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SquamousLesionsoftheCervix
Terminology
Historically,therehavebeenseveralsystemsforclassifyingpreneoplasticlesionsofthe
cervix, and over the years, the classification systems have moved toward fewer, more
clinicallyrelevantcategories.Itisusefultobefamiliarwithallthesystemsbecausetheterms
can be used interchangeably (Table 6.1). In 2012, the College of American Pathologists
(CAP) and the American Society for Colposcopy and Cervical Pathology (ASCCP)
sponsored a consensus conference to propose uniform terminology for HPV-related
squamousintraepitheliallesions and early invasive carcinoma(1).The LowerAnogenital
Squamous Terminology (LAST) Project recommended a two-tiered nomenclature
system—low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous
intraepitheliallesion(HSIL)—whichcanbefurtherqualifiedbythegradeofintraepithelial
neoplasia(IN).TheSILterminologyparallelstheBethesdaSystem,whichhasbeeninuse
since 1988, and was developed to provide uniform diagnostic terminology for cervical
cytologic specimens. The LSILcategory encompasses condyloma and CIN 1, whereas the
HSILcategoryencompassesCIN2andCIN3.CIN1isequivalenttomilddysplasia,CIN2
to moderate dysplasia, and CIN 3 to severe dysplasia and carcinoma in situ. The LAST
recommendationsapplyacrossthe anogenitaltractforHPV-relatedpreneoplasticsquamous
lesions.
Low-GradeSquamousIntraepithelialLesion
There are three main subtypes of LSIL. Flat condylomas lack the exophytic growth
patternandaremorefrequentlyassociatedwithintermediateandhigh-riskHPVtypes.These
arethemostcommoninthecervix.Condylomaacuminatumistheclassicgenitalwartwith
an exophytic growth pattern. It is typically associated with low-risk HPV types 6 and 11.
Immature condylomas are the least common and exhibit a filiform, papillary growth
pattern;theyareassociatedwithlow-riskHPVtypes.
LSILischaracterizedbythickenedmucosawithenlarged,darkcellsthathavelownuclearto-cytoplasmic ratios in the upper layers (Fig.6.1). Binucleation can be seen in 90% of
LSIL,andwhenthenucleiaresurroundedbyanirregularlyshapedandsharplypunchedout
halo,theyareknownaskoilocytes.However,binucleationandhaloscanbeseenaspartofa
reactive process. With reactive change, the nucleus is minimally enlarged, not
hyperchromatic, and the halo is less distinct, round, and uniform. Glycogen vacuoles can
appearas round, uniform halos. LSILcanbemimickedby a squamous papilloma(also
knownas an ectocervicalorfibroepithelialpolyp).Squamous papillomas lack koilocytes
andhavecentralfibrovascularcoresthatarenottypicalofcondylomas.
Table6.1TerminologyforCervicovaginalSquamousIntraepithelialLesions
Low-gradeSquamousIntraepithelialLesion High-gradeSquamousIntraepithelialLesion
CervicalIntraepithelialNeoplasia(CIN)
Condyloma CIN1 CIN2 CIN3
Milddysplasia Moderatedysplasia Severedysplasia
TheASCUS-LSILTriageStudyinvestigatedinterobservervariabilityinthediagnosisof
squamousintraepitheliallesion(SIL)onbiopsy(2).Morethan2,700cervicalbiopsiesand
loop electrosurgical excision procedure (LEEP) specimens were examined by one of two
staffpathologistsatoneoffourcentersacrosstheUnitedStatesandreviewedbyoneoffour
qualitycontrol(QC)pathologists.TherewasagreementonthediagnosisofLSILin43%
of cases, but 41% of the cases diagnosed by the staff pathologists as LSIL were
downgradedby the QC pathologists to negative. Most of the downgraded cases were
positive for high-risk HPV, raising the question of which diagnosis was correct. The
significanceofthisfindingwasnotaddressedbythestudy.
High-GradeSquamousIntraepithelialLesion
HSIL is characterized by atypical,dark cells with high nuclear-to-cytoplasmicratios,
whichinvolveone-thirdtotwo-thirdsoftheepitheliumincasesofCIN2(Fig.6.2),or
more than two-thirds in cases of CIN 3 (Fig. 6.3). The involved mucosa is notable for
disorderly arrangement of cells, with loss of polarity and crowding. Mitotic figures in the
upperhalfofthemucosaarecommonlyidentified.
ImmaturesquamousmetaplasiaandatrophycanbedifficulttodistinguishfromHSIL,
becausetheyarecharacterizedbycellswithhighnuclear-to-cytoplasmicratios.However,the
nucleiinsquamousmetaplasiaandatrophyshouldlackcrowdingandappearuniform,with
smoothnuclearmembranes. Mitoticfigurescan beseennearthebasallayer,butnotinthe
upperhalfofthemucosa.Inindeterminatecases,immunohistochemicalstainingfor p16,a
surrogatemarker forhigh-risk HPV, canbe helpful(3). In some cases, forvarious reasons
(e.g.,tangentialsectioning,smalldissociatedfragments,cauteryartifact),adistinctioncannot
be made between LSIL and HSIL. These are best characterized as SIL of indeterminate
grade.
TheALTstudy found goodreproducibility forthe histologicdiagnosisof CIN3,with
concordance in 72.8% of cases (4). The reproducibility for the diagnosis of CIN 2 was
significantly lower at 43.4%. Aseparate joint National Cancer Institute (NCI)-Costa Rica
studyreportedsimilardisparitiesintheratesofagreement:13–31%forCIN2and81–84%
forCIN3(5).RecognizingthatCIN2isanequivocaldiagnosisthatencompassesbothCIN
1 and CIN 3, the CAP-ASCCP LAST Project recommended the use of p16
immunohistochemistry when considering a diagnosis of CIN 2. Strong and diffuse block
positivep16resultssupportadiagnosisofHSIL(CIN2),whilenegativep16resultssupport
a LSIL (CIN 1) or a non-HPV–associated lesion (1). The presence of block positive p16
correlateswiththe presenceofhigh-risk HPVthathasintegrated intothehostgenomeand
correlateswithadiagnosisofaprecancerouslesion.SinceLSILcanexhibit blockpositive
p16expression,gradingofdysplasiaisbasedprimarilyonH&Emorphology.
Figure 6.1 Low-grade squamous intraepithelial lesion (mild dysplasia, CIN 1). The
mucosaisthickenedwithdysplasticcellsandkoilocytesintheupperlayers.
Figure 6.2 High-grade squamous intraepithelial lesion (moderate dysplasia, CIN 2).
Dysplastic cells with high nuclear-to-cytoplasmic ratios involve less than two-thirds of the
mucosa.
Figure 6.3 High-grade squamous intraepithelial lesion (severe dysplasia, CIN 3). The
squamous mucosa is notable for full thickness atypia and extension of the dysplastic cells
downintoendocervicalglands.
Figure 6.4 Superficially invasive squamous cell carcinoma of the cervix. Invasion is
measuredfromthebasementmembraneatthepointofinvasion(upperarrow)tothedeepest
invasivefocus(lowerarrow).FIGOstageIA1cervicalcancerisdefinedbyadepthofinvasion
<3mminaspecimenwithnegativemargins.
SquamousCellCarcinoma
Cervical squamous cell carcinomas can be subdivided into two main groups: superficially
invasive carcinomas and invasive carcinomas. Superficially invasive carcinoma (FIGO
stageIA1)isdefinedasmicroscopicdiseasewith<3mmof stromalinvasion.In 2018,
horizontal extent was removed as a criterion for FIGO staging, because it was often
difficulttoaccuratelyassess(6).Foraccuratemeasurement,theentirelesion needsto
bevisible,andrequiresnegativesurgicalmargins.Althoughlymphatic-vascularinvasion
(LVI)isacknowledgedasapoorprognosticfactor,thepresenceorabsenceofLVIdoesnot
changetheFIGOstage.Thedepthofinvasionismeasuredfromthebasementmembraneat
thepointofinvasiontothedeepestinvasivefocus(Fig.6.4).Morphologically,superficially
invasivecarcinomaischaracterizedbyjaggedfingersextendingfromthebaseofHSILinto
thesubmucosa,andsurroundedbychronicinflammationandloose,fibroblasticstroma(i.e.,
desmoplasia).Oftenatthepointofinvasion,theneoplasticcellsbecomemoredifferentiated
and have abundant eosinophilic cytoplasm that may be keratinizing. Superficially invasive
carcinoma can be difficult to distinguish from HSIL, especially when HSIL involves
endocervicalglands,orisassociatedwithpreviousbiopsysitechanges.Examiningmultiple
levelsectionsofthesamefocuscanbehelpful.
Squamous cell carcinomas that are clearly invasive, can be keratinizing or
nonkeratinizing, and range from well differentiated to poorly differentiated. Well-
differentiatedtomoderatelydifferentiatedinvasivesquamouscellcarcinomaischaracterized
bycohesivenestsand sheets of neoplastic cells with abundant eosinophilic cytoplasm and
distinctcellborders(Fig.6.5).Keratin pearl formation, central keratinization,andnecrosis
withinnestsmaybeidentified.Withpoorlydifferentiatedcarcinomas,keratinizationmaybe
minimal or absent, and they may be difficult to distinguish from other types of poorly
differentiatedcarcinomas(e.g.,adenocarcinomas).Gradeandtypehavenotbeenfoundto
be prognostically significant. Instead, depth of invasion, lymphatic or vascular invasion,
andsizeareimportantprognosticvariables.
HumanPapillomaVirus
Humanpapillomavirus(HPV)DNAhasbeendetectedinvirtuallyallcasesofcervical
dysplasiaandcarcinomaandisconsideredtobeanecessary,butnotsufficientcausefor
thedevelopmentofthevastmajorityofinvasivecervicalcarcinomas.Althoughavariety
of HPV types may infect epithelial cells, the risk of oncogenic transformation is most
stronglylinkedtoseveralspecifichigh-risktypes.In2003,alargeepidemiologicstudyby
the International Agency for Research on Cancer (IARC) pooled data from nine
countries,andidentified15high-riskHPVtypes(16,18,31,33,35,39,45,51,52,56,58,
59,68,73,and82),3probablehigh-risktypes(26,53,and66),and12low-risktypes(6,11,
40,42,43,44,54,61,70,72,81,andCP6108).TheIARCmetagainin2005toreassess
thecarcinogenicityofHPVandrevisedtheoriginallistofhigh-risktypestoinclude13
types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 66(7). Most investigators now
believethatpersistentinfectionwithhigh-riskHPVtypesisassociatedwiththesubsequent
developmentofhigh-gradedysplasiaandinvasivecarcinoma(8).Asubstantialproportionof
LSILisassociatedwithinfectionbyhigh-riskHPVtypes,butmanyinfectionsaretransitory
(8,9).
Figure 6.5 Invasive squamous cell carcinoma of the cervix, moderately differentiated
keratinizing. Keratinization and necrosis within nests of malignant squamous cells are
present.
CervicovaginalCytology—PapTesting
SpecimenPreparationMethods
Therearetwomainspecimentypesforcervicovaginalcytology:theconventionalsmear
andtheliquid-basedpreparation.Conventionalsmearsinvolvedirectlysmearingmaterial
onto a glass slide, and immediately fixing the specimen with ethanol. The advantages of
conventional smears are their low cost, and the lack of need for specialized equipment to
processspecimens.The disadvantages are lack of uniformity in specimenpreparation,and
unsatisfactorysmearsbecauseofobscuringinflammation,blood,orthickareasinthesmear.
Liquid-basedpreparationsinvolveplacingthecytologicmaterialinaliquidfixativeinstead
of directly smearing it on a glass slide. The two most commonly used are ThinPrep
(Hologic,Bedford,MA)andSurePath(BDDiagnostics,Burlington,NC).ThinPrepusesa
methanol-based fixative and a filter preparation for making the slide. SurePath uses an
ethanol-based fixative and a Ficoll gradient. SurePath employs a detachable head for the
collection device so that the entire specimen can be submitted for processing. The
advantagesofliquid-basedpreparationsareuniformityinslidepreparationandfewer
unsatisfactoryspecimens.Thedisadvantagesaresignificantlyhighercost,andthenecessity
forspecializedprocessingequipmentforeachliquid-basedmethod.
WhoSignsOutPapTests?
Cervicovaginal cytologic specimens are predominantly screened by board-certified
cytotechnologists. In some small laboratories, the primary screening of the slides is
performed by a pathologist. If the Pap test is negative for an intraepithelial lesion or
malignancy and lacks reactive or reparative changes, the final report can be issued by the
cytotechnologist. Quality control review by a second senior cytotechnologist or a
pathologistshouldbeperformedonatleast10%ofallnegativecases,andonallcases
for patients with a history of an abnormal Pap test. If any reactive, reparative, or
epithelialabnormalitiesarefound,theslidemustbereviewedbyapathologistwhowillissue
thefinalreport.
TheClinicalLaboratoryImprovementActof1988setlimitsonthenumberofPapteststhat
could be reviewed by a cytotechnologist in a 24-hour period. The nationwide limit is 100
nonimagedor200imagedslidesperday,butindividualstatescansetlowerlimits(e.g.,80
nonimagedor160 imagedslidesin California).Thereis arequirementthat allpathologists
andcytotechnologistswhointerpretPaptestspassanannualproficiencytest.
TheBethesdaSystem
In1988,theNationalCancerInstitutesponsoredaworkshopinBethesda,Maryland,to
develop a uniform diagnostic terminology for Pap tests. The resulting classification
systemunderwentmultiplerevisionsandthesystemcurrentlyinuseisBethesda2014
(10)(Table6.2).
According to the Bethesda System, the Pap test report should include the following
categories: specimen type (e.g., conventional, liquid based, or other), specimen adequacy,
and interpretation or result. A general categorization section and educational notes and
suggestionsareoptional.Ifautomatedscreeningisperformed(e.g.,ThinPrepImagerorBD
FocalPoint),the device andresultshould be reported. Ifancillarytesting is performed,the
resultsmaybeindicatedinthePaptestreportorreportedseparately.
Table6.22014BethesdaSystem
Bethesda2014
SpecimenType Conventional
Liquid-based(specifytype:e.g.,ThinPrep,SurePath)
Other
SpecimenAdequacy Satisfactoryforevaluation
Unsatisfactoryforevaluation
GeneralCategorization(Optional) Negativeforintraepitheliallesionormalignancy
Epithelialcellabnormality
Other:Endometrialcellsinawoman≥45yrsofage
InterpretationorResult Negativeforintraepitheliallesionormalignancy(specify
organisms,othernonneoplasticfindings)
Squamous Atypicalsquamouscellsofundeterminedsignificance(ASC-US)
orcannotexcludeHSIL(ASC-H)
Low-gradesquamousintraepitheliallesion(LSIL)
High-gradesquamousintraepitheliallesion(HSIL)
Squamouscellcarcinoma
Glandular Atypicalendocervical,endometrial,orglandularcells(NOSor
favorneoplastic)
Endocervicaladenocarcinomainsitu
Adenocarcinoma
Other Endometrialcellsinawoman≥45yrsofage
Othermalignantneoplasms
AdjunctiveTesting HPV,GC,Chlamydia:Includedescriptionoftestmethod(s)and
results
Computer-AssistedInterpretation Specifydeviceandresultifslideisexaminedbyanimaging
system
EducationalNotesand
Suggestions(Optional)
BasedonASCCPmanagementguidelines
HPV,humanpapillomavirus;GC,gonorrhea;ASCCP,AmericanSocietyforColposcopyandCervicalPathology;
NOS,nototherwisespecified.
Specimenadequacyisdividedinto“satisfactoryforevaluation”and “unsatisfactoryfor
evaluation.”Thepresenceorabsenceoftransformationzonecells(i.e.,endocervicalcellsor
squamous metaplastic cells) and quality indicators (e.g., obscuring blood or inflammation,
scantcellularity)areindicatedundertheumbrellaof“satisfactoryforevaluation.”Specimens