#175 Cervical Cancer Screening and HPV

September 30, 2019 | By Elena Gibson

Clarify cervical cancer screening and HPV with Dr. Karen Smith-McCune

Summary

We dive deep into the relationship between HPV and cervical cancer and identify when and how to screen women with tips from Dr. Karen Smith-McCune (UCSF), Professor in the Department of Obstetrics and Gynecology! We review common cytology findings, screening guidelines, and basic indications for HPV vaccination. 

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Credits

• Producer: Molly Heublein MD
• Writer: Elena Gibson MD and Molly Heublein MD
• Infographic: Beth Garbitelli MS2
• Cover Art: Kate Grant MBChB DipGUMed
• Hosts: Molly Heublein MD; Matthew Watto MD, FACP
• Editor: Emi Okamoto MD; Matthew Watto MD, FACP
• Guest: Karen K. Smith-McCune MD, PhD

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Time Stamps

• 00:00 Sponsor: I.M. Proud National Internal Medicine Day Story Contest
• 01:00 Reminder: We’ll be at CHEST 2019 in NOLA!
• 01:33 Intro, guest bio
• 04:35 Guest one-liner; Check out our classic Curbsiders’ Top Picks
• 08:00 Sponsor: I.M. Proud National Internal Medicine Day Story Contest
• 09:49 Case of HPV; Background; Is HPV an STI?
• 13:47 Frequency of screening; Discussion of testing types & pitfalls
• 18:11 Summary of testing for cervical cancer
• 20:20 Is co-testing every helpful?
• 24:05 Choosing a testing interval
• 24:40 Colposcopy; Risks
• 32:19 Screening women under 30 years old? Under 21 years old?
• 33:22 Interpreting a PAP (cytology) result; Algorithm for cervical cancer screening
• 42:08 Women over 65 years old; When to stop screening
• 46:02 Will Vaginal swabs replace traditional cervical screening
• 48:40 Screening after Hysterectomy or “Partial” hysterectomy
• 50:25 HPV vaccine in older adults and shared decision making
• 54:21 HPV vaccine in children, young adults
• 58:12 Take home points
• 59:40 Outro

Cervical Cancer and HPV Pearls

Most adults are infected with HPV during their lifetime, but HPV is usually cleared by the immune system. 

Cervical cancer screening should not start before age 21 (unless a woman has HIV).

Women ages 21-29 should be screened every 3 years with cytology alone.

There are two preferred options for screening women ages 30-65 for cervical cancer 1) cytology every 3 years or 2) HPV testing alone every 5 years.

The two most common cytology results, ASCUS and LSIL, have a low likelihood of predicting future malignancy and usually heal on their own.

During colposcopy, biopsies are taken for histopathologic evaluation. Precancerous findings include CIN I (low grade) and, CIN II or III (which are higher grade and usually treated). 

HPV vaccine is recommended for patients aged 9-26, but can be offered to women up to age 45.

Cervical Cancer Screening and Human Papillomavirus (HPV)

HPV and Cervical Cancer

HPV is present in nearly all cervical cancer cases (Bosch 2002, Schiffman 2003).  Furthermore, approximately 80% of adults will be infected with HPV in their lifetime (CDC 2019).The virus is usually cleared by the immune system, but it can also cause cells to enter a proliferative state leading to the development of cervical cancer (Schiffman 2011).

HPV Transmission

HPV is most often transmitted by direct contact in the genital and anal regions (CDC 2019). As such, HPV is a sexually transmitted infection (STI). However, Dr. Smith-McCune describes avoiding this label because of the negative connotations associated with the term STI and the high prevalence of HPV. 

Cervical Cancer Screening 

Most deaths from cervical cancer occur in women who are not adequately screened (USPSTF 2018). In otherwise healthy women, screening should not occur until age 21 and should stop after age 65. Cervical Cancer screening guidelines include three major age groups : 1) 21-29 years 2) 30-65 years and 3)over 65 years (USPSTF 2018).

Women Ages 30-65 

There are two preferred screening methods for women ages 30-65: 1) Cytology from a Papanicolaou (Pap) test every 3 years or  2) HPV testing every 5 years (USPSTF 2018).  Co-testing with cytology + HPV every 5 years is an option, but not preferred.  Research has shown that the costs of more frequent screening outweighs the potential benefit (USPSTF 2018). 

Choosing How to Screen

Dr. Smith-McCune describes how much of the decision between cytology or HPV testing comes down to a conversation with the patient, and frequently comfort with a prolonged screening interval influences the decision. 

Cytology 

Liquid-based Pap tests have largely replaced conventional Pap tests, but there are no proven differences in outcomes between the modalities (USPSTF 2018). There are two types of liquid-based Pap tests: 1)SurePath Pap Test and 2)ThinPrep Pap Test, and they differ in how the sample is placed in the vial (Joste 2008). 

HPV Testing 

Only two tests are approved by the FDA for primary HPV screening. Check with your lab to verify the test used has an internal standard for specimen adequacy to reduce the chances of a false negative result (Carozzi 2016). HPV testing is very sensitive, but it is not very specific for risk of developing cervical cancer, as the majority of HPV viruses are cleared independently (Rodriguez 2008).   Because it is so sensitive, HPV based screening is only suggested every 5 years, testing more often can lead to a higher cost and burden of care (more colposcopies) without benefit.

Although self-collected vaginal HPV testing is not approved or recommended at this point, it could help address disparities in cervical cancer screening and mortality in the future (Freeman 2005). 

Women Ages 21-29

Given the high prevalence of HPV in young women, HPV testing is not recommended for screening. The only option for screening women under 30 years old is cytology every 3 years (USPSTF 2018).  

When to Screen before 21

Healthy women should not be screened before age 21, regardless of initiation of sexual intercourse.  HIV infected individuals should begin screening at the time of diagnosis if sexually active or at age 21 regardless of sexual activity (NIH 2018).

Women Ages 65+

Older women are low risk for developing cervical cancer, so women who have been adequately screened can stop testing at age 65.  Either 3 negative cytology tests or 2 negative co-tests (or HPV tests) within the past ten years are needed to stop screening (USPSTF 2018). 

Other Screening Groups 

Recommended screening among individuals who are vaccinated against HPV is currently the same, but this could change in the future as a larger proportion of the population is vaccinated (Lynge 2009). Following a complete hysterectomy (hysterectomy with removal of the cervix) that was not performed for cervical dysplasia or pre-cancer, no additional screening is needed. If a hysterectomy was completed for one of those reasons, screening should be continued with a vaginal swab. In the case of a partial hysterectomy (removal of the uterus with intact cervix remaining), regular screening guidelines apply (USPSTF 2018). 

Positive Screening

The ASCCP (American Society of Colposcopy and Surgical Pathology) website and mobile application publish resources for the management of positive screening tests. There are a series of algorithms to follow after various positive results based on cytology, histopathology and high-risk HPV status (ASCCP 2014).

Positive HPV Screening 

If a general HPV test is positive, the next step is HPV genotyping to see if the high-risk HPV strains are present (16 or 18). If HPV 16/18 is positive, colposcopy is recommended. If the high risk strains are not present, cytology is recommended. Colposcopy is recommended if  cytology is abnormal and retesting in 1 year for viral clearance is recommended if cytology is normal (Sawaya 2019). Most HPV infections clear independently in 1-2 years (Rodriguez 2008). 

Cytology Findings 

The most common abnormal finding is atypical squamous cells of undetermined significance (ASCUS), seen on 5-10% of histopathology results (Joste 2008).   ASCUS is a common, non-specific finding where the cells are slightly tweaked. Normal vaginal flora, recent intercourse, or HPV can cause these changes (Schiffman 2011).  This can be thought of as “indeterminate” (CDC 2019) and not necessarily a pre-cancerous lesion.

If ASCUS is identified there are two options: 1)repeat the Pap in one year or 2) reflex HPV testing. If HPV testing is positive, the patient should have a colposcopy (ASCCP 2014). If  HPV is negative then their likelihood of disease is about the same as someone with a negative PAP so they can come back in 3 years (ASCCP 2014). 

Two other common findings on cytology are low grade squamous intraepithelial lesion (LSIL) and high grade squamous intraepithelial lesion (HSIL)(Katki 2013).  HPV testing is not required following an LSIL result, as LSIL represents a viral infection (Schiffman 2011).   HSIL always needs follow up with a gynecologist for colposcopy, LSIL can be managed with a repeat screen in 1 year or colposcopy, depending on the age, check your guidelines. (ASCCP 2014)

ASCUS and LSIL are the two most common findings on cytology,  but they rarely predict the presence of precancerous lesions requiring treatment (CIN II+) (Silver 2018).

Colposcopy

Dr. Smith-McClune describes this procedure to patients as “an intervention where we start out as if we are doing a Pap smear then we bathe the cervix with different liquids and look for color changes that might dictate active HPV infection”.  Potential side effects following the procedure include pain and rarely bleeding (Pierce 2013). Biopsy samples from colposcopy are sent for histopathologic evaluation (Pierce 2013). 

Biopsy Findings 

Biopsies are performed to look for histologic evidence of HPV infection and precancer, termed cervical intraepithelial neoplasia (CIN) I, II, and III (Schiffman 2011). Only CIN II and III require treatment (ASCCP 2014). Dr. Smith-McCune discusses how CIN I is left alone because it is equivalent to LSIL cytology. Both are evidence of active HPV that will hopefully resolve independently. 

Cervical Treatments and Complications

If CIN II or CIN III are identified, a procedure is usually recommended for treatment (ASCCP 2014). Typical procedures include Loop Electrosurgical Excision Procedure (LEEP), cryotherapy and excisional laser therapy (Montz 2000).  Risks associated with LEEP in the current literature include a probable increased risk of preterm labor (Conner 2014), a possible increased risk of miscarriage 6 to 12 months after the procedure (Ciavantinni 2015), and no identified effect on fertility (Kyrgiou 2015). In Dr. Smith-McCune’s opinion, the data supporting the risk of miscarriage is not strong enough at this time to counsel women against pregnancy for 12 months following a LEEP. However, patients should be informed about these findings, so they can take this risk into account. 

HPV Vaccination

The ACIP recommends nonavalent HPV vaccination (2 low risk and 7 high risk strains of HPV) starting at age 9. Individuals ages 9-14 should receive two injections occurring 6-12 months apart. Individuals over 15 years of age require a 3 injection regimen. The FDA recently approved HPV vaccination for women 26-45 years old, and the ACIP recommends the use of “shared decision making” in these patients (Meites 2019).  Our guest explains how those most likely to benefit from screening after 25 include adults with few sexual exposures at a young age at increased risk of exposure to new strains of HPV in the future.   Those who have already had multiple sexual partners likely already have immunity to multiple HPV strains and will get minimal benefit.

Goal

Listeners will develop an understanding of cervical cancer screening guidelines and how these are impacted by our understanding of HPV infections. 

Learning objectives

After listening to this episode listeners will…  

1. Describe the relationship between human papillomavirus and cervical dysplasia/cancer development
2. Apply current guidelines for cervical cancer screening intervals in different age ranges
3. Examine why cytology vs. HPV testing may be more appropriate for certain women
4. Describe what to do next after an initial screening test is positive 
5. Explain who should get HPV vaccines.

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References

1. Bosch FX, et al. The causal relation between human papillomavirus and cervical cancer, J Clin Pathol.2002. [https://www.ncbi.nlm.nih.gov/pubmed/11919208]
2. Mark H. Schiffman, Philip Castle, Epidemiologic Studies of a Necessary Causal Risk Factor: Human Papillomavirus Infection and Cervical Neoplasia, JNCI: Journal of the National Cancer Institute, [https://www.ncbi.nlm.nih.gov/pubmed/12644550]
3. Centers for Disease Control (CDC). Human Papillomavirus (HPV). 2019.[https://www.cdc.gov/std/hpv/default.htm]
4. U.S. Preventive Services Task Force (USPSTF). Final Recommendation Statement: Cervical Cancer: Screening.2018. [https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/cervical-cancer-screening2]
5. Schiffman M, et al.Human papillomavirus testing in the prevention of cervical cancer. J Natl Cancer Inst. 2011.[https://academic.oup.com/jnci/article/103/5/368/905734]
6. Freeman HP & Wingrove BK. Excess Cervical Cancer Mortality: A Marker for Low Access to Health Care in Poor Communities. National Cancer Institute, Center to Reduce Cancer Health Disparities. 2005. NIH [https://www.cancer.gov/about-nci/organization/crchd/about-health-disparities/resources/excess-cervical-cancer-mortality.pdf]
7. Joste, Nancy. Overview of the cytology laboratory: specimen processing through diagnosis.Obstet Gynecol Clin North Am.2008. [https://www.ncbi.nlm.nih.gov/pubmed?term=19061816]
8. Carozzi FM, et al. HPV testing for primary cervical screening: Laboratory issues and evolving requirements for robust quality assurance. J Clin Virol. 2016. [https://www.ncbi.nlm.nih.gov/pubmed/26669512]
9. Rodriguez, AC et al. Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. J Natl Cancer Inst. 2008. [https://www.ncbi.nlm.nih.gov/pubmed/?term=18364507]
10. The National Institutes of Health (NIH).Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: human papillomavirus disease.2018. [https://aidsinfo.nih.gov/guidelines/brief-html/4/adult-and-adolescent-opportunistic-infection/343/human-papillomavirus-disease]
11. Lynge E, et al. What’s next? Perspectives and future needs of cervical screening in Europe in the era of molecular testing and vaccination. Eur J Cancer. 2009.[https://www.ncbi.nlm.nih.gov/pubmed/19695870]
12. American Society for Colposcopy and Cervical Pathology (ASCCP). Algorithms: Updated Consensus Guidelines for Managing Abnormal Cervical Cancer Screening Tests and Cancer Precursors. 2014. [http://www.asccp.org/Assets/51b17a58-7af9-4667-879a-3ff48472d6dc/635912165077730000/asccp-management-guidelines-august-2014-pdf]
13. Sawaya GF, Smith-McCune K, Kuppermann M. Cervical Cancer Screening: MoreChoices in 2019. JAMA. 2019. [https://www.ncbi.nlm.nih.gov/pubmed/31135834] 
14. Katki, HA et al. Benchmarking CIN 3+ risk as the basis for incorporating HPV and Pap cotesting into cervical screening and management guidelines. J Low Genit Tract Dis. 2013. [https://www.ncbi.nlm.nih.gov/pubmed?term=23519302]
15. Silver, MI, et al.Risk of Cervical Intraepithelial Neoplasia 2 or Worse by Cytology, Human Papillomavirus 16/18, and Colposcopy Impression: A Systematic Review and Meta-analysis. Obstet Gynecol. 2018. [https://www.ncbi.nlm.nih.gov/pubmed/30095780]
16. Pierce, JG & Bright, S.Performance of a colposcopic examination, a loop electrosurgical procedure, and cryotherapy of the cervix. Obstet Gynecol Clin North Am. 2013.[https://www.ncbi.nlm.nih.gov/pubmed?term=24286998]
17. Montz, F. J Management of high-grade cervical intraepithelial neoplasia and low-grade squamous intraepithelial lesion and potential complications. Clin Obstet Gynecol, 2000.[https://www.ncbi.nlm.nih.gov/pubmed?term=10863636]
18. Conner, SN et al. Loop electrosurgical excision procedure and risk of preterm birth: a systematic review and meta-analysis. Obstet Gynecol. 2014. [https://www.ncbi.nlm.nih.gov/pubmed/24785601]
19. Ciavattini, A et al. Loop electrosurgical excision procedure and risk of miscarriage. Fertil Steril. 2015. [https://www.ncbi.nlm.nih.gov/pubmed/25624192]
20. Kyrgiou M et al. Fertility and early pregnancy outcomes after conservative treatment for cervical intraepithelial neoplasia. Cochrane Database Syst Rev. 2015.[https://www.ncbi.nlm.nih.gov/pubmed/26417855]
21. Meites E, et al.Human Papillomavirus Vaccination for Adults: Updated Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019. [https://www.ncbi.nlm.nih.gov/pubmed/31415491]

Disclosures

Dr. Smith-McCune reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. 

Citation

Smith-McCune K, Heublein M, Gibson E, Garbitelli B, Okamoto M, Watto MF. “#175 Cervical Cancer Screening and HPV”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list. September 30, 2019.

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