HPV and Cervical Cancer

Pap Cytology: Impact and Limitations

Over the last 80 years, Pap cytology screening has had a tremendous impact on women’s health. For the last 60 years since the ACS promoted the Pap test as part of cervical cancer screening,1 the use of regular Pap cytology screening, together with the diagnosis and treatment of precancerous lesions, has contributed to an 80% reduction in the incidence and mortality of cervical cancer in countries with systematic screening.2 HPV is a very common virus; it is predicted that 80% of women will be exposed at some point in their life.3 Despite this, in 2020 alone, 604,127 new cases were diagnosed and 341,831 women lost their lives to cervical cancer.4 To reduce the incidence and mortality rates, attention must focus in part on the screening, triage and management of women found to be at risk for cervical cancer. Furthermore, the majority of cervical cancer deaths occur in low to middle income countries where the infrastructure needed to support widescale Pap cytology does not exist.5 New screening solutions are necessary to increase women's access and to implement more optimal prevention strategies.

The Limits of Pap Cytology

Although Pap testing has proven to be a useful screening tool in countries with organized or opportunistic screening programs, there are limitations and drawbacks to using Pap cytology alone:

  • Limited sensitivity: Pap cytology has limited sensitivity. When used without adjunct testing, disease may be missed.6,7,8,9    

  • Subjective interpretation: Interpretations of samples are based on individual judgments of pathologists or technicians, which can compromise reproducibility. Guidelines are provided, but no definitive objective standard exists.2,10  

  • Interpretation errors: False-negative reports may occur when pathologists or technicians fail to detect abnormal cells. False-positive results may also occur when normal cells are incorrectly categorized as abnormal.2   

  • Sample quality: When samples are prepared as a smear, quality may not be sufficient to enable acceptable analysis.11

These issues can lead to over- or underestimation of risk. Overestimation of risk may lead to unnecessary tests or treatments. This can be of particular concern to younger women, who have many false-positive tests and for whom treatment for suspicious lesions may have long-term consequences for fertility and pregnancy. Underestimation of risk can result in delays or absence of action that might prevent or compromise treatment.




Normal cytology does not always mean cancer-free: Up to one-third of cervical cancers occur in women who received a normal Pap test result8,9

The Case for HPV Primary Screening

The discovery of HPV as the cause of cervical cancer has revolutionized cervical cancer prevention strategies.6,12  An HPV DNA test is a more sensitive indicator of risk for a woman's future cervical health than a Pap test alone.13  In fact, leading US medical societies (ACOG,14 ASCCP,15 SGO,16 ACS17) now support HPV primary screening as an option for cervical cancer screening for women ages 25 and older.

Evidence supports high-risk HPV (hrHPV) testing for primary screening of cervical cancer:

  • In primary screening, hrHPV testing was proven more sensitive than cytology for detecting ≥CIN2 and ≥CIN3.13
  • There is an opportunity to identify those at highest risk, since 70% of cervical cancers are caused by HPV genotypes 16 and 18.18

Multiple U.S. and International guidelines recommend HPV primary screening. Learn more

Sensitivity is vital in Primary HPV Screening

There is risk of missed disease if a clinically relevant hrHPV infection is not detected in the first round of routine screening. Women with undetected hrHPV infections may progress to cancer.

"Per U.S. guidelines every 3-5 years, many other countries follow every 5 years interval"

HPV Genotyping: Identify Women at Greatest Risk

Since HPV 16 and 18 confer a higher risk of having precancerous lesions and cervical cancer than other genotypes,19 focusing on these genotypes gives physicians useful details upon which to make effective treatment decisions. Distinguishing HPV 16 and 18 from other high-risk HPV types may identify women at the greatest risk of ≥CIN315 and those that would benefit from colposcopy.

 

Know now if she is progressing toward cervical cancer with CINtec® PLUS

Women with a positive high-risk HPV result may benefit from a biomarker-based triage test that can be run from the same sample collected for HPV DNA screening or Pap cytology. Immediate triage can give more information sooner, to help guide next step clinical decisions. 

Click here to learn more about CINtec® PLUS Cytology.

 

References

  1. https://www.cancer.org/cancer/cancer-basics/history-of-cancer/cancer-causes-theories-throughout-history11.html (accessed 11 January 2021)
  2. National Cancer Institute. Cervical Cancer Screening (PDQ®). https://www.cancer.gov/types/cervical/hp/cervical-screening-pdq (accessed 29 April 2020)
  3. Chesson HW, Dunne EF, Hariri S, Markowitz LE. The Estimated Lifetime Probability of Acquiring Human Papillomavirus in the United States. Sex Transm Dis. 2014;41(11):660–4.
  4. Cancer Today, International Agency for Research in Cancer (IARC) GLOBOCAN 2020 Registry: https://gco.iarc.fr/today/data/factsheets/cancers/23-Cervix-uteri-fact-sheet.pdf (accessed 11 January 2021)
  5. Arbyn M, Weiderpass E, Bruni L, Sanjosé S de, Saraiya M, Ferlay J, et al. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. Lancet Global Heal. 2019;8(2):e191–203.
  6. Saslow D, Solomon D, Lawson HW, et al; for the ACS-ASCCP-ASCP Cervical Cancer Guideline Committee. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012;62:147-172.
  7. Barcelos AC, Michelin MA, Adad SJ, Murta EF. Atypical squamous cells of undetermined significance: Bethesda classification and association with Human Papillomavirus. Infect Dis Obstet Gynecol. Epub 2011 Jun 29.
  8. Andrae B, Kemetli L, Sparén P, et al. Screening-preventable cervical cancer risks: evidence from a nationwide audit in Sweden. J Natl Cancer Inst. 2008;100(9):622-629.
  9. Leyden WA, Manos MM, Geiger AM, et al. Cervical cancer in women with comprehensive health care access: attributable factors in the screening process. J Natl Cancer Inst. 2005;97(9):675-683.
  10. Stoler MH, Schiffman M, Group for the ASC of USSILTS (ALTS). Interobserver Reproducibility of Cervical Cytologic and Histologic Interpretations: Realistic Estimates From the ASCUS-LSIL Triage Study. Jama. 2001;285(11):1500–5.
  11. Strander B, Andersson-Ellström A, Milsom I, Rådberg T, Ryd W. Liquid-based cytology versus conventional Papanicolaou smear in an organized screening program : a prospective randomized study. Cancer. 2007 Oct 25;111(5):285-91. doi: 10.1002/cncr.22953. PMID: 17724676.
  12. Rijkaart DC, Berkhof J, Rozendaal L, et al. Human papillomavirus testing for the detection for high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomized controlled trial. Lancet Oncol. 2012; 13:78-88.
  13. Wright TC, Stoler MH, Behrens CM, Sharma A, Zhang G, Wright TL. Primary cervical cancer screening with human papillomavirus: End of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol. 2015;136(2):189–97.
  14. Practice Bulletin No. 168: Cervical Cancer Screening and Prevention, Obstetrics & Gynecology: October 2016 - Volume 128 - Issue 4 - p e111-e130 doi: 10.1097/AOG.0000000000001708
  15. Perkins RB, et al. 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors. J Low Genit Tract Dis. 2020;24(2):102-31 doi: 10.1097/LGT.0000000000000525
  16. Huh WK, Ault KA, Chelmow D, Davey DD, Goulart RA, Garcia FAR, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: Interim clinical guidance. Gynecol Oncol. 2015;136(2):178–82.
  17. Saslow D, Andrews KS, Manassaram‐Baptiste D, Smith RA, Fontham ETH, Group the ACSGD. Human papillomavirus vaccination 2020 guideline update: American Cancer Society guideline adaptation. Ca Cancer J Clin. 2020;70(4):274–80.
  18. Sanjose S de, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 2010;11(11):1048–56.
  19. Clifford GM, Smith JS, Aguado T, Franceschi S. Comparison of HPV type distribution in high-grade cervical lesions and cervical cancer: a meta-analysis. Brit J Cancer. 2003;89(1):101–5.