1. American Society of Cytopathology’s CELL Talks
Cervical Cancer Screening Guidelines
2012 Update – Changes
Welcome to the American Society of Cytopathology’s Cell Talks! Today’s topic in the Laboratory Management Series is…What has changed in the 2012 Update to Cervical Cancer Screening Guidelines

2. Director of Cytopathology Mayo Clinic Rochester, Minnesota
Insert photo here
Insert photo here
This presentation is brought to you by myself, Dr. Jennifer Sauter, as well as my mentor, Dr. Michael Henry who is the Director of Cytopathology at the Mayo Clinic.
Jennifer Sauter, M.D.
Cytopathology Fellow
Mayo Clinic
Rochester, Minnesota
Michael Henry, M.D.
Director of Cytopathology
Mayo Clinic
Rochester, Minnesota

3. Objectives Understand the updated cervical cancer screening guidelines
Become familiar with primary hrHPV screening as an alternative to traditional screening methods
Following the completion of this cell talk, participants should be able to:
Better understand what has changed with the 2012 update in cervical cancer screening guidelines. This will be the main focus of this CELL Talk
Additionally we will touch on the use of primary hrHPV screening for cervical cancer, and following this talk, participants should have a better understanding of primary hrHPV screening as an alternative screening method.

4. Cytopathology Milestones
The information in this CELL Talk applies to the cytopathology milestone, Medical Knowledge 2, which focuses on cervical cancer screening. Management guidelines will be presented in a separate ASC CELL Talk at a later date.

5. Background Updated cervical cancer screening guidelines:
Cancer J Clin. 2012;62(3):147-72
J Low Genit Tract Dis. 2012;16(3):
Am J Clin Pathol. 2012;137(4):516-42
In 2011, the American Cancer Society, American Society for Colposcopy and Cervical Pathology, the American Society for Clinical Pathology along with representatives from 25 other organizations met in a consensus conference and created updated screening guidelines for the prevention and early detection of cervical cancer. In 2012, this update was jointly published in three journals, which can be accessed using any of these three hyperlinks.
This CELL Talk will focus mainly on this 2012 Update. At the time of that Update, high risk HPV testing had not yet been FDA approved for primary cervical cancer screening and was not recommended for that purpose at that time. At the end of this CELL Talk, the recent interim guidance for primary hrHPV screening will be discussed briefly.

6. ASC/ASCCP/ASCP Guidelines (2012)
Screening Recommendations
Link to article in J Low Genit Tract Dis
ASCCP PowerPoint presentation
App
ASCCP Mobile
Available for iPad/iPhone/Android
The 2012 ASC/ASCCP/ASCP Screening Recommendations may be accessed through the ASCCP website by clicking this hyperlink.
On the ASCCP website, you will find a link that can be used to access the article through the Journal of Lower Genital Tract Disease.
There is also a link to a PowerPoint presentation created by the ASCCP to help educate both physicians and the public on the new recommendations.
Finally, there is also and App that iPad, iPhone and Android users can download to access the new algorithms using patient data.

7. What are the goals of screening?
Recommendations should:
Maximize the benefits of screening
Minimize potential harms of screening
There are two important goals of screening:
The first goal is to maximize benefits of screening by identifying women with cervical cancer precursors that are likely to progress to invasive cancers. The aim of the screening guidelines is to identify these women so that they can be appropriately managed by referral to colposcopy.
2. The second goal of screening is to minimize the potential harms associated with screening by avoiding the detection and unnecessary treatment of transient HPV infection and associated benign lesions that will not progress to cancer. The hope is that screening recommendations will lead to conservative management for these women.
With these goals in mind, the updated guidelines for cervical cancer screening generally advise a reduction in the number of tests women get over their lifetime to better ensure that they receive the benefits of testing while minimizing the harms. In interest of time, the evidence available to support each recommendation will not be discussed in this CELL talk, but if interested, participants are encouraged to refer to the original guideline for these details.

8. Screening Population General population Not high-risk populations:
Cervical cancer history
Exposure to DES in utero
Immunocompromised
The guideline emphasizes that these recommendations were developed to address cervical cancer screening in the general population and these guidelines do not address special, high-risk populations of women who may need more intensive or alternative screening. These special populations include women 1) with a history of cervical cancer, 2) who were exposed in utero to diethylstilbestrol (DES), and 3) who are immune-compromised (e.g., infection with human immunodeficiency virus).

9. What has changed? 2012 Cervical Cancer Screening Update:
Screening intervals
Age-specific screening strategies
Management of discordant cotest results
Exiting from screening
Impact of HPV vaccination
Potential utility of molecular screening
When developing the updated guidelines, six working groups were formed and were assigned the tasks of addressing the following topic areas:
(1) Optimal cytology screening intervals
(2) Screening strategies for women 30 years and older
(3) Management of discordant combinations of cytology and HPV results (e.g., HPV positive, cytology negative and HPV negative, atypical squamous cells of undetermined significance (ASC-US) results)
(4) Exiting women from screening
(5) Impact of HPV vaccination on future screening practices
(6) Potential utility of molecular screening (Specifically, HPV testing for primary screening was assessed as a potential future strategy)
These topic areas will be discussed in this CELL Talk.

10. Screening Intervals Annual screening is not appropriate
Intervals based on age and clinical history
In the past, screening was recommended annually for women under age 30. However, due to the high incidence of transient infections, the guideline states that currently there is little evidence to support annual screening of women at any age.
Instead, working groups assigned screening intervals based on age and clinical history according to the evidence available at that time.

11. Age-specific screening strategies
Women ages 21-29:
hrHPV testing should not be used
Screening Method
Time Interval
Cytology alone
Every 3 years
Screening should begin at age 21, not before, regardless of age of sexual onset
For women ages 21-29, the guideline recommends screening with cytology alone every 3 years.
The second recommendation is that hrHPV testing should not be used to screen women in this age group either as a cotest with cytology or, at that time, as a primary stand-alone screen.

12. Age-specific screening strategies
Women ages 30-65:
Screening Method
Time Interval
Cotesting (preferred)
Every 5 years
Cytology alone (acceptable)
Every 3 years or
For women years of age, the guideline recommends screening with cotesting, that is, with both cytology in the form of a Pap test and a concurrent hrHPV test, every 5 years. This was determined by the working groups to be the preferred screening strategy for women ages
Since hrHPV testing is not available in every screening setting, screening with cytology alone was deemed to be an acceptable strategy for cervical cancer screening, but due to the lower negative predictive value of cytology compared to cotesting, the screening interval for cytology alone in women ages is 3 years rather than 5 years.
One way to remember the extended screening interval for cotesting, is that a “double negative”, i.e. negative cytology and negative hrHPV test, is the best we can do, so it is acceptable to wait 5 years until cotesting again.

13. Discordant cotest results
hrHPV positive, cytology negative:
Management
Repeat cotesting in 12 months:
-Positive (cytology or hrHPV)
Colposcopy
-Negative (cytology and hrHPV)
Routine screening
Immediate HPV 16 or HPV 16/18 genotype testing:
-HPV 16 or 18 positive
-HPV 16 and 18 negative
Repeat cotesting in 12 months
Since cotesting is recommendation as the preferred screening strategy in women ages 30-65, the updated guideline provided recommendations for managing discordant cotest results.
For an hrHPV positive, cytology negative cotest result, two management options were determined to be appropriate:
Option 1 is to repeat cotesting in 12 months. If at that time, either cytology or hrHPV testing is positive, then the woman should be referred to colposcopy.
If both cytology and hrHPV tests are negative, then the woman should return to routine screening.
The 2nd management option for a hrHPV positive, cytology negative cotest result is immediate genotype specific testing for hrHPV 16 or both hrHPV 16 and 18.
If the hrHPV 16 or 16/18 test is positive, the woman should be referred to colposcopy, but these tests are negative, the woman should repeat cotesting in 12 months as in option 1 and with the management as described in option 1, which as you remember is if positive for either cytology or hrHPV test, the woman should be referred to colposcopy at that time, but should return to routine screening if negative for both cytology and hrHPV testing.

14. Discordant cotest results
Negative hrHPV, ASCUS cytology:
Routine screening as per age-specific guidelines
According to the updated guideline, women ages undergoing cotesting who are negative for hrHPV but have ASCUS cytology results should return to routine screening.
Because HPV is so sensitive, an ASCUS/HPV- gives some reassurance and can be followed in 3 years.

15. Exiting from screening
Who qualifies?
Criteria
Women > 65 years of age
Evidence of adequate negative prior screening required
No history of CIN2+ within 20 years
Following hysterectomy
Removal of cervix
No history of CIN2+
*Evidence of adequate negative screening not required
The guideline addressed two situations in which women should exit from screening.
First, the guideline states that women over 65 years of age with evidence of adequate negative prior screening and no history of CIN2+ within the last 20 years should not be screened for cervical cancer with any modality. The age for exiting screening is younger than previously recommended.
According to the updated guideline, the second situation in which women should exit from screening is:
Women at any age following a hysterectomy with removal of the cervix who have no history of CIN2+ should not be screened.
The guideline emphasizes that evidence of adequate negative prior screening is not required.
Once screening is discontinued, whether it is because a woman is age 65 or older, or if following a hysterectomy in a woman without CIN2+, screening should not resume for any reason, including a woman’s report of having a new sexual partner.
^Once discontinued, screening should not resume for any reason

16. History of CIN2+ or AIS: Continue screening for 20 years
Even if screening is extended past age 65
In women with a history of CIN2+ or AIS, routine screening should continue for 20 years following spontaneous regression or appropriate management of these lesions.
And screening should continue for 20 years even if this extends screening past age 65.

17. Impact of HPV vaccination
Screening after HPV vaccination:
Screening practices should not change on the basis of HPV vaccination status
At the time of the 2012 Uptate, there was insufficient evidence to make recommendations regarding screening in HPV vaccinated women, therefore the guideline recommends that screening practices should not change on the basis of HPV vaccination status. However, this recommendation may change in future guidelines as evidence regarding this population accumulates over time.

18. Utility of molecular screening
Screening with hrHPV testing alone:
Women should not be screened with hrHPV testing alone
As mentioned previously in the CELL Talk, at the time of the updated guideline, no hrHPV test had yet been FDA approved for primary hrHPV screening. Therefore, the guideline states that In most clinical settings, women ages years should not be screened with HPV testing alone as an alternative to contesting at 5-year intervals or cytology alone at 3-year intervals.

19. hrHPV Primary Screening
FDA news release
Cobas hrHPV Test
Roche Molecular Systems, Inc (Pleasanton, CA)
However, In April of 2014, the United States Food and Drug Administration approved the modified labeling of Roche’s Cobas hrHPV test to include primary hrHPV screening for cervical cancer in women ages 25 years and older older. The test specifically identifies HPV genotypes 16 and 18 while also detecting 12 other hrHPV subtypes.

20. hrHPV Primary Screening
Interim guidance report:
Gyn Oncol. 2015;136(2):178-82
J Low Genit Tract Dis. 2015;19(2):91-6
Obstet Gynecol. 2015;125(2):330-7
Since clinical practice guidelines for primary hrHPV screening did not exist at the time of FDA approval and there was a growing body of evidence to support the use of primary HPV screening, expert representatives from several organizations including the American Society of Cytopathology met to provide interim guidance for primary hrHPV screening. The interim guidance report was simultaneously published in these 3 journals. Unfortunatley, hyperlinks to this article are not provided since free access is not available online.

21. hrHPV Primary Screening
Interim guidance report:
Primary hrHPV screening should not be initiated prior to 25 years of age
Primary hrHPV screening is safe and effective
Cytology and cotesting remain recommended screening strategies
The interim guidance report states that primary hrHPV screening should not be used in women younger than 25 years of age.
The report acknowledged primary hrHPV screening as safe and effective and therefore, can be considered as an alternative to cytology-based cervical cancer screening methods.
However, the report emphasized that cytology and cotesting remain the screening options specifically recommended in major guidelines.

22. hrHPV Primary Screening
Recommended Management:
hrHPV Result
Management
hrHPV 16/18 positive
Colposcopy
hrHPV other positive
Cytology
hrHPV negative
Routine screening
(at least 3 year intervals)
Management
> ASCUS
Colposcopy
NILM
12 month F/U
The interim guidance report describes a management algorithm that may be used for primary hrHPV screening.
Women who test positive for hrHPV and positive for either 16 or 18 subtypes, should be referred to colposcopy.
Women who test positive for other subtypes of hrHPV should be triaged with cytology.
Women who test negative with hrHPV screening would return to routine screening,
and rescreening after negative hrHPV screen should occur no sooner than every 3 years.
Management for women triaged with cytology, that is, those who are positive for high risk HPV types other than 16 and 18, should be managed depending on their reflex cytology results. Those with ASCUS or greater should be referred to colposcopy, and those with NILM reflex cytology results should have follow up screening in 12 months.

23. ASC Lab Management Cell Talk: Recap
2012 Cervical Cancer Screening Update:
Screening intervals
Age specific screening strategies
Management of discordant cotest results
Exiting from screening
Impact of HPV vaccination
Potential utility of molecular testing
This concludes our ASC Lab Management Cell Talk on the updated cervical cancer screening guidelines. We hope you have learned about….

24. Thank you! ASC Foundation
ASC Cytopathology Program Directors Committee
Members involved in CELL Talk initiative:
Deborah Chute, M.D.
Roseann Wu, M.D. M.P.H.
Christina Kong, M.D.
Anne Mills, M.D.
Deborah Sheldon
Mayo Clinic Department of Cytopathology
Consultants and fellow trainees
Finally, we would like to thank…

25. Quiz Question #1
A 35 year old woman undergoes cotesting with a positive hrHPV test but negative cytology. hrHPV 16/18 genotype specific testing is negative. According to the updated 2012 ASCCP guidelines, what is the proper management for this patient?
Immediate colposcopy
Repeat cotesting in 5 years
Repeat cytology only in 3 years
Repeat cotesting in 12 months
Answer D is correct

26. Quiz Question #2
12 months later, the same woman from question #1 undergoes repeat cotesting. Again, hrHPV test is positive, but cytology is negative. According to the updated 2012 ASCCP guidelines, what is the appropriate management of this patient?
Immediate colposcopy
Repeat cotesting in 5 years
Repeat cytology only in 3 years
Repeat cotesting in 12 months
Answer A is correct.

27. Quiz Question #3
A 68 year old woman has a new sexual partner. She has no history of CIN2 or greater. Her most recent hrHPV test and Pap test was performed 3 years ago. According to the updated 2012 ASCCP guidelines, what is the appropriate management of this patient?
Immediate primary hrHPV screening
Immediate cytology screening
No management necessary
HPV vaccination
Answer C is correct.

28. Quiz Question #4
A 28 year old woman undergoes primary hrHPV screening and is positive for hrHPV “other” (not hrHPV 16 or 18). According to the 2015 interim guidance report, what is the appropriate management?
Follow up primary hrHPV screening in 12 months
Immediate colposcopy
Triage to cytology
Cotesting in 5 years
Answer C is correct.

29. Quiz Question #5
The same woman from question #4 has an ASCUS cytology result. According to the 2015 interim guidance report, what is the appropriate management?
Follow up primary hrHPV screening in 12 months
Immediate colposcopy
Triage to cytology
Cotesting in 5 years
Answer B is correct.