Cervical Cancer Screening Alternatives for the Developing World Edith H. Harte MD October 22, 2003

Focus of Presentation: Cervical Cancer Screening Review incidence, etiology, and natural history of cervical cancer Discuss cervical cancer screening Limitations of PAP screening in low resource areas Alternatives to PAP, particularly Visual Inspection with 5% acidic acid (VIA) Discuss potential screening program for Santa Lucia, Intibuca in Honduras

Review incidence, etiology, and natural history of cervical cancer

Discuss cervical cancer screening

Limitations of PAP screening in low resource areas

Alternatives to PAP, particularly Visual Inspection with 5% acidic acid (VIA)

Discuss potential screening program for Santa Lucia, Intibuca in Honduras

Cervical Cancer Incidence Key Facts Incidence in USA markedly decreased since 1941 when Papanicolou screening started Organized cytology programs have reduced the incidence of and mortality from cervical CA in developed world Burden of disease highest in developing nations where populations are unscreened

Incidence in USA markedly decreased since 1941 when Papanicolou screening started

Organized cytology programs have reduced the incidence of and mortality from cervical CA in developed world

Burden of disease highest in developing nations where populations are unscreened

Cervical Cancer Incidence USA 3 rd most common malignancy of female lower genital tract 12,000 new cases; 4,600 deaths annually 6 cases/100,000 Honduras Most common female cancer 40 cases/100,000

USA

3 rd most common malignancy of female lower genital tract

12,000 new cases; 4,600 deaths annually

6 cases/100,000

Honduras

Most common female cancer

40 cases/100,000

Cervical Cancer Most cases found in women never screened or not screened for more than 5 years. High rates in the developing world directly related to the lack of screening programs As in the USA introduction of screening programs in other countries has decreased the incidence of invasive disease

Most cases found in women never screened or not screened for more than 5 years.

High rates in the developing world directly related to the lack of screening programs

As in the USA introduction of screening programs in other countries has decreased the incidence of invasive disease

Age – Adjusted Death Rate for Cervical Cancer in US

Characteristics of Cervical Cancer Long time period of pre-invasive state May take 10 yrs or more to progress Begins as mild dysplasia Many regress spontaneously( at least 50%) Most are squamous cell types (80%) Local spread Lymphatic spread

Long time period of pre-invasive state

May take 10 yrs or more to progress

Begins as mild dysplasia

Many regress spontaneously( at least 50%)

Most are squamous cell types (80%)

Local spread

Lymphatic spread

Stages of Cervical Cancer I. Confined to cervix II. Tumor extends beyond uterus, but not to pelvic side wall or lower 1/3 of vagina III. Tumor extends to pelvic side walls or lower 1/3 of vagina IV. Spread to bowel or bladder or distant metastasis

I. Confined to cervix

II. Tumor extends beyond uterus, but not to pelvic side wall or lower 1/3 of vagina

III. Tumor extends to pelvic side walls or lower 1/3 of vagina

IV. Spread to bowel or bladder or distant metastasis

Risk Factors for Cervical Cancer Multiparity Early intercourse Early childbearing Multiple and high risk sexual partners Sexually transmitted infections HPV infection Low socioeconomic status Previous dysplasia

Multiparity

Early intercourse

Early childbearing

Multiple and high risk sexual partners

Sexually transmitted infections

HPV infection

Low socioeconomic status

Previous dysplasia

Other Risk Factors Immunosuppression Cigarette smoking DES Exposure OCPs

Immunosuppression

Cigarette smoking

DES Exposure

OCPs

Role of HPV 95% squamous cervical cancers may have HPV DNA HPV infects reproducing cells of basal layer If HPV integrates into cell’s DNA May lead to cell transformation May result in high grade SIL or CA Many types exist; 16,18,31&45 high risk

95% squamous cervical cancers may have HPV DNA

HPV infects reproducing cells of basal layer

If HPV integrates into cell’s DNA

May lead to cell transformation

May result in high grade SIL or CA

Many types exist; 16,18,31&45 high risk

Rational for Cervical Cancer Screening To detect pre-invasive disease Cervical cancer has long pre-invasive state allowing for detection in the pre-malignant state Can potentially prevent progression to invasive cancer

To detect pre-invasive disease

Cervical cancer has long pre-invasive state allowing for detection in the pre-malignant state

Can potentially prevent progression to invasive cancer

OBJECT To find a screening test that will differentiate between a healthy and a diseased cervix Pap testing has been the standard in USA VIA has compared favorably with cytology in several studies done in China, India, and Africa

To find a screening test that will differentiate between a healthy and a diseased cervix

Pap testing has been the standard in USA

VIA has compared favorably with cytology in several studies done in China, India, and Africa

How to Evaluate a Screening Test Sensitivity: proportion of truly diseased people in a study population that are correctly identified as having the disease by the test. Specificity: proportion of non diseased persons correctly identified as not having the disease. Positive Predictive Value: Proportion of people with a positive test who have the disease

Sensitivity: proportion of truly diseased people in a study population that are correctly identified as having the disease by the test.

Specificity: proportion of non diseased persons correctly identified as not having the disease.

Positive Predictive Value: Proportion of people with a positive test who have the disease

Pap Screening Limitations Relatively poor sensitivity (51-66%) Imperfect collection methods Imperfect transfer of cells to slide or bottle Lesions that may not exfoliate Cytologist error

Relatively poor sensitivity (51-66%)

Imperfect collection methods

Imperfect transfer of cells to slide or bottle

Lesions that may not exfoliate

Cytologist error

Pap Screening Problematic in low resource areas Lack of organized screening and follow-up programs Lack of technology and availability Lack of resources for reading cytology Lack of colposcopy resources for abnormal Paps Lack of follow-up procedures

Problematic in low resource areas

Lack of organized screening and follow-up programs

Lack of technology and availability

Lack of resources for reading cytology

Lack of colposcopy resources for abnormal Paps

Lack of follow-up procedures

Alternative Strategies for Detecting Cervical Cancer Visual Inspection Visual Inspection with Acetic Acid (VIA) Cervicography Speculoscopy- VIA with chemiluminescent light source HPV DNA testing

Visual Inspection

Visual Inspection with Acetic Acid (VIA)

Cervicography

Speculoscopy- VIA with chemiluminescent light source

HPV DNA testing

Visual Inspection with Acetic Acid (VIA) Unmagnified visualization of cervix after application of 5% acetic acid Acetic acid application has a long history of use during colposcopy to locate abnormal areas. Aceto white changes after application may indicate Abnormal transformation zone Areas of increased cellular density with increased abnormal nuclei and DNA content

Unmagnified visualization of cervix after application of 5% acetic acid

Acetic acid application has a long history of use during colposcopy to locate abnormal areas.

Aceto white changes after application may indicate

Abnormal transformation zone

Areas of increased cellular density with increased abnormal nuclei and DNA content

Precedents for VIA Studies done in India , Africa and China indicate that VIA compares favorably with pap screening in terms of sensitivity and specificity

Studies done in India , Africa and China indicate that VIA compares favorably with pap screening in terms of sensitivity and specificity

VIA Meets criteria for a good screening test Compares favorably with pap screening May be more sensitive (66-96%) Is less specific (more false positives) Has the potential to improve screening, follow-up and treatment rates in low resource settings

Meets criteria for a good screening test

Compares favorably with pap screening

May be more sensitive (66-96%)

Is less specific (more false positives)

Has the potential to improve screening, follow-up and treatment rates in low resource settings

Biology of the Transformation zone External cervix covered with squamous epithelium – looks smooth Endocervical canal populated by columnar epithelium cells- looks red Squamocolumnar junction: border between these cell types Its location changes according to age and hormonal status Migrates to portia in reproductive age women

External cervix covered with squamous epithelium – looks smooth

Endocervical canal populated by columnar epithelium cells- looks red

Squamocolumnar junction: border between these cell types

Its location changes according to age and hormonal status

Migrates to portia in reproductive age women

Transformation Zone Area between the old and new squamocolumnar junctions where squamous metaplasia occurs Area where most (95%) cervical dysplasias and cancers occur

Area between the old and new squamocolumnar junctions where squamous metaplasia occurs

Area where most (95%) cervical dysplasias and cancers occur

Squamocolumnar Junction

Normal Squamocolumnar Junction Squamous epithelium is smooth and pink Columnar epithelium appears red There are no aceto white changes

Squamous epithelium is smooth and pink

Columnar epithelium appears red

There are no aceto white changes

Squamocolumnar Junction with Squamous Metaplasia Normal Junction Minimal white ring at junction Squamous Meta- plasia –normal variant

Normal Junction

Minimal white ring at junction

Squamous Meta-

plasia –normal variant

VIA Advantages Quick, easy, and non-invasive Requires minimal equipment Results are immediately available Good sensitivity-especially for higher grade lesions Few false negatives

Quick, easy, and non-invasive

Requires minimal equipment

Results are immediately available

Good sensitivity-especially for higher

grade lesions

Few false negatives

VIA Disadvantages Lower specificity (more false positives) Increased costs for referrals to colposcopy Potential of unnecessary biopsies Follow up of abnormals that don’t get colposcopies

Lower specificity (more false positives)

Increased costs for referrals to colposcopy

Potential of unnecessary biopsies

Follow up of abnormals that don’t get colposcopies

How to Screen GYN Patients Take gyn history focusing on risk factors and symptoms Examine patient starting at top Perform speculum exam Carefully inspect vulva ,vagina & cervix Do bimanual exam Perform VIA

Take gyn history focusing on risk factors and symptoms

Examine patient starting at top

Perform speculum exam

Carefully inspect vulva ,vagina & cervix

Do bimanual exam

Perform VIA

Gyn History Cycles : Lmp; reg; irreg; length; flow Abnormal bleeding; Intermenstrual; postcoital bleeding Abnormal vaginal discharge Pelvic or back pain Assess risk factors

Cycles : Lmp; reg; irreg; length; flow

Abnormal bleeding;

Intermenstrual;

postcoital bleeding

Abnormal vaginal discharge

Pelvic or back pain

Assess risk factors

Physical Exam General appearance; evidence wasting Lymph nodes; supraclavicular Abdomen; mass Pelvic cervix: gross lesions, elongated or unusual shape, tactile bleeding, ulcerations vagina: presence of lesions Bimanual: very hard cervix, palpable mass Rectovaginal: mass may extend laterally

General appearance; evidence wasting

Lymph nodes; supraclavicular

Abdomen; mass

Pelvic

cervix: gross lesions, elongated or unusual shape, tactile bleeding, ulcerations

vagina: presence of lesions

Bimanual: very hard cervix, palpable mass

Rectovaginal: mass may extend laterally

How to Perform VIA Do speculum exam Wipe away secretions Apply 5% acetic acid Wait 3 minutes Look for white areas Record results Biopsy any opaque white areas Biopsy obvious lesions

Do speculum exam

Wipe away secretions

Apply 5% acetic acid

Wait 3 minutes

Look for white areas

Record results

Biopsy any opaque white areas

Biopsy obvious lesions

Normal VIA Normal appearing cervix No aceto-white changes seen Minimal translucent or very pale white epithelium at SCJ is normal and may indicate squamous metaplasia Record result No further testing needed

Normal appearing cervix

No aceto-white changes seen

Minimal translucent or very pale white epithelium at SCJ is normal and may indicate squamous metaplasia

Record result

No further testing needed

Normal VIA Normal SCJ No white areas

Normal SCJ

No white areas

Abnormal VIA Opaque white epithelium results after acetic acid application Record result Biopsy whitest area Biopsy any gross lesion Biopsy and do ecc in elongated or abnormally shaped cervices

Opaque white epithelium results after acetic acid application

Record result

Biopsy whitest area

Biopsy any gross lesion

Biopsy and do ecc in elongated or abnormally shaped cervices

Cervical Dysplasia Opaque white epithelium Occurs at SCJ

Opaque white epithelium

Occurs at SCJ

Cervical Dysplasia Aceto white epithelium surrounds cervical os Internal margins of more densely white epithelium

Aceto white epithelium surrounds cervical os

Internal margins of more densely white

epithelium

Cervical Dysplasia Diffuse aceta white changes Most prominent at 6& 10 o’clock

Diffuse aceta white changes

Most prominent at 6& 10 o’clock

Severe Dysplasia Marked acetowhite epithelium Abnormal raised contour

Marked acetowhite epithelium

Abnormal raised contour

Carcinoma In Situ

Features of early cancer lesions Oyster shell white Rolled edges Abnormal vessels Friable Uneven surface

Oyster shell white

Rolled edges

Abnormal vessels

Friable

Uneven surface

Invasive Cancer Raised lesion Rolled edges Raised white epithelium Abnormal vessels Important to biopsy this

Raised lesion

Rolled edges

Raised white epithelium

Abnormal vessels

Important to biopsy this

What Needs to be Done in Santa Lucia Develop screening program Develop recording system Find reliable pathology lab Develop follow-up systems Untreated positives Post treatment patients Develop system for referral for treatment Teach local physicians and nurses to perform screening

Develop screening program

Develop recording system

Find reliable pathology lab

Develop follow-up systems

Untreated positives

Post treatment patients

Develop system for referral for treatment

Teach local physicians and nurses to perform screening

What Have We Done this Week? Screened 80 women ( 7 days) for breast and pelvic cancers 70 had normal VIA 10 had abnormal VIA and had cervical biopsies 3 had cervical polyps removed 2 required endometrial biopsies for abnormal or postmenopausal bleeding 1 case of advanced invasive cervical cancer was found Developed registration and recording system Found a Pathology Lab

Screened 80 women ( 7 days) for breast and pelvic cancers

70 had normal VIA

10 had abnormal VIA and had cervical biopsies

3 had cervical polyps removed

2 required endometrial biopsies for abnormal or postmenopausal bleeding

1 case of advanced invasive cervical cancer was found

Developed registration and recording system

Found a Pathology Lab