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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5186_Библиотеки_им_академика_М_И_Перельмана.pdf
High-grade lesions are commonly found within a broader field of low-grade disease,
suggestingthatCIN3maydevelopinhigh-riskHPV-infectedepitheliumindependentof,and
within a CIN 1 lesion, rather than as a classical stepwise progression. The reported
progressivepotentialofhistologicallyconfirmedlow-gradelesionstoCIN3variesfrom
12–33% (20,21,87,88). Traditional models of cervical carcinogenesis suggested that
persistentHPVinfectionwouldprogressivelyleadtoCIN1,CIN2,CIN3andfinallycancer
(89).AnalternativemodelwasthatCIN1maynotbenecessaryforthedevelopmentofCIN
3(90,91).CIN3couldevolvedirectlyandrapidlyfromnormalepitheliuminfectedbyHPV
followinga“molecularswitch”model(92).Invasivecancermaythentake10–12yearsto
developfromCIN3(93,94).Littleisknownaboutspecificgeneticandepigeneticmutations
thatunderpintheevolutionofCIN3. Itisnotpossibleto accurately predict whethera
womanwilldevelopcervicalcancer.
When low- and high-grade CIN lesions coexist, genetic alterations that accumulate during
cervical neoplastic transformation indicate a common cellular origin for such multifocal
lesions.Thissuggestsdifferentintraepitheliallesionsarisefromthesameorclonallyrelated
progenitor cells (91). Recent research has demonstrated simultaneous development of
multifocalCINlesionsofdifferentgrades.Thissuggeststhe“molecularswitch”modelmight
bemorelikelythanthe“sequentialprogression”model(91,95).
ManipulationofhostcellDNAmethylationmachineryisanimportantmechanismbywhich
HPVinfluencescellularandviralgeneexpressionandislikelytobeoneofthemechanisms
by which HPV evades antiviral immunity (96). DNAmethylation is a potent epigenetic
regulatorofgeneexpression. Hypermethylation of promoter regions of tumor suppressor
genes,resultingfromtheupregulationofDNAmethyltransferase(DNMT)expressioncaused
bytheviraloncogenesE6andE7,leadstogenesilencingandthisisknowntobeinvolvedin
cervical carcinogenesis (97–99). Some methylation patterns have been shown to be HPV
type–specific(100,101),whichmayreflectacapacityofspecificHPVtypestodominatethe
methylationmachineryofthehost.
IfaCIN3lesionarosefromcoexistingadjacentCIN 1,methylationin theadjacentCIN1
lesionshoulddemonstrateabridgingpatternsimilartoorthesameas thenearbyCIN3. It
shouldbedistinctly differentfromaseparate primaryCIN1 lesion.Thishasrecentlybeen
demonstratedtobenotthecase,whichisconsistentwithamodelwhereCIN3canemerge
directlyfromnormalepithelium,possiblysimultaneouslytoCIN1(95).
Persistent lesions can enlarge over time but retain characteristic epigenotypes. Initial
rapidprogressiontoCIN3maybedrivenbyaseriesofepigeneticchangeshappeningboth
before and during HPV infection. Distinct epigenotypes may underpin the distinct
morphologicpatternsinCIN1andCIN3lesions,explaining, inpart,differentprogression
characteristicsoftheselesions(95).
Adjacent CIN lesions of different grades usually contain the same hrHPV type(s) but
methylation patterns within the different lesions will usually be significantly differentand
characteristicofthe lesion grade. Methylation testing may be an effective futuretriage
tooltodetectandcharacterizewomenathigherriskofdevelopingCIN3andcancer.
LowerAnogenitalSquamousTerminologyStandardizationProjectfor
HPV-AssociatedLesions(LASTProject)
HPVinteracts with genital tract squamous epithelia in two basic ways. Firstly,HPV
infectionmayproducetransientlesions,whichsupportvirionproduction.Suchlesions
havebeenvariously described as low-grade lesions, intraepithelial neoplasiagrade1,mild
dysplasia or condylomata. Such lesions may be undetected clinically. Secondly, HPV-
epithelial interaction may produce lesions classified as precancerous. Viral oncogene
overexpression drives cell proliferation to produce a clonal expansion of undifferentiated
cells, characterized clinically by persistent viral detection, persistent and advancing
colposcopic abnormalities, and increasing risk of malignant transformation. These
precancerouslesions are notreliablydistinguishable by routinehistology,regardless ofthe
siteofthelesionorthesexoftheindividual(102,103).
OnthebasisofspecifiedprinciplesofHPV-associateddisease(Table8.1)andissuesrelated
toterminology,aconsensusprocesswassponsoredbytheCollegeofAmericanPathologists
(CAP)andtheAmericanSocietyforColposcopyandCervicalPathology(ASCCP).In2012,
the Lower Anogenital Squamous Terminology (LAST Project) published a
comprehensivere-evaluationoftheterminologyofHPV-associatedlesionsofthelower
anogenitaltractincludingthecervix,vagina,vulva,perianalarea,anus,penis,andscrotum
(72).
Table8.1GeneralPrinciplesUnderlyingtheLASTProject
1. ThereisunifiedepithelialbiologytoHPV-relatedsquamousdisease
2. Eachcytologicorhistologicsampleisonlyastatisticalrepresentationofthepatient’struebiology
3. Themoresamplesordatapointsavailable,themoreaccuratetheassessmentofthepatient’strue
biology
4. Thetruebiologyrepresentstheriskforcanceratthecurrenttimeand,toalesserextent,theriskfor
cancerovertime
5. Diagnosticvariationcanbeimprovedby:
a. Aligningthenumberofdiagnostictermswiththenumberofbiologicallyrelevantcategoriesand
b. Theuseofbiologicmarkers
ReproducedfromDarraghTM,ColganTJ,CoxJT,etal.TheLowerAnogenitalSquamousTerminology
StandardizationProjectforHPV-AssociatedLesions:backgroundandconsensusrecommendationsfromthe
CollegeofAmericanPathologistsandtheAmericanSocietyforColposcopyandCervicalPathology.JLowGenit
TractDis2012;16:205–242.
TheLASTProjectrecommendationsinclude:
1. Thereshouldbeaunifiedhistopathologicnomenclaturewithasinglesetofdiagnostic
terms. A two-tiered nomenclature was recommended for noninvasive HPV-associated
squamous proliferations of the lower anogenital tract, which may be further qualified
withtheappropriate–INterminology.(–INreferstothegenericintraepithelialneoplasia
terminologywithoutspecifyinglocation.)
2. HPV-associatedsquamouslesionsoftheloweranogenitaltractshouldbeclassified
as low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous
intraepitheliallesion(HSIL),whichmaybefurtherclassifiedbythe–INclassification.
3. Thebiomarkerp16immunohistochemical(IHC)stainingshouldbeused whenthe
hematoxylinandeosin(H&E)morphologicdiagnosisisbetweenprecancer(–IN2or
–IN3)andamimicofprecancer(e.g.,processesknown tobeunrelatedtoneoplastic
risk, such as immature squamous metaplasia, atrophy, reparative epithelial changes,
tangential cutting). Strong and diffuse block-positive p16 results would support a
categorizationofprecancerousdisease.
4. IfthepathologistisentertaininganH&Emorphologicinterpretationof–IN2(under
the old terminology, which is a biologically equivocal lesion falling between the
morphologic changes of HPV infection and precancer), p16 IHC is recommended to
help clarify the situation. Strong and diffuse block-positive p16 results support a
categorizationof precancer.Negative or non–block-positive staining stronglyfavorsan
interpretationoflow-gradediseaseoranon–HPV-associatedpathology.
5. p16 IHC should be used as an adjudication tool for cases in which there is a
professionaldisagreementin histologicspecimeninterpretation with thecaveatthat
thedifferentialdiagnosisshouldincludeaprecancerouslesion(–IN2or–IN3).
6. p16IHCshouldnotbeusedasaroutineadjuncttohistologicassessmentofbiopsy
specimenswithmorphologicinterpretationsofnegative,–IN1,and–IN3.
The LAST terminology for squamous HPV-associated lesions and associated p16
biomarkerusagereflectsmodernclinicalpractice(Fig.8.2A,B).IftheLASTterminology
isbroadlyaccepted,squamoushistologyandcytologicreportingshouldbeindistinguishable
and consistent in the United States. Potential reconciliation of LAST terminology and the
three-tieredCINsystemincytologicandhistologicdiagnosesisrepresentedinTable8.2.
AsaresultofimplementationoftherecommendationsoftheLASTWG4,p16usehas
increasedconsiderably,which has resultedin anincreasein theHSIL diagnosis rate,
particularlyinyoungwomen(104).Toavoidovertreatingyoungwomen,observationmay
be recommended for HSIL requiring p16 immunohistochemistry for confirmation, as this
wouldcorrespond closelyto CIN2. Thisflexibilityaffordedto treatingphysicians reduces
the likelihood that overcalling HSIL, based on p16-positive results, would have negative
consequencesforyoungerpatients.
Figure 8.2 A: Pathologic diagnoses using p16 and potential clinical management
optionsforcervical biopsies. (a) Use of p16 to evaluate the differential diagnosis of HSIL
versus a mimic, such as immature squamous metaplasia and atrophy. (Modified with
permission.Courtesyof PhilipE.Castle.)(b)Use ofp16toevaluatemorphologic CIN2.The
choice of clinical management for HSIL depends on the entire clinical scenario including
patient’sage,colposcopicfindings,andbiopsydiagnosis.(Modifiedwithpermission.Courtesy
ofPhilipE.Castle.)B: Cervicalbiopsywith SILshowingpartialmaturation.Gradingisdifficult
(? CIN 2). H&E morphology at medium power shows atypical parabasal-like cells extending
into the middle third of the epithelium. Corresponding p16 IHC stains reveals diffuse strong
stainingmeetingthedefinitionofp16strongdiffuseblock-positive.Thiscaseisbestinterpreted
as HSIL. (Reproduced with permission from Darragh TM, Colgan TJ, Cox JT, et al. The
LowerAnogenitalSquamousTerminologyStandardizationProjectforHPV-associatedlesions:
BackgroundandconsensusrecommendationsfromtheCollegeofAmericanPathologistsand
the American Society for Colposcopy and Cervical Pathology. Arch Pathol Lab Med
2012;136:1266–1297, with permission from Archives of Pathology & Laboratory Medicine.
Copyright©2012CollegeofAmericanPathologists.)
Table8.2LASTTerminologyandtheThree-TieredCINSysteminCytologicandHistologicDiagnoses
UnderstandingtheCervicalTransformationZone
Embryogenesis
Thecervixandvaginaarederivedfromthemüllerianductsandareinitiallylinedbyasingle
layer of müllerian-derived columnar epithelium. At 18 to 20 weeks of gestation, the
columnarepitheliumliningthevaginaltubeiscolonizedbytheupwardgrowthofstratified
squamousepitheliumderivedfromcloacalendoderm.
OriginalSquamocolumnarJunction
The junction in fetal life between the stratified squamous epithelium of the vagina and
ectocervix, and the columnar epithelium of the endocervical canal is called the original
squamocolumnarjunction(105).OriginalsquamousepitheliumextendsfromHart’slineor
the mucocutaneous, vulvovaginal junction to the original squamocolumnar junction. The
positionoftheoriginalsquamocolumnarjunctionisvariable,lyingontheectocervixin
66%,withintheendocervicalcanalin30%,andonthevaginalfornicesin4%offemale
infants(106).Thepositionoftheoriginalsquamocolumnarjunctiondeterminestheextentof
cervicalsquamousmetaplasia(107,108). Embryogenesis,in determiningthedistribution of
native squamous and columnar epithelia, is an important early influence in determining
futureriskofneoplastictransformation(Fig.8.3),althoughsexualbehaviorandsubsequent
exposuretoHPVinfectionaretheprimarydeterminantsofoverallrisk.
NewSquamocolumnarJunction
Increasedestrogensecretion,particularlywithpubertyandwiththefirstpregnancy,causesan
increase in cervical volume and an eversion of endocervical columnar epithelium to an
ectocervical location (106). This eversion of columnar epithelium onto the ectocervix is
calledanectropion.An“ectropion”isoftenmistakenlyreferredtoasan“erosion.”
Theestrogensurgeofpubertyresultsintheestablishmentoflactobacilliaspartofthe
normalfloraofthevagina.Thesemicroorganismsproducelacticacid,reducingthevaginal
pH to 4 or less (106,107). Everted endocervical columnar epithelium is exposed in the
postpubertal years to the acidity of the vaginal environment. Damage to the everted
columnar epithelium caused by vaginal acidity results in proliferation of a stromal
reservecellunderlyingthecolumnarepithelium.Thisreplacesthecolumnarepithelium
with an immature, undifferentiated, stratified, squamous, metaplastic epithelium
(106,107).Immaturesquamousmetaplasiathenundergoesamaturationprocess,producinga
mature,stratifiedsquamousmetaplasticepithelium,distinguishableonlywithdifficultyfrom
theoriginalsquamousepithelium.
The original linear junction between squamous and columnar epithelium is replaced by a
zone of squamous metaplasia at varying degrees of maturation. At the upper or cephalad
margin of this zone is a sharp demarcation between epithelium, which appears
morphologicallysquamous,andvillousepithelium,whichappearscolposcopicallycolumnar.
Thiscolposcopicjunctioniscalledthenewsquamocolumnarjunction(SCjunction).
TheTransformationZone
The transformation zone (TZ) is defined as that area lying between the original
squamocolumnarjunctionandthecolposcopicnewsquamocolumnarjunction(23,108).
The initial clinical assessment for most women is in the postpubertal years, when mature
squamous metaplastic epithelium has often replaced the distal or caudad limit of the
columnar epithelium. As the TZ matures, the original squamocolumnar junction becomes
impossibletodelineate,andonlythepresenceofNabothianfolliclesandglandopeningshint
attheoriginalcolumnaroriginofmaturesquamousmetaplasia.
Figure8.3 Locationofsquamocolumnarjunctionatvarioustimesinawoman’slife.CE,
columnarepithelium;SE,squamousepithelium;SCJ,squamocolumnarjunction.
CervicalneoplasiaalmostinvariablyoriginateswithintheTZ(Fig.8.4).Forreasonsthat
are poorly understood, persistent HPVinfection causes cancers mainly at the TZ between
different kinds of epithelia (e.g., cervix, anus, and oropharynx) (109). Carcinogenic HPV
infectionis equallycommon inthe cervicalandvaginal epithelia(110).However,cervical
cancer is the fourth most common cancer among women worldwide, while vaginal
cancerisrare.Thisreflectsthepivotalimportanceofthemetaplasticepitheliumofthe
TZincervicalcarcinogenesis(111).
Researchfrom HarvardMedical Schoolhas describedanembryonic cellpopulation within
the TZ with specific morphologic and molecular features that may represent the cells of
originformostcervicalprecancersandcancers(112,113).Early inlife,embryoniccervical
epithelialcellsareseenthroughoutthecervix.Thesecellssubsequentlydiminishinnumber
andconcentrateattheSCjunctionintheadult.Thesecuboidalembryonic/SCjunctioncells
have been demonstrated to give rise to subjacent metaplastic basal/reserve cells. This
downward or basal (rather than upward or apical) evolution from progenitor cell to
metaplasticprogenyhasbeentermedreverseor“topdown”differentiation.
Figure8.4 Theanatomyofthetransformationzone.
AsimilarpatternhasbeennotedinHSILs,suggesting thatHPVinfectionofthecuboidal
SCjunctioncellsmayinitiateoutgrowthof basally oriented neoplastic progeny.Most
low-gradeSILs are SC junction-negative, implyinginfectionof metaplastic progeny rather
thantheoriginalSCjunctioncells.This“modelof‘topdown’differentiationmayresolvethe
mysteryofhowSCjunctioncellsremodelthecervixandparticipateinneoplasia.Themodel
definesanalternativepopulationofmetaplasticprogeny(includingbasalandreservecells),
the infection of which is paradoxically less likely to produce a biologically aggressive
precursor.ItalsoprovidesnewtargetsinanimalmodelstodeterminewhytheSCjunctionis
uniquelysusceptibletocarcinogenicHPVinfection”(113).
TheTZ containsmetaplasticsquamous cells derivedfromstemcells(reservecells)of
the endocervix. The majority of cervical cancers originate from the TZ but it is still
unclearwhysuch animmunecell–richregionandstrategic immunologic“border”or
landmark(114)isthemostsusceptibletomalignantconversion.Hypothesesincludethe
existence of localized immune suppression in this region (115), increased expression of
estrogenreceptorsonmetaplasticepithelialorstromalcells(116),increasedcellproliferation
andunstabledifferentiationofmetaplasticcells(117),oranincreasedconcentrationofstem
cellswithintheTZ(118).RecentresearchhasdemonstratedthatHPV-16–immortalizedcells
from the TZ and endocervix become more dysplastic and invade collagen rafts more
frequentlythanimmortalizedcelllinesfromtheectocervix(119).Thisshowstheinherently
increased susceptibility of TZ and endocervical cells to develop severe precancerous
changes,whichcontributestocervicalcancerrisk.
Squamous metaplasia is a permanent process. It occurs in “spurts,” with greatest
activity during puberty and the first pregnancy. During the maturation phase, the
columnarvillifuse,losingthedistinctiveappearanceofcolumnarepithelium(Fig.8.5)and
producing a myriad of cytologic, colposcopic, and histologic appearances. The process
fluctuates in response to hormonal influences, but ultimately produces a mature,
glycogenated squamous epithelium. The presence of a subepithelial inflammatory
infiltrate in biopsy specimens of immature squamous metaplasia may lead to a
histologicmisdiagnosisofchroniccervicitis(Fig.8.6).Thepresenceofsuchinflammatory
whitecellsisanormalpartofthemetaplasticprocessandisnotaresponsetoaninfectious
organism.Ahistologicdiagnosisof“chroniccervicitis”isoftenmisleadingandshouldnotbe
acceptedasasatisfactoryexplanationforanabnormalPapanicolaou(Pap)smear.
If the new squamocolumnar junction is seen in its entirety in the absence of
premalignantdisease,the incidenceof squamousdiseaseabove thenew squamocolumnar
junction is very low and the colposcopic examination of the cervix is described as
adequateinthecurrentASCCPGuidelines(120).Ifthenewsquamocolumnarjunctionisnot
seeninitsentirety,thecolposcopicexaminationisdescribedasinadequate.TheTZfurther
defines the distal limit of high-grade glandular intraepithelial neoplasia, which is the
precursorlesiontoinvasiveadenocarcinomaofthecervix.
Figure8.5 Colposcopyofimmaturesquamousmetaplasia.