CIN & Cervical CancerCIN & Cervical Cancer

WomenWomen’’s Hospital, School of Medicine, s Hospital, School of Medicine, Zhejiang universityZhejiang university

Cervical Intraepithelial Cervical Intraepithelial Neoplasia (CIN) Neoplasia (CIN)

It is the premalignant disease related It is the premalignant disease related to the invasive cervical cancerto the invasive cervical cancer

Two different develop ways:Two different develop ways:

fade naturelyfade naturely

run to invasive cervical cancerrun to invasive cervical cancer

Cervical CancerCervical Cancer It is the most common type of gynecologic It is the most common type of gynecologic

cancerscancers The incidence and mortality of cervical The incidence and mortality of cervical

cancer have continued to declinecancer have continued to decline

Reasons : Reasons :

●●A long time of the premalignant stageA long time of the premalignant stage

●● Cervix cytologic examinationCervix cytologic examination

Estimated New Cancer Cases and Deaths by Sex,United States,

2011

Jemal A,et al.CA Cancer J Clin 2011

Estimated New Cancer Cases and Deaths by Sex,United States,

2011

Jemal A,et al.CA Cancer J Clin 2011

EtiologyEtiology

Virus infectionVirus infection HPV HSV-IIHSV-II CMVCMV Early onset of sexual activity and Early onset of sexual activity and multiple sexual partnersmultiple sexual partners Sexual sanitation and multiparity Sexual sanitation and multiparity OthersOthers ：： oral contraceptive pill , smoking, oral contraceptive pill , smoking,

immunodeficiency and so on immunodeficiency and so on

HPV HPV --------prime etiologic prime etiologic factorfactor

• More than 100 types of HPVMore than 100 types of HPV

• About 35 types associated with About 35 types associated with

genital infectiongenital infection

• About 20 types associated with About 20 types associated with

cancercancer

• 13 high-risk type of cancer 13 high-risk type of cancer

associated:associated:

16, 18, 31, 33, 35, 39, 45, 51, 16, 18, 31, 33, 35, 39, 45, 51,

52, 56, 58, 59, 6852, 56, 58, 59, 68

• Low-risk type:6,11,40,42,43,44Low-risk type:6,11,40,42,43,44

Prevalence of HPV Genotypes in Invasive

Cancers

Prevalence of HPV Genotypes in Invasive

Cancers

0 100 200 300 400 500

Number of Invasive Cancers

P291

HPV 6

HPV 11

HPV 55

HPV 26

P238A

W13B

HPV 51

HPV 68

HPV 39

HPV 59

HPV 35

HPV 56

HPV 58

HPV 52

HPV 33

HPV 31

HPV 45

HPV 18

HPV 16

Bosch, et al. JNCI 1995

Occurring and development Occurring and development of CINof CIN

Normal cervical epitheliumNormal cervical epithelium

squamous epithelium squamous epithelium

columnar epitheliumcolumnar epithelium Squamo-columnar junction (SCJ)Squamo-columnar junction (SCJ)

originaloriginal SCJSCJ activeactive SCJSCJ

tranformation zonetranformation zone

Replace mechanisms of transformation Replace mechanisms of transformation zonezone

squamous metaplasiasquamous metaplasia Undifferentiation reserve cells under Undifferentiation reserve cells under

columnar epithelium hyperplasy and changecolumnar epithelium hyperplasy and change Most of the squamous cells are immaturity Most of the squamous cells are immaturity Squamous metaplasia of the glandSquamous metaplasia of the gland ：： gland gland

cells replaced by the squamous epithelium cells replaced by the squamous epithelium squamous epithelization squamous epithelization

squamous epithelium enters and replaces squamous epithelium enters and replaces directlydirectly

squamous epithelization cells are completely squamous epithelization cells are completely similar with the squamous epitheliumsimilar with the squamous epithelium

Most appears in the concrescence of cervical Most appears in the concrescence of cervical erosionerosion

Occurring and development of Occurring and development of CINCIN

CIN means disordered growth and CIN means disordered growth and development of the epithelial lining of the development of the epithelial lining of the cervix cervix grade Igrade I ：： the lower third of the epithelial lining the lower third of the epithelial lining grade IIgrade II ：： two-thirds of the lining two-thirds of the lining grade IIIgrade III ：： more than two-thirds of the lining or more than two-thirds of the lining or

full-thicknessfull-thickness((carcinoma in situ carcinoma in situ )) CINI: 60% regress to normal, 30% persistent, CINI: 60% regress to normal, 30% persistent,

10%have disease progression to CINIII10%have disease progression to CINIII CIN progress to cancer may take 10 to 15 yearsCIN progress to cancer may take 10 to 15 years Those metaplasia squamous epithelium can Those metaplasia squamous epithelium can

develop to invasive cancers directly. develop to invasive cancers directly.

Occurring and development Occurring and development of CINof CIN

Invasive cancersInvasive cancers

Cells abnormalityCells abnormality Break the basement membrane Break the basement membrane

and stroma involvementand stroma involvement Active stimulate factors is Active stimulate factors is

neededneeded

Occurring and development Occurring and development of CINof CIN

PathologyPathology

CINCIN

Cells abnormality arrangeCells abnormality arrange

CIN I light CIN I light disordered a little disordered a little

CIN II obviously CIN II obviously disordereddisordered

CIN III remarkably polarity CIN III remarkably polarity disappeareddisappeared

PathologyPathology

Pathological types of invasive cervical Pathological types of invasive cervical cancerscancers Squamous cellSquamous cell ：： 80-8580-85 ％％ adenocarcinomaadenocarcinoma ：： 15-2015-20 ％％

Squamous cellSquamous cell samplesample CIN and early-stage CIN and early-stage of invasive cervical of invasive cervical

cancers looks like the cervical erosioncancers looks like the cervical erosion Four types of Four types of invasive cervical cancersinvasive cervical cancers

outer-growthouter-growth endogenesisendogenesis cankerouscankerous cervix canalcervix canal

PathologyPathologyMicroscope:Microscope: Early invasive cancers under microscopeEarly invasive cancers under microscope

Ia1 depth≤3 mmIa1 depth≤3 mm ，， width≤ 7mmwidth≤ 7mm Ia2 depth3Ia2 depth3 －－ 5mm5mm ，， width≤ 7mmwidth≤ 7mm

Invasive cancers Invasive cancers ：： differentiated differentiated degreedegree Grade IGrade I ： ： large cell keratinizing typelarge cell keratinizing type keratinizationkeratinization ， ， fewer than 2 fewer than 2

mitoses/HPmitoses/HP Grade IIGrade II ： ： large cell nonkeratinizing typelarge cell nonkeratinizing type moderate keratinization moderate keratinization ，， 2-4 2-4

mitoses/HP mitoses/HP Grade IIIGrade III ：： small cell carcinomassmall cell carcinomas poor differentiatedpoor differentiated ，， more than 4 more than 4

mitoses/HPmitoses/HP

Metastasis pathwayMetastasis pathway

Spread directlySpread directly ：： frequently frequently commoncommon

Lymph metastasisLymph metastasis

Vascular metastasis Vascular metastasis ：：infrequencyinfrequency

Staging

Clinical FindingClinical Finding

SymptomsSymptoms ：： vaginal bleeding vaginal bleeding ：： postcoital postcoital

bleeding bleeding Menstruate disordered in young womenMenstruate disordered in young women Abnormal vaginal bleeding in eldersAbnormal vaginal bleeding in elders

vaginal liquiding vaginal liquiding Pelvic painPelvic pain the late stages the late stages ：： metastastic metastastic

symptomssymptoms weakness, weight loss, and anemiaweakness, weight loss, and anemia

Clinical FindingClinical Finding

SignsSigns ：：

A grossly normal-appearing A grossly normal-appearing cervix with CIN or early stage cervix with CIN or early stage invasive cancersinvasive cancers

Signs may be related to the Signs may be related to the growth types growth types

Metastatic signs in the late Metastatic signs in the late stagesstages

DiagnoseDiagnose

HistoryHistory ： ： postcoital bleedingpostcoital bleeding Physical examinationPhysical examination BiopsyBiopsy ：： diagnose standarddiagnose standard Clinical stagingClinical staging

Assistant examinationAssistant examination Cervical cytologyCervical cytology

pap pap

smearsmear

TCTTCT

Assistant examinationAssistant examination

Pap smearsPap smears ：： II ： ： normalnormal IIII ： ： inflammationinflammation IIIIII ： ： suspicionsuspicion IVIV ：： highly suspicionhighly suspicion VV ： ： malignantmalignant II considered as inflammationII considered as inflammation Ⅲ Ⅲ to Ⅴrequire further to Ⅴrequire further

evaluation.evaluation.

Assistant examinationAssistant examinationThe Bethesda System (TBS)The Bethesda System (TBS) Abnormal epitheliumAbnormal epithelium （ （ require require

further evaluation further evaluation ）） squamous epithelium squamous epithelium

ASC-US and ASC-HASC-US and ASC-H LSILLSIL HSILHSIL

AdenoepitheliumAdenoepithelium AGCAGC Adenocarcinoma in siteAdenocarcinoma in site AdenocarcinomaAdenocarcinoma

Assistant examinationAssistant examination

Schiller testSchiller test ：： ①①glycogen, which combines with iodine glycogen, which combines with iodine

toto

produce a deep mahogany-brown produce a deep mahogany-brown colorcolor

② ② low speciallow special

help to choose the sites for biopsyhelp to choose the sites for biopsy ColposcopyColposcopy ：： be required when reports of abnormal be required when reports of abnormal

cells are made by former examinations.cells are made by former examinations.

Assistant examinationAssistant examination

BiopsyBiopsy ：： diagnose standarddiagnose standard 33 ，， 66 ，， 99 ，， 12points of 12points of Squamo-Squamo-

columnar junctioncolumnar junction suspicion sites by Schiller test or suspicion sites by Schiller test or

ColposcopyColposcopy Sample requires epithelium and Sample requires epithelium and

stromastroma endocervical curettage is endocervical curettage is

necessary(abnormal cervical cytology necessary(abnormal cervical cytology smearsmear , ,cervix smooth or biopsy cervix smooth or biopsy negative )negative )

Assistant examinationAssistant examinationConization:Conization:

Abnormal cervical cytological Abnormal cervical cytological examination ,negative biopsyexamination ,negative biopsy

a biopsy revealing carcinoma in situ, a biopsy revealing carcinoma in situ, where invasion cannot be ruled outwhere invasion cannot be ruled out

Tissues be divided into 12 pieces ,each Tissues be divided into 12 pieces ,each piece includes 2-3 slices.piece includes 2-3 slices.

meansmeans ：： cold knife conization(CKC)cold knife conization(CKC) LEEPLEEP laserlaser

CKC

Differential diagnosisDifferential diagnosis

Cervical inflammation:Cervical inflammation:

cervical erosioncervical erosion

cervical polypuscervical polypus

Cervical mass:Cervical mass:

tuberculosis tuberculosis

papilla tumorpapilla tumor

endometriosisendometriosis

TherapyTherapy

depends on staging,age,common depends on staging,age,common condition and medical equipmentcondition and medical equipment

Primary treatmentsPrimary treatments ：： surgery and surgery and radiationradiation approximately equalapproximately equal with different complicationswith different complications

The role of chemotherapy has been The role of chemotherapy has been newly evaluatednewly evaluated

TreatmentTreatment

CINCIN ：： Grade IGrade I ： ： expectant management, follow up every 3 to 6 expectant management, follow up every 3 to 6

months.biopsy again if necessary or months.biopsy again if necessary or conization(excise the lesion)conization(excise the lesion)

Grade IIGrade II ：： cryo or laser or conizationcryo or laser or conization ，， follow up follow up

every 3to6 monthsevery 3to6 months Grade III: Grade III: conization or conization or hysterectomyhysterectomy

Treatment of invasive cervical Treatment of invasive cervical carcinomacarcinoma

surgery therapysurgery therapy radiation therapyradiation therapy surgery concomitant surgery concomitant

radiation therapyradiation therapy chemotherapychemotherapy

Radical treatment

Surgery therapySurgery therapy Appropriates inAppropriates in those:those:

Ia-IIa stageIa-IIa stage without surgical forbiddancewithout surgical forbiddance can keep ovary function in young womencan keep ovary function in young women

Ia1Ia1 hysterectomyhysterectomy Ia2 -IIaIa2 -IIa Radical hysterectomy and Radical hysterectomy and

therapeutictherapeutic lymphadenectomylymphadenectomy

Radical hysterectomyRadical hysterectomy

Radiation therapyRadiation therapy

abdominal cavity therapyabdominal cavity therapy Back-install therapy machineBack-install therapy machine Early stage cases,to control local Early stage cases,to control local

lesionlesion Outer body therapyOuter body therapy

Beeline acceleratorBeeline accelerator Late stage casesLate stage cases Pelvic LN and Pelvic LN and parametrial parametrial

involvementinvolvement

Radiation therapyRadiation therapy

Radiation therapy aloneRadiation therapy alone : IIb : IIb toⅣb stagetoⅣb stage

Postoperative adjuvant radiationPostoperative adjuvant radiation :: positive lymph nodespositive or positive lymph nodespositive or close resection margins, or close resection margins, or parametrial involvementparametrial involvement

PreoperativelyPreoperatively ：： large tumor size large tumor size of stage Ibof stage Ib or beforeor before

Radiation therapyRadiation therapy

ComplicationsComplications : : radiocystitis and radiorectitisradiocystitis and radiorectitis divide into near and future datesdivide into near and future dates

The former can recover by itselfThe former can recover by itself The later will develop to The later will develop to

ulcer,hemorrhage, straitness and ulcer,hemorrhage, straitness and fistula after 1-3yearsfistula after 1-3years

Be related to the radiation dose and Be related to the radiation dose and positionposition

ChemotherapyChemotherapy

AAdaptiondaption ：： recurrence or late recurrence or late stagestage

Drugs:Drugs:

platinumplatinum ，， CTXCTX ，， plant-alkaliplant-alkali ChemotherapyChemotherapy ：：

combination therapycombination therapy Squamous cell carcinomasSquamous cell carcinomas ：：

PVBPVB ，， BIPBIP adenocarcinomasadenocarcinomas ：： PMPM ，， FIPFIP

ApproachApproach ：： vein or artery vein or artery perfusionperfusion

Follow-upFollow-up

timetime ：： 2 years 2 years ，， once each 3monthonce each 3month 3-5 years3-5 years ， ， once each 6monthonce each 6month >6years>6years ，， once every yearonce every year

contentcontent ： ： PVPV Cytological examination of Cytological examination of

residual vaginaresidual vagina Chest X-RayChest X-Ray Blood RTBlood RT