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Cervical Cancer Screening: Addressing the Confusion/Making Friends with the Algorithms Sally Hersh, DNP, CNM

October 2014, NPO Conference

How far did you travel for your last pap smear?

Words from Women

• “I feel like a heavy mountain is gone from my chest.”

• Age 36, sells snacks in Bangkok

• Travelled 12 hours to native village for free cervical cancer screening

• No white spots seen

New York Times 9/26/11 Donald G. McNeil

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Words from Women

• “Everything’s okay! Everything’s okay!”

• Age 37, restaurant cashier in Ko Chang

• Travelled home to rice-farming village after her mother urged her to undergo second cervical cancer screening

• First screening 3 years prior: one visit

• White spot on cervix seen

• Cryotherapy by RN

• Risk of Cervical Cancer (CxCa) reduced by 65% with 2 screenings

New York Times 9/26/11 Donald G. McNeil

Fighting Cervical Cancer with Vinegar and Ingenuity • Magical ingredient: household vinegar

• Procedure: VIA

• Visualization of cervix with acetic acid

• Followed by cryotherapy if acetowhitening of cervix seen

New York Times 9/26/11 Donald G. McNeil

Learning Objectives

• At the end of this presentation, the learner will be able to:

• Identify the prevalence rate of cervical cancer worldwide

• Describe the role of HPV in cervical cancer disease and screening

• Define cervical cancer screening terms

• Apply concepts of cervical cancer disease process to the use of ASCCP algorithms on cervical cancer screening

“The lesson viewed as a planned, exciting journey with instructional objectives used as milestones along the route, in no way removes the wonder of learning and the satisfaction which comes with achievement.”

-L.B. Curzon

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Visual inspection with acetic acid

• VIA

• Acetic acid

• Dehydrates cells

• Squamous cells with large nuclei (dysplastic) reflect white and appear white

• No contraindications

• Complications:

• None

• Side effects:

• Transient sensation of vaginal burning from acetic acid

Cervical cancer

• Third most common cancer in women worldwide

• Late stage cancers

• correlated with late screening

• especially in older women and Hispanic women

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Medicaid and Screening

• Medicaid programs in all states and DC cover breast, cervical, and colorectal cancer screening

• Coverage does not equal compliance with screening

• Medicaid beneficiaries

• Less likely to be screened for cancer than those with private insurance

• More likely to present with advanced-stage cancers

• Reimbursement varies substantially from state to state

• Usually below Medicare reimbursement levels

• Office visit copayments may decrease access to care

• Increased reimbursement: linked to increase access of care for children and adults

Halpern et al (2014) Cancer online Aug 25, 2014

Cervical Cancer

Estimated new cancer cases and deaths in women in US 2013

Siegel, R (2013) CA: Cancer Journal for Clinicians, Jan/Feb, Vol 63, 1: 11-30

New Cases Deaths

Oral cavity and pharynx

11,760 2,390

Uterine Cervix 12,340 4,030

Anus, anal canal, anorectum

4,430 550

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Cervical cancer screening

• Detects early changes

• If left untreated:

• Risk of transition to invasive disease over many years

• Long interval between detection of abnormal changes and development of cervical cancer

• Allows for longer intervals between testing

Cofactors for pathogenesis of cervical cancer • Immunosuppression

• Cigarette smoking

• HSV and chlamydia infection

• Surrogate marker for HPV infection?

• Oral contraceptives

• Surrogate marker for HPV infection?

• Familial link?

• Parity?

• MJ?

Types of cervical cancer

• Squamous cell carcinoma • Squamous epithelium

• Most prevalent type

• Screening via pap smear testing

• HPV infection with high risk types is key to development

• Adenocarcinoma • Glandular epithelium

• Less common than squamous cell

• Most cases are associated with HPV infection

• Detection via cytology is limited

Massad LS et al (2013) Journal of Lower Genital Tract Disease 17(5) S1-S27.

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Questions: HPV

• Epidemiologic case studies have shown that HPV is found in which percent of cases of cervical cancer?

• Nearly 100%

• Nearly 85%

• Nearly 50%

• Nearly 25%

Questions: HPV

• Current HPV vaccinations have been found to be useful in preventing disease progression in women with pre-existing HPV related cervical lesions?

• True

• False

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Questions: HPV

• A current HPV vaccine, Gardasil, protects against:

• Low grade HPV infection

• High grade HPV infection

• Low and high grade HPV infection

Questions: HPV

• The most carcinogenic genotype of HPV is:

• 11

• 18

• 16

• 6

Questions: HPV

• The second most carcinogenic genotype of HPV is:

• 11

• 18

• 16

• 6

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Questions: HPV

• Approximately what percent of HPV infections is transient and resolve spontaneously without symptoms?

• 25%

• 50%

• 75%

• 90%

Questions: HPV

• According to the latest ASCCP recommendations, HPV vaccinated women are allowed longer intervals between screening.

• True

• False

Questions: HPV

• Which Hollywood stars have been in the news in the past few years due to disease related to HPV?

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ROLE OF HPV IN CERVICAL CANCER

Human papillomavirus

HPV

• The major etiologic agent in cervical pre-cancer and cancer.

• Necessary for the development of cervical neoplasia

HPV

• Most women infected with HPV do not develop high grade lesions or cancer

• So, HPV alone is not sufficient for causing abnormalities

• 2 major factors:

• Subtype of HPV virus

• Persistence of the virus

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HPV

• A group of double-stranded DNA viruses

• Belong to family of Papovaridiae

• Infects wide variety of organisms

• Birds to mammals

• More than 120 types

Asiaf A et al (2013) European J of Cancer Prevention pp1-19.

Mucosal/genital HPV subtypes High risk HPV types (oncogenic)

16,18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82

cause dysplasia that may lead to cancer

Low risk HPV types (non-oncogenic)

6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, CP6108

usually cause low grade dysplasia, genital warts

Asiaf A et al (2013) European J of Cancer Prevention pp1-19.

Mucosal/Genital HPV subtypes • Cervical Cancer

• HPV 16 accounts for about 50% of cases

• HPV 18 accounts for about 20% of cases

• Anal Cancer

• Increased incidence in the past 30 years, mostly attributed to high risk types seen in Cervical CA, in particular HPV 16 (90%) and 18

• Oro-pharyngeal Cancer

• HPV related accounts for >60% of certain subsites: found in younger populations

• Associated with HPV 16 Jamal, A. (2013) J Natl Cancer inst 105:175-201

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Genital HPV

• Genital HPV

• Acquired through sexual and genital skin-skin contact

• One of the most common STIs among both men and women

• Risk increases with number of partners and age at sexual debut

Asiaf A et al (2013) European J of Cancer Prevention pp1-19.

Genital HPV

• 90% of HPV infections

• Transient and resolve spontaneously without symptoms

• Most women clear infection through intact immune system

• Average length of infection

• 4-20 months

• High risk subtypes take longer to clear

• Adolescent and young women have higher rate of regression

Asiaf A et al (2013) European J of Cancer Prevention pp1-19.

HPV

• Chronic and persistent infection:

• Required for development of pre-cancer and cancers of cervix

• Natural history through defined steps:

• Pre-neoplastic lesions with increasing levels of dysplasia

• Gradually progressing from mild to severe dysplasia to micro-invasive lesions, finally invasive cancer

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Counseling women

• Who gave it to me?

• How do I tell my partner?

• Do I change my sexual behaviors because of this?

• Can I increase my odds of clearing the infection?

• Does it clear completely?

• Is it suppressed or gone?

• Still contagious?

Patient education: HPV

• http://www.cdc.gov/std/hpv/stdFact-HPVandoralcancer.htm

• http://www.cdc.gov/std/HPV/STDFact-HPV-and-men.htm

• http://www.cdc.gov/std/HPV/STDFact-HPV.htm

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HPV Vaccine

• Disclaimer:

• Not enough time in this presentation

• Take home points:

• Numbers who have been vaccinated (females and males) are climbing slowly

• Can do better!

• May change how patients are screened when a majority of the population has been vaccinated

• No difference in screening or management at this time between those who have been vaccinated and those who have not

HPV testing: two uses

• Primary screening

• Triage of pap smear results

HPV Tests

• Primary Screening:

• Alone or co-testing with cytology

• More sensitive than cytology in detecting high grade and low grade lesions

• Poor specificity: limits use as primary screening in younger women

• In young women, testing

• increased detection of transient HPV infections and subsequent procedures: increased colposcopy

• In women aged 30 or over

• earlier diagnosis of high grade lesions

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Primary HPV Testing for Cervical Cancer Screening • FDA: May 2014

• Approved HPV test Cobas 4800 by Roche Diagnostics for primary screening for cervical cancer

• FDA algorithm released

• ASCCP provided webinar on primary HPV testing: June 2014

• Limits of pap test: sensitivity is low

• Compensate for this by doing frequent screening

• Highly subjective test

• Cervical cytology misses some disease

• HPV test is more sensitive and more reproducible

• Assesses future risk, not just current status

• Finds more women at high 5-year risk of cancer or precancer

• Can be automated

ASCCP Algorithms 2013

• Learning objective: To synthesize information from today’s lecture as applied to ASCCP algorithms on cervical cancer screening/surveillance.

• Reminders:

• Guidelines are never a substitute for clinical judgment.

• Guidelines may not apply to all patient-related situations.

• Most cases of cervical cancer can be prevented through screening and surveillance, but

• No screening or treatment regimen is 100% effective.

Massad LS et al. (2013) 2012 Updated Consensus Guidelines for the Management of Abnormal Cervical Cancer Screening Tests and Cancer Precursors. J Lower Genital Tract Disease. 17 (5): S1-S27.

Summary of Primary HPV Screening: ASCCP Webinar June 2014

• FDA approval of cobas HPV test, April 2014

• ATHENA trial: end of trial results pending:

• > 40,000 participants >/= age 25

• Followed up in 3 years if HPV test negative

• Colposcopy if HPV 16+ or 18+

• Cytology if HPV 16 or 18 negative

• Interim recommendations will be provided later this year by ASCCP/SGO

• Downstream management currently uncertain as few long term data exist

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Sensitivity and specificity

• Sensitivity:

• The number of patients with a positive test who have a disease divided by all patients with the disease. High sensitivity means the test will not miss many patients with the disease

• Specificity:

• The number of patients who have a negative test and do not have the disease divided by the number of patients who do not have the disease. High specificity infrequently identifies patients as having the disease when they do not.

HPV testing

• Triage of pap smear results

• Reflex testing for indeterminate results (ASC-US)

• Increased use of HPV testing in most recent updated algorithms

• Genotyping for HPV 16 and 18

HPV testing

• High risk types only!

• 4 types of tests in US, approved by FDA

• Algorithms by ASCCP are intended only for application in those tests approved by FDA

• Cervista 16/18

• Detects only 16, 18

• Approved for women 30 and over

• As f/u test after positive HPV screen for 14 high risk types

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“I’ll have the pap smear”

Cervical Cancer Screening Terminology • Former terminology for premalignant squamous changes of

cervix

• Mild, moderate, severe dysplasia

• “New” terminology system introduced in 1988 and revised.

• Bethesda system

• Cytology= pap test finding

• Squamous intraepithelial lesion (SIL)

• Histology= biopsy (tissue) findings

• Cervical intraepithelial lesion (CIN)

Terminology

• Cervical squamous epithelial lesions = cytology

• LSIL

• Low-grade squamous intraepithelial lesion

• Usually transient HPV infection

• HSIL

• High-grade squamous intraepithelial lesion

• More likely be associated with persistent HPV infection

• Higher risk of progression to cervical cancer

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Terminology

• Cervical intraepithelial neoplasia = histology

• A pre-malignant condition of the cervix

• CIN 1: low grade lesion

• Mildly atypical cell changes

• HPV changes often seen

• CIN 2: high-grade lesion

• Moderately atypical cell changes

• CIN 3: high grade lesion

• Severe atypical cell changes

• Previously called severe dysplasia or carcinoma in situ

• CIN 2 and 3 are classified together as high grade lesions and followed up clinically almost identically

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My explanation to women undergoing colposcopy • Pap smear results

• Carcinoma in situ

• HSIL

• *************

• LSIL

• ASC-H

• ASC-US

• Biopsy Results

• Carcinoma in situ

• CIN 3

• CIN 2

• ***********

• CIN 1

Treatment options

• If CIN 1=low grade

• See algorithms by ASCCP

• Observe and re-test over time

• If persistent, ???

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Treatment options

• If CIN 2 or 3 or cancer:

• See algorithms by ASCCP

• Ablative

• Cryosurgery

• Laser ablation

• Excisional

• Laser conisation

• Surgical or laser knife

• LEEP (loop electrosurgical excision)

• Hysterectomy

Screening or surveillance?

• Cervical cancer screening:

• The testing of asymptomatic individuals to determine who is likely to develop cancer

• Cervical cancer surveillance:

• The monitoring of individuals who have pre-cancerous conditions or who have received treatment

Expert Recommendations Cervical Cancer Screening

ACS-ASCCP-ASCP 2012 ACOG 2012

Age to Start Age 21 Age 21

Testing Frequency

Age 21-29 (pap

only)

Every 3 years Every 3 years

Testing Frequency

Age >/= 30

Pap only

Every 3 years=

acceptable

Every 3 years=

acceptable

Testing Frequency

Age >/= 30

Pap plus HPV

co-testing

Every 5 years =

preferred

Every 5 years =

preferred

Age to Stop 65 y/o after 3

consecutive neg paps or

2 neg co-tests in past 10

years with most recent

less than 5 years.

Women with h/o CIN

2+ continue routine

age-based screening for

at least 20 years after

diagnosis.

65 y/o after 3

consecutive neg paps or

2 neg co-tests in past 10

years with most recent

less than 5 years.

Women with h/o CIN

2+ continue routine

age-based screening for

at least 20 years after

diagnosis.

After Hysterectomy Discontinue if no h/o

dysplasia or cancer

Discontinue if no

dysplasia or cancer

Screening after HPV

vaccine

Same as unvaccinated Same as unvaccinated

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Online resources

• www.cancer.org

• www.cdc.gov/cancer

• www.asccp.org

• www.cancer.gov

3 Key References

• Saslow D. et al. (2012) American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology Screening Guidelines for the Prevention and Early Detection of Cervical Cancer. Am J Clin Pathol 137: 516-542

• ACOG Practice Bulletin # 13 (November, 2012) Screening for Cervical Cancer

• Massad LS et al. (2013) 2012 Updated Consensus Guidelines for the Management of Abnormal Cervical Cancer Screening Tests and Cancer Precursors. J Lower Genital Tract Disease. 17 (5): S1-S27.