ed in
a speci ici y o 70% and
a sensi i i y o 60%. In
addi ion, a 3- old ise in
miRNA-184 was linked o
a speci ici y o 75% and a
sensi i i y o 80%.
miRNA-184 was ound
o disc imina e
be ween OSCC and
PMDs wi h DP.
No high le els o speci ici y
and sensi i i y in his
me hod. (75%-80%,
espec i ely)
Chen e al,
2006
P ospec i e
uncon olled
58 Me hylene blue
s aining
His ological examina ion iden i ied
16 cases o squamous cell
ca cinomas and 13 p ecance ous
lesions, which included a
spec um o DPs ea u ing a ying
concen a ions o a ypical cells in
he basal and pa abasal laye s. In
addi ion, 29 benign lesions we e
diagnosed, which encompassed
condi ions such as epi helial
hype plasia, hype ke a osis, and
lichen planus.
I achie ed a sensi i i y o
90%, he speci ici y was
69%, e lec ing i s abili y o
co ec ly ecognize hose
wi hou he condi ion. The
posi i e p edic i e alue
s ood a 74%, he NPV was
87%.
Low oxici y and
cheape han oluidine
blue
High numbe o alse
nega i es and alse
posi i es.
Du e al,
2007
P ospec i e
uncon olled
132 RB s aining RB s aining appea ed o be a
p omising echnique o iden i ying
dysplas ic changes wi hin o al
leukoplakia, lichen planus, and
leukoke a osis. In he con ex o
his s udy, he s aining me hod
success ully iden i ied 5 ou o
6 cases o DP o OSCC p io
o con i ma ion by his ological
examina ion.
The sensi i i y and speci ici y
o de ec epi helial DP
and OSCC a e 93.9%
and 73.7%, espec i ely.
The posi i e and nega i e
likelihood a ios a e 3.570
and 0.082, espec i ely.
RB s aining seems
p omising o de ec
DP in OLKia,
lichen planus, and
leukoke a osis.
High a es o alse posi i es
and alse nega i es.
Fa ima e al,
2016
Re ospec i e
uncon olled
100 Lugol’s iodine
s aining
E ec i e in dema ca ing he
p ecance ous lesions’ ma gins,
iden i ying he p ecance ous
lesion’s co ec size and ex en .
The sensi i i y and speci ici y
we e 100% o su gical
ma gins o dysplas ic issue
lesions.
Good a ailabili y,
ease o use, cos -
e ec i eness, and
widesp ead use by
clinical in iden i ying
in aepi helial
neoplasia o he o al
ca i y.
The speci ici y o Lugol’s
iodine s ain anged om
60%-84.2%.
(con inued)
8
Table 1. (con inued)
Au ho s, yea S udy design
Sample
size Type o es s Resul s Sensi i i y/speci ici y Ad an ages Disad an ages
Guze and
Pawluk,
2014
P ospec i e
con olled
18 Raman
spec oscopy
The di e en ial spec a de i ed om
p emalignan and malignan lesions
exhibi ed clea dis inc ions om
hose o no mal, benign issues.
The p edic i e accu acy o
p emalignan and malignan
lesions was ex emely high,
wi h a sensi i i y o 100%
and a speci ici y o 77%.
Nonin asi e, con enien ,
and ela i ely
inexpensi e echnology.
Du ing da a acquisi ion,
he ope a o can iew
he lase ligh , hus
allowing illumina ion
o he lesion si e
o ensu e accu a e
posi ioning.
The de ec ion needs a
sensi i e and highly
op imized ins umen a ion.
Fluo escence o impu i ies
o o he sample i sel can
hide he Raman spec um.
Sha wani
e al, 2006
P ospec i e
uncon olled
25 ESS Ou o he 11 biopsies ha we e
his ologically con i med as dysplas ic,
ESS co ec ly classi ied 8 o hese
cases as dysplas ic. Con e sely, ESS
mis akenly iden i ied 3 dysplas ic
si es as no mal, ma king hem
as alse nega i es. Rega ding he
no mal issues, 4 biopsies we e
ound o be no mal his ologically.
ESS co ec ly iden i ied 3 o hese
as no mal, which a e ue nega i es,
while i inco ec ly classi ied 1
biopsy as dysplas ic, a alse nega i e.
On ob aining 2 se s o
spec a and applying linea
disc iminan analysis,
he au ho s achie ed a
sensi i i y o 72% and
a speci ici y o 75% o
iden i ying DP in o al
issues.
ESS has he ad an age
o being as , eliable,
and cos -e ec i e and
po en ially o e s a
nonin asi e diagnosis
in si u and in eal
ime.
When compa ing
spec oscopy o
his opa hology, he
accu acy o no mal
issues was 91.6% (22/24)
compa ed o 97% (33/34)
o abno mal issues. When
examining DP, hese igu es
ell a 64.3% (9/14) and
ca cinoma, 50% (5/10).
S ephen
e al, 2013
P ospec i e
con olled
55 ac i e
s 23
con ols
DR spec oscopy
s biopsy
The median pixel alue o he
R545/R575 image a io was 0.87
(IQR = 0.82-0.94) o no mal/
clinically heal hy issue, while
i was 1.35 (IQR = 1.13-1.67)
and 2.44 (IQR = 1.78-3.80) o
p emalignan and malignan
lesions, espec i ely. The AUC
showed di e en ia ing malignan
om no mal/clinically heal hy
yielded an AUC o 0.99 (95% CI:
0.99-1.00), p emalignan om
no mal/clinically heal hy an AUC
o 0.94 (95% CI: 0.86-1.00),
malignan om p emalignan an
AUC o 0.84 (95% CI: 0.73-0.95),
and p emalignan and malignan
om no mal/clinically heal hy an
AUC o 0.97 (95% CI: 0.94-1.00).
High sensi i i y and speci ici y
in di e en ia ing be ween
malignan and no mal
issues, wi h bo h alues
a 97%. When iden i ying
p emalignan s no mal
issues, sensi i i y emains
high a 95%, while
speci ici y is sligh ly lowe
a 92%. In dis inguishing
be ween p emalignan
and malignan lesions,
wi h lowe sensi i i y and
speci ici y o 76% and 80%,
espec i ely. Finally, in
de ec ing bo h malignan
and p emalignan lesions s
no mal issues, he me hod
shows s ong sensi i i y a
92% and speci ici y a 95%
The imaging me hod
has he ad an age o
nonin asi ely scanning
he en i e lesion
and i s su ounding
a eas in eal ime and
ca ego izing o al lesions
in o no mal/clinically
heal hy, p emalignan ,
and malignan issue.
Fu he mo e, i
e icien ly delinea es
he bounda ies o
neoplas ic changes and
loca es he si e wi h
he mos malignan
po en ial o a biopsy,
he eby a oiding
unnecessa y epea ed
biopsies and delays in
diagnosis.
Rela i ely good diagnos ic
accu acy while compa ing
i o he gold s anda d
his opa hology.
(con inued)
9
Table 1. (con inued)
Au ho s, yea S udy design
Sample
size Type o es s Resul s Sensi i i y/speci ici y Ad an ages Disad an ages
Na a e al,
2021
P ospec i e
uncon olled
160 NBI The di e ence be ween NBI and
HD WL sensi i i y was s a is ically
signi ican (P <.001). The NBI
diagnos ic ad an age was 62.5%,
highes in he hypopha ynx
(P = .05), and was no in luenced by
p e ious RT o CT (P = .49). Index
umo si e s a is ically ela ed wi h
ecu ence si e (P < .001), bu
no wi h he isk o de eloping
ecu ence (P = .81).
Among he pa ien s, 30
lesions om 21 indi iduals
we e biopsied. NBI
iden i ied 26 lesions as
posi i e, o which 24 we e
con i med as ue posi i es
on his ological examina ion,
while 2 we e alse posi i es.
No signi ican co ela ion
was ound be ween he
ini ial umo si e and
ecu ence isk. Howe e ,
he e was a signi ican
associa ion be ween he
o iginal umo si e and he
si e o ecu ence, wi h
he pa e n o ecu ence
a ying based on he ini ial
umo loca ion.
The use o NBI wi h
lexible ideo-
endoscope was be e
ole a ed by he
pa ien and allowed
close inspec ion
o he la yngeal and
hypopha yngeal
subsi es wi h
he ip o he
endoscope, wi h
in-dep h isualiza ion
o mucosal and
submucosal ascula
pa e ns and wi hou
he need o local
sp ay anes hesia in he
majo i y o pa ien s.
A lea ning cu e
cha ac e izes NBI, and i
is an ope a o -dependen
in es iga ion. NBI uses ligh
a speci ic wa eleng hs o
enhance he isibili y o
supe icial blood essels.
The in e p e a ion o NBI
images can be subjec i e
and equi es conside able
expe ise.
Quang e al,
2016
P ospec i e
uncon olled
177 HRME The able -in e aced HRME
demons a ed compa able imaging
pe o mance a a lowe cos han
i s -gene a ion lap op-in e aced
HRME sys ems. In a pos hoc
quan i a i e analysis, he algo i hm
iden i ied neoplasia wi h
The sensi i i y and speci ici y
o 95% and 91% in he
alida ion se compa ed
wi h 84% and 95% achie ed
in he o iginal s udy.
HRME uses a low-
cos , ibe -op ic
luo escence
mic oscope o
image he cellula
mo phology o he
su ace epi helium.
The cos o goods o
build an HRME sys em
is less han $5000
Al hough p omising,
widesp ead use o he
HRME is limi ed by he
need o a bulky lap op o
con ol he sys em and
he need o aining o
in e p e acqui ed images.
Chang e al,
2005
P ospec i e
uncon olled
20 Pho odynamic
diagnosis
O he pa ien s s udied, 25% showed
hype ke a osis, 45% exhibi ed
squamous hype plasia, and 30%
had SCC.
The sensi i i y was
app oxima ely 92% and
94%, and he speci ici y
was abou 96% and 98%
in he mac oscopic and
mic oscopic s udies,
espec i ely.
Ligh -induced
luo escence
de ec ion using opical
Pho o in p o ides a
sensi i e, nonin asi e
echnique o he
ea ly iden i ica ion o
malignan neoplasms
in he o al ca i y.
The lesions mus be scanned
poin by poin wi h he
ip o he collec ion ibe
o assess he o al issue
mucosa. This me hod is
ime-consuming, especially
o examining la ge a eas
o lesions.
(con inued)
16 Ea , Nose & Th oa Jou nal 00(0)
sensi i i y. Howe e , he sensi i i y o CLE has dec eased
o 80% while speci ici y inc eased o 100%, indica ing an
imp o emen in excluding nonmalignan lesions.71
Con ocal e lec ance mic oscopy u ilizes lase ligh a a
nea -in a ed wa eleng h (830 nm), pene a ing he issue o
in e es and illumina ing a single poin . A s udy ha com-
pa ed con ocal e lec ance mic oscopy and his opa hology
wi h hema oxylin and eosin s aining showed ha his is a
p omising me hod o diagnosis, wi h a sensi i i y o 96.3%,
speci ici y o 92.3%, posi i e p edic i e alue o 93%, and
nega i e p edic i e alue o 96%.72
The HRME is a diagnos ic ool ha le e ages a cohe -
en ibe bundle o cap u e high- esolu ion luo escence
images o he issue in con ac wi h he de ice’s dis al ip.
In his se up, a came a plays he c ucial ole o seizing
high-quali y digi al images, which a e hen ans e ed o a
compu e o u he analysis.73 The HRME p o ides a
nonin asi e me hod o isualize issue a chi ec u e and
changes in cellula beha io , po en ially aiding in he ea ly
de ec ion and diagnosis o condi ions like o al leukopla-
kia. Howe e , his echnique equi es specialized equip-
men and ained pe sonnel, and he e ec i eness o
HRME can be in luenced by ac o s such as he speci ic
loca ion o he issue being examined and he pa ien ’s
indi idual cha ac e is ics.
Fluo escence li e ime imaging (FLIM) is a p omising
diagnos ic echnique ha analyzes a issue a ea o abou
1.6 cm × 1.6 cm. I ope a es by measu ing bo h issue
au o luo escence and he decay o luo escence o e ime.
This unique app oach allows o he po en ial es ima ion
o he con ibu ions o speci ic luo opho es like,
Nico inamide Adenine Dinucleo ide (NADH), Fla in Adenine
Dinucleo ide (FAD), and collagen, which a e molecules ha
emi luo escence when exci ed by ligh . The di e en ial
p esence o hese luo opho es can p o ide aluable in o -
ma ion abou issue heal h and po en ial abno mali ies.
Pa icula ly use ul in di e en ia ing dysplas ic lesions
om benign in lamma o y lesions,74 FLIM o e s a nonin-
asi e me hod o iden i y p ecance ous o cance ous
changes. Howe e , he echnique equi es specialized
equipmen and expe ise in da a in e p e a ion, and i s
e ec i eness can be a ec ed by ac o s such as he pa ien ’s
indi idual cha ac e is ics and he speci ic loca ion o he
issue being examined.
Mul ipho on mic oscopy ep esen s a luo escence
imaging echnique ha p o ides c oss-sec ional images
o issues a di e en dep hs, eaching up o 1 mm.75 This
app oach allows o he assessmen o cellula in asion
beyond he basemen memb ane, a key cha ac e is ic o
in asi e diseases. By o e ing a de ailed look a issue
a chi ec u e and cellula beha io in hei na i e en i on-
men , mul ipho on mic oscopy can con ibu e o he ea ly
de ec ion and diagnosis o condi ions like o al leukopla-
kia. In a s udy conduc ed by Ma sui e al, his echnique
demons a ed a high sensi i i y o 96% and a speci ici y
o 84%,76 indica ing i s po en ial as a p ecise diagnos ic
ool. Howe e , like all diagnos ic echniques, mul ipho-
on mic oscopy comes wi h i s own se o equi emen s,
including he need o specialized equipmen and ained
pe sonnel o accu a e ope a ion and in e p e a ion o
esul s.
Ligh -based sys ems. Ligh -based de ec ion sys ems such as
chemiluminescence and pho odynamic diagnosis ha e
been de eloped o aid in diagnosing o al leukoplakia a an
ea ly s age. By u ilizing he s uc u al abno mali ies in o al
leukoplakia, heal hy and cance cells emi di e en wa e-
leng hs o ligh . The e a e 2 main ypes o ligh -based sys-
ems, namely chemiluminescence and pho odynamic
diagnosis.
The e a e mul iple chemiluminescen de ices ha a e
a ailable on he ma ke . These de ices use a ligh -based
de ec ion sys em o de ec he di e en wa eleng hs
e lec ed due o changes in cance cell mo phology. The
main de ices on he ma ke a e ViziLi e (Zila
Pha maceu icals, Phoenix, AZ, Uni ed S a es), ViziLi e
Plus (Zila Pha maceu icals, Phoenix, AZ, Uni ed S a es),
and Mic olux/DL (Mic olux DL - AdDen , Inc., Danbu y,
CT, Uni ed S a es).
The o al ca i y is i s insed wi h ace ic acid be o e
being examined unde chemiluminescen illumina ion.
This allows he use o di e en ia e be ween no mal and
hype ke a inized epi helium. Dysplas ic o hype plas ic
issue has inc eased nuclea con en ha e lec s ligh and
hence appea s whi e when iewed a low-ene gy wa e-
leng hs. Con e sely, he no mal epi helium appea s da k.77
S udies ha e shown ha ViziLi e has a high sensi i i y
o 77.3% o 100% bu a low speci ici y o 0% o 55.56% in
de ec ing o al ca cinoma.78-80 Howe e , i has been shown
o de ec leukoplakia mo e han o he o ms o o al
lesions.75 A newe e sion o ViziLi e called ViziLi e Plus
combines bo h ViziLi e and TB and has been shown o
imp o e he speci ici y o 75.5% o 78% bu a dec eased
sensi i i y a e. The p inciples o Mic olux/DL a e simila
o ViziLi e. I uses a ba e y-powe ed LED ligh ha emi s
blue ligh . Acco ding o Ib ahim e al, he speci ici y and
sensi i i y o iden i ying o al lesions we e 100% and 32%,
espec i ely, meaning ha i could loca e possible lesions
bu could no di e en ia e he ypes o lesions.80
Pho odynamic diagnosis in ol es ea ing cells wi h a
pho oac i a ed compound ha accumula es mo e in cells
wi h malignan po en ial when exposed o pho oi adia-
ion. A common compound used is 5-aminole ulinic acid
(ALA), which induces he luo escence o p o opo phy in
IX in cance ous and p ecance ous cells. The p ocedu e
in ol es insing he o al ca i y wi h a 0.4% ALA solu ion
ollowed by exposu e o a speci ic ligh wa eleng h o
405 nm. This echnique boas s a high sensi i i y, as s udies
Khong e al 17
ha e epo ed a ange be ween 80% and 99%.81 Howe e ,
i s speci ici y can be comp omised in pa ien s wi h a his-
o y o adio he apy, as indica ed by some s udies.82
Despi e his limi a ion, using ALA and pho odynamic
diagnosis can p o ide aluable in o ma ion o he ea ly
de ec ion and diagnosis o condi ions like o al leukopla-
kia. I is wo h no ing, howe e , ha he e ec i eness o
his echnique can be in luenced by ac o s such as he
pa ien ’s indi idual cha ac e is ics and he speci ic loca-
ion o he issue being examined.
Discussion
Al hough se e al diagnos ic me hods o he ea ly de ec-
ion o he o al ca i y neoplas ic lesions ha e been dem-
ons a ed, hei use cu en ly emains con o e sial and
deba ed.20 We aimed o c i ically desc ibe he nonin asi e
de ec ion echniques o p emalignan o al ca i y lesions
conce ning each me hod’s sensi i i y and speci ici y.
Den is s, ENTs, o maxillo acial su geons a e he special-
is s who a e he i s o deal wi h p emalignan lesions o
he o al ca i y. Iden i ica ion o such lesions should occu
as ea ly as possible.25 Ea ly diagnosis o p emalignan
lesions o he o al ca i y is essen ial. I is based on o al
sc eening. The la e could a oid delayed e e als, hus
educing mo ali y in he SCC.19 I has been epo ed ha
SCC can de elop om o al po en ially malignan diso -
de s, and i s diagnosis is an impo an p e en i e s ep
wi h a majo impac on pa ien su i al and u u e quali y
o li e.21 Howe e , isual inspec ion has se e al limi a-
ions, such as he inabili y o dis inguish high- isk benign
lesions om o he diseases and mo bid condi ions o he
o al mucosa.
Tissue biopsy is an in asi e, ime-consuming, pain ul,
ope a o -dependen me hod equen ly no eadily accep ed
by pa ien s.24 Despi e his, o al biopsy emains he gold s an-
da d me hod oday. Typically, nonea ly de ec ion o a p ema-
lignan lesion leads o an ad anced s age a diagnosis.82-84
Howe e , se e al ollow-ups ha e shown ha he isk o
malignan ans o ma ion can pe sis o o e 10 yea s. Fo
his eason, long- e m ollow-up wi h egula checkups by
he o al su geon, maxillo acial, o ENT specialis is equi ed.
The ea ly diagnosis o p emalignan lesions o he o al
ca i y can make use o nonin asi e, easy- o-use, and
e ec i e me hods.21 Sali a y diagnos ics is a me hod ha
has sp ead in ecen yea s.39 Sali a has a e y complex
composi ion, including enzymes, an ibodies, ho mones,
an imic obial elemen s, and cy okines.40 The sali a collec-
ion is easy, sa e, nonin asi e, and inexpensi e. In ecen
yea s, in e es has g own in miRNAs ( ound in a ious
biological luids, including sali a) being he la e consid-
e ed as po en ial ma ke s o diagnosing, p ognosis, and
e alua ing he e ec i eness o ea ing mul iple diseases.6
I is likely ha miRNA exp ession p o iling no only
allows he iden i ica ion o neoplas ic issue and i s his o-
logical o igin bu also disc imina es be ween di e en sub-
ypes o malignan lesions.40 Rega ding in lamma ion,
unde s anding he ole o miRNAs in i s egula ion could
be impo an in helping unde s and he pa hogenesis o a
la ge g oup o diseases.
Among he diagnos ic me hods based on i al s aining,
RB s aining and Lugol’s iodine s aining mus be ci ed. RB
s aining was used o delinea e he ex en o co neal and
conjunc i al neoplasms. The e o e, such cha ac e is ics o
RB ha e enligh ened us o pe o m su eying esea ch on
p emalignan and malignan lesions o he o al ca i y.
Lesions mo e s ained by RB had a highe likelihood o
being OSCC o epi helial dysplasia han hose less
s ained.45 Thus, RB s aining migh ha e he po ency o be
used as a diagnos ic aid o de ec o al p emalignan o
malignan lesions o clinicians. Wi h ega d o he me h-
ods based on diagnos ics wi h op ical sys ems, pa icula
in e es is gi en o me hods based on luo escence/au o-
luo escence and NBI.64 In so issues, po en ially malig-
nan lesions and umo lesions can be de ec ed. Thus, he
op ical luo escence sys em allows o simple, nonin a-
si e, eal- ime diagnosis and iden i ica ion o s uc u es
and al e a ions in he o al ca i y, e ealing lesions ha a e
no easily de ec able wi h ligh ing.73
NBI is a new op ical echnology al eady widely applied
in diagnosing gas oin es inal lesions. Unlike he epide -
mal issue, he mucous memb ane o he o al ca i y has
ew ke a inized laye s and lacks appendages de i ing om
he ou le o he mino sali a y glands.64 Hence he capil-
la ies in he papillae o he connec i e issue unde he epi-
helium a e ha dly obse ed om he ex e nal mucosal
su ace. While in he heal hy o al mucosa, he pegs o he
epi helial ne wo k and he connec i e issue papillae a e
egula ly connec ed, in cance , his connec ion becomes
i egula .76 The e o e, isually, he capilla ies will assume
an i egula and dense dis ibu ion. By obse ing a umo
lesion unde magni ica ion, he p oli e a ion o capilla ies
can be ecognized as a cha ac e is ic spo ing o he issue.
Ano he me hod used o he ea ly diagnosis o o al p e-
malignan lesions is chemiluminescence.77 Many sys ems
use his me hod; he 2 mos used a e he ones based on
luminol and based on pe oxyoxala e.
Rega dless o he sys em, blue-whi e ligh is abso bed by
heal hy cells and e lec ed by cells wi h abno mal nuclei,
including dysplas ic and neoplas ic cells. The ace ic acid
inse pu a i ely emo es deb is and dis up s he glycop o ein
ba ie on he epi helium’s su ace, allowing ligh pene a-
ion.34 Va iable dye up ake was obse ed be ween exophy ic
and ulce a ed SCC. The dye showed excellen e en ion and
s aining in ulce a es compa ed o exophy ic lesions due o
he inc eased in e cellula spaces ha allow o be e dye
18 Ea , Nose & Th oa Jou nal 00(0)
pene a ion.85,86 In conclusion, chemiluminescen ligh is
use ul as an addi ional diagnos ic ool o o al cance ca e
and ollow-up Po en ially Malignan Epi helial Lesions
(PMELs) o subjec s ea ed o he same.
A signi ican limi a ion in diagnosing o al po en ially
malignan lesions, such as o al leukoplakia, is he need o
mo e awa eness and knowledge among den al and medical
p o essionals. Despi e he a ailabili y o a ious ech-
niques o o al examina ion, he challenge pe sis s due o a
limi ed unde s anding o o al leukoplakia and i s diagnos-
ic p ocess.87-92 B idging hese gaps by enhancing awa e-
ness and knowledge is c ucial o acili a e ea ly de ec ion
and p e en he p og ession o OSCC and o he po en ially
malignan lesions in he o al ca i y.
Subjec i i y in diagnosis due o isual in e p e a ion and
he a iabili y in lesion appea ance u he complica e accu-
a e iden i ica ion.93,96 In addi ion, sampling bias du ing
biopsy p ocedu es, he absence o eliable p edic i e bio-
ma ke s, limi ed accessibili y o specialized ca e, and pa ien
compliance wi h ollow-up appoin men s all con ibu e o
he challenges in achie ing ea ly and p ecise diagnoses.
O e coming hese limi a ions equi es s anda dized diag-
nos ic c i e ia, diagnos ic echniques, bioma ke esea ch
ad ancemen s, imp o ed accessibili y o specialized ca e,
and enhanced pa ien educa ion and engagemen .
Conclusion
The ea ly diagnosis o o al p emalignan condi ions is c u-
cial o minimizing in asi e su gical in e en ion, p o iding
a be e p ognosis, and imp o ing he quali y o li e o
pa ien s. Cu en ly, se e al diagnos ic ools o sc eening
a e a ailable, enhancing he cha ac e iza ion o suspicious
lesions. Today, su gical biopsy and his ology emain he p i-
ma y he apeu ic choices, bu he ad en o sali a y bio-
ma ke s p esen s p omising new echniques. Scien i ic
p og ess is con inually mode nizing diagnos ic p ocedu es o
acili a e ea ly de ec ion o o al cance and educe diagnos ic
delay. Al hough any ligh -based diagnos ic de ice could
aid in diagnosing o al mucosal lesions, chemiluminescence
examina ion can delinea e o al lesions mo e e ec i ely, as
he edges o he lesions exhibi imp o ed b igh ness and cla -
i y. O he eme ging echniques include OCT and molecula
imaging, which o e high- esolu ion imaging capabili ies.
Mo eo e , when combined wi h quan i a i e au o luo es-
cence analysis, he au o luo escence-based sys em could di -
e en ia e be ween umo s and benign o al dysplasia.
Acknowledgmen s
None.
Da a A ailabili y
No new da a we e c ea ed.
Decla a ion o Con lic ing In e es s
The au ho (s) decla ed no po en ial con lic s o in e es wi h
espec o he esea ch, au ho ship, and/o publica ion o his
a icle.
Funding
The au ho (s) ecei ed no inancial suppo o he esea ch,
au ho ship, and/o publica ion o his a icle.
E hical App o al
The s udy was conduc ed in acco dance wi h he Decla a ion o
Helsinki.
G an Numbe
No g an was associa ed.
In o med Consen
In o med consen was wai ed o he e iew s udy.
ORCID iDs
Je ome Rene Lechien h ps://o cid.o g/0000-0002-0845-0845
Ca los Chiesa-Es omba h ps://o cid.o g/0000-0001-9454-9464
An onino Maniaci h ps://o cid.o g/0000-0002-1251-0185
Thomas Radulesco h ps://o cid.o g/0000-0002-5939-5372
T ial Regis a ion
The ial egis a ion was wai ed o he e iew s udy.
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