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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5186_Библиотеки_им_академика_М_И_Перельмана.pdf
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Thediagnosisof“endometrialcellsinawoman45yearsofageandolder”isusedwhen
benign-appearingexfoliatedendometrialstromalorglandularcellsareidentifiedinacervical
cytologicspecimenfromawomanaged45orolder.TheagecutoffwassetbytheBethesda
System because menstrual data, menopausal status, hormonal therapy, and clinical risk
factorsarefrequentlyunknowntothelaboratory.Forasymptomatic,premenopausalwomen,
nofurtherstudiesarerecommended.Endometrialsamplingisrecommendedforsymptomatic
premenopausalwomenandallpostmenopausalwomen(11).
Figure 6.14 Endometrial carcinoma. Three-dimensional papillary clusters of cells with
enlargednuclei.(Papanicolaoustain)
AncillaryTesting
HPV testing became routine after the ASCUS LSIL Triage (ALT) Study (12) and the
publication of the American Society for Colposcopy and Cervical Pathology (ASCCP)
Consensus Guidelines for the Management of Women with Cervical Cytological
Abnormalities. Initially, Digene Hybrid Capture II (HC2) was the only commercially
available HPV test and had the additional distinction of being the assay used in the ALT
study. In the intervening time, several different assays that use multiple different
methodologieshavebecomecommerciallyavailable.
Figure 6.15 Metastatic breast carcinoma. Adenocarcinoma cells in a background without
inflammation and necrosis raise the possibility of spread from an extrauterine source.
(Papanicolaoustain)
TherearefourUnitedStatesFoodandDrugAdministration(U.S.FDA)-approvedHPV
assays for use in ASC-US triage and for co-testing in women over the age of 30: HC2
(Qiagen), Cervista HPV HR (Hologic), cobas HPV Test (Roche), and Aptima HPV
Assay(Gen-Probe).Roche cobas HPVis FDA-approvedfor primary HPVscreening. The
high-riskprobesforallfourassaystargethigh-riskHPVtypes16,18,31,33,35,39,45,51,
52, 56, 58, 59, and 68. The probes for Cervista, cobas, and Aptima target HPV type 66,
whichwasclassifiedashigh riskbytheIARCin 2005.Although theHC2high-riskprobe
does not directly target HPV 66, studies showed that HPV 66 is detected through crossreactivity.One ofthemaincriticisms ofHC2is decreasedspecificity becauseofcross-
reactivity, but the benefit of cross-reactivity is increased clinical sensitivity. As
exemplified by HPV 66, cross-reactivity can allow for the detection of HPV types not
classifiedashighrisk.
The use of HPV genotyping has been incorporated into the ASCCP Consensus
Guidelines since HPV types 16 and 18 were recognized as more carcinogenic and
responsibleforthemajorityofcervicalcancers.ThecobasHPVTestscreensfor14high-
risk HPV types, and specifically identifies HPV types 16 and 18. Cervista has a separate
HPV16/18probethatcanbe usedfor genotypingiftheinitialCervista HPVHRscreen is
positive.HPV testing was initially validated by the ALT study using HC2; the newer
assays are required to show similar or better test characteristics. In comparison with
HC2,theotherthreesystemsexhibitsimilarsensitivityandoffertheadvantageofincluding
aninternalpositivecontrol.
Positive results with HC2 testing for high-risk HPV have been reported in many
patientswhohavenocytologicorhistologicevidenceofdysplasia.False-positiveresults
withHC2canoccuras theresultofcross-reactivityor signalleak. DeCremouxetal.(13)
reported a false-positive rate of 6.2%, with 1.9% because of cross-reactivity and 4.3%
becauseofsignalleak.Cross-reactivitywithhigh-riskHPVDNAcanoccurincasesthat
have very high loads of low-risk HPV; similar cross-reactivity with low-risk types can
occurwithhighloadsofhigh-riskHPV.Inaddition,the chemiluminescent signal in cases
with high viral loads can lead to false-positive results in contiguous samples because of
leakingofthesignal.
HC2resultsarereportedaspositive,negative,orequivocalbasedontheassignedcutoff
of 1.0 RLU/PC. Although HC2 testing has been shown to have good interlaboratory
reproducibility, there is poor reproducibility near the cutoff point of 1 RLU/PC (14).In a
significantportionofcaseswithborderlinepositiveHC2results,PCRanalysisforHPV
isnegative(15).Casesthatarenearthecutoffpointarereportedasequivocalbecausethey
mayrepresentafalse-positiveresult.ThenewerHPVassaysexhibitlesscross-reactivityand
equivalentorbetterspecificitythanHC2.
AutomatedScreening
The main impetus behind developing automated screening systems has been to increase
productivityandimprovequality.ThinPrepandSurePathhaveimagingsystemsthatcanbe
usedwiththeirliquid-basedpreparations.TheThinPrepImagingSystemwasapprovedby
the U.S. FDA in 2003 for dual review of ThinPrep cervical cytology slides. After the
imagingsystemscreenstheslide,thecytotechnologistreviews22selectedfieldsofview.If
any abnormal cells are seen, the slide is manually rescreened by the cytotechnologist.
StudieshaveshownthattheThinPrepsystemhasequivalentorbettersensitivitythan
manual screening for the detection of LSIL and HSIL, and higher specificity for the
diagnosisofHSIL(16).
TheBDFocalPointSlideProfilerhasbeenU.S.FDAapprovedforprimaryscreeningof
SurePath or conventional cervical cytologic slides. It functions as a triage device,
allowingaportionofslidestobearchivedwithnofurtherreviewbyacytotechnologist,and
identifyingcases thatare morelikely tocontainsignificantabnormalities,requiring further
review. The BD FocalPoint GS Imaging System is a U.S. FDA-approved location-guided
screeningsystemthatcanbeusedinconjunctionwiththeSlideProfiler.Theguidedscreener
willdirectthecytotechnologisttothefieldsofviewcontainingtheabnormalareasdetected
byimageanalysis.
GlandularLesionsoftheCervix
Terminology
A variety of terms have been used to describe preinvasive glandular lesions of the cervix,
includingatypia,dysplasia,andAIS.Unlikecervicalsquamouslesions,cervicalglandular
dysplasiaisapoorlydefinedandcontroversialentity.Glandularlesionsthatexhibitsome
but not all the features of adenocarcinoma in situ have been associated with in situ and
invasive adenocarcinoma, but the diagnostic criteria, clinical implications, prevalence, and
progressionrateoftheselesionsarenotuniformlyagreedupon(17).
An international panel of pathologists recently proposed an etiology-based (i.e., HPV
infection) classification for endocervical adenocarcinomas to replace the traditional
classificationthat included categories thatwere not clinically relevant(18).The proposed
International Endocervical Adenocarcinoma Criteria and Classification (IECC) uses
morphologic features to segregate endocervical adenocarcinomas into one of two
categories:HPV-associatedandHPV-independent.
AdenocarcinomaInSitu
ThehistologicdiagnosisofAISrequiresunequivocaldysplasticchanges,whicharetypically
manifested by low-power basophilia, nuclear hyperchromasia with either fine or coarsely
granularchromatin,nuclearapoptoticorkaryorrhecticdebris,apicalmitoticfigures,andloss
of polarity (which may be subtle) (Fig. 6.16). The involved glands exhibit a lobular
architecturethatmayappearmorepronouncedthanadjacentuninvolvedendocervicalglands,
butirregularinfiltrationintothestromaisabsent.Partialglandularinvolvementiscommon.
A superficial form of AIS has been described in the superficial columnar mucosa
featuringsimilarcytologic alterations, but with less pronouncedatypia.Thislesionis
thoughttooccurmorecommonlyinayoungeragegroup(mean26years)andsomaybe
interpretedasan“early”formofAIS(19).
Figure 6.16 Adenocarcinoma in situ of the cervix. In situ carcinoma exhibits nuclear
hyperchromasia, stratification, irregular chromatin, and apical mitotic figures. A normal
endocervicalglandispresentontheright.
A variety of processes mimic AIS, including tubal or tuboendometrial metaplasia,
endometriosis,reactiveendocervicalcells,and several endocervical cell alterations that do
notnecessarilyappeartorepresentareactiveprocess(19).Theselatteralterationsoftenpose
the most diagnostic difficulty and are classified on the basis of the abnormality present:
endocervical glandular hyperplasia, mitotically active endocervical mucosa, stratified
endocervicalmucosa,andatypicaloxyphilicmetaplasia.
Biomarkers,particularlyacombinationofKi-67andp16,arehelpfulinthedifferential
diagnosisofAIS.Strong,diffuseexpressionofp16inconjunctionwithincreasedKi-67
is more commonly associated with AIS, whereas weak or focal p16 expression with or
withoutincreasedKi-67is more supportive of an AIS mimic (20). Because not all AIS is
HPV-related(e.g.,gastrictype)andextensivep16stainingcanoccurinbenignlesions(e.g.,
tuboendometrial metaplasia), it is important to be thoroughly aware of the variable
expressionpatternsofthesemarkersintheindividuallesions,inorder topreventunder-or
overdiagnosisonthebasisofstainingpatternsalone(21).
InvasiveAdenocarcinoma
The diagnosis of invasive cervical adenocarcinoma can be very difficult in early or
superficially invasive lesions, and in limited (superficial) biopsy specimens. Unlike
squamous carcinoma of the cervix, invasion may not be associated with a significant
stromal reaction; in these instances, the distinction between bulky AIS and invasive
adenocarcinomacanbesomewhatarbitrary.TheSilvaSystem,proposedin2013,introduced
apattern-based classificationsystemfor endocervicaladenocarcinomasthat correlateswith
outcome (22). Pattern A consists of well-demarcated glands without a desmoplastic
responseorlymphatic-vascularinvasion;thisgroupexhibitednolymphnodemetastasis,no
recurrences,andnodeathfromdisease.PatternBencompassesearlystromalinvasion and
may be associated with lymphatic-vascular invasion; outcome for this group fell between
those for patterns A and C. Pattern C is characterized by extensive destructive stromal
invasion;24%ofpatientshadpositivelymphnodes,22%recurred,and9%diedofdisease
(Fig. 6.17). The Silva System removes the need for distinguishing bulky AIS from
endocervicaladenocarcinomaswith apushing,nondestructivemarginbecauseitrecognizes
thattheybehavesimilarly.
FIGOstagingisbasedondepthofstromalinvasionanddoesnotconsiderthepatternof
invasion. The multi-institutional, international group that developed the Silva System is
evaluatinghow thepattern-based system canbetter alignwithFIGO stagingandexploring
thepossibilityofredefiningdepthofinvasiontoencompassonlydestructivestromalinvasion
(23).Thiswouldshiftallpattern-AtumorstostageIA1regardlessoftumorthickness.Until
FIGOstagingisbetterintegratedwiththeSilvaSystem,itisrecommendedthatthepattern,
overall size (i.e., depth of involvement, width, and thickness), and extent of destructive
stromalinvasionshouldbereported.
Figure 6.17 Invasive adenocarcinoma of the cervix, Silva pattern C. Deeply infiltrative
glandsareirregularincontourandsurroundedbyedematousstroma.(top,lowpower;bottom,
highpower)
Because of the difficulties in diagnosing early invasive lesions, the concept of
“microinvasiveadenocarcinoma”isnotaswellacceptedasitisforsuperficiallyinvasive
squamous cell carcinoma; nevertheless, a maximum depth of invasion of <3 mm with
negative margins and no lymphovascular invasion is considered by most clinicians as the
upperlimitforconsiderationofconservativemanagement.Measurementsaremadefromthe
surfaceortheclosestnoninvasivegland(ifitcanbeidentified)andexpressedinmillimeters.
About 70% of endocervical adenocarcinomas are HPV-associated and the most
commonsubtypeistermedusualorendocervical.OtherHPV-associatedtypesinclude
villoglandular, mucinous, intestinal, and stratified. HPV-independent carcinomas
encompass gastric-type, clear cell, endometrioid, mesonephric, and miscellaneous and not
otherwisespecified.Gastric-typeadenocarcinomaisthemostcommonHPV-independent
tumorandencompassesminimaldeviationadenocarcinoma(adenomamalignum),whichis
considered a very well–differentiated variant. Only subtypes with distinctive clinical or
differentialdiagnosticproblemsthataffectprognosisortreatmentarediscussedbelow.
Gastric-TypeAdenocarcinoma
This tumor, which can range from deceptively bland (minimal deviation) to overtly
malignant,accountsforabout10%ofallcervicaladenocarcinomas(24).Regardlessof
degreeofdifferentiation,gastric-typeadenocarcinomashaveasignificantlyworseprognosis
—30–42%disease-specific survivalat 5years versus77–91%for nongastrictype. Patients
rangeinagefrom37to84years(mean49)andmaypresentwithirregularbleeding,diffuse
cervicalenlargement,and/orwateryvaginaldischarge.Approximately10%ofgastric-type
adenocarcinomasareassociatedwithPeutz–Jegherssyndrome.
Voluminous clear or pale pink cytoplasm and distinct cell borders are characteristic of
gastric-typeadenocarcinoma. The tumor features cysticallydilated, irregular (claw-shaped)
glands with stromal reaction that can be minimal or absent in some cases and marked in
others(Fig.6.18).Nuclearatypiacanrangefromdeceptivelyblandto markedlyabnormal.
Attheverywell–differentiatedendofthespectrum,thediagnosisismosteasilyestablished
bycarefulsearchforfociofcytologicatypiaorstromalreaction.Themalignantglandscan
replace normal endocervical and endometrial glandular tissue, mimicking mucinous
metaplasiainuterinecurettingsandbiopsy.
Althoughgastric-typeadenocarcinomasareHPV-independent,p16canbepositiveinup
to33%ofcasesandcannotbefullyreliedonasasurrogatemarkerforHPV.
VilloglandularCarcinoma
ThisHPV-associatedtumoroccurspredominantlyinyoungwomenandischaracterized
byavilloglandulararchitecturalgrowthpatternandlownucleargrade.Thesetumorshavea
goodprognosis,butonlyiftheyareexophyticwithminimalornoinvasion(Fig.6.19).
ClearCellCarcinoma
Clear cell carcinoma is HPV-independent, may occur in young (diethylstilbestrol
exposureinutero)orolderwomen,andmayariseintheectocervix(typically,associated
with diethylstilbestrol exposure) or endocervix. A variety of patterns—including
tubulocysticorglandular,solid,andpapillary—maybeseen(22).
MesonephricCarcinoma
Mesonephric remnants may develop hyperplasia and carcinoma; often a spectrum of
thesechangesisseeninthecarcinomas(22).TheHPV-independentmesonephriccarcinomas
oftenposesignificant diagnosticdifficultybecauseoftheirlateral anddeep locationwithin
the cervix. There may be no surface component. Ductal, retiform, tubular, solid, and
spindlepatternsmaybeseeninthecarcinomas.Mosthavelowtomoderatenucleargrade,so
some cases may be difficult to distinguish from florid mesonephric hyperplasia. The
distinctionisoftenbasedonlossoflobulararchitectureandinfiltrativepattern.Diagnosisof
higher-grademesonephric adenocarcinoma is based on identification of residual normal or
hyperplastic mesonephric tubules with their characteristic eosinophilic luminal material.
Prognosisisuncertainbecauseofthelimitednumbersofcases,butprobablysimilartousual
endocervicaladenocarcinoma.These tumorsarenotknownto be associated with HPV
andmostarep16negative.
NeuroendocrineCarcinoma
Neuroendocrinecarcinomas,small-andlarge-cellvariants,accountforlessthan5%of
allcervicalcarcinomas.Thesehighly aggressivetumors maypresent assmalllesions,but
mostaredeeplyinvasive.Theyexhibittheusualfeaturesofaneuroendocrinecarcinoma,and
high mitotic indices and necrosis are common (Fig. 6.20). Neuroendocrine carcinoma is
oftenassociated with AIS, HSIL, and conventional invasive cervical adenocarcinoma.
Most harbor HPV-18 and are p16-positive. Rarely, well-differentiated neuroendocrine
tumors (carcinoid) may occur in the cervix and the prognosis for these tumors may be
better.Metastasisshouldalwaysberuledout.
AdenoidBasalCarcinoma—AdenoidBasalEpithelioma
Adenoidbasal cell carcinoma(epithelioma) occurs inpostmenopausal,elderly women
(meanage65years).Mostareasymptomaticandthetumorisdiscoveredduringevaluation
ofanatypicalPapsmear.Indeed,itisoftenassociatedwithHSIL.Thecervixisoftennormal
oncolposcopicandphysicalexamination.Thetumoriscytologicallybland(oftenlooking
like “bland squamous cell carcinoma”), and features basaloid, adenoid, and squamoid
differentiation.Theadenoidareasconsistofsmall,closelypackedtubules,occasionallywith
intraluminalsecretionsreminiscentofmesonephrictubules(Fig.6.21).Thereistypicallyno
stromal response. Mitotic figures are rare or absent. The tumor has a favorable
prognosis and needs to be distinguished from the adenoid cystic pattern of cervical
adenocarcinoma,whichdoesnothaveafavorableprognosis(24).Becauseoftheextremely
favorable prognosis associated with classic, superficial adenoid basal carcinoma, the
diagnostictermadenoidbasalepitheliomaispreferred.
Figure 6.18 Gastric-type adenocarcinoma (minimal deviation adenocarcinoma). Large,
irregular mucinous glands typically show bland or minimally atypical cytologic features. (top,
lowpower;bottom,highpower)