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SECTION
II
DISEASESITES
8
PreinvasiveDisease
MichaelJ.Campion
KarenCanfell
Cervix
Cervical cancer is the fourth most common cancer among women worldwide and is
almostentirelyattributabletoinfectionwiththeHumanPapillomavirus(HPV).Global
estimatesindicatethat630,000newlyincidentHPV-relatedcancersoccurannually,including
cancers at several sites in the female and male anogenital and oral tracts (1). Of these,
cervical cancer was estimated to account for 570,000 new cases, representing 6.6% of all
female cancers. There were estimated to be 311,000 deaths from cervical cancer, with
approximately 90% of deaths occurring in low- and middle-income countries (LMICs).
Ratesofcervicalcancerhavebeenestimatedtobeatleastfourfoldhigherincountries
witha“low”rankingHumanDevelopmentIndexcomparedtothosewitha “veryhigh”
HumanDevelopmentIndex(2).
AlthoughdifferencesinHPVexposureinvariouscountriesmayplaysomeroleinexplaining
thedifferencesbetweencervicalcancerrates(3),thehigherincidenceanddeath ratesin
lowresourcesettingsarelikelytoresultfromthelack oforganizedcervicalscreening
and inadequate access to treatment. In many developed countries, screening with cervical
cytology has resulted in large-scale reductions in cervical cancer incidence and mortality
overtime(4,5).
Theprimarygoalofcervicalscreeningistopreventcervicalcancer.Thisisachievedby
the detection, treatment and follow-up of preinvasive cervical lesions (6,7). Modern
understanding that almost all cervical cancers are caused by persistent infection with
approximately 15 types of HPV has led to important new approaches to primary and
secondary prevention via prophylactic HPV vaccination (8,9) and primary HPV-based
screening(9,10).
ClassificationofPreinvasiveCervicalDisease
Theproposalthatinvasivesquamouscarcinomaofthecervixarisesthroughprogressionofa
preinvasivelesion,asopposedtoadenovoevent,wasinitiallypostulatedbySchauensteinin
1908(11).Theterm“carcinomainsitu”waslaterintroducedtodescribecancerouschanges
confinedtotheepithelium (12). It is now understood that precancerous lesions arise from
persistingHPVinfectionofthecervix,eventhoughthe majorityofHPVinfectionsregress
(13).
TheDysplasiaTerminology
Although referred to earlier by Papanicolaou and Traut (14), Reagan and Hamonic (15)
describedcytologicdifferencesbetween“carcinomainsitu”andagroupof“lessanaplastic”
lesionsin1956andintroducedthetermdysplasiain1962(16).In1975,theWorldHealth
Organization(WHO)defineddysplasiaasa“lesioninwhichpartoftheepitheliumwas
replacedbycellsshowingvaryingdegreesofatypia.”Dysplasticchangesweregradedas
mild,moderate,andsevere, but precise guidelines for these subdivisions were not defined
andgradingalwaysremainedhighlysubjective(17–19).
Adualterminologydeveloped,leadingtoinconsistenciesintreatmentpolicies.Ifadiagnosis
of “dysplasia” was made, this was considered a nonspecific change and the patient was
subjected to a cone biopsy. If the diagnosis of “carcinoma in situ” was made, this was
considered a “preinvasive cancer” and the patient underwent an obligatory hysterectomy
(20).
CervicalIntraepithelialNeoplasia
In 1969, invasive squamous cell carcinoma of the cervix was demonstrated to be the
resultof progressiveintraepithelial dysplastic atypia occurringwithinthemetaplastic
epithelium of the cervical transformation zone (TZ) (21). The classification of lesions
from mild dysplasia to carcinoma in situ did not truly reflect either the morphologic or
biologiccontinuumofpreinvasivecervicaldisease.Thediagnosiswashighlysubjectiveand
wasnotreproducible.
Afterpioneeringresearchintothenaturalhistoryofcervicalcancerprecursors,Richart(22)
proposed the term “cervical intraepithelial neoplasia” (CIN) in 1973 to describe the
biologic spectrum of cervical preinvasive squamous disease. Three grades of CIN were
described, CIN 1 (mild dysplasia), CIN 2 (moderate dysplasia), and CIN 3 (severe
dysplasia/carcinomainsitu).Thissystemwasconsistentwithbiologicevidencethatstrongly
impliedasingleprocessofcervicalsquamouscarcinogenesis(23–28).
Fiftyyears’ experiencewiththeCINterminology,coupled withadvanced understandingof
theroleofHPVinthecausationofcervicalneoplasia(29–34),hasledtoacriticalreappraisal
of this model and to further reclassification of the terminology for reporting cytologic
abnormalitiesconsistentwithpreinvasivedisease(35–40).
TheCINgradingisverysubjective.Noreproduciblecytologicorhistologicdistinction
atthelowerendoftheCINcontinuumexistsbetweenCIN1andHPVinfectionalone.
Bothinter-andintraobserverconsistencyindiagnosisarepoor(37,38,41,42).Separating
CIN 2 from CIN 3 is often not reproducible (43–45). The two critical questions in the
assessment of the cervical epithelium are: (i) do the changes represent a genuine cancer
precursor;and(ii)isthelesioninvasivecancer?
In histologic terms, CIN 3 is clearly established as a bona fide cancer precursor,
althoughtherearefewidentifiedriskfactorsforprogressionofCIN3tocancerother
thantime (46). CIN 3 is a reliable and more highly reproducible morphologic diagnosis,
with undifferentiated cells having fixed genetic abnormalities replacing almost the full
thicknessofthecervicalepithelium.ItisreliablydistinguishedfromrecentlyacquiredHPV
infectionandisagenuinesurrogatemarkerofsubsequentcancerrisk.Uncertaintystillexists
in relation to the progressive potential of less severe dysplastic lesions including CIN 2
(47–49).
CIN 1 is increasingly viewed as an insensitive histologic marker of HPV infection. The
diagnosis includes errors of processing and interpretation of colposcopically directed
biopsies.Standardized for positivityofa given high-riskHPVtype, adiagnosisof CIN1
doesnotpredictameaningfullyhigherriskofCIN3thandoesanegativebiopsy(50).
By contrast, longitudinal outcomes after HPV infection have demonstrated higher risk of
CIN2+andCIN3+inHPV-positiveversusHPV-negativewomen,withfollow-uptimes
upto18years(51).HPVtypes16and18areassociatedwithahigherriskofsubsequent
high-gradeCINthantheotheroncogenictypes(51,52).
Thereappears tobe considerable heterogeneityin the microscopicdiagnosis, biology,
andclinical behaviorof CIN2 lesions(48,49,53).CIN 2 can sometimes be produced by
noncarcinogenicHPVtypesandisequivocalinitscancerpotential(53).SomeCIN2lesions
representacuteHPVinfectionwithamoreseveremicroscopicappearancethataredestined
to regress. Others are incipient precancer (CIN 3) that will persist and progress with an
attendanthighriskoffutureinvasionifleftuntreated.
Theriskfactorprofiles(53–55)anddistributionsofHPVgenotype(56)inCIN2andCIN3
aredifferent.CIN2ismorelikelytospontaneouslyregressthanCIN3(49,57,58).There
isanincreasingtendencytofollowCIN2lesionsprospectivelyratherthantreat,particularly
among young, nulliparous women, providing they are good candidates for prospective
follow-up(59,60).The clinical dilemma remains the inability to reliably predict those
lesionslessseverethanCIN3thatareatgreatestriskofprogressiontocancer.
New molecular markers hold promise in this regard (61–65) and there is evidence that
technologies such as dual immunohistochemical (IHC) staining for the markers Ki-67
and p16 can improve histologic classification of CIN 3 abnormalities (66–70) and
resolve CIN 2 diagnoses (71). The Lower Anogenital Squamous Terminology
Standardization Project (LAST nomenclature) relies on p16 IHC staining to triage CIN 2
(72);p16isabiomarkerfordisruptionoftheRbpathwaybyHPV(68,72).CIN2thatisp16
positive is combined with CIN 3 as a high-grade lesion. CIN 2 that is p16 negative is
combinedwithCIN1asalow-gradelesion,thehistologicdiagnosisofHPVinfection(Fig.
8.1).
CervicalPrecancer—ModernConcepts
HPV infection is a necessary precursor of true precancer (73,74). A defined precancerous
lesion remains the target of screening and preventive treatment programs and represents a
genuinesurrogateforcancerrisk(75–77).CIN3 isthe mostcertainhistologicsurrogate
markerof cancerrisk. CIN 3 lesions demonstrate the same aneuploid DNA(78) content
andgeneticinstability(79)asisseenininvasivecancer.SomeCIN3lesionsaresmallanda
proportionmayregress,particularlyafterbiopsy,butatthistime,allCIN3lesionsshouldbe
managedasdefiniteprecancerlesions.
CIN2hasthepoorestinterobserverreproducibilityofanycervicalhistologicdiagnosis
(42). Despite the emergence of biomarkers such as p16 IHC staining, it is often
recommendedthatCIN2lesionsshouldbetreatedtoprovideafurthersafetymarginagainst
thedevelopmentofcancer.NobiomarkeryetdenesthedistinctintermediatestateofCIN2.
Currentconsensus is that CIN 2 is a mix of CIN 1 (productiveinfection)and CIN 3
(precancer) (80). In order to permit the possibility of regression of CIN 2 lesions under
carefulclinicalfollow-upforselectedyoungerwomenoflow-parity,cliniciansmayrequest
distinctionofCIN2fromCIN3.
InfectionwithoncogenicHPVtypesisstronglypredictiveof futureriskofhigh-grade
abnormalities/precancer (51,52,81). HPV infection might not be associated with any
microscopic abnormality, while most low-grade abnormalities will regress (82,83),
particularly among young women (84). LSIL should be managed conservatively by
observation without treatment with an expectation of regression within 2 years.
Persistencelongerthan2yearscorrelateswithanincreasedHSILrisk.
Figure8.1 Changes to the terminologyand number of tiers used to describe cervical
precancer over time with corresponding management options (procedure). CKC, cold-
knife conization; Cryo, cryotherapy; Rx, treatment. (Modified with permission. Courtesy of J.
ThomasCox.FromDarraghTM,ColganTJ,CoxJT,etal.TheLowerAnogenitalSquamous
TerminologyStandardizationProjectforHPV-associatedLesions:Backgroundandconsensus
recommendations from the College of American Pathologists and the American Society for
ColposcopyandCervicalPathology.ArchPatholLabMed2012;136:1266–1297.)
HSIL, particularly CIN 3, should be treated, usually by electrosurgical excision.
Balancing the benefits of screening and treatment against the potential harm of over
diagnosisandovertreatmentistheclinicalchallenge(85,86).Manywomenmustbetreated
topreventonecancer.
PrimarypreventionofcervicalprecancerandcancerthroughHPVvaccinationmeans
the diagnosis and management of CIN are now part of a secondary prevention
program.