1. HPV & Cervical Cancer: Review of New Screening and Management Guidelines
Sarah Feldman MD MPH
Co-Director Ambulatory Gynecologic Oncology
Brigham & Women’s Hospital
Dana Farber Cancer Institute
Lowell Cancer Center
Harvard Medical School

2. Financial Disclosures
I, Sarah Feldman have no relationships to disclose.

3. Objectives Review HPV and its association with cervical cancer
Be familiar with new guidelines
Understand the data behind the guidelines
When I state HPV + this means positive for one of the high risk HPV subtypes

4. WE SHOULD BE ABLE TO ERADICATE CERVICAL CANCER
The etiology of cervical cancer is known (HPV)
HPV infections are usually transient and low risk
There is a long precancerous phase
There are reasonable screening tests
We have treatments that prevent progression of pre-cancers
HPV vaccine technology is rapidly progressing thus we should be able reduce the prevalence of HPV disease.
WE SHOULD BE ABLE TO ERADICATE CERVICAL CANCER
Known since 1190s that cervical CA is associated with one of the HPV high risk subtypes, most infections with these clear spontaneously
Only persistent infections cause problems after a long period of time
Good news—reasonable screening and interventions we can prevent precancers from progressing to cancer.
2 vaccines FDA approved for the most oncogenic 16/18 subtypes
Nanovalent vaccine by Merck in study for 4-5 high risk subtypes, will cover 98% of cervical CA and most condylomata

5. Estimated Annual Incidence of HPV Cervical Infection/Dysplasia1
10 million
300,000
High-grade dysplasia
30 million
1 million
Low-grade dysplasia
United States
300 million
HPV infection with “normal” cytology
Worldwide
Cervical Infection/Dysplasia
Key Point
Virtually all cases of cervical cancer come from high-grade dysplasias.
Biopsy proven low or high grade abnormality. 15% of ASCUS /HPV + will have high grade dysplasia on biopsy.
Background
According to estimates from the World Health Organization, in the United States each year there are about 10 million new cases of cervical HPV infection without detectable cytologic abnormalities, 1 million new cases of low-grade dysplasia, and 300,000 new cases of high-grade dysplasia. Worldwide annual incidence of HPV infection and low- and high-grade dysplasia is 300 million, 30 million, and 10 million cases, respectively.1
Longitudinal studies have demonstrated that nearly all high-grade cervical dysplasias are preceded by HPV infection, and the distribution of HPV types in these high-grade dysplasias is similar to that found in cervical cancer.1
Cervical infection with high-risk HPV types is an important biomarker associated with the development of high-grade dysplasia, and the genomes of these high-risk HPV types contain oncogenes that are preferentially retained and expressed in cervical tumors.1
The largest number of cases of cervical HPV infection have no detectable cytologic abnormalities, and many of these are self-limited. However, an important subset will subsequently become associated with cytologic abnormalities. It is widely recognized that virtually all cases of cervical cancer come from high-grade dysplasias.1
Reference
1. World Health Organization. The current status of development of prophylactic vaccines against human papillomavirus infection. Report of a technical meeting, 16–18 February Geneva, Switzerland: World Health Organization; 1999:1–22.
Almost all cases of cervical cancer come from high-grade dysplasias.
Low grade are not considered precancers.
50- 80% women will test positive for the HRHPV at some point.
1. World Health Organization. Geneva, Switzerland: World Health Organization; 1999:1–22.

6. 90% of HPV infections -transient, undetectable within 1-2 yrs
>100 types
Only “high-risk” types important
Common infection—only persistent infections of concern
More easily cleared in young women
30 types in the lower genital tract
13-14 high risk types
Patient factors: age, smoking, immune status(HIV, transplants) affect persistenceOncogenic HPV types
Oncogenic HPV Types55-60 % Type 16 most carcinogenic
10-15 % Type 18 - higher proportion glandular CA
25-35% other types
Between 60-70% of cervical cancer world wide is due to HPV16/18
90% of HPV infections -transient, undetectable within 1-2 yrs

7. Natural History of CIN/dysplasia
Linked to high risk/oncogenic HPV
CIN 1: 60% regress/ 1 year, 90% /3yrs (Moscicki 2004)
CIN 2: 40% regress/1 year (Fuchs 2007, Moscicki 2010)
CIN 3:
Untreated CIN 3: 30% risk of invasive CA /30 yrs
Treated CIN 3: 1% risk of invasive cervical CA
Higher levels of dysplasia -more likely to progress to cancer
Most HPV infections are transient and do not confer significant risk of cancer or dysplasia
Most biopsy proven lesions regress
Guidelines not aggressive

8. Prevalence of HPV Infection among US females Dunne EF et al Jama 2007 Feb 28; 297(8) 876-8
14-59 years old
Self collected vaginal swabs
HPV prevalence overall 24.5%
14-19: 25%
20-24: 45%
25-29: 28%
30-39: 25%
50-59: 20%
HPV 16: 1.5%; HPV 18: 1.5% overall
Underestimate of prevalence since self collected swabs ( would be higher if done by clinicians)
Almost 50% of yo HPV +---Therefore not a useful test for triage
HPV is common , 16/18 is less common
Still it is not whether one is infected, rather persistent infection confers risk

9. Duration of HPV infections in young women
Women aged 16-23
Studied incidence and duration of HPV 6, 11,16 and 18 infection
Mean duration of 6/ months
Mean duration of 16/ months
HPV 16/18 persists 2x longer than HPV 6/11 on average
< 25 yo women, most infections are transient
16/18 more virulent, more persistent
Insinga, RP, Dasbach EJ, Elbasha, EH, Liaw KL, Barr I.
Incidence and duration of cervical humanpapillomavirus 6,11,16 and 18 infections
in young women: an evaluation from multiple analytic perspectives.
Cancer Epidemiol Biomarkers Prev 2007 Apr; 16:
Insinga RP, bCancer Epidemiol Biomarkers Prev 2007 Apr; 16 (4):

10. Long Term Risk of CIN3+ after HPV infection: role of persistence Kjaer, et al. J Natl cancer Inst 2010 Oct 6; 102(19):1451-3
8656 women in Denmark
Co-testing-underwent pap and HC2 testing
2 exams, two years apart
Then followed in registry for 12 years
Estimated risk of CIN3+ for women who were HPV 16+ at both exams=47.4% (over 12 years of f/u)
Risk of CIN3+ after HPV negative= 3%
Suggests less frequent follow up appropriate for HPV negative women, and aggressive follow-up should be considered for those persistently positive for HPV 16.
Shows safe to go to testing at longer interval
Registry study using Hybrid Capture 2, 13 HPV types, 1st FDA approved test. Used cotesting 2 yrs apart and followed 12 yrs
If positive for both tests 2 yrs apart

11. Challenges in managing cervical pre-cancers
Lesions may change over time
Special populations differ with respect to risk of progression/regression (ie. Adolescents, pregnant, immunocompromised)
Fertility desires may affect relative risk of treatment versus observation
The data is complicated and constantly changing
Moderately hard to predict who will progress
Clinical challenge of interpretation of test results
Guidelines complicated, variable change---different pops—influence how lesions change over time, pts have different preferences and circumstances ex. Fertility
New info out there…what do we trust?

12. There are many Screening Options (and the technology continues to evolve….)
Cytology (aka Pap Tests)—conventional or thin layer easier for downstream testing as well as cost.
HPV testing-4 FDA approved types, some for use with specific Pap preparations, some which can differentiate HPV types, some not.
Co-testing refers to a screening test that includes both a Pap and an HPV test
Reflex testing ex. HPV testing after an ASCUS Pap– this is used to triage patients to more or less subsequent evaluation
Primary HPV screening (Cobas FDA approved 4/2014)
4 HPV tests Cervista, Hybrid capture, Optima, Cobas

13. Successful Cervical Cancer Prevention
Requires a programmatic approach which includes primary vaccination, as well as screening and active management of abnormalities to prevent progression

14. 2012 Guidelines for Cervical Cancer Screening 3/14/2012 ACS, ASCCP, ASCP ( USPSTF ( ACOG Practice Bulletin #131 Reviewed similar data
Evidence Based
Logical, simple to understand and clearly written
Clearly address areas of patient and provider confusion

15. Cervical Cancer Screening Guidelines 2012 (Healthy Low Risk Women)
<21 No screening pap/cytology
Pap q 3 years regardless of sexual activity
(no HPV screening)
Pap alone q 3 years or Cotesting/Pap with HPV q 5 years if both results negative
(and normal and adequate screening history)
> age 65 or hysterectomy stop screening
In well screened women
Defined as 3 neg Paps within prior 10 years or 2 neg cotests within 10 years
Poorly screened women still need to be screened in this age group.
Any abnormal findings require more aggressive evaluation and follow up as per the new management guidelines

16. Women at increased risk need more frequent screening (2012)
HIV infected
(screen 2x in first year and then annually if normal)
Immunosuppressed (eg organ transplants, chronic steroids or immunosupressive drugs, auto-immune illnessses, etc)
h/o DES exposure
Previously treated CIN2/ CIN3/ Adenocarcinoma in situ (AIS)or cancer-more frequent screening should occur for at least 20 years.
Women with h/o mildly abnormal Paps should still be followed closely, and abnormalities evaluated per recommended guidelines.

17. Reminder : these guidelines are for low risk women only
These recommendations apply to average risk women
and are not appropriate for women who have a history
of high grade precancer or cervical cancer,
are immunosuppressed or are DES exposed.
More frequent testing should continue
for women with a history of high grade dysplasia,
adenocarcinoma in situ or cancer for at least 20 years,
regardless of age.
Do not apply to women with visible lesions
These women will need to be screened more aggressively.

18. 2013 Management Guidelines ASCCP 2013/ACOG 2013 www. ASCCP.org
Management of Abnormal Pap Smears (cytology)
Management of Colposcopy Biopsies
(histology)
Follow up after treatment (excision, ablation)
I only figured out these 3 categories after many hours reading and rereading the guidelines

19. 2013 Management Guidelines
Very complicated and difficult to follow
Very hard to understand despite 20+ hours pouring over them, impossible to follow, need to keep article open on my desk, not clear what is evidence based vs opinion
opaque process in coming up with the guidelines

20. Management Guideline Problems
30 pages long
12 algorithms
7 for pap smear follow up
5 for colposcopy finding follow up
Unclear which are evidence based and which are only expert opinion

21. The guidelines divide patients in many ways:
What’s the principle behind the new management guidelines (“risk based assessment”)?
The guidelines divide patients in many ways:
2 basic cytology categories: ASCUS/LSIL vs. ASC-H/HSIL
Special groups: HIV+, DES, Immunosuppressed, pregnancy
Age groupings: when to do paps and use HPV testing
<21, 21-24, 25-29, >30, >65 or hyst, “young women”
Sometimes it is not clear which group a patient belongs to or what her actual risk is.
treat like adolescents “young women”
Ex. Lsil.ascus—suggest repeat pap q 12 mo x 2, only do colpo after 3rd abnormal pap----triage on cytology instead makes sense
Hsil pap---colpo, follow q 6 mo, only treat if persists x 2 years---this is ok, but return to “routine screening” does not make sense

22. Management Guideline 2013 ASCCP & ACOG www.acog.org and www.asccp.org
6 different age categories
Recommend less aggressive evaluation and management of year olds, year olds and “younger women”
Data is clearer for women <21 and > 30.
Much less evidenced based for women aged 21-29; These are women for whom a missed early cancer diagnosis is most crucial for maintenance of fertility
Now screening -less frequent, An abnormal test may reflect a more concerning abnormality, especially in young women without a documented reassuring screening history
Goal of less frequent screening—reduce false + , lesions that resolve on own, thus + test now more likely a lesion that has already persisted
Management Guidelines take into account: age, prior screening, prior management, HPV status
Example yo now is previously unscreened
LSIL/ASCUS repeat 1 year x 2, 15% have HSIL/AIS
Could colpo any abnormality, triage by biopy, if cin1 then f/u 1 yr, if Cin2/3 closer f/u
HSIL colpo q 6 months x 2 yrs, only CIN3 LEEP
>30 yo—good data

23. Is it safe to return to the new “routine” screening after an abnormality?
-after any abnormal cytology ? -after any abnormal histology? -after treatment for histologic abnormality? Recommendations for surveillance post abnormality -based on weakest data, may be misleading

24. Update on Management Guidelines- What’s the data
Update on Management Guidelines- What’s the data? ASCCP 2013/ACOG 2013 www. ASCCP.org
Based mostly Kaiser’s large dataset
Health system with excellent tracking, insurance, systems to bring patients back for appropriate testing and management
Data based on earlier screening practices with more frequent evaluation and more aggressive management
true rates of cancer or precancer with the current guidelines cannot be assessed (since patients are not being detected and treated as often)
May not be generalizable to all settings
2006 guidelines based on ALTS data
All of these complicated subcategories based on age, prior paps, reproductive plans etc---must be based on many studies---actually just one, large dataset

25. Variable Risk of Cervical Precancer and Cancer After a Human Papillomavirus-Positive Test Castle, P. Obstet Gynecol 2011:117:650-6
Kaiser
>30 year old women, tested positive for HPV
Risk of precancer/cancer based on co-test and prior history
Past positive HPV test OR abnormal Pap -significantly higher risk CIN2+ than newly acquired infection
unknown prior screening history
for ASCUS /HPV+ women with unknown screening history:
-the 4 year cumulative risk of CIN2 was 23 % and of CIN3 was 13%
-similar to women known to have had known prior abnormal results
THUS KNOWLEDGE OF THE PAST SCREENING AND RESULT HISTORY MATTERS

26. Follow-up testing after colposcopy: five-year risk of CIN2 after a colposcopic diagnosis of CIN1 or less Katki, et al. J Low Genit Tract Dis 2013
Kaiser women >25 years old
Screening results antecedent to colposcopy affected 5 year risk of CIN2
No group had sufficiently low risk to return to “routine” screening
If prior Pap showed ASC-H or HSIL, there was no group that could be returned to even less frequent co-testing
Pap
cytology
Colposcopy histology
5 year risk of CIN2+
ASCUS/LSIL
CIN1 or less
10 %
ASC-H
16%
HSIL
24%
Guidelines say >29 yo
ASCUS PAP/CIN1 bx--cotest 12 mo—then if both negative age appropriate retesting at 3 yrs—then routine testing, colpo if abn
ASCH/HSIL pap, cin1 bx cotest 12.and 24 or LEEP, if both cotesting neg age specific retesting at 3 yrs, then routine by age

27. Five Year risk of recurrence after treatment of CIN2/CIN3 or ACIS Katki, HA. J Low Genit Tract Dis 2013
Kaiser >30 year old women
5 year risks of recurrence after treatment varied by antecedent screening result and path
No subgroup of women achieved risk sufficiently low to return to the new routine screening
Recommendation is co-test at 12,24,36 months then “routine”
Pap –Cytology
Colpo biopsy-histology
5 year risk of recurrence post rx
ASCUS/HPV+ or
LSIL
CIN 2 5%
ASCUS –H or worse
CIN3/ACIS
16%
Pap is not predictive, all women remain high risk—this was published AFTER guidelines
Complicated that each subgroup has a different plan
Could combine groups, follow closely based from 5% for CIN2 preceded by ASCUS HPV positive or LSIL,
to 16% for CIN3/AIS preceded by ASCUS-H or worse Pap
Women with a h/o antecedent AGC/ASC-H/HSIL+ Pap results or those treated for CIN3/AIS had significant risk of developing CIN2+ post treatment
on histology not cytology

28. Surveillance after treatment for CIN 2/3 Melnikow, J et al Obstetrics & Gynecology 116, 5, November 2010
Cost effectiveness study
Surveillance strategies after treatment for HSIL
Hypothetical
Women >30 yo British Columbia Cohort Study
Results: Paps at 6 and 12 months followed by annual conventional cytology surveillance reduced cervical cancers and cancer death compared with triennial cytology
HPV cotesting increased cost but did not improve outcome
Adding colposcopy at 6 months for high risk women, increased life expectancy
Cost effectiveness study great study rx for cin2/3 follow as in slide
Supports yearly pap alone for follow up
Instead of currently recommended cotesting yearly x 2 yrs, then 5 yrs, then “routine”

29. Factors affecting screening and management of cervical precursors
The strength of data supporting different options and improved outcomes
A patients’s personal results, history and preferences
The availability and costs of different tests
The preferences of providers and health care systems
Ability to comply with care—competing concerns and constraints
Systems concerns such as inadequate support to track and manage abnormalities, insurance issues, patient mobility

30. So What Should You do? Can the New Cervical Cancer Screening and Management Guidelines Be Simplified? Feldman, S. JAMA Intern Med 2014

31. So what should you do? Follow the published guidelines OR
Divide your patients into two buckets to start:
GROUP 1:
LOW RISK: asymptomatic women should start screening at 21 and screen q 3 years until 30 if all tests are normal. At that time you and your patient may decide to go with either q 3 year Pap screening if all normal or q 5 year co-testing. If any results are abnormal, they go to group 2
GROUP 2:
Everyone else—that includes a history of any abnormality of Pap, HPV or biopsy, any cervical treatment, anyone with symptoms, or anyone with an unknown/undocumented history.

32. Step 2-What you should do? the “High Risk Group”
Option 1->follow the guidelines as written
Option 2->colpo anyone with an abnormality and then triage by pathology conditional on prior pap:
Pap shows ASCUS or LSIL Pap (first one)->colpo is either negative or CIN1->repeat Pap in one year and recheck colpo if abnormal. Continue for up to 2 years. If still abnormal, or if HSIL, offer treatment
Pap shows ASC-H, HSIL, AGC or worse-> follow guidelines for each age
If you don’t know prior Pap history and or if patient reports abnormals and you don’t have records (and can’t get) treat as at least second abnormal, possible HSIL and do colpo
After treatment
Pap at 6 and 12 months. If both normal Pap annually
Consider cotest at first year and colpo if either test is abnormal (most cost –effective strategy)
Higher risk x 20 yrs, may change for now follow annually x 20 yrs

33. Barriers to effective cervical cancer prevention
Patient does not come in
Provider does not perform Pap
Pap is read incorrectly
Abnormal Pap is not appropriately evaluated
Patient does not get appropriate therapy
HPV vaccine not offered or accepted before sexual debut
Confusion barriers
Compliance
Pt and providers unsure of guidelines and recommendations
With new screening guidelines and abnormal pap more likely to represent a serious problem

34. Future uses of HPV testing
HPV 16/18 account for 77% cervical cancers and 54% high grade lesions in US
As successive cohorts are vaccinated, fewer women may get these infections—but not yet known
Primary screening with HPV and triage to cytology might be the logical next step
Athena study
As patients vaccinated the underlying prevalence changes

35. Primary HPV testing April 2014
Cobas® HPV (Human Papillomavirus) Test
U.S. Food FDA approved as first-line, primary screening tool
women 25 years and older.
3 year intervals
Women with no prior screening abnormalities
Limited published data
Athena trial only examined 3 years of follow up.
Comparison group was not the current standard of care
Multiple national societies are meeting to examine data and publish interim guidance around primary HPV testing.

36. Looking Towards the Future
Ultimately a combination of vaccine in younger women and screening for carcinogenic HPV in older women may revolutionize cervical cancer prevention
See Schiffman, M, Castle, PE. The Promise of Cervical Cancer Prevention. NEJM 353:20, , 2005

37. References
2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors.Massad LS, et al ASCCP Consensus Guidelines Conference.Obstet Gynecol Apr;121(4): doi: /AOG.0b013e a3
Markowitz, LE et al. JID epub June 19,
Related websites with guidelines:
Asccp.org
Uspstf.org
Acs.org