cervical intra epithelial neoplasia

Aboubakr Elnashar Benha university, Egypt

https://www.facebook.com/groups/227744884091351/

2. PREMALIGNANT STAGE

Cervical intraepithelial neoplasia (CIN): includes

Dysplasia & CIS

CIN 1 = Mild D.

CIN 2= Moderate D.

CIN 3= Severe D or CIS.

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CIN I CIN II

CINIII Aboubakr Elnashar

Squamous intraepithelial lesion (SIL): includes HPV

& CIN.

Low grade SIL= CIN 1 or HPV.

High grade SIL= CIN 2 or 3

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Aboubakr Elnashar

HPV types

Oncogenic potential HPV TYPES

LOW 6, 11,14,43,44

INTERMEDIATE 31,33,35,51,52,

HIGH 16,18, 45, 56

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13 high-risk HPV

16, 18,

31, 33, 35, 39

45,

51, 52, 56, 58, 59,

68.

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Transition time of CIN

Stages Mean years

Normal to CIN 1-2 1.62

Normal to CIN 2-3 2.2

Normal to CIN 3 4.51

Clinical picture

Symptoms:

No symptoms: majority of cases

Postcoital bleeding

Vaginal spotting

Abnormal vaginal discharge

Suggestive findings

Clinically suspicious cervix

II. METHODS OF

CERVICAL CANCER

SCREENING A. Cytological

1. Conventional Pap. Smear

2. Liquid-based monolayers: LBC

3. Automated cytological screening

B. HPV testing

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C. Visual

1. Visual inspection of the cervix

a. Visual inspection with acetic acid (VIA)

b. Visual inspection with acetic acid and magnification (VIAM)

c. Visual inspection with Lugol’s Iodine (VILI)

2. Colposcopy.

3. Gynocular

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A. CYTOLOGY

1. Conventional Pap test used for ≥50 y all across the globe.

widely used for in most developed countries

Meets all the requirements for mass screening:.

Fairly tolerated by patients

Easy to administer

Reasonable sensitivity & specificity.

Detection of endocervical lesions.

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Precautions:

No sexual intercourse, vaginal douche, medication

No lubrication, powder, pelvic examination , acetic acid

Instruments & materials:

Speculum

Spatula:

Cytobrush or cotton tipped swab for the endocervical canal

Ayre s spatula for the ectocervix

Fixative

Jar

Slide

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Steps:

Taking the sample: from the ectocervix and endocervix, either with a spatula or brush

Smearing: circular motion

Fixation: Ethyl alcohol, Coating spray

Staining:

Examination under

a microscope by specially

trained technologists and

doctors.

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CINIII

CINIII

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Limitations

Moderate to low sensitivity: High rate of false-negative test results 20-40%

Women must be screened frequently

Rater dependent

Requires:

Complex infrastructure: Complex laboratory test

Trained cytologist

Multiple visits

Continuous monitoring to maintain high-quality results

Results are not immediately available

Less accurate among post-menopausal women

Impossible to locate the lesion.

Usually available only in large cities in many

countries

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Aboubakr Elnashar

Frequency of Pap test

CDC recommendation

21 to 29y: Pap test /3 y.

30 to 65y: Pap test /3 y or

Pap test plus HPV test/5 y.

2. Liquid-based monolayers

(ThinPrep, CytoRich)

Steps:

•Cells are collected using a brush instead of a spatula.

•Head of the brush is vigorously shaken or broken off into a small pot of liquid containing preservative solution.

•The sample is filtered or centrifuged to remove excess blood and debris.

•The cells are then transferred to the slide in a “mono” layer.

•Staining.

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Advantages:

•It removes most mucus, protein& fresh blood cells,

•distributes the cells uniformly

•improves fixation

•maintains diagnostic clusters

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LBC Vs Conventional Pap

More expensive

Repeat smear rates: 1 to 2% Vs 9%

Less false negative rate

No difference in the relative sensitivity.

No difference in the relative specificity, when H

and L- GSIL were considered as cutoff.

Better in predicting CIN

It is the preferred tool for cervical cytology

screening

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Aboubakr Elnashar

3. Automated Pap smears

To reduce errors by using computerized analysis to evaluate Pap smear slides.

1. Autocyte

•Composed of an algorithmic & neural network scanner

•Scans the slides & records images of 128 of the most abnormal fields found on the slide, with the most significant abnormality found in the center.

•It reduces costs & shortens screening time.

•Detects 97.2% of the abnormal tests (Koss et al,1994).

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Aboubakr Elnashar

2. AutoPap.

The material on the slide is reviewed and scored based on an algorithm, as to the likelihood of an abnormality being present.

Typically, it does not show the cytotechnologist which of the cells are likely to be abnormal.

Variety of visual characteristics, such as shape and optical density of the cells, are included in the algorithm.

•It reviews all normal & satisfactory smears

•As a primary screener, it removes 30 % of slides from the workload

•97% sensitivity (Lee et al, 1997) Aboubakr Elnashar

B. HPV TESTING

Role of HPV as a causative agent of cervical

cancer has been well established.

However, most HPV infections in young women regress rapidly, without causing clinically significant disease. infection is a marker of sexual activity than of cervical cancer risk.

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Hybrid Capture II kit (HC II, Qiagen Inc., USA)

Approved by FDA : frequently used. The sample is collected similar to Pap, with a

cervical swab from TZ and placed into transport

medium.

Detects whether a person is infected with one or

more of the 13 high-risk HPV viral types (types16,

18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68).

It is used as

Routine screening test above 30 to 35 y

To evaluate equivocal Pap test. ASCUS or LGSIL:

Oncogenic HPV: Colposcopy.

≥35 y: HPV testing/5 years & if +ve: Pap smear

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•Negative predictive value: very high

•HPV testing could augment but not replace cytological screening Sensitivity for detecting CIN 2–3 lesions: 45.7 to

80.9%

Specificity: 91.7 to 94.6%.

HPV testing (Qiagen HCII) most objective and reproducible of all cervical screening tests less demanding in terms of training and quality assurance.

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HPV testing

sophisticated lab

unaffordable ($20 to $30/test) in less-developed

countries.

HPV DNA- PCR testing (HPV typing): [Current technique (HC2) Hybrid Capture 2] Isolated HPV types could be detected.

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Care HPV test (Qiagen Inc. USA)

Detect several types of HPV rapidly (within 3 h)

No need:

specially trained personnel or

sophisticated lab.

{simplicity and rapid completion}: screening and

clinical follow-up to be completed on the same day.

low cost: $8/test

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C. VISUAL

1. Visual examination of cervix

a. Visual inspection after application of acetic acid

(VIA)

b. VIA with magnification (VIAM)

c. Visual inspection after application of Lugol’s iodine

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Effects of acetic acid:

Coagulates the proteins of the nucleus &

cytoplasm: protein opaque & white.

Dehydrates the cells: cytoplasmic volume is

reduced & the reflection is increased.

Duration:

appears after 20 seconds

disappears after 2 minutes.

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Category Clinical Findings

Negative

No acetowhite lesions or

faint acetowhite lesions;

polyp,

cervicitis, inflammation,

Nabothian cysts.

Positive Sharp, distinct, well-defined,

dense (opaque/dull or oyster white) acetowhite with

or without raised margins touching SCJ;

leukoplakia and

warts.

Suspicious

for cancer

ulcerative, cauliflower-like growth or

ulcer; oozing and/or bleeding on touch. Aboubakr Elnashar

2 . Visual inspection with acetic acid (VIA)

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Normal NAAT

Positive

Suspicious for cancer

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VIA Performance:

Source: Adapted from Gaffikin, 2003

Sensitivity Specificity

Pap 47-62 60-95

VIA 76-84 79-83

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3. Visual Inspection with Acetic Acid Using

Magnification (VIAM) Gynoscopy = Aided VIA

visualization of cervix after application of aa using low power magnification

(2.5x to 4x)

Inexpensive, easy to use portable system, which can be used to screen cervical cancer in developing countries.

Sensitivity: 80%

Specificity: 95% compared to Pap smear

Magnascope (4X)

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4. Visual inspection after application of Lugol’s

iodine

Test performance:

(Sankaranarayanan et al., 2008).

Specificity Sensitivity

85.5 76.8 VIA

85.4 91.7 VILI

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Categories for VILI test results:

Category Clinical Findings

Negative Squamous epithelium turns brown

Columnar epithelium does not change

color; or

Irregular, partial or non-iodine uptake

areas.

Positive Well-defined, bright yellow iodine non-

uptake areas touching SCJ or close to the

os if SCJ is not seen.

Suspicious

for cancer

Ulcerative, cauliflower- like growth or

Ulcer; oozing and/or bleeding on touch.

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VILI: test-positive

Well-defined

bright yellow iodine non-uptake areas

touching the SCJ

2. Colposcopy

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Colposcope :

Microscope

Low-power, stereoscopic, binocular field

Powerful light source

Moving system

The most common indication:

positive screening tests: positive cytology

positive on VIA.

Biopsies from suspicious areas

Endocervical curettage:

when the colposcopy is unsatisfactory, i.e. scj

cannot be visualized.

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Aboubakr Elnashar

Swede score

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Swede score of 4 and above:

Punch biopsies of the cervix

Swede score 6 and above:

immediate tt

with cold coagulation under visualisation with the Gynocular and local anaesthesia. patients not suitable for cold coagulation or with biopsies revealing microinvasive cervical disease or worse: appropriate diagnostic workup and management protocol.

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Aboubakr Elnashar

3. Gynocular Mini colposcope portable colposcope

Easy to use: Handheld or used with a tripod

Pocket-size battery: Battery operated (2 h of working time/charge)

Provide gold-standard examination: Red-free/green filter mode

Capture digital images

Take videos

low-resource countries.

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Aboubakr Elnashar

charger and mounting clip

for camera tripod.

lens, green filter,and warm

white LED illumination.

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Aboubakr Elnashar

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III. SCREENING IN DEVELOPING COUNTRIES

Difference between developing & developed countries

I. Higher incidence: 80%

II. Higher mortality: 90%

III. Different risk factors

IV. Poor financial, human & technical resources

V. Inadequate follow up

Screening used in the developed world is inappropriate in developing countries (Singer,1995) Aboubakr Elnashar

Alliance for Cervical Cancer Prevention

2009 1. optimal age-group for cervical cancer screening

to achieve the greatest public health impact is 30–39-y-olds.

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2. Cytology-based screening programs using Pap smears have been shown to be effective in

developed countries, sustaining high-quality

cytology- based programs is difficult in low-resource

settings.

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3. The most efficient and effective strategy

VIA or

HPVDNA testing and then to treat using

cryotherapy.

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TREATMENT

I. Ablative (destructive)

1. Cryotherapy

2. Cold coagulation

3. Laser vaporization

II. Excisional

A . LETZ B. Conization:

1. LEEP

2. Cold knife (CKC)

3. Laser

III. Hysterectomy

CIN: WHO Recommendation 2014. CIN 1:

(i) immediate tt

(ii) follow the woman and then tt if the lesion is

persistent or progressive after 18 to 24 months.

CIN 2 and CIN 3:

Cryotherapy or LEEP.

AIS (adenocarcinoma in situ)

CKC

Strategy Three visits strategy

one for screening

one for colposcopy,

one for treatment: poor compliance, especially

among rural women.

Single visit: see-and-treat strategy

satisfactory results

no significant extra morbidity [Emam et al, 2009].

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See & treat (Single visit diagnosis & tt)

•It means

(Cryo therapy, cold coagulator or LEEP) at first visit to women with (VIA or colposcopic) findings suggestive of SIL.

•Advantages:

False negative histology is low (4.7% )

Reduce waiting lists & anxiety

•Disadvantages:

Over tt of insignificant lesions

•It should be limited to HGSIL (Pastner,1994)

III. Hysterectomy

Indications

1. Other gynecological conditions:

.fibroid, prolapse, endometriosis, PID .

2. Refuse all other forms of therapy

3.SIL at limits of conization specimen

4. Poor compliance with follow-up

Sterilization is not an indication

Treatment of CIN during pregnancy

•Abnormal cytology Colposcopy

•Colposcopically directed punch biopsy or

small loop biopsy

•Knife or LLE cone: rarely indicated

•Colposcopy/ 3 m to ensure that the lesion is not

progressing

•CIN 3: treatment after delivery

Prof. Aboubakr Elnashar Benha University Hospital, EGYPT

E-mail: elnashar@hotmail.com