5/7/2016 AVeryUnusualCaseofOcularSurfaceSquamousNeoplasia

AVeryUnusualCaseofOcularSurfaceSquamousNeoplasia
ErinBoeseM4,GinaM.RogersMD,andAnnaS.Kitzmann,MD

February14,2013

ChiefComplaint:Enlargingconjunctival/corneallesion,lefteye

HistoryofPresentIllness

Ahealthy,22yearoldCaucasianmanpresentedtotheUniversityofIowaDepartmentofOphthalmologywithconcernsofanew,
enlargingconjunctival/cornealmassonhislefteye.Hefirstnoticedthemass2to3monthspriortopresentationwhenhedeveloped
redness,irritation,andforeignbodysensation.Shortlythereafter,henoticedasmall,elevatedlesiononhiscornea.Thelesionhas
continuedtoincreaseinsizeovertheserecentmonths.

PastOcularHistory
Thepatientfirstpresentedtothecorneaclinicatage11withsymptomsofintermittentdiscomfortandepiphorawith360degreesof
vascularpannusnotedonexaminationonhisleftcornea.Atthetime,thepannuswaspresumedtobesecondarytochronicasymmetric
meibomianglanddysfunction,butdidnotimprovesignificantlywithdoxycycline,topicalsteroids,topicalolopatadine(Patanol),and
warmcompresses.

In2002,duetopersistentsymptoms,hewasevaluatedatanoutsideinstitutionwhereseveraltestsweredone,includingimpression
cytologyofthecornea,whichwasnegative.Whenhehadresumedcareatourinstitutionin2004,twosuperficialkeratectomieswere
performed,whichshowedmildtomoderateepithelialdysplasia,mostlikelyreactiveinnatureratherthanneoplastic.Noorganismsor
inflammatorycellswerenotedonthebiopsies,butduetocontinuedconcernofpossibleAcanthamoebakeratitis,thepatientwasalso
treatedwithtopicalcyclosporine,oralVitaminC,oralVitaminA,andchlorhexidineforashortperiodoftimewithoutanyclinical
improvement.Thepatientwaspresumedtohaveadiffuseepitheliopathy,ofuncertainetiology,andpossiblestemcelldeficiency.The
patientwassubsequentlyfollowedlocallyuntilthedevelopmentofthepresentingconjunctival/corneallesion.

PastMedicalHistory

Noneotherwisehealthy

Medications
Nocurrentmedications

FamilyHistory

Noncontributory

SocialHistory
Nonsmoker

ReviewofSystems
Negativeotherthantheocularissues

OCULAREXAMINATION

Visualacuity,withcorrection:

20/20righteye(OD)
20/200lefteye(OS),pinholeto20/50+1OS

Pupils:6mmto4mm,briskreflexes,noRAPD

Intraocularpressure:18mmHgbotheyes(OU)

ExtraOcularMotility:FullOU

AnteriorSegmentExam:

OD:mildmeibomianglanddysfunction,traceconjunctivalinjection
OS:mildmeibomianglanddysfunction,2+conjunctivalinjection.7.5x7mmcornealmassextendingfrom5:00to9:00from
thelimbustonearthevisualaxis.Thelesioniselevatedwithanirregularsurfaceandvascularcore.Thelesionisfixedandnot
mobile.Another1.5x1mmelevatedlesionislocatedat12:00.Pannusispresentsurrounding270degreesofthelimbusexcept
intheareaofthelimbalmass(Figures1and2).
http://webeye.ophth.uiowa.edu/eyeforum/cases/163OSSN.htm 1/11
5/7/2016 AVeryUnusualCaseofOcularSurfaceSquamousNeoplasia
intheareaofthelimbalmass(Figures1and2).

Figures1and2:Presentingslitlampphotographsofthelefteye.Notetheelevated,gelantinousappearanceandabnormalvascularityofthelesion.

Dilatedfundusexam:NormalOU

CLINICALCOURSE
Thepatient'sclinicalpresentationwasveryconcerningforasquamouscellcarcinoma.TestingforHIVwasnegative.Fourweeksafter
presentationheunderwentanexcisionalbiopsywithcryotherapy,intraoperativemitomycinC,absolutealcohol,andanamniotic
membranegraftonthelefteye.Histopathologicanalysisdemonstratedinvasivesquamouscellcarcinoma,moderatelydifferentiated,
extendingintoallhorizontalanddeepsurgicalmargins(Figures3&4).

Adjuvanttreatmentwithtopicalinterferonalpha2B(1millionunits/mL)fourtimesperdaywasstartedwithplanstocontinuethis
medicationforatleast12months.Inaddition,monthlysubconjunctivalinjectionsof10millionunitsofinterferonalpha2Bwere
performedfor6months.Atthe4monthpostoperativevisit,thevisualacuityonthelefteyewithcorrectionwas20/60,pinhole20/40.
Althoughtherewassomepannusandconjunctivalinjectioninferonasally,theclinicalappearanceoftheocularsurfacewasmuch
improvedwithoutanyevidenceofrecurrentsquamouscellcarcinoma(Figures5and6).Atthe10monthpostoperativevisit,thevisual
acuityonthelefteyewas20/25,pinhole20/20,andtherewasnoclinicallyvisibleevidenceofsquamouscellcarcinoma(Figure7).

Figure3:Photomicrographillustratingconjunctivalepithelialthickeningwithfullthicknessdysplasia.Scattered
cellswithlarge,pleomorphicnucleiandscatteredmitoticfiguresarepresent.(H&E,originalmagnification=50X).

http://webeye.ophth.uiowa.edu/eyeforum/cases/163OSSN.htm 2/11
5/7/2016 AVeryUnusualCaseofOcularSurfaceSquamousNeoplasia
{clickimageforhigherresolutionimage}

Figure4:Highermagnificationphotomicrographshowinglackofnormalmaturation(dysplasia)withatypicalcells
withlargeirregularnucleiandprominentnucleoli.Mitosesandapoptoticbodiesarepresentalongwithfocal
dyskeratosis(keratinpearls).Shortarrow=keratinpearlStars=apoptoticbodiesLongarrow=mitoticfigure.
(H&E,originalmagnification=200X).{clickimageforhigherresolutionimage}

Figures5and6:Fourmonthpostoperativeslitlampphotos.

http://webeye.ophth.uiowa.edu/eyeforum/cases/163OSSN.htm 3/11
5/7/2016 AVeryUnusualCaseofOcularSurfaceSquamousNeoplasia

Figure7:Tenmonthpostoperativeslitlampphotograph.

http://webeye.ophth.uiowa.edu/eyeforum/cases/163OSSN.htm 4/11
5/7/2016 AVeryUnusualCaseofOcularSurfaceSquamousNeoplasia

Discussion

Ocularsurfacetumorsarerelativelyrarewithanincidenceof0.131.9per100,000.[1,2]Ocularsurfacesquamousneoplasia(OSSN)is
anumbrellatermthatencompassesdysplasticlesionsinvolvingthesquamousepitheliumoftheconjunctivaorcornea,whichincludes
squamouspapilloma,conjunctivalcorneaintraepithelialneoplasia(CIN),carcinomainsitu(CIS),andinvasivesquamouscellcarcinoma
(SCC).TheclinicalpresentationofOSSNvariesacrossawidespectrumandisclassifiedbythedegreeofepithelialandstromal
(substantiapropria)infiltration.Theepithelialinfiltrationcanrangefrommildtoseveredysplasia(i.e.mild,moderate,orsevereCIN)to
fullthicknessepithelialdysplasia(CIS)toinvasiveSCC,whentumorcellsinvadethroughtheepithelialbasementmembrane.[1,3]
Fortunately,oftheseconditions,invasiveSCCistheleastcommon.

RiskFactors
ThehighestincidenceofOSSNoccursinmenbetweentheagesof50and75yearsofage.[1,2]Fairskin,paleirises,highpropensityto
sunburn,andapasthistoryofskincancerhaveallproventoberelatedriskfactors.[3,4]OtherriskfactorsforOSSNinclude:chronic
infectionbyHPV(humanpapillomavirus),HIV,ortrachoma,vitaminAdeficiency,xerodermapigmentosum,chronicirritants,and
chronicepitheliopathies.[1,35]Immunosuppression,whetherduetoorgantransplantationorsecondarytoAIDS,isamajorriskfactor,
especiallyinconjunctionwithoneoftheaboveriskfactors.itisestimatedthattheriskofconjunctivalmalignanciesincreases13foldin
patientswithHIV.[6]ThediseasealsobehavesinamuchmoreaggressivemannerinpatientswithAIDSorxerodermapigmentosa.

AnOSSNlesioninayoungerpatientshouldraisesuspicionforthepossibilityofunderlyingimmunodeficiencyastudyconductedin
Miamisuggestedthatasmanyashalfofpatientsyoungerthan50yearswithOSSNhaveHIV.[7]InadditiontoHIVtesting,athorough
investigationofotherpotentialsourcesofimmunodeficiencyshouldbeperformed.

Intheparticularcasepresentedabove,thepatientisaveryatypicalpresentationOSSNthepatientisveryyoung,andathorough
investigationrevealedthatthepatientisHIVnegativeandnotimmunosuppressed.Evenattheageof22,thepatientalreadyhada
decadelonghistoryofanepitheliopathy.ItispossiblethatthechronicocularsurfaceirritationputthepatientathigherriskforOSSN.

ClinicalPresentation

Lesionsrarelyaffectvisionpriortopresentation,butduetoitsreadilyvisiblelocation,OSSNisoftenrecognizedearly.OSSNcan
involvetheconjunctivaorthecorneaindividuallybutmorecommonlyinvolvesboth.

Over95%ofOSSNcasesoriginateinthelimbus,oftenintheinterpalpebralregion(i.e.at3:00or9:00onthebulbarconjunctiva).[8]
Thereasonforthepropensityofthelesionstothisregionisthoughttobeduetoacombinationoffactors,includingthepresenceof
transitionaltypeepithelium,highUVexposure,andahighmitoticrate.[8]

Lesionshavebeendescribedasvaryinginappearancewithcolorrangingfromapearlygraytoareddishbrown(ifpigmented),and
surfacefrompapilliformtogelatinous.Awhiteplaque(leukoplakia)maydeveloponthesurfaceofthelesion,whichindicates
secondaryhyperkeratosissecondarytosquamouscelldysfunction,andisconcerningforinvasivedisease.Theremayormaynotbe
prominentfeedervessels,butunfortunately,theirpresencedoesnothelpnarrowthedifferential.[3]Clinically,symptomsmayrange
fromasymptomatictoachronicallyirritated,redeye.Massesareinitiallymobiletheconjunctivainlaterstagesbecomingfixedtothe
globewithdeeperscleralinfiltration.RoseBengalstainingcanhelpidentifytheextentofthelesion.

Diagnosis

Throughclosecarefulexamwithslitlampbiomicroscopy,OSSNlesionscanfrequentlybedistinguishedfromotherconjunctivallesions,
suchaspterygiaandconjunctivallymphoma.However,studieshaveshownitisverydifficulttodistinguishbetweenthedifferenttypes
ofOSSNexperiencedphysicianswereonlyabletoaccuratelydiagnoseOSSNstages40%ofthetime.[2]Thus,atissuespecimenis
neededforhistologicdiagnosistodistinguishCINfrominvasiveSCC.

Duetoitsmalignantseedingpotential,itisrecommendedthatanexcisional,ratherthanincisional,biopsybeperformedwhenpossible.
Thisincludesallsmallertumors(limbaltumors<4clockhoursor<15mmbasaldimension).[8]Ifthelesionistoolarge,anincisional
biopsy(punchorincisionalwedge)tofirstobtainahistopathologicdiagnosismaybenecessarybeforeproceedingtomoreextensive
treatment.[8]

Inadditiontoahistologicalsample,impressioncytologyhasbeenoccasionallyusedinthediagnosisofOSSNlesions,suchasinour
patient'searlyworkup.Despiteit'sahighpositivepredictivevaleof97.4%,itsnegativepredicativevalueisonly52.9%,makingita
poordiagnostictoolbutvaluableasanoninvasivescreeningtechnique.[9]

ItisnotunusualforinvasiveSCCtoinvadelocallyintothesclera,intraocularly,orintotheorbit,withonestudyestimatingincidence
ratestobe37%,13%and11%respectively.[10]Incaseswhereextensivespreadissuspected,itisimportanttoassesstheextentofthe

http://webeye.ophth.uiowa.edu/eyeforum/cases/163OSSN.htm 5/11
5/7/2016 AVeryUnusualCaseofOcularSurfaceSquamousNeoplasia
lesionwithultrasoundbiomicroscopy(toassessscleralorintraocularinvasion),gonioscopy(ifangleinvasionissuspected),or
GadoliniumenhancedMRIscans(toassessorbitalextension).Fortunately,eventhemostaggressiveformofOSSN,invasiveSCC,
usuallyisnotassociatedwithregionalordistantmetastases,andonlyafewcaseshavebeenreported.[11,12]

Treatment

AllformsofOSSNtumorsaretreatedaggressivelybutwithmarkedlydifferentanticipatedtherapeuticendpointsthegoalofless
invasivediseaseiscompleteeradication,whilethegoalofinvasivediseaseistominimizespreadofthedisease.Dependingonthelesion
andhistopathologicfindings,treatmentcanrangefromtopicalchemotherapyorexcisionaloneforsmallerlesionsversusacombination
ofsurgicalexcision,cryotherapy,andchemotherapyforlargerorinvasive.Rarely,radiotherapy,andinextremecases,enucleationand
evenexenteration,maybenecessary.[3,8,13]

A2to4mmmarginbeyondclinicallyevidentdiseaseisperformed.Intraoperative,cryotherapycanbeappliedtotheedgeofthe
excisiontofreezeanyresidualviablecells.Duringtheprocedure,mitomycinC(0.2mg/mLor0.4mg/mL)canbeappliedtopicallyfor
12minutes.Ifthelesionextendsontothecornea,absolutealcoholcanbeusedtoremovetheinvolvedcornealepithelium.Copious

irrigationneedstobeperformedfollowingtheapplicationofmitomycinCorabsolutealcohol.Afterremovaloflargertumors,
conjunctivalautograftsoramnioticmembranegraftscanbeusedtohelpclosetheconjunctivaldefect.[8,13]

Chemotherapyhasbecomethemainstaytoadjunctivetreatmentwithsurgicalexcision,andhasshowntobeveryeffective.Thisis
typicallyaccomplishedthroughtopicaleyedropsofmitomycinC,5fluorouracil,orinterferonalpha2B.MitomycinCdropsare
typicallyprescribedfourtimesperdayfor13weeks,followedby13weeksofnodropstoallowforocularsurfacerecovery.This
cycleisrepeated2to4timesdependingontheclinicalresponse.[8]Sideeffectsfromtopicalchemotherapyincludedryeye,superficial
punctateepitheliopathy,punctualstenosis,andrarelystemcelldeficiency.Punctalocclusionwithpunctalplugsisrecommendedpriorto
startingtheseregimenstopreventpunctalstenosis.[3,8,13]

Ageneralmechanismofeachofthemainchemotherapeuticagentsisoutlinedbelow.

MitomycinC(MMC)isanalkylatingagentthatbindstoDNAduringallphasesofthecellcycle,leadingtoirreversiblecross
linkingandinhibitionofnucleosidesynthesis.[1417]
5Flurouracil(5FU)isanantimetabolitethatinhibitsthymidylatesynthestaseduringtheSphaseofthecellcycle,preventing
DNAandRNAsynthesisinrapidlydividingcellsbecauseofalackofthymidine.[18]
Interferon(INF)Alpha2B:Interferonsareafamilyofglycoproteinmoleculesthatactatcellsurfacereceptorstoproduce
antiviralandantitumoractivitiesthroughdirectandindirectmechanisms.TopicalINFalpha2BistherecombinantformofINF
alphaandthemechanismofactionfortreatingOSSNlesionsmayberelatedtoanindirectantiproliferativeeffectoftopical
interferononsuperficialtumorcellsbypromotingthehostimmuneresponseandhostcytotoxiceffectorcells.[19]

Therearetwotypesofradiationtherapyemployed:externalbeamradiotherapyandcustomdesignedplaqueradiotherapy.Radiotherapy
aloneoraccompanyingenucleationisreservedforparticularlysevereandwidespreadcaseswheretheextentofthelesionprecludes
excision.[8]

Prognosis

ManycasesofinvasiveSCCaretreatedsuccessfullywithexcisionalbiopsycombinedwithadjuvanttopicalchemotherapyandgenerally
carryafavorableprognosis.Cautionmustbetakentoevaluateforspreadofdisease.InvasiveSCCcaninvadethescleralwalland
infiltrateothertissuesoftheglobeorspreadintotheorbit.Intraocularspreadistypicallytreatedwithenucleationandorbital
involvementwithexenteration.

RecurrenceofanyformofOSSNispossible,withanoverallrecurrencerateof12.9%.[20]Tumorrecurrenceislargelypredictedbythe
size(>5mmindiameter),stage,andhistologicdiagnosisofthetumoratthetimeofpresentationnoneofthetumorsdefined
histologicallyasdysplasiarecurred,while12.8%ofCIStumorsand22.2%ofSCCshowedrecurrance.[20]

TakeHomePoints:

Thisisaveryatypicalcaseofocularsurfacesquamousneoplasia.
YoungpatientswithocularsurfacesquamousneoplasiashouldhaveHIVtesting.

Epidemiology

Incidence:0.131.9per100,000
Men>Women
Advancedage
Extensivesunexposure
Otherriskfactorsincludeimmunosuppression(HIV,chemotherapy),otherinfections(HPV,trachoma)andirritants(chemical,
chronicepitheliopathies).

Signs

Massoriginatingfromthelimbuswiththefollowingcharacteristics:

Pearlygraytoreddishbrown
Papilliformtogelatinoussurface
http://webeye.ophth.uiowa.edu/eyeforum/cases/163OSSN.htm 6/11
5/7/2016 AVeryUnusualCaseofOcularSurfaceSquamousNeoplasia
Papilliformtogelatinoussurface
Mayhaveprominentfeedervessels
Mayhaveleukoplakia
Massesareinitiallymobileandlaterbecomefixedtosclera

Symptoms

Chronicirritation
Redeye
Tearing
Rarelyaffectsvision
*Maybeasymptomatic*

Treatment

Topicalchemotherapyalone
Excisionalone
Combinationofexcisionandadjuvantchemotherapy
Rarelyradiation,enucleation,orexenteration

DifferentialDiagnosisofOSSN

Cornealpannus
Pterygium
Pinguecculum
Melanoma
Conjunctivalnevus
Dyskeratosis
Pyogenicgranuloma
Keratoacanthoma
Conjunctivallymphoma(salmonpatch)

References

1. CoroiMC,RoscaE,MutiuG,CoroiT.Squamouscarcinomaoftheconjunctiva.RomJMorpholEmbryol201152(1):513515.
2. LeeGA,GirstLW.Occularsurfacesqamousneoplasia.SurvOphthalmol199539(6):429450.
3. BirkholzES,GoinsKM,SutphinJE,KitzmannAS,WagonerMD.Treatmentofocularsurfacesquamouscellintraepithelial
neoplasiawithandwithoutmitomycinC.Cornea201130(1):3741.
4. NewtonR.Areviewoftheaetiologyofsquamouscellcarcinomaoftheconjunctiva.BritishJournalofCancer199674:1511
1513.
5. LeeGA,WilliamsG,HirstLWGreenAC.Riskfactorsinthedevelopmentofocuarsurfaceepithelialdysplasia.Ophthalmology
1994101:360364.
6. MargoCE,MackW,GuffeyJM.Squamouscellcarcinomaoftheconjunctivaandhumanimmunodeficiencyvirusinfection.Arch
Ophthalmol1996114:349.
7. KarpCL,ScottIU,ChangTS,etal.Conjunctivalintraepithelialneoplasia:apossiblemarkerforhumanimmunodeficiencyvirus
infection.ArchOphthalmol1996114:25761.
8. PapaioannouIT,MelachrinouMP,DrimtziasEG,GartaganisSP.Cornealconjunctivalsquamouscellcarcinoma.Cornea
200827(8):957958.
9. TananuvatN,LertprasertsukN,MahanupapP,NoppanakeepongP.Roleofimpressioncytologyindiagnosisofocularsurface
neoplasia.Cornea.200827:26974.
10. TuncM,CharDH,CrawfordB,MillerT.Intraepithelialandinvasivesquamouscellcarcinomaoftheconjunctiva:Analysisof60
cases.BrJOphthalmol.199983:98103.
11. ZimmermanL.Thecancerous,precancerous,andpseudocancerouslesionofthecorneaandconjunctiva:corneoplasticsurgery.
ProceedingsoftheSecondAnnualInternationalCorenoplasticConference.London:PergamonPress1969.
12. TabbaraKF,KerstenR,DaoukN,BlodiFC.Metastaticsquamouscellcarcinomaoftheconjunctiva.Ophthalmology1998
95(3):318321.
13. ZakiAA,FaridSF.Managementofintraepithelialandinvasiveneoplasiaofthecorneaandconjunctiva:alongtermfollowup.
Cornea200928(9):986988.
14. FruchtPeryJ,RozenmanY.MitomycinCtherapyforcornealintraepithelialneoplasia.AmJOphthalmol1994117:164168.
15. FruchPeryJ,SugarJ,BaumJ,etal.MitomycinCtreatmentofconjunctivalcornealintraepithelialneoplasia:amulticenter
experience.Ophthalmology1997104:20852093.
16. PapandroudisAA,DimitrakosSA,StangosNT.MitomycinCtherapyforconjunctivalcornealintraepiethelialneoplasia.Cornea
200221:715717.
17. McKelviePA,DaniellM.ImpressioncytologyfollowingmitomycinCtherapyforocularsurfacesquamousneoplasias.BrJ

http://webeye.ophth.uiowa.edu/eyeforum/cases/163OSSN.htm 7/11
5/7/2016 AVeryUnusualCaseofOcularSurfaceSquamousNeoplasia
Ophthalmology200185:11159.
18. MidenaE,AngeiliCD,ValentiM,etal.Treatmentofconjunctivalsquamouscellcarcinomawithtopical5fluoruracil.BrJ
Ophthalmology20084:26872.
19. BaronS,TyringSK,FleischmannWR,etal.Theinterferons.Mechanismsofactionandclinicalapplications.JAMA
1991266:137583.
20. YousefYA,FingerPT.Squamouscarcinomaandysplasiaoftheconjunctivaandcorneaananalysisof101cases.Ophthalmology
2012119(2):233240.

SuggestedCitationFormat:BoeseE,RogersGM,KitzmannAS.AVeryUnusualCaseofOcularSurfaceSquamousNeoplasia.
EyeRounds.org.February14,2013Availablefrom:http://EyeRounds.org/cases/163OSSN.htm

http://webeye.ophth.uiowa.edu/eyeforum/cases/163OSSN.htm 8/11
5/7/2016 AVeryUnusualCaseofOcularSurfaceSquamousNeoplasia

http://webeye.ophth.uiowa.edu/eyeforum/cases/163OSSN.htm 9/11
5/7/2016 AVeryUnusualCaseofOcularSurfaceSquamousNeoplasia

http://webeye.ophth.uiowa.edu/eyeforum/cases/163OSSN.htm 10/11
5/7/2016 AVeryUnusualCaseofOcularSurfaceSquamousNeoplasia

02/14/2013
UIHospitals&Clinics
UICarverCollegeofMedicine
UIOphthalmologyDept.

Copyright2013TheUniversityofIowa

http://webeye.ophth.uiowa.edu/eyeforum/cases/163OSSN.htm 11/11