1. Current guidelines for Cervical Cancer Screening
Rachael Chambers, DO
May 29, 2015

2. Objectives Review current cervical cancer screening guidelines
Discuss role of HPV testing in cervical cancer screening
Discuss role of primary HPV testing in cervical cancer screening

3. Background Initial Bethesda system classification
revised in 2001
ASCCP consensus conference 2006
Updated guidelines in 2008
Not from a national consensus conference
2012 follow up consensus conference
Data from KPNC, NCI, ALTS
Screening decreases incidence and mortality of cervical squamous cell cancer and increases cure rate of cervical cancer

4. 2012 Consensus Conference 47 experts 23 professional societies
Goal to provide revised evidence-based consensus guidelines for managing women with abnormal cervical cancer screening tests, cervical intraepithelial neoplasia and adenocarcinoma in-situ
Literature review and data from ~1.4 million women in the Kaiser Permanente Northern California Medical Care Plan
Most prior guidelines were reaffirmed

5. Major changes 2012 guidelines
ECC showing CIN 1
manage as CIN 1
Repeat unsatisfactory cytology
Even when HPV results are known
Negative cytology with absent or insufficient endocervical cells can be managed without early repeat

6. Major changes 2012 guidelines
Genotyping triages HR HPV positive women to colposcopy earlier after negative cytology
Colposcopy indicated for ASCUS +HPV regardless of genotyping
HPV negative ASCUS
Follow up at 3 years with co-testing
Not sufficient for exiting women from screening at age 65

7. Major changes 2012 guidelines
CIN 2+ follow up is more clearly defined with incorporation of co-testing
Women age 21-24
Conservative management
Pap only
Co-test in certain circumstances
Incorporate co-testing post colposcopy

8. Guidelines Available at:
App available for iPad, iPhone and Android

9. Routine Screening Cytology every 3 years Co-testing every 5 years
Women age only
Multi-year intervals ok only if risk of developing CIN 3+ is low
2006 routine screening not defined and shorter screening intervals recommended.
2006 guidelines recommended return to “routine screening”
2012

10. Case 1 55 year old G2P2 Menopause at age 52
No history of abnormal pap testing
Pap test with physical shows:
Insufficient cellularity. HPV co-testing is negative.
Now what?

11. Unsatisfactory Cytology
1% or less across all preparations
Decreased with use of liquid based pap
Most cases now due to insufficient squamous cells
Most studies find higher risk in women that had unsatisfactory cytology employed by conventional pap test
May be unsatisfactory due to blood, inflammation or other processes
Some HPV testing does not have a control for epithelial cellularity so negative HPV can not be relied on

12. Repeat cytology in 2-4 months
Consider treatment to resolve atrophy (vaginal estrogens) or obscuring inflammation if infection is present
Colposcopy is acceptable alternative to repeat pap testing if HPV is positive.

13. Case 2 Same patient as in Case 1
Now pap test shows normal results, but no EC/TZ
HPV remains negative
Now what?

15. Cytology NILM but EC/TZ Absent/Insufficient
Suggests squamocolumnar junction may not have been adequately sampled
Reported rates 10-20%
More prevalent in older women
Good specificity and negative predictive value
HPV testing is independent of TZ sampling
Adds margin of safety when co-testing is performed.
Personal bias: Cervical broom may not be adequate when dealing with stenotic cervix
Previously recommended to repeat cytology early.
Women with absent EC/TZ have fewer concurrent cytologic abnormalities and do not have a higher risk for CIN 3+ over time compared to women with adequate EC/TZ. Appears to be due to older population with this finding which goes with lower CIN 3+ risk.
Absent EC/TZ component is NOT associated with increased incidence of cervical disease after treatment of CIN 2+

16. Management Age 21-29: routine screening Age 30-64
HPV negative: Routine screening
HPV unknown: Test for HPV or repeat cytology in 3 years
HPV positive: Cytology +HPV in 1 year or HPV genotyping
Category of evidence BIII
Genotyping for type 16/18. If present proceed to colposcopy, if negative repeat co-testing in 12 months.

18. Case 3 32 year old G1P0 No previous pap testing available
Here for initial prenatal care
How do we screen her?

19. Case 3 continued
Pap test normal
HPV co-test is positive
Now what?

20. Management Negative Cytology, HPV positive
Due to increased risk for CIN 3+ if hrHPV positive guidelines balance risk of observation vs intervention
Return for earlier retesting
HPV genotyping
Higher risk of CIN 3+ with type 16/18
Colposcopy if 1 year follow up is ASC or HPV + or immediately if HPV 16/18 are positive
Co-testing is the preferred screening strategy ages 30-64
HPV+ women higher risk for CIN 3+ especially if HPV persistent infection
HPV type 16 high risk, but type 18 is higher risk for cervical adenocarcinoma which is less efficiently detected by cytology

22. Case 4 30 year old referred to you for management of ASCUS pap
What else do you want to know?
Was she HPV co-tested?

23. Atypical Squamous Cells of Undetermined Significance
Most common cytologic abnormality
Lowest risk of CIN 3+
2/3 are NOT HPV associated
Women >60 years have higher risk for cervical cancer even if HPV negative compared to women with negative co-testing.
ALTS trial= ASCUS-LSIL triage study
Conducted before 2001 Bathesda system update
ALTS separated ASC-H from ASCUS
With the separation of ASCH and ASCUS in 2001 and the observed 3% risk of CIN 3+ in women age 30+of Kaiser Permanente Northern California annual cytology was recommended wit update.
Women >60 years have higher risk for cervical cancer even if HPV negative compared to women with negative co-testing.

24. ASC-US Reflex HPV testing preferred HPV negative HPV positive
Type 16/18 positive women have twice the risk of CIN 3+ compared to other hrHPV positive women
HPV negative
Repeat cotesting in 3 years
HPV positive
Colposcopy
If no CIN co-test at 12 months
Recommend endocervical sampling for colposcopy if no lesions are seen or if inadequate colposcopy
LEEP is not an acceptable treatment unless CIN 2+ is identified.

25. ASC-US Cytology only Repeat cytology in 1 year Colposcopy if > ASC
Routine screening if normal
Routine screening is 3 year cytology follow up

27. ASC-US in Special Populations
Postmenopausal
Manage the same as general population
Women age 65 and older
Repeat screening in 1 year when considering exit from screening
Cytology
Co-testing (preferred)

28. ASC-US in Special Populations
Pregnant women
Identical to nonpregnant women
Acceptable to defer colposcopy until 6 weeks postpartum
ECC is unacceptable
If no suspected CIN 2+ at initial colposcopy, follow up postpartum

29. Case 5 21 year old, G0 No previous pap test Seen for complete physical
Pap test shows LSIL.
What next?

30. Young Women No screening before age 21
Routine screening with initial normal pap test is every 3 years
Cervical CA risk is low through age 25
HPV is common
Most lesions will regress
Less intensive management
Encourage HPV vaccination, smoking cessation
Risk of cervical cancer for weomen age is 1.4/100,000 and almost 55,000 cytology tests must be obtained for each cancer diagnosis

31. Young women ASCUS/LSIL Cytology every 12 months preferred
HPV reflex is acceptable
Follow up is repeat cytology if positive
Routine screening if negative
Colposcopy only if ASC-H, AGC, HSIL at follow up
Colposcopy is not recommended for ASCUS or LSIL

33. Low-grade Squamous Intraepithelial Lesions
ALTS Trial showed natural history to be similar to ASC-US HPV+
Women have lower risk CIN 3+
Estimated 77% of LSIL are HPV positive
High positive rate does not allow for HPV testing to select efficiently for colposcopy

34. LSIL Management Colposcopy (recommended)
Manage based on colposcopic findings
If co-test is negative, repeat co-test in 1 year
If cytology negative and HPV negative
Repeat co-testing in 3 years
If >ASC or HPV positive
Colposcopy

36. LSIL Management Pregnant women: Colposcopy preferred
ECC unacceptable
Acceptable to defer until 6 weeks postpartum
If no CIN 2+, follow up post partum

38. LSIL Management Postmenopausal Obtain HPV test
Repeat cytology at 6 and 12 months
Colposcopy
Repeat cytology in 12 months if HPV negative or no CIN on colposcopy
If HPV+ or ASC-US or greater on repeat cytology perform colposcopy
Routine screening after 2 negative cytology

39. Atypical Squamous Cells, Cannot Exclude High-Grade Squamous Intraepithelial Lesion
Higher risk of CIN 3+ compared to ASC-US or LSIL
Risk also elevated for women age 21-24, but overall CIN 3+ risk remains lower than older women

40. ASC-H Management Colposcopy for all women
High rate of HPV + makes reflex testing unsuitable
5 year cancer risk among ASC-H, HPV negative is 2%
2% risk is too high to justify observation

42. High-Grade Squamous Intraepithelial Lesion
CIN 2+ identified in 60% of women at colposcopy
Consider immediate excision of transformation zone
Cervical cancer found in 2% at colposcopy
Risk rises with age
Risk modifies with HPV result
HPV result from co-test may help inform choice
Substantial risk
Immediate excision justified for women due to high risk, especially for women at risk for loss to Follow-up or who have completed childbearing
5 year Cervical cancer risk 8% in women 30+
HPV negative 5 year risk for Cin 3+ 29%, while 7% will develop cancer
In KPNC cohort women 30+, HPV + SIL 5 year CIN 3+ risk was 50%, cancer risk 7%
Choice of immediate excision vs colposcopy and between diagnostic excision and cytology and colposcopic surveillance if no CIN 2+ identified.

43. Management HSIL Immediate LEEP Colposcopy
Diagnostic excisional procedure recommneded for inadequate colposcopy
Except if pregnant
Triage with repeat cytology or reflex HPV testing is unacceptable

45. HSIL in Young Women Colposcopy
If no CIN 2+ observe with colposcopy and cytology at 6 month intervals for 24 months.
If CIN 2/3 present manage with colposcopy and biopsy or treat
See and treat (Immediate treatment) is unacceptable
Colposcopy must be adequate and ECC negative or CIN 1 to continue observation

47. Atypical Glandular Cells
Interpretation is poorly reproducible and uncommon
Associated with
Polyps
Metaplasia
Neoplasia
Adenocarcinomas
Endometrium, cervix, ovary, fallopian tube and other sites

48. AGC Risk of neoplasia higher if reported as AGC favor neoplasia or AIS
Cancer risk is lower in women <35, but risk of CIN 2+ is higher
Commonly associated with squamous lesions including CIN 1
In KPNC women 9% rate of Cin 3+ in womein30+ with cancer in 3%

49. AGC Management Colposcopy with ECC Do not use HPV testing to triage
Endometrial sampling is recommended in women 35+
Also for women <35 if clinical indictors suggesting risk for endometrial neoplasia.
If no CIN 2+ co-test at 12 and 24 months and routine screening if both are negative.
Risks for endometrial neoplasia: unexplained vaginal bleeding, conditions suggesting chronic anovulation
Same management for women 21-24
No ECC/endometrial biopsy in pregnant women

52. What’s next?
Primary HPV Screening

53. Primary hrHPV screening
Rate of hrHPV is common in sexually active population
Most infections are transient
FDA previously approved hrHPV testing
For triage of ASCUS
Adjunct to cytology for women age 30+
April 2014 FDA approved labeling of hrHPV assay to include primary hrHPV screening in women 25+
Some women will develop persistent hrHPV infection and are at risk for cervical cancer and its precursors
Triage of hr HPV subtypes also FDA approved in select settings
Consider 70% of cervical cancer is associated with type 16/18

54. Primary hrHPV screening
Highly sensitive
Specificity depends on subsequent evaluation strategies and screening frequencies
FDA approval does not include specific recommendations for applying hrHPV screening in the US
Clinical practice guidelines do not yet exist

55. 2011 guidelines
American Cancer Society, American Society for Colposcopy and Cervical Pathology and American Society for Clinical Pathology
“in most clinical settings, women age should not be screened with HPV testing alone as an alternative to co-testing at 5 year intervals or cytology alone at 3 year intervals”
Guidelines did not suggest settings that are appropriate, despite stating “most”
Recommendation primarily based on concerns about specificity of screening and potential harms such as excess colposcopy and treatment of non-neoplastic HPV lesions.
Additional concerns: lack of well-defined and evaluated strategy to manage hrHPV+ women, inadequate information to define appropriate screening intervals, for hrHPV – women, lack of data on testing errors due to specimen inadequacy, cost-effectiveness, and adherence to implementation within the current US opportunistic screening setting
At the time of the guideline update several screening studies had reported on only a single round of screening, limiting the evaluation of hrHPV screening
Several large studies have since been published including new primary screening data and updates on subsequent rounds of data from previously published trials
All concerns from 2011 screening guidelines are not fully addressed but the evidence strengthens the support of primary hrHPV screenign

56. Consensus panel Met via conference call and face to face
Invited to scientific summary presentation by Roche Diagnostics of the Addressing the Need for Advanced HPV Diagnostics (ATHENA) trial
MEDLINE database review
11 papers reviewed in addition to significant papers published prior to November 2011
Co-sponsored by: Society of Gynecologic Oncology and American Society for Colposcopy and Cervical pathology
Included 13 experts representing SGO, ASCCP, ACOG, ACS, American Society of Cytopathology, College of American Pathologists, American Society of Clinical Pathology
Observers invited from Centers for Disease Control and Prevention and the US Food and Drug Administration
ATHENA trial data and findings related to the hrHPV screening components. Panel members were able to submit questions before and after the discussion. Roche Diagnostic’s staff and experts participation limited to presentation of ATHEN data including answering of specific questions regarding trial data from panel members
Articles reviewed by at least 3 members of the panel and members commented on relevance of article to clinical update and how article should be considered in the guidance document

57. Consensus panel: Primary question
Is hrHPV testing for primary screening as safe and effective as cytology-based screening?
Negative hrHPV provides greater reassurance of low CIN3+ risk than negative cytology.
Several large trials have evaluated this
Gage studied Kaiser permanent Northern California: >1 million women
Wright ATHENA 42, 209
Ronco analyzed follow up data from 4 previously published trials from Europe 176,464
Dillner Combined follow up data from 7 European screening trials to compare risk of Cin 3+ 24,295

58. Consensus panel: Primary question
Can primary hrHPV screening be considered as an alternative to current US cervical cancer screening methods?
hrHPV can be considered as an alternative to current cytology-based screening because of equivalent of superior effectiveness.
Cytology alone and co-testing remain the screening recommended in major guidelines

59. Additional questions How Should Positive hrHPV be managed?
Combination of triage of genotyping and reflex cytology appears to be a reasonable approach
Based on data from ATHENA and other studies
What is the Optimal Screening interval?
No sooner than every 3 years
Limited data available
Ronco et al reported hrHPV screening interval of every 5 years is safer than cytology every 3 years, but 3 of 4 studies analyzed screened at 3 year intervals.
ATHENA follow up data restricted to 3 years, but CIN3+ cumulative incidence less than 1%
Rate unlikely to sharply increase after 3 years, but due to limited data there is insufficient prospective data to recommend screening interval beyond 3 years.

60. Additional questions
At What Age Should One initiate primary HPV screening?
Not before age 25
ATHENA trial shows 30% of CIN3+ in women (more than half had normal cytology), 37% in Women 30-39
Primary screening at age 25 doubled number of colposcopies, but resulted in 54% greater detection rate of CIN3+ when compared to the same strategy at age 30
Panel concerned with risks due to increased number of colposcopies. Unclear if this will translate to a meaningful reduction in cervical cancer

61. Additional questions
How does the performance of primary hrHPV screening compare to co-testing?
Most reassurance from co-test comes from the HPV component.
Data shows the 3 year risk following HPV negative test is less than the 5 year risk following co-testing.
Primary hrHPV test every 3 years is at least as effective as 5 year co-testing.

63. Currently only 1 hrHPV test is FDA-approved for primary screening.
Comparative effectiveness studies are needed
Look for future updates

64. Summary Cervical cancer screening continues to evolve.
Trend is toward less invasive methods of screening and managing.
hrHPV screening may become the primary screening tool in the future.

65. References
Massad, et al Updated Consensus Guidelines for the Management of Abnormal Cervical Cancer Screening Tests and Cancer Precursors. Journal of Lower Genital Tract Disease, Volume 17, Number 5, 2013, S1-S27.
Huh , et al. Use of Primary High-Risk Human Papillomavirus Testing for Cervical Cancer Screening: Interim Clinical Guidance. Journal of Lower Genital Tract Disease, Volume 19, Number 2, 2015,
Partridge et al. Cervical Cancer Screening: Featured Updates. Journal of the National Comprehensive Cancer Network. Volume 12, number 3, march 2014,
ACOG Practice Bulletin. Management of Abnormal Cervical Cancer Screening Test Results and Cervical Cancer Precursors. Number 140, Volume 122, No. 6, December 2013,
Saraiya, et al. Evolution of cervical cancer screening and prevention in United States and Canada: Implications for public health practitioners and clinicians. Preventive Medicine, Volume 57, 2013,
Dinkelspiel and Kinney. State of the Science: Cervical cancer screening in transition. Gynecologic Oncology, 133, 2014,
Cannistra and Niolff. Cancer of the Uterine Cervix. The New England Journal of Medicine. Volume 334, number 16, 1996,