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

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

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

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)

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):453-459, 2007

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

http://www.womenshealthsection.com/content/gyno/gyno019.php3

Cervical Cancer Rates per 100,000 population https://www.cdc.gov/vaccines/pubs/surv-manual/chpt05-hpv.html

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

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 15-26 yrs and for immunocompromised

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 1-888-825-5249 (for bivalent), or Merck at 1-877-888-4231 (for quadrivalent HPV).

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

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

Screening and management of abnormal Paps

Screening and management of abnormal Paps Women 21-24 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 http://www.asccp.org/portals/9/docs/algorithms%207.30.13.pdf

Screening and management of abnormal Paps Women 25 -29 y/o +HR HPV (16,18) and/or LSIL/HSIL → colposcopy CIN 2 or 3: excision → co-testing annually x 2

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

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

Answer Women 21-24 y/o: Pap only; no HPV unless ASCUS/LSIL/HSIL (called a reflex HPV)

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+).

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 30 - 65 yrs who wish to lengthen the screening interval (Grade A)

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)

(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.

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):524-532. 2. Insinga RP, Glass AG, Rush BB. The health care costs of cervical human papillomavirus–related disease. Am J Obstet Gynecol. 2004;191(1):105-113

HPV vs Pap testing Cytology + HPV testing in women 30-64 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 1987-2010. http://www.cdc.gov/nchs/data/hus/2013/084.pdf. 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: 10.1093/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: 10.1002/cncy.21544

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):312-320.

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

Take home points: All patients with HSIL (regardless of HPV) → colposcopy No Pap <21 y/o Cytology and HPV 30-65 y/o Reflex HPV ages 25-29 See the ASCCP guidelines at http://www.asccp.org/portals/9/docs/algorithms %207.30.13.pdf

The End!