1. Montana Academy of PAs CME conference Elyse Watkins, DHSc, MS, PA-C
HPV and Pap Testing
Montana Academy of PAs CME conference
Elyse Watkins, DHSc, MS, PA-C

2. I have no conflicts to disclose.
No financial relationships
No commercial interests
No sponsorship

3. Learning Objectives
At the conclusion of this presentation, learners will be able to:
Describe the differences between ASCUS, AGUS, HSIL, LSIL
Describe the oncogenic potential of HPV subtypes
Utilize prevention strategies against HPV infection
Utilize the evidence to determine the management of abnormal Pap tests
Describe the risks and benefits of replacing the Pap test with HPV testing

4. Terminology: ASCUS, AGUS, HSIL, LSIL, CIS
ASCUS (atypical squamous cells of undetermined significance)
AGUS (atypical glandular cells of undetermined significance)
LSIL (low grade squamous intraepithelial lesion)
HSIL (high grade squamous intraepithelial lesion)
CIS (carcinoma in situ)

7. From Lancet Infect Dis. de Sanjose et al. 207(7):453-459, 2007
HPV
The most common STI in the US
About $8 billion is spent on HPV in the US
management of abn Paps, tx for cervical dysplasia & neoplasia
From Lancet Infect Dis. de Sanjose et al. 207(7): , 2007

8. HPV
Bowen’ disease is Squamous Cell Carcinoma in Situ. Looks like eczema, psoriasis. Scaly.

11. Cervical Cancer Rates per 100,000 population

12. The oncogenic potential of HPV subtypes
Over 40 mucosal HPV genotypes infect the lower female genital tract
About 15 HPV types cause all cervical cancer worldwide
HPV 16 and 18 cause ~ 70% of all cervical cancers worldwide
HPV 6 and 11 cause ~ 90% of genital condyloma
Carcinogenic HPV infections also cause most anal, vaginal, vulvar, penile, and almost 1/2 of oropharyngeal CA

14. Prevention of HPV
Quadrivalent (Gardasil®): HPV types 6, 11, 16, and 18
9-Valent (Gardasil 9®): HPV types 6, 11, 16, and 18; AND 31, 33, 45, 52, and 58
Bivalent (Cervarix®): HPV types 16 and 18
Approved for ages 9-26
*2 or 3 doses: 1st ; 2nd dose 2 months after 1st ; 3rd dose 6 months after 1st
2-dose schedule for girls and boys who start the series ages 9-14 yrs
3 dose schedule for pts who start the series at ages yrs and for immunocompromised

15. Notes on HPV vaccination
Prevaccination assessments are not recommended!
Prior infection with one genotype: can still immunize!
MSM up to 26 y/o should receive vaccination even if HIV +
Hx of anaphylaxis with latex is a contraindication to bivalent (tip of syringe is latex)
Vaccination in pregnancy not recommended
If pt is pregnant and received vaccine, may contact manufacturer:
GlaxoSmithKline at (for bivalent), or
Merck at (for quadrivalent HPV).

16. Question Which of the following statements are true?
a) HPV 6 & 11 cause about 90% of cervical cancers
B) The Bivalent HPV vaccine is 6 & 11
C) HPV 16 & 18 cause most cervical cancers
D) The quadrivalent HPV vaccine can help prevent genital condylomas and cervical cancers

17. Answer HPV 6 and 11 cause ~ 90% of genital condyloma
Bivalent HPV is 16 & 18, not 6 & 11
HPV 16 & 18 cause almost 70% of all cervical cancers worldwide
The quadrivalent HPV vaccine can help prevent genital condylomas and cervical cancers

18. Screening and management of abnormal Paps

19. Screening and management of abnormal Paps
Women y/o
Pap only; no HPV unless ASCUS/LSIL/HSIL
+HR HPV (16,18) and LSIL → repeat cytology and HPV in one year
+HR HPV (16,18) and HSIL → colposcopy
CIN 2: repeat co-testing q 6 months x 2
CIN 3: excision

20. Screening and management of abnormal Paps
Women y/o
+HR HPV (16,18) and/or LSIL/HSIL → colposcopy
CIN 2 or 3: excision → co-testing annually x 2

21. Screening and management of abnormal Pap
Women >30 y/o
Every 3-5 years if HPV and cytology negative
If HPV HR + (16, 18) → colposcopy
CIN 2 or 3: excision → co-testing annually x 2

22. Question
21 y/o female presents for her first Pap. Do you co-test?

23. Answer
Women y/o:
Pap only; no HPV unless ASCUS/LSIL/HSIL (called a reflex HPV)

24. USPSTF Current Recommendation for Cervical Cancer Screening
These recommendations apply to women who have a cervix, regardless of sexual history.
These recommendations do not apply to women who:
Have received a diagnosis of HGSIL/CIS
Have had exposure to DES
Are immunocompromised (i.e. HIV+).

25. USPSTF Current Recommendation FOR Cervical Cancer Screening
Screen women 21 to 65 yrs with cytology Q 3 yrs
Screen with a combo of cytology and HPV testing Q 5 yrs for women yrs who wish to lengthen the screening interval (Grade A)

26. USPSTF Current Recommendation AGAINST Cervical Cancer Screening
In women >65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer (Grade D)
In women s/p hysterectomy [with removal of the cervix] without a hx of CIN 2, CIN 3, or cervical cancer (Grade D)
Using HPV testing, alone or with cytology, in women < 30 yrs (Grade D)
In women < 21 yrs (Grade D)

27. (What do the grades mean?)
A The USPSTF recommends the service. There is high certainty that the net benefit is substantial. B The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial. C Clinicians may provide this service to selected patients depending on individual circumstances. However, for most individuals without signs or symptoms there is likely to be only a small benefit from this service. D The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.

28. HPV vs Pap testing For women ages 21 to 29:
Current consensus guidelines recommend a Pap test
Women in their 20s have a high incidence of CIN but their rates of cervical CA are low
Screening with HPV alone has not demonstrated clinical benefit over cytology
Ronco G, Meijer CJ, Segnan N, et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet. 2014:383(9916): Insinga RP, Glass AG, Rush BB. The health care costs of cervical human papillomavirus–related disease. Am J Obstet Gynecol. 2004;191(1):

29. HPV vs Pap testing
Cytology + HPV testing in women y/o q 5 yrs is preferred
Cytology alone q 3 yrs is acceptable
Centers for Disease Control and Prevention. Use of Pap smears among women aged 18 and over, by selected characteristics: United States, selected years Accessed April 13, 2015.
Gage JC, Schiffman M, Katki HA, et al. Reassurance against future risk of precancer and cancer conferred by a negative human papillomavirus test. J Natl Cancer Inst. 2014;106(8). pii: dju153. doi: /jnci/dju153. Print 2014 Aug.
Blatt AJ, Kennedy R, Luff RD, Austin RM, Rabin DS. Comparison of cervical cancer screening results among 256,648 women in multiple clinical practices. Cancer Cytopathology. 2015;Apr 10. doi: /cncy.21544

30. What’s coming…
mRNA Biomarker Detection in Liquid-based Cytology: A New Approach in the Prevention of Cervical Cancer
Marta del Pino; Cecilia Svanholm-Barrie; Aureli Torné; Lorena Marimon; Jina Gaber; Amaia Sagasta; David H Persing; Jaume Ord. Mod Pathol. 2015;28(2):

31. mRNA vs HPV Genotype Testing
mRNA detection has the advantage of being less subjective than morphologic assessment.
Extraction of high-quality RNA is a prerequisite for the application of RNA transcripts as biomarkers for clinical purposes
The use of mRNA from cervical samples consist of mucus and exfoliated cervical cells
this can prove challenging because the RNA might be degraded
mRNA E6/E7 are oncogenes and expression is required for malignant transformation

32. Take home points:
All patients with HSIL (regardless of HPV) → colposcopy
No Pap <21 y/o
Cytology and HPV y/o
Reflex HPV ages 25-29
See the ASCCP guidelines at % pdf

33. The End!