J. Coloproctol. (Rio J.) vol.37 número1

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w w w . j c o l . o r g . b r

Journal

of

Coloproctology

Review

Article

Anal

canal

squamous

carcinoma

夽

Maricruz

Nunes

Magalhães

a,∗

,

Laura

Elisabete

Ribeiro

Barbosa

b

a_Universidade_do_Porto,_Faculdade_de_Medicina,_Porto,_Portugal

b_Universidade_do_Porto,_Faculdade_de_Medicina,_Centro_Hospitalar_São_João,_Servic¸o_de_Cirurgia_Geral,_Porto,_Portugal

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received21June2016

Accepted24August2016

Availableonline17September2016

Keywords:

Squamouscellcarcinoma

Analcanal

HPV HIV

a

b

s

t

r

a

c

t

Background:Analcanalcarcinoma isa rareneoplasm, representing2%ofthe digestive

tumors,andthemostcommonissquamouscellcarcinoma,withanincreasingincidence.

Objective:Thestudyaimstoelucidatethepathogenesisofanincreasinglyprevalentdisease,

aswellastoupdatetreatmentandprognosis.

Methods:AliteraturesearchinPubmeddatabase,includingarticlesfrom2005to2015and

cross-researcharticleswiththeinitialresearch.

Results:SeveralstudiesprovetheroleofHPVasamajorriskfactorinthedevelopment

ofsquamouscellcarcinomaofanalcanal,aswellasagreaterprevalenceofthis

neopla-siainHIV-positivepeopleandinthosewhopracticereceptiveanalintercourse.Inthelast

twodecadeschemoradiotherapyremainsthetreatmentofchoice,andabdominoperineal

resectionisreservedforthosecasesoftreatmentfailureorrecurrence.Evidenceadvances

inordertoadaptthetreatmenttoeachpatient,takingintoaccountindividualprognostic

factorsandbiologicaltumorcharacteristics.

Conclusions:SquamouscellcarcinomaoftheanalcanalisaneoplasmassociatedwithHPV;

therefore,screeningandvaccinationprogramsofmaleindividuals,bywayofprevention,

shouldbestarted.Manystudiesareneededinordertoachievedevelopmentinthetreatment

aswellasintheevaluationofthebiologicalcharacteristicsofthetumor.

isanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/

licenses/by-nc-nd/4.0/).

Carcinoma

epidermóide

do

canal

anal

Palavras-chave:

Carcinomaescamoso

Canalanal

HPV HIV

r

e

s

u

m

o

Introduc¸ão:Ocarcinomadocanalanaléumaneoplasiarara,representando2%dostumores

digestivos,sendooepidermóideomaiscomumcomumaincidênciacrescente.

Objetivo:Esteestudopretendeelucidarsobreaetiopatogeniadestapatologiacadavezmais

prevalente,assimcomoatualizarsobreotratamentoeprognóstico.

Métodos:PesquisabibliográficanabasededadosPubmed,incluindoartigosde2005a2015,

assimcomoartigosdepesquisacruzadacomosartigosiniciais.

夽

StudyconductedattheDepartamentodeCirurgia,FaculdadedeMedicina,UniversidadedoPorto,Porto,Portugal.

∗ _{Corresponding}_author_.

E-mail:maricruznunes@live.com.pt(M.N.Magalhães).

http://dx.doi.org/10.1016/j.jcol.2016.08.003

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Resultados: DiversosestudosprovamopapeldoHPV comoumfatorderiscomajorno

desenvolvimentodecarcinomaepidermóidedocanal,assimcomoumamaiorprevalência

destaneoplasianapopulac¸ãoHIVpositivaenosquepraticamsexoanalrecetivo.O

trata-mentocontinuaaserdesdeháduasdécadasaquimioradioterapia,reservandoaressec¸ão

abdominoperinealparacasosdefalênciadotratamentoourecorrência.Aevidênciaavanc¸a

nosentidodeadequarotratamentoacadadoente,tendoemcontafatoresprognósticos

individuaiseascaracterísticasbiológicasdotumor.

Conclusões: OcarcinomaepidermóidedocanalanaléumaneoplasiaassociadaaoHPV,

logodeveriainiciar-seprogramasderastreioevacinarosexomasculinocomoprevenc¸ão.

Muitosestudossãonecessáriosparaevoluirnotratamento,assimcomonaavaliac¸ãodas

característicasbiológicasdotumor.

´eumartigoOpenAccesssobumalicenc¸aCCBY-NC-ND(http://creativecommons.org/

licenses/by-nc-nd/4.0/).

Introduction

Anatomyandhistologyoftheanalcanal

Theanalcanalmeasuresapproximately4cminlength,being

shorterinwomen.Thischannelisthelower portionofthe

gastrointestinaltract.1_Its_surgical_margins_are_the_anal_verge

distallyandtheanorectaljunctionproximally.1,2

Histologically,intheanalcanal,onecanfindseveraltypes

ofepithelia.1,2 _Proximally,_the_channel _is_formed_by

colum-narepitheliumsimilartotheintestinalepithelium,which,in

theanalcanal,hasfoldsinthemucousmembraneforming

theanalcolumns.Thesecolumnsareconnectedtransversely

byfolds called anal valves, which, together constitute the

pectinealline.1,2 _The_{non-keratinized}_squamous_epithelium

thatislocateddistallytothepectineallinelackshair

folli-clesandsebaceousandsweatglands,unlikethekeratinized

epitheliumwhichiscontinuousintheanalverge.1–4_in

addi-tion, between the pectineal line and the non-keratinized

squamousepitheliumthereisatransitionzoneinwhichthe

epitheliummaybeofthecolumnar,cubic,transitional(asin

bladder),orsquamoustype.Thistransitionzoneisvery

spe-cifictotheanalarea,andmayalsobecalledofcloacogenic

zone,forembryologicalreasons.1–4

Classificationofneoplasmsoftheanalcanal

Classically,thegenericterm“anus”comprisestheanalcanal

andtheanalverge.5_Thus,_neoplasms_of_this_zone_are_divided

betweenthesetwolocations.5_The_tumors_of_the_anal_verge,

knownasperianalcancers,areidenticaltosquamousor

epi-dermoidcutaneoustumors,andthereforedonotenterinto

theWorldHealthOrganization(WHO)classificationof

diges-tivetumors.5_In_view_of_the_lack_of_clarity_between_tumors_of

theanalcanalandanalverge,WHOhasproposedapragmatic

definition,statingthat“atumoroftheanalcanalisatumor

thatcannotbeseenentirelywiththehelpofasubtlepullof

thebuttocks”.5 _There _are _several _types_of_tumors,

depend-ingonthetypeofepitheliuminvolved,includingsquamous

or epidermoid tumor, which is the predominant

histo-logictype,whileotherrarertypesincludeadenocarcinoma,

neuroendocrinetumors,stromaltumors,lymphomasand

sec-ondarytumors.5

Giventhesimilaritiesbetweentheepidermoidcarcinoma

oftheanalcanalandthatoftheuterinecervix,thereisa

cyto-logicalandhistologicalclassificationforanallesionssimilarto

theclassificationforthecervix.6_The_modified_Bethesda

cyto-logical classificationsystemdivides squamousanal lesions

into high- and low-grade intraepithelial lesions, and these

lesionsstillhaveintermediateclassifications,called“probable

low-andhigh-gradelesions”.6_There_is_also_a_{classification}_of

invasivesquamouscellcarcinoma.6

Despite the high malignant potential of the high-grade

intraepitheliallesions,7_less_than_1%_per_year_will_progress_to

cancer.3

Epidemiologyofanalcanalneoplasms

Malignant tumorsof the anal canal represent 0.43% of all

malignancies and 2%ofthe digestive malignant tumors.5,8

Overall,themostprevalentcanceroftheanalcanalis

squa-mous cell carcinoma (85%), followed by adenocarcinoma

(10%).Theothertypesarerare,representinglessthan5%of

alldiagnosedtumorsoftheanalcanal.8

Analcancerincreasedby50%overthepast25years,but

thisisstillarareneoplasm.6_Its_annual_incidence_has_been_of

1in100,000people,andishigherinwomen.Inthelasttwo

decades,asignificantmodificationinsurvivalafter5yearswas

notobserved,rangingfrom66%to44%inCentralandEastern

Europe,respectively.9

Mostexistingepidemiologicalinformationrefersto

squa-mous cell carcinoma. Thus, according to statistics, the

squamous cell type is more prevalent in women, its risk

increaseswithage(theaverageageatdiagnosisis60years)

and when it occurs in young, often these patients are

immunocompromised.5_However,_the_occurrence_of_diagnoses

inincreasinglyyoungerpeoplehasbeenfound.6

Methods

The literature survey was conducted inPubmed database.

Thephrases“epidermoidcarcinomaoftheanal canal”and

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articlespublishedfrom2005to2015andperformedinhumans

wereconsidered.AlanguagefilterforsearchonlyinEnglish,

Portugueseand Spanishwasincluded.Opinionarticlesand

letterstotheauthorswereexcluded.Afterreadingthetitle

andabstract,andsubjecttoanavailabilityofthearticle,36

articleswereobtainedinPubmed.Articlesobtainedby

cross-searchingwiththearticlesoftheinitialresearchandbooks

withrelevantinformationwerealsoadded.

Results

Etiologyandpathogenesisofsquamouscellcarcinoma

Someriskfactorshavebeensuggestedforthedevelopment

ofthis neoplasm, particularlyfemale gender, Human

pap-illomavirus (HPV) infection,history ofsexually transmitted

disease,a number greater than 10 sexual partners,

recep-tive anal sex history, previous history of warts or genital

malignancyinjuries, Human immunodeficiency virus (HIV)

infection,immunosuppression,smoking,andprolongeduse

ofcorticosteroids.3,4

Overtheyears,ithasbeenfoundthatHPVinfectionisan

importantcause.10_Ouhoummane_et_al.,_in_a_study_conducted

inQuebec,obtainedresultsfavoringthishypothesis.11

Ninety-twopercentofcasesofepidermoidcarcinomawerecolonized

withHPV,andthemostprevalenttypewasHPV16.11

HPVinfectionisthemostprevalentsexuallytransmitted

disease.12 _This_agent _is_a _{double-stranded}_DNA _virus _with

160differenttypesdescribedandwithspecifictissuetropism.

Thirtytypesexhibittropismforanogenitalepithelium,and

types16and18arethosewithgreatermalignantpotential,

althoughtheyarealsoinvolvedinbenignlesions.12

Thepathogenesisofthe lesionscausedbythis agentin

theanal canalhasbeenrelated tothepathogenesisinthe

uterinecervix.10 _Similar_to_what_happens_in_the_cervix,_the

carcinogenesisintheanalcanalbyHPVcoursesthefollowing

timesequence:Infection,persistenceofinfection,dysplasia

development,andprogressiontoaninvasivecancer.10_These

stepscanbereversedbytheregressionoftheinfection.10

AlthoughtheHPVlifecycleintheepitheliumofthecervix

and in the anal canal is the same, the natural history of

theintraepitheliallesionsisnotidentical,sincetheanatomy,

physiology,andimmuneresponsearedifferentinthecervix

andintheanalcanal.6

Initially, themethod thatthe virus uses tocolonizethe

hostisto evadethe innateimmunity mechanisms,

partic-ularly the physicalbarrier, antimicrobial peptides, Toll-like

receptors,andvarious immunecells.6 _{Circumventing} _these

mechanismsdelaysactivationofadaptiveimmunity,6_which

facilitatesvirusentryintocells.Byintegratingintothehost

genome,the viruswillcausecellularchanges thatare

pre-dominantly theresponsibility oftwoviral proteins,E6and

E7.13_One_of_the_mechanisms _used_to_modify_the _cell_cycle

isthealterationoftumorsuppressorgenes.13_p16_(inhibitor

of kinase 4), a cell-cycle regulatory protein, interacts with

CDK4and CDK6inhibiting the bindingofthesesubstances

tocyclinDandconsequentlyreducingitskinaseactivity.This

inhibitionpreventsthe phosphorylationofRbprotein,thus

inhibitingthetranscriptionalactivationbytheE2Fcomplex,

which,inturn,preventsthepassageofG1totheSphaseof

thecellcycle.14_The_E7_protein,_by_integrating_into_the_genome,

changes thenormalp16proteinfunctioning.6_On_the _other

hand,E6isresponsibleforsuppressingthenormalfunctioning

ofp53,anotherregulatoryproteinofthecellcycleand

respon-sible foractivating the transcription ofgenes that encode

p16-likeproteins.6_E6_protein_also_promotes_the_activation_of

telomerase,perpetuatingthetransformationand

immortal-izationofthecell.6

The changeof p16and p53 expressionhasbeen linked

toHPV,tothepointofdifferentiatingHPV-positiveand

HPV-negativecanceroftheanalcanalbasedonthederegulationof

theexpressionofthesegenes.13_The_expression_of_p16_is_the

mostaffectedincasesofHPVinfection,whilep53mutation

isassociatedwithHPV-negativecarcinoma.15_This_distinction

betweenHPV-positiveandHPV-negativecarcinomaprovesto

beimportantbecausethereisadirectimplicationofthe

bio-logicaldifferencesbetweenthetwotypesintheresponseto

treatmentandinprognosis.13

Asalreadymentionedinthispaper,HIVinfectionisarisk

factorforsquamouscellcarcinoma.10_Even_not_being_a

pri-maryetiologicagent,HIVisaco-infectionmarkerforother

sexuallytransmitteddiseases,includingHPV,10_and_one_may

observe a high prevalence of co-infection by HPV in

HIV-positivepopulations.16_However,_not_all_patients_infected_with

HPVdevelopintraepitheliallesionsresultingfrominfection.6

Overtheyearsandespeciallyintheeraofantiretroviral

ther-apy, the carcinoma epidermoid of anal canal has become

the more prevalent acquired immunodeficiency syndrome

(AIDS)non-definingneoplasminHIV-positiveadultsubjects,

being30timesmoreprevalentinthispopulationthaninthe

generalpopulation.6 _in_addition _to_the _higher_incidence_in

relationtothegeneralpopulation,patientswithHIValsoshow

higherlikelihoodofprogressiontoahigh-grade,

intraepithe-liallesion-invasive,analcarcinoma.17

Anotheralreadycitedriskfactoristhepracticeofreceptive

analintercourse.6_Some_studies_have_compared_the_frequency

ofhigh-gradeintraepithelialanallesionsinHIV-positiveand

HIV-negative menwho haveanal sexwithothermen, and

theresultsrevealednosignificantdifferencebetweenthese

groups.6 _This _finding _may _suggest _that _the _{immunological}

deficits in HIVinfection may not playsucha decisive role

ashadbeenpreviouslythoughtinthedevelopmentof

high-gradelesionsthroughhigh-riskHPV.6_Some_studies_conducted

specificallywithHPV16foundthatincertainvariantsofthe

virusthereisaprogressiontocarcinomawhetherornotin

the presence ofHIV infection and irrespective of CD4+

T-lymphocytecount.6

Thosestudieswhichwereconductedinordertoevaluate

theimpactoftheimmunesystem,particularlyofregulatory

CD4+ T cells,in HPV infection, focused on intra-epithelial

lesionsandoncarcinomasoftheuterinecervix.6_These

stud-ies showed that these cells play an important role in the

regressionofinfection,andconsequentlyinthelesionscaused

byHPV,especiallyHPVtype16.6_Therefore,_given_that_the_HIV

infection induces immunodeficiency in CD4+ lymphocytes,

theHIVinfectionisconsideredasariskfactorforinfection

byHPV,forintraepitheliallesionsandforinvasiveanal

car-cinoma, takinginto accounttheroleofCD4+Tcellsinthe

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authorssticktothehypothesisthatthereareother

determi-nantsinthecarcinogenesisprocess,6_taking_into_account_that

theantiretroviraltherapydidnotreducetheincidenceofanal

cancerinpeoplewithHIV.18

Preventionandscreening

Theidentificationofamajoretiologicalagent,suchasHPV,has

allowedthedevelopmentofavaccinepreventinginfectionby

certainstrains,particularlythemostcommonand

pathologi-cal,andconcomitantlypreventingsquamouscellcarcinoma.9

Thisvaccinehasbeendevelopedinordertopreventcarcinoma

ofthecervix,however,itisanticipateditalsoprevents80%of

analcarcinomata.9

Basedontheresultsofcervicalcytologyintheprevention

ofcervixcarcinoma,screeningprogramswithanal cytology

and high-resolution anoscopy have been proposed forrisk

groupsforanalcancer,includingindividualspracticing

recep-tiveanal sex, HIV patients, and patientswith a history of

anogenitalmalignanciescausedbyHPV.9_In_conjunction_with

thehigh-resolutionanoscopy,onecanaddaceticacid,which

differentiateslow-andhigh-gradeintraepitheliallesions,

sta-ining in white color those precursor lesions of high-grade

dysplasia.19

Thescreeningcanenabletheidentificationof

malignan-ciesintheir earlystageand atimelytreatment, aswell as

thediagnosisofthoseprecursorintraepitheliallesions,often

asymptomatic.20

Anal cytology haslow sensitivitybut greatspecificity.21

Inadequatespecimencollectioncontinuestobeamajor

limi-tationofthistest,andthisprocedureshouldbeimprovedfor

makingtheanalcytologyarecommendedscreeningtestfor

allpatientsatriskofanalcarcinoma.21

Diagnosis

Clinical history isalways critical, regardlessof the area of

medicine,andanalcancerisnoexception.Onemust

deter-mine all the symptoms and predisponent riskfactors that

couldsuggestthisdiagnosis.9

Anal carcinoma is characterized by an indolent

natu-ralhistory,9 _with_a_presentation_of_anal _bleeding,_the _most

commonsymptom,3_often_confused_with_a_bleeding_of

hem-orrhoidalorigin,whichdelaysdiagnosis.9 _The_second _most

common symptom isproctalgia,3 _which _may _be

accompa-niedbyamass,anulcerwhichdoesnotheal,itching,mucus

emission,fecalincontinence,andfistulae.9_However,_20%_of

patientsareasymptomaticatdiagnosis.22

Currently,therecommendeddiagnostictestsarethe

digi-talrectalexaminationandproctoscopy,thatshouldbecarried

outbyanexpertdoctorand,ifnecessary,undersedationto

allowforanadequate histologicalbiopsy,a criticalstep to

diagnosis.9,23_{Additionally,}_a_diagnostic_test_for_HIV_and_a_CD4+

T-lymphocytecountshouldbecarriedout.23

The gynecological exam is an important procedure for

female patients, in order to evaluate vaginal involvement,

especiallyinlowerandearliertumors,aswellastoruleoutthe

presenceoffistulae.9_The_gynecologic_evaluation_is_also

impor-tantbecause oftensynchronous andmetachronous genital

neoplasmsrelatedtoHPVdevelopinthecontextofananal

squamouscellcarcinomainwomen.9_A_cytology_test_for_cervix

cancerscreeningshouldalsobeheld.23

Staging

For thestagingofneoplasia,theTNMsystemisused.This

systemisbasedontumorsize(T),onregionalnodular

involve-ment (N),and on thepresenceofmetastasis(M).9 _Nodular

involvementisassessedtakingintoaccountthedistanceto

theprimarysiteandnotthenumberofnodesinvolved.9

Imagingevaluationisessentialtoassesslocalinvolvement,

withthehelpofnuclearmagneticresonance(NMR)imagesor

ofanendoanalpelvicechography,aprocedurequiteeffective

todeterminethetransmuraldepthofthetumor,especiallyin

thecaseofsmallT1lesions,wherethisprocedureshowsbetter

accuracy.9_With_magnetic_resonance,_one_can_obtain

informa-tiononthesizeofthetumor,invasionofadjacentorgans,and

nodularinvolvement.9

Obtainingathoracicandabdominalcomputedtomography

(CT)isalsodesirable,inordertodetectdistantmetastases,9,23

which are present at diagnosis in 5–8% of cases.9 _On _the

otherhand,onecanalsoconsideraPET(positronemission

tomography)study,althoughthisdoesnotreplaceaCTscan.23

However,whenthisprocedureisperformedwith

fluorodeoxy-glucose,showshighsensitivitytodetectnodularinvolvement,

suchthat severalstudies havedemonstrated ashift inthe

tumorstagein20%ofcases.9,22_When_this_occurs,_the_trend

isinfavorofincreasingthestage,whichchangesthe

treat-ment plan andinfluencing particularly the radiotherapyin

approximately3–5%ofcases.9_This_technique_is_of_importance

becauseatdiagnosisnodalinvolvementisfoundin30–40%of

cases.9_{Additionally,}_an_assessment_by_palpation_of_the

pres-enceofinguinaladenopathy,particularlysurfaceandmedial

ones,9,23_is_critical;_if_detected,_these_injuries_should_be

biop-sied byfine-needle aspiration,23 _as_well _as_those_increased

nodeswithmorethan10mm,detectedonimagingstudies.9

Inguinallymphinvolvementisanindependent

prognos-tic factor in patients with anal carcinoma.24 _Therefore, _to

improvethediagnosticaccuracywithrespecttonode

involve-mentandradiotherapyregime,JohnSprattin2000proposed

asentinellymphaticnodebiopsyasadiagnostictestof

gan-glionmicro-metastases.25_At_the_same_time,_Spratt_suggested

thattheprophylacticsurgicaldissectionoftheinguinallymph

nodesisnotrequired,butmaybecurativeinmanycaseswith

nodularinvolvementorwhichpresentapositivesentinelnode

biopsy.25_However,_due_to_the_high_{false-negative}_rate_found_in

somestudies,thisprocedureisnotyetpartoftheroutinetests

advised.24_However,_Mistrangelo_et_al.,_in_2013,_in_the_study_in

whichareviewofclinicaltrialsthatassesstheprecisionof

thistechniquewasperformed,obtainedafalsenegativerate

of3.7%,whichwasconsideredacceptable.Theseauthors

con-cludedthattheprocedurecanbeperformedinpatientswith

analcarcinomaandthatthisisaneasyandperfectlyfeasible

technique,withahighdetectionrateof98.4%reportedinthe

literature.24

Treatmentandcomplications

Themaingoaloftreatmentistoobtainacurewith

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sphincterfunctionandmaintainingthebestpossiblequality

oflife.9

Treatmentofsquamouscellcarcinomaoftheanalcanal

requiresamultidisciplinaryapproach,essentiallywheninthe

presenceof a state ofimmunosuppression.26 _The

involve-ment ofradiotherapists, oncologists,surgeons, radiologists

andpathologistsismandatory.9

Initially,uptothe1980ssurgerywasthetreatmentforall

analcarcinomas,mainlywithabdominoperinealresection.9,23

Severalstudiescarriedoutinthe1970s26_prompted_the

pub-licationbyNigroet al.in1983ofastudywhich concluded

thatcombinationtherapywithchemotherapyandradiation

therapywaseffectiveenoughtodismisssurgeryiftheinjury

wouldhavecompletelyregressed,andthatthiswasproven

through appropriatediagnostic ancillary laboratory tests.27

Thisconservativetherapeuticstrategyallowedanexcellent

localcontrol,disease-freesurvival,andqualityoflife.27

Theexclusiveuseofsurgeryhasahighrecurrenceanda

survivalat5yearsof30–70%.23_This_strategy_also_presents_the

disadvantagesofapermanent colostomy andhigh ratesof

genitourinarycomplications.23_{Chemoradiotherapy}_has_given

betterresultsversussurgery,withfewercomplicationsanda

survivalat5yearsof61–85%.18

Thus, the standard treatment for non-metastatic

squa-mous cell carcinoma of the anal canal has been a

combinationtherapy,withchemotherapyusing5-fluorouracil

(5FU)750mg/m2_/day_by_continuous_infusion_and_mitomycin

C(MMC)12mg/m2_on_day₁_of_each_cycle,23_and_radiotherapy

witharadiationtypicallybetween50and54Gy,26_providing_a

completeregressionin80–90%ofpatients.9_These

recommen-dationsarebasedonsixmulticenterclinicaltrialsevaluating

theresultsofthecombinedtreatment.28

Abdominoperinealresectionandpermanentcolostomyare

proceduresreserved forpatientswithresidual or recurrent

diseaseafteracompletetreatmentofchemoradiotherapy.29

Surgeryafterrecurrenceallowsalocalcontrolin60%ofcases

andasurvivalat5yearsof30–60%.9_The_fact_that_we_are_in

faceofaradicalsurgicalintervention,inanirradiatedsite,

increasestheriskofcomplicationsofthesurgicalwound.26

Inordertominimize thesecomplications,amyocutaneous

reconstructionusingtherectusabdominismusclecanbeheld,

andthatwasshowntobeaneffectivetechnique.26

Theriskofneedingapermanentcolostomyhasbeen

eval-uatedinseveralstudies,withtheconclusionthatthereare

pretreatmentindependentriskfactors,particularlymale

gen-der,tumorsize,andhemoglobinlevels,thatmayproveuseful

forpredictionofcombinationtherapyfailure,withthe

possi-bilityofofferingtothesepatientsthesurgicaltreatmentasan

initialtherapy.30

One consideration that must be borne in mind during

treatment is HIV infection.26 _Other _than

immunosuppres-sion, these patients show little tolerance tothe treatment

andapoorertoxicityprofile.26_Some_studies_have_found_that

HIV-positivepatientshaveaworseprognosiswith

chemora-diotherapythanHIV-negativepatients.31_One_of_the_problems

withthetreatmentarethehighdosesofradiation,poorly

tol-eratedbypatientswithHIV.Somestudieshaveproposedto

reducethe dose commonlyused infavorofless toxic

lev-elsthatcould simultaneouslyachieve theregression ofthe

neoplasm.26_Most_of_these_patients_who_showed_a_profile_of

little tolerance with routine radiation levels had a low

CD4+cell count.26_Thus,_some_studies_suggest_initiating_an

antiretroviraltherapyinordertoincreasethepatient’sCD4+

cellcounttomorethan200cells/L,beforestartingthe

treat-ment foranalcarcinoma.23,28 _This_strategy _is_supported_by

Wexleretal., that,intheirstudy,obtainedtherapeutic

out-comessimilarbothinHIV-negativeandHIV-positivepatients

treatedwithantiretroviraltherapy.32_However,_these_authors

found significant toxicity in HIV-positivepatients with the

standardizedtreatmentforanalcarcinoma,despitethe

con-trolledviralloadlevelsandCD4+cellcounts.32_On_the_other

hand,evidencesuggeststhataftertheimplementationofthe

appropriatetreatmentoftheHIVinfection,thetreatmentfor

analcarcinomaisstandardized,thatis,acombination

ther-apyusing5-FUand,andradiotherapywithnormalradiation

doses.28,33

Although we refer to the usual doses of radiation, the

truthisthattheoptimaldoseofradiationhasnotyetbeen

established, nor the ideal scheme.28,34 _There _are _different

approachestoradiationtherapy,butingeneralconventional

radiotherapyencompassesprimarytumorandaffectedlocal

lymph nodes.9 _A _number _of_studies _suggest _that _the

opti-maldoseofradiationvarieswiththetumor;therearetumors

thatneedahigherdose,aswellasothers thatmayregress

atalowerdose.35_Thus,_a_biomarker_would_be_useful_for_the

predictionoftumorresponse.Accordingly,multi-parameter

magneticresonanceisusedassuchinothersquamous

car-cinomas during chemoradiotherapy, and there is evidence

which suggestsits effectivenessinthe anal squamous

car-cinoma as a predictor of the individual patient response,

allowinganadjustmentofthedoseandoftheradiation

ther-apyregimen.35

Another group thatshould betaken into accountwhen

usingradiotherapyaretheelderly,asthisagegroupmaynot

toleratethefulldoseofradiationcommonlyused.3_This_puts

thematriskofbeingundertreated;thus,thecurrent

recom-mendations are that one donotevaluatethe suitabilityof

radiotherapyonlytakinginto accountthepatient’sage, but

alsoassessinghis/herphysiologicalstatus,which hasbeen

increasinglybetterwiththeincreaseinmeanlifeexpectancy.9

The high toxicity of radiation therapy has stimulated

the use of moreconformational techniques, witha

three-dimensionalplanningthatallowsamoredirectedapproach,

such as modulated-intensity radiotherapy,26 _which _has

proventoreducemorbidityinsomestudies,particularlyin

theRadiationTherapyOncologyGroup(RTOG)0529study.36

Thistechniqueachievesinalesserdegreetheadjacentorgans

freeofneoplasia,asthebladder,rectum,smallintestine,

gen-itals,femoralhead,andperianalskin.9,26_With_the_use_of_this

technique,onecanachieveafulldoseinashorterperiodof

time.9

Brachytherapy isa variantof conventional radiotherapy

but atan interstitial level, in which a high dose of

radia-tion,directlyincontactwiththeprimarytumor,isemitted,

notreachingthenormalsurroundingtissue,thecontralateral

mucosa,andthesphincter.9_In_isolation,_{brachytherapy}_is_not

recommended,butthetechniquecanbeusedafteraresponse

tostandardchemoradiotherapy.9_However,_Falk_et_al._in₂₀₁₄

publishedtheresultsofaclinicaltrial,inwhichtheseauthors

(6)

techniqueforspecificallytargetingtumorsandreducingthe

totaltimetotaloftreatment.37

Theacutetoxicityofradiationtherapyinvolvesprimarily

theskin, yieldingaradiation dermatitis,hematologic

com-plications,including myelosuppression; onthe other hand,

thepatientmayalsopresentwithfatigueandgastrointestinal

complications.9,26_The_long-term_{complications}_can_be_fibrosis

oftherectumandanalcanal,analsphincterdysfunction,skin

irritation,vaginalatrophy,anderectiledysfunction3,35_;

radia-tionenterocolitiscanalsooccurandisasevere,howeverrare,

adversesideeffect.38

Sideeffectsandlong-termcomplicationsofradiotherapy

andchemotherapyhaveraisedthehypothesisofusing

alter-nativetreatments,suchassubmucosalendoscopicdissection,

restrictedtocarcinomasinsitu,andthathasproved

success-fulin similar squamouscarcinomas inthe esophagus and

pharynx.38

Metastaticdiseaseoccursin10–20%ofpatients,andthe

mostaffectedsitesaredistantlymphnodes,liver,andlung.29

The less affected sites are the peritoneum, bones, brain

andskin.29 _The_5-year_survival_for_these_patients,_reported

in the literature, is 18–21%.29 _The _mean _time _to _onset _of

metastaticdiseasewas2yearsaftertreatmentforinsituanal

carcinoma.18

Duetothelowprevalenceofmetastasizedanalcarcinoma,

no clinical phase III clinical study was completed on the

treatmentofsquamouscellcarcinomaofthemetastasized

analcanal.26_Currently,_the_only_recommended_treatment_for

patientswithdistantmetastasesorwithlocalrecurrenceunfit

forsurgeryischemotherapywithcisplatinand5-FU,duetothe

hematologicaltoxicityassociatedwiththeprolongeduseof

5-FUandMMC,9_with_a_one-year_survival_rate_of_62.2%_and_with

a5-yearsurvivalof32.2%,andmeansurvivalof34.5months.39

Cisplatinwasalsostudiedinpatientswithinsituanal

carci-nomainplaceofMMC,andshowedsimilarresults,andthat

drugcanbeconsideredforcombinationtherapywith5-FU,not

onlyincasesofmetastaticcarcinomaasincarcinomalocally

advanced.40

The treatment regimen consists of a continuous

infu-sionof5-FU 750mg/m2_/day _for₅_days,_and_an_intravenous

dose 75mg/m2 _of _cisplatin _on _day _one _every ₂₈ _days.18,39

PhaseIIstudiescomparing5-FUandcisplatinwithcarboplatin

andpaclitaxelforthetreatmentofmetastaticsquamouscell

carcinomaoftheanalcanalareunderway,butwith

limita-tions,since5-FU/cisplatincombinationismostwidelyused,

whichmakesdifficultadirectcomparisonbetweenthetwo

combinations.18,26 _Trials_with_other_{chemotherapeutics}_that

have proven effective in other squamous carcinomas are

also under way.39 _The _results _reported _by _Kim _et _al.

sug-gestthatthe combination ofdocetaxel,cisplatin, and5-FU

canbebeneficialfortheremission oflong-termmetastatic

analcarcinoma,howeverthenumberofpatientsisagaina

restriction.41

Palliativesurgery andradiation should beconsidered in

the treatment of such patients.26 _Eng _et _al. _showed _that

patients undergoing resection ofmetastases, notably liver,

obtainbetterresultsindisease-freetimeandmeansurvival,

whencompared withpatients not undergoingresection of

metastases.23_However,_this_procedure_is_not_recommended,

andmorestudiesareneededtoexploresurgicalcriteria.23

Squamous cell carcinoma of the anal canal, as well

as other squamous carcinomas in other sites, exhibits an

increased expression ofepidermal growth factor receptors

(EGFR),alsoknown asHER-1 andc-erB-1.26 _Biological

ther-apytargetingthesereceptorshavebeenwidelydevelopedin

the treatmentofother squamouscarcinomas,andrecently

clinical trials have been conducted in order to evaluate

their effectivenessinlocally advancedand metastaticanal

carcinomata.23

Follow-up

There is controversy regarding the period of time that

mustelapsetoconsiderthatchemoradiotherapyhadfailed;

typically, 6 months should elapse for the occurrence of

tumorregression,but insomepatients, the periodmaybe

longer.23

Patientsincomplete remissionarereferredformagnetic

resonance imagingevery6monthsfor3years,asevidence

suggests that only<1%oftumorswill recurafter3years.9

Anoscopyishighlypainfulinthesepatientsundergoing

radi-ation therapy,sothisprocedureisnotrecommended.9 _Any

suspiciouslesionshouldbebiopsied.9

Patientsundergoingabdominoperinealresectionforlackof

therapeuticresponseorrecurrenceshouldbereassessedevery

3–6monthsfor5years,withaclinicalevaluation.Additionally,

thesepatientsshouldperformachestandabdominalCTand

apelvicNMRannuallyfor3years.23

Immunodepressed patientsshould beevaluated every 4

weeks from the onset of treatment, in order to monitor

regressions.23

Prognosis

Poorprognosticfactorsforanalcancerincludemalegender,

positivelymphnodes(especiallyinguinalnodes),andprimary

tumor>5cm.9_Skin_ulceration_was_also_identified_in_clinical

trialsasapoorprognosticfactorforlocalcontrolandmean

survival.9_Baseline_hemoglobin_levels_were_also_pointed_out_as

aprognosticfactorforpoorlocal-regionalcontrol,death,and

lowmeansurvival.9_Smokers_with_anal_carcinoma_appear_to

haveaworsemeansurvival,whencomparedtononsmoker

patients.9

Insquamouscarcinomasofthepharynxandlarynx,a

bet-terprognosiswasseen,whenHPVinfectionandmutationof

p16weredetected,withconsequentabnormalexpression.42

Meulendjiks et al. proved in their study that the presence

ofHPV infection and ofan alterationof p16expressionin

patients with squamous cell carcinoma of the anal canal

also provide a better prognosis, taking into account that

thesepatientsshowedbetterlocal-regionalcontrolandmean

survival.15

Studies related to serum antigenfrom squamous

carci-nomaestablishedacorrelationbetweenpretreatmentserum

levelsandclinicalclassificationofthetumor,nodular

involve-ment,responsetotherapy,riskofrecurrence,anddeath.Their

authorsconcludedthatelevatedserumlevelsofantigenwere

(7)

Discussion

Afterthissystematicreview,itappearsthatthereisstillmuch

tobeclarified,especiallyinthetreatmentarea.Despitea

ris-ingincidenceofanalcarcinoma,thelownumberofpatients

andthe exclusionofHIV-positivepatients inclinicaltrials,

inwhomthe prevalenceofthisdisease ishigher,havenot

allowedthecompletionofstudiesevaluatingnewtherapies.

Recently,somestudieshaveincludedpatientswithHIVin

clinicaltrials,23_which_is_crucial_since_there_is_much

contro-versyonthepossibleincreasedtoxicitywiththeuseofthe

standardtreatmentinthesepatients,inadditiontoallowing,

asalreadymentioned,alargersamplewithmoresignificant

andgeneralizableresults,sinceoneofthelimitationsofthose

studiesexcludingpatientswithHIVisthattheydonotallow

ageneralizationoftheirresultstothispopulation.Similarly,

womenshouldbeincludedinstudiesthattestreceptiveanal

intercourse as a risk factor, since most studies have only

reportedthis influenceinmen,excluding womenwiththe

samesexualbehavior.

Asstatedabove,areductionof80%ofanalcancerswith

the administration of the HPV vaccine occurs; it appears,

therefore,thatthenationalvaccinationplanshouldalsobe

extendedtomen.

Thetreatmentofbothlocalandmetastaticcarcinomahas

shownlittleprogressinthelasttwodecades,againthanks

totheshortageofthenumberofpatients;however,positive

resultsbegintoemergeinstudiestestingtherapiesthathave

provedeffectiveinother squamouscarcinomasfrom other

sites,notablybiologicaltherapy.

Thesuitabilityoftheindividualuseofradiotherapy,

tak-ing into account the individual prognostic factors (already

mentioned)andthebiologicalcharacteristicsofthetumor,is

apromisingstrategy.Inlinewiththis,moredirected

radia-tiontechniqueshaveevolvedandareofextremeimportance

inordertoreducethetoxicity,morbidity,andtheimpacton

qualityoflife.

Conclusion

Squamouscellcarcinomaoftheanalcanalisoneofthemost

prevalentmalignanciesinpatientswithHIV,whichisarisk

factorforHPVinfection,whichinturnisamajorcauseofanal

carcinoma.Receptiveanalsexisalsoanimportantriskfactor.

Somestudieshavebeenpublishedandcontinuetoemerge

inanattempttofindmoreeffectiveandalternativecytostatic

agents;however,wedonotcountonasufficientbodyof

evi-denceinordertoreplacetherecommendedcombinationof

5-FUandMMCinlocalizedcarcinomata,andof5-FUand

cis-platininmetastatictumors.23

Manystudiesareneededtopromoteprogressinthe

treat-mentofsquamouscellcarcinomaoftheanalcanal,aswellas

intheevaluationofthebiologicalcharacteristicsofthetumor

thatenableaprognosisoftheanswertotreatment,besidesan

individualandmoreeffectivetherapeuticsuitability.Onthe

otherhand,consideringthatthisneoplasiaisapreventable

diseaseinmostcases,inthefuture,onecancountonadvances

inprimaryandsecondarypreventionthroughvaccinationand

screening,respectively.

Conflicts

of

interest

Theauthordeclaresnoconflictsofinterest.

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1.SinnatambyCS.Last’sanatomy:regionalandapplied.10th ed.Edinburgh:ChurchillLivingstone;1999.

2.AgurAMR,LeeMJ,GrantJCB.Grant’satlasofanatomy.10th ed.London,UK:LippincottWilliamsandWilkins;1999.

3.WebbSP,LeeCS.Epidermoidcanceroftheanalcanal.Clin ColonRectalSurg.2011;24:142–8.

4.RobbBW,MutchMG.Epidermoidcarcinomaoftheanalcanal. ClinColonRectalSurg.2006;19:54–60.

5.FlejouJF.Anupdateonanalneoplasia.Histopathology. 2015;66:147–60.

6.TongWW,HillmanRJ,KelleherAD,GrulichAE,CarrA.Anal intraepithelialneoplasiaandsquamouscellcarcinomain HIV-infectedadults.HIVMed.2014;15:65–76.

7.BerryJM,JayN,CranstonRD,DarraghTM,HollyEA,Welton ML,etal.Progressionofanalhigh-gradesquamous intraepitheliallesionstoinvasiveanalcanceramong HIV-infectedmenwhohavesexwithmen.IntJCancer. 2014;134:1147–55.

8.ShridharR,ShibataD,ChanE,ThomasCR.Analcancer: currentstandardsincareandrecentchangesinpractice.CA CancerJClin.2015;65:139–62.

9.Glynne-JonesR,NilssonPJ,AscheleC,GohV,PeiffertD, CervantesA,etal.Analcancer:ESMO-ESSO-ESTROclinical practiceguidelinesfordiagnosis,treatmentandfollow-up. RadiotherOncol.2014;111:330–9.

10.NagleD.AnalsquamouscellcarcinomaintheHIV-positive patient.ClinColonRectalSurg.2009;22:102–6.

11.OuhoummaneN,StebenM,CoutleeF,VuongT,ForestP, RodierC,etal.Squamousanalcancer:patientcharacteristics andHPVtypedistribution.CancerEpidemiol.2013;37:807–12.

12.Mendez-MartinezR,Rivera-MartinezNE,Crabtree-RamirezB, Sierra-MaderoJG,Caro-VegaY,GalvanSC,etal.Multiple humanpapillomavirusinfectionsarehighlyprevalentinthe analcanalofhumanimmunodeficiencyvirus-positivemen whohavesexwithmen.BMCInfectDis.2014;14:671.

13.GilbertDC,WilliamsA,AllanK,StokoeJ,JacksonT,LinsdallS, etal.p16INK4A,p53,EGFRexpressionandKRASmutation statusinsquamouscellcancersoftheanus:correlationwith outcomesfollowingchemo-radiotherapy.RadiotherOncol. 2013;109:146–51.

14.LodishH,BerkA,KaiserCA,KriegerM,ScottMP,BretscherA. Molecularcellbiology.6thed.NewYork,UnitedStatesof America:Freeman;2008.

15.MeulendijksD,TomasoaNB,DewitL,SmitsPH,BakkerR,van VelthuysenML,etal.HPV-negativesquamouscellcarcinoma oftheanalcanalisunresponsivetostandardtreatmentand frequentlycarriesdisruptivemutationsinTP53.BrJCancer. 2015;112:1358–66.

16.Garcia-EspinosaB,Moro-RodriguezE,Alvarez-FernandezE. Humanpapillomavirusgenotypesinhuman

immunodeficiencyvirus-positivepatientswithanal pathologyinMadrid,Spain.DiagnPathol.2013;8:204.

(8)

18.EngC,ChangGJ,YouYN,DasP,Rodriguez-BigasM,XingY, etal.Theroleofsystemicchemotherapyand

multidisciplinarymanagementinimprovingtheoverall survivalofpatientswithmetastaticsquamouscellcarcinoma oftheanalcanal.Oncotarget.2014;5:11133–42.

19.GimenezF,Costa-e-SilvaIT,DaumasA,AraujoJ,MedeirosSG, FerreiraL.Thevalueofhigh-resolutionanoscopyinthe diagnosisofanalcancerprecursorlesionsinHIV-positive patients.ArqGastroenterol.2011;48:136–45.

20.WassermanJK,BatemanJ,MaiKT.Differentiatedsquamous intraepithelialneoplasiaassociatedwithsquamouscell carcinomaoftheanalcanal.Histopathology.2016;68:834–42.

21.SananpanichkulP,PittyanontS,YuthavisuthiP,Thawonwong N,TechapornroongM,BhamarapravatanaK,etal.Anal papanicolaousmearinwomenwithabnormalcytology:a Thaihospitalexperience.AsianPacJCancerPrev. 2015;16:1289–93.

22.OsborneMC,MaykelJ,JohnsonEK,SteeleSR.Analsquamous cellcarcinoma:anevolutionindiseaseandmanagement. WorldJGastroenterol.2014;20:13052–9.

23.EngC,AhmedS.Optimalmanagementofsquamouscell carcinomaoftheanalcanal:wherearewenow?ExpertRev AnticancerTher.2014;14:877–86.

24.MistrangeloDM,BelloM,CassoniP,MilanesiE,RaccaP, MunozF,etal.Valueofstagingsquamouscellcarcinomaof theanalmarginandcanalusingthesentinellymphnode procedure:anupdateoftheseriesandareviewofthe literature.BrJCancer.2013;108:527–32.

25.SprattJS.Canceroftheanus.JSurgOncol.2000;72:173–4.

26.AhmedS,EngC.Optimaltreatmentstrategiesforanalcancer. CurrTreatOptionsOncol.2014;15:443–55.

27.NigroND,SeydelHG,ConsidineB,VaitkeviciusVK,Leichman L,KinzieJJ.Combinedpreoperativeradiationand

chemotherapyforsquamouscellcarcinomaoftheanalcanal. Cancer.1983;51:1826–9.

28.SpithoffK,CummingsB,JonkerD,BiagiJJ,Gastrointestinal CancerDiseaseSiteGroup.Chemoradiotherapyforsquamous cellcanceroftheanalcanal:asystematicreview.ClinOncol. 2014;26:473–87.

29.RogersJE,CraneCH,DasP,DelclosM,GouldMSJr,OhinataA, etal.Definitivechemoradiationinoligometastaticsquamous cellcarcinomaoftheanalcanal.GastrointestCancerRes. 2014;7:65–8.

30.Glynne-JonesR,KadalayilL,MeadowsHM,CunninghamD, SamuelL,GehJI,etal.Tumour-andtreatment-related colostomyratesfollowingmitomycinCorcisplatin

chemoradiationwithorwithoutmaintenancechemotherapy insquamouscellcarcinomaoftheanusintheACTIItrial. AnnOncol.2014;25:1616–22.

31.Oehler-JanneC,HuguetF,ProvencherS,SeifertB,NegrettiL, RienerMO,etal.HIV-specificdifferencesinoutcomeof squamouscellcarcinomaoftheanalcanal:amulticentric cohortstudyofHIV-positivepatientsreceivinghighlyactive antiretroviraltherapy.JClinOncol.2008;26:2550–7.

32.WexlerA,BersonAM,GoldstoneSE,WaltzmanR,PenzerJ, MaisonetOG,etal.Invasiveanalsquamous-cellcarcinomain theHIV-positivepatient:outcomeintheeraofhighlyactive antiretroviraltherapy.DisColonRectum.2008;51:

73–81.

33.AbunassarM,ReindersJ,JonkerDJ,AsmisT.Reviewofanal cancerpatientsattheOttawahospital.EurJSurgOncol. 2015;41:653–8.

34.ThindG,JohalB,FollwellM,KenneckeHF.Chemoradiation withcapecitabineandmitomycin-CforstageI-IIIanal squamouscellcarcinoma.RadiatOncol(London,England). 2014;9:124.

35.JonesM,HrubyG,StanwellP,GallagherS,WongK,ArmJ, etal.MultiparametricMRIasanoutcomepredictorforanal canalcancermanagedwithchemoradiotherapy.BMCCancer. 2015;15:281.

36.KachnicLA,WinterK,MyersonRJ,GoodyearMD,WillinsJ, EsthappanJ,etal.RTOG0529:aphase2evaluationof dose-paintedintensitymodulatedradiationtherapyin combinationwith5-fluorouracilandmitomycin-Cforthe reductionofacutemorbidityincarcinomaoftheanalcanal. IntJRadiatOncolBiolPhys.2013;86:27–33.

37.FalkAT,ClarenA,BenezeryK,FrancoisE,GautierM,GerardJP, etal.Interstitialhigh-doseratebrachytherapyasboostfor analcanalcancer.RadiatOncol(London,England).2014;9: 240.

38.TsujiS,DoyamaH,YamadaS,TominagaK,OtaR,Yoshikawa A,etal.Endoscopicsubmucosaldissectionofasquamouscell carcinomainsituintheanalcanaldiagnosedbymagnifying endoscopywithnarrow-bandimaging.ClinJGastroenterol. 2014;7:233–7.

39.KhawandanahM,BaxleyA,PantS.Recurrentmetastaticanal cancertreatedwithmodifiedpaclitaxel,ifosfamide,and cisplatinandthird-linemitomycin/cetuximab.JOncolPharm Pract.2015;21:232–7.

40.EngC,ChangGJ,YouYN,DasP,XingY,DelclosM,etal. Long-termresultsofweekly/dailycisplatin-based chemoradiationforlocallyadvancedsquamouscell carcinomaoftheanalcanal.Cancer.2013;119:3769–75.

41.KimS,JaryM,MansiL,BenzidaneB,CazorlaA,DemarchiM, etal.DCF(docetaxel,cisplatinand5-fluorouracil)

chemotherapyisapromisingtreatmentforrecurrent advancedsquamouscellanalcarcinoma.AnnOncol. 2013;24:3045–50.

42.KoerberSA,SchonewegC,SlynkoA,KrugD,HaefnerMF, HerfarthK,etal.Influenceofhumanpapillomavirusand p16(INK4a)ontreatmentoutcomeofpatientswithanal cancer.RadiotherOncol.2014;113:331–6.