The up-to-date evidence on colposcopy practice and treatment of cervical intraepithelial neoplasia :...

OBGY R4 Eun Suk Lee

Cancer Treatment Review (2006)32, 516-523

Introduced early in the last century (1925) by Hinselman

Visualisation of the lower genital tract before and after

applying an acetic acid solution under magnification

with an appropriate light source

Introduction Introduction

Colposcopy as a Colposcopy as a screening toolscreening tool

Combination of cytology & colposcopy in primary screening to

reduce the impact of false negative results of cytology

Cervical cytology :Cervical cytology : reported by Georgios Papanicolaou (1943)

Proven its efficacy during the last 50 years by reducing both

incidence & mortality from cervical cancer

False negative rate ☞ vary from 10% to 80% with an estimate of 20–25% being generally

acceptable

Known prevalence of CIN in the general population(1–2%)

False negative rate of cytology ☞ 20% In a total population of 10,000 women screened, 100 → pre-invasive lesion

80 → detected with cytology 20 → missed

9920 women ☞ referred & undergo colposcopic exam

in order to detect the 20 missed ones

Colposcopy in primary screening ☞ Expensive Time-consuming Requires extensive training Unnecessary psychological morbidity in women Long-term pregnancy-related morbidity

Colposcopy as a Colposcopy as a screening toolscreening tool

Obvious Disadvanta

ges

Diagnostic accuracy of Diagnostic accuracy of colposcopycolposcopy ① <Colposcopic findings>② Unsatisfactory colposcopy (upper limit of transformation

zone or squamous columnar junction not

visible) ① Subtle (e.g. simple HPV infection) Normal (e.g. immature or metaplasia changes)

Histological Dx ☞ punch bx or excision of transformation zone

Diagnostic deficiencies of colposcopy : Colposcopic impression vs histological Dx

In a series of 2100 women, Colposcopic & histological agreement only 37%

∴ Colposcopy → an excellent secondary test for cervical disease

in women with abnormal cytology

The HPV DNA testing, as a The HPV DNA testing, as a triage tool for colposcopic triage tool for colposcopic referralreferral

10% of screened population ☞ borderline or minor cytological

abnormalities (such as ASCUS, AGUS, LgSIL) on cervical smear

5–47% of lesions presenting c low grade cytological phenotype

☞ Reveal in histology an occult high grade CIN

Management options : ① Immediate referral to colposcopy for every woman c minor findings in cytology ② Selection of those likely to have underlying high-grade

ds

Currently available triage methods Repeat cytology

HPV DNA test

Recent meta-analysis by Arbyn et al. (2004)Recent meta-analysis by Arbyn et al. (2004)Accuracy of HPV DNA test & repeat cytology as

triage methods for equivocal cytological findings (ASCUS/AGUS) & for an histological outcome of CIN II+ or CIN III+

HPV DNA test, in Hybrid Capture-2 (HC-2) I. Increased sensitivity (95%) vs repeat cytology

(82%)II. Specificity : Low without statistically significant

difference HC-2 (67%) vs Repeat Cytology (58%)

The Conclusion : HPV DNA test → improved accuracy (higher sensitivity, similar specificity) Compared to repeat Pap smear


HPV DNA testing in the triage of cases with low-

grade cytology (i.e. HPV infection and CIN1) Sensitivity of HC-2 ☞ high (97%) Specificity ☞ low (29%)

Significantly lower specificity than repeat Pap smear (40%)

Not more performable to women c LSIL than repeat cytology

More research identify accurate LSIL triage methods such as HPV typing & molecular progression markers (HPV specific viral load, mRNA E6/7, cell cycle

proteins, etc.)


Management of low grade squamous intraepithelial lesion I. Immediate referral to colposcopyII. Repetition of Pap smear in six months

Accuracy parameters of cytology & HPV DNA test as triage tools

☞ geographically vary

HPV infection and subtypes’ rate may vary between countries

These phenomena might influence cost-benefit calculations

as the costs of these tools vary quite significantly in countries


Colposcopy during Colposcopy during pregnancypregnancy

During pregnancy, the need for colposcopy

① Women that conceive after the punch biopsies but prior to the definite treatment of the lesion② Those with a lesion detected after an

opportunistic smear during usually the first antenatal visits ③ After abnormal cytology → subsequently to be

pregnant

Conservative management and surveillance even when the index smear indicates high-

grade SIL with repeat cytology & colposcopy every 2–

3 months

Extension of the squamous columnar junction to the ectocervix

→

Treatment for preinvasive lesions during pregnancy

Increased risk of severe intraoperative haemorrhage Possibility of incomplete excision & disease

persistence↑

Biopsy Where there is cytologic or colposcopic impression of stromal invasion

Conventional knife wedge Bx → Small loop wire excision which contain stroma in order to safely confirm or exclud invasion

Colposcopy during Colposcopy during pregnancypregnancy

Satisfactory colposcopy

CIN – how to treatCIN – how to treat

The majority of women who are diagnosed with CIN ☞ Young & yet to start or complete their family

Need for conservative treatment Not compromise therapeutic efficacy Preserve Cx anatomy & future cervical function

Hysterectomy Radical procedure rarely used today Limited to older women with coexisting uterine

pathology or women who have completed their families

CIN – how to treatCIN – how to treat Prior to hysterectomy, invasive ds needs to be excluded by histological evaluation of the transformation zone

Cold knife conzationCold knife conzation Conservative Tx aimed at preserving cervical

anatomy Rarely used today by out-patient conservative

procedures Requires general anaesthesia & hospitalisation Fertility & pregnancy-related morbidity is associated

Restricted in selected cases (particularly in older women)

I. Suspicion of microinvasionII. Severe glandular lesions III. Residual/recurrent ds after more conservative Tx

The more recent conservative methods of Tx

Destructive (electrocoagulation, cryotherapy, laser ablation)

Excisional (laser conization & electrosurgical excision -LLETZ/

LEEP/NETZ)

Destructive techniques

Rather easier to perform Destroy the transformation zone epithelium Cone specimen is not provided Marginal status can not be evaluated Precise grade of the treated lesion – not

guarantied More intensive or longer f/u


Excisional techniques ☞ Comprehensive histological evaluation of

excised tissue with precise evaluation of excision margins

LLETZ :: Most popular, by combining all the

advantages of the excisional techniques

Relatively shorter duration Low cost Good compliance Simplicity Easier learning curve


In incomplete excision, histologically residual disease ☞ 30–40%

More likely to exist when the endocervical margins are involved

Clear excisional margins ☞ 3–5% risk of residual ds

Extension of the CIN to the endocervical glands & increased age

Augment the possibilities of an incomplete Tx

Detection, via colposcopy, of HPV satellite lesions outside the transformation zone →→ Independent factor towards treatment failure


Excisional methods as part of “see and treat” policy ☞ Both evaluation & treatment are performed in

the first visit

Risk of over-treatment Implemented if unnecessary treatment(+) in

less than 10%

“Select and treat” policy involves biopsy Prior to treatment which confirms or excludes

the presence & the exact grade of the lesion

Minimise the over-treatment rates↓ Demand a repeat visit for the appropriate Tx


Randomized controlled trial comparing LLETZ followed or not by cautery of remaining cervical

crater

Avoiding generalized haemostatic cauterization following

LLETZ, particularly around the newly created os, Better follow-up satisfactory colposcopy rates Significantly lower cervical stenosis rates

Bleeding ↓↓after loop electrosurgical excision ☞ significantly less bleeding when treatment was

performed during the follicular rather than the luteal phase

--- J. Nuovo, J. Melnikow, A.R. Willan and B.K. Chan, Treatment outcomes for squamous intraepithelial lesions, Int J Gynaecol Obstet 68 (2000), pp. 25–33.


Despite the theoretical advantages of excisional techniques,

the evidence base clearly suggests that all the conservative

methods of treatment present more or less similar efficacy

in terms of eradicating intra-epithelial lesions

Systematic review on the risk of invasive cervical cancer

following conservative therapy

4–5-fold greater risk in this group compared to the general population that

remains stable throughout next eight postoperative years


Long-term effects on future fertility & Long-term effects on future fertility & pregnancy outcome following pregnancy outcome following conservative treatment for CINconservative treatment for CIN

Recent meta-analysis by Kyrgiou et al.(2006)

Cold knife conization risk of preterm delivery low birth weight caesarean section rate

LLETZ : risk of preterm delivery, low birth weight

& premature rupture of the membranes ↑↑

Laser conization : similar pregnancy-related morbidity

Laser ablation : none of the parameters to be affected

Figure 3. (A) Cumulative forest plot presenting the risk for obstetric outcomes & different methods of treatment. (T): favours treatment, (C): favours control. Black: statistically significant. Grey: trends (but failed to reach level of signifi-cance). White: non-significant. (B) Relative risks and 95% confidence intervals For each outcome and method used.

The limited data on fertility outcome presented in this review

did not reveal any adverse effects

Prospectively designed studies dealing with long-term effects

on fertility do not exist & would be very difficult to undertake

All the original studies were retrospective c all the limitations

that this implies and the data on confounding factors that

predispose to prematurity might have been incomprehensive


Future prospectively designed research might give more

insight onto whether possible different patterns of cervical

behaviour during subsequent pregnancy Related to the proportion of either the cervical

volume or the endocervical canal excised

Meta-analysis supports observation management of low grade

lesions, who have an extremely low risk of progression

For young nulliparous women ☞ Reintroduction of laser ablation in selected cases


Follow up after treatmentFollow up after treatment Both cytology & colposcopy are used in different

schemes, combinations, intervals and duration

In the majority of cases the residual lesion → picked-up during

the first few years following Tx, by performing cytology

CIN I ☞ follow-up protocol is cytology at 6, 12 and 24 months

if every examination is negative then return to national screening programme

HgSIL ☞ more intensively monitored with cytology at 6 and 12 months afterwards

If cytology turns positive, colposcopy necessity

Follow up after treatmentFollow up after treatment Involved or uncertain margins following excisional

treatment ☞ Combination of cytology and colposcopy

Reported of higher sensitivity than cytology alone Specificity is reduced, but to a less extend than

performing colposcopy in all cases (clear and involved margins)

An immediate second excision in case of involved endocervix

margins(+) in cases of women older than 50 years of age or

in cases of glandular intraepithelial neoplasia

In case of an ablative treatment → a longer and closer follow-up surveillance is essential involving probably colposcopy

An increased risk for invasive cervical disease lasting nearly

20 years following CIN treatment

Reported that HPV DNA test is more sensitive, compared to

colposcopy or cytology in detecting CIN treatment failures

Both HPV DNA test & cytology aiming to minimize possibility

of false negative findings

Estimation of HPV viral load → Relation to the higher or lower possibility of Tx

failure

Follow up after treatmentFollow up after treatment

Application and combination of cytology, colposcopy

& more recently developed follow-up markers incorporated within the existing

guidelines & alter the follow-up algorithms

Follow up after treatmentFollow up after treatment

Colposcopy should not be used as a screening method for the detection of CIN

HPV DNA test (HC-2) has a role in the triage of women c ASCUS, but not in those cases presenting c low grade abnormalities in the index smear

Excisional conservative methods of treatment of CIN present long term obstetric morbidity

Follow up policy could introduce HPV DNA test for the earlier recognition of treatment failures

The up-to-date evidence on colposcopy practice and treatment of cervical intraepithelial neoplasia :...

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