Current choices in cervical cancer screening

The Papanicolaou (Pap) smear test came into widespread use in the 1950s and is considered to be the most successful screening test in modern medicine.¹ For more than 5 decades, cervical cytology was the only way to detect precancer or early invasive cancer.

The discovery of the causative role of human papillomavirus (HPV) in the 1970s has laid the foundation for new ways to screen for, and potentially eradicate, this largely preventable disease.²

Over the past decade, data have strongly suggested that primary HPV nucleic acid screening will eventually supplant cytology-based technology.³ This evolution toward primary HPV testing for optimal cervical cancer screening will require considerable provider support, patient education, and updated laboratory technology and procedures before existing cytology-based screening options (cytology alone and cotesting) can be phased out.

The prevention of cervical cancer can be primary or secondary. Cytology and HPV screening provide secondary prevention as they detect asymptomatic precancer and early cancers. Primary prevention focuses on the avoidance of genital HPV infection and its consequences by the use of HPV vaccination and behavioral steps such as condom use and smoking cessation.

We should do everything we can to support primary prevention efforts, particularly through HPV vaccination as recommended by current guidelines.⁴

At least half of the approximately 14,000 cervical cancers diagnosed annually in the United States will be in unscreened or underscreened (not screened in the previous 5 years) women.^5,6

Cervical cancer disproportionally affects racial minority, rural, and uninsured populations.^7,8 It is essential to expand access to all available, effective cervical cancer screening options for the most vulnerable populations. The targeted use of any particular screening modality in higher-risk populations is not supported by evidence-based guidelines; any effective screening is the priority.

Current screening components

Cytology: Cervical cytology can be collected as a conventional slide (“smear”); cells are taken directly from the cervix using a broom device or spatula (with or without an endocervical brush) and spread on a glass slide with immediate spraying with or immersion in a fixative.

Liquid-based cytology calls for the similarly collected cells to be transferred directly into a liquid fixation and transport medium, a Pap “test.” Conventional slide and liquid-based cytology have equivalent performance in the detection of cervical cancer and its significant precursors.^9,10

Liquid-based cytology now accounts for nearly all cervical cytology testing in the United States, as automated slide preparation and preliminary review are possible, and the remaining transport medium can be used for HPV and other testing.

HPV testing: By convention, HPV testing refers to clinical testing only for either 13 or 14 high-risk HPV types. Cells are collected from the cervix using the same collection devices, technique, and transport media as those recommended for cytology sampling.

These HPV types account for nearly all cervical cancers.^11,12 Some HPV tests provide “genotyping.” This refers to testing that specifically identifies HPVs 16 and 18, whereas the other high-risk HPVs are detected within a pooled group. HPVs 16 and 18 are considerably more oncogenic than the others and their detection may influence management.¹³

At this time, 5 clinical HPV tests are available in the United States that are US Food and Drug Administration approved. Only 2 of these are currently approved for primary HPV testing in individuals aged 25 years and older (cobas 4800 HPV Test, Roche Diagnostics; and BD Onclarity HPV Assay, Becton, Dickinson and Company).

It is widely accepted that testing for low-risk HPV types (types 6 and 11) has no role in clinical practice and it is strongly discouraged; the presence of these types does not increase the risk of developing anogenital cancers.

Also, HPV testing should not be used to screen for sexually transmitted infections, as it detects only a specific group of genital HPV types at levels indicative of an elevated risk of cervical intraepithelial neoplasia 3 or cancer (CIN 3+). Therefore, a negative test does not mean that HPV is not present.

Current screening options

Three effective screening options are supported by clinical guidelines: cytology, cotesting, and primary HPV testing (Table 1).^3,14,15 They can be selected based on patient and provider preference (shared decision-making optimal), financial considerations (patient and/or health care system resources), and familiarity with the triage of results.¹⁶ Few labs are set up for primary HPV screening, but this option is expected to become more widely available in the near future.

Cervical cytology

Cervical cytology screening can be ordered as cytology alone but is most commonly ordered with reflex HPV testing. Reflex HPV testing is arranged in advance with the clinical laboratory with established parameters for when an HPV test should be performed once the cytology results have been obtained. Its main use is to stratify the risk of CIN 3+ of an atypical squamous cell of undetermined significance cytology, which is the most common and lowest-risk Pap abnormality.

Cytology, usually with reflex HPV testing, remains a mainstay of cervical cancer prevention and is highly cost-effective.¹⁷ It is repeated at shorter intervals (3 years) than cotesting or primary HPV testing to compensate for its lower sensitivity and less durable reassurance that CIN 3+ will not develop.¹⁸

Cotesting

Cotesting is cytology with a concurrent HPV test. The HPV test is carried out regardless of the Pap result, even if that was negative. Concurrent HPV negativity offers stronger reassurance that CIN 3+ is not present and will not develop over the next several years than cytology alone; this reassurance allows for screening intervals to be extended safely to 5 years.^18-22

Cotesting was deemed the preferred screening modality (over cytology) in 2012 by 2 of 3 major gynecologic institutions^23,24; however, this is not the case for the latest guidelines.^3,14

Disadvantages of cotesting include complex results to manage appropriately and more expense (doubles the number of tests), and it is less specific than cytology alone. Cotesting also results in more colposcopy referrals, which can lead to more treatment of transient HPV infections and lesions that may have regressed over time without intervention.^3,25

Primary HPV testing

Primary HPV testing reverses the traditional cytology-based screening paradigm by obtaining the results of the HPV test first and calling for a reflex cytology result only if the specimen is HPV positive.

The rationale for this strategy is that the presence of high-risk HPV infection is necessary to develop CIN 3+ and therefore there is no need for a cytology test if the HPV test is negative. The HPV positivity rate in the general population varies between studies.

The results of 1 large US study using the cobas test found HPV positivity rates were higher (10.5%) than the baseline abnormal cytology rates (6.4%).²⁵ For now, the collection of cells is the same as for cytology or cotesting.

Contact with the cervix, particularly the squamocolumnar junction, is not as critical for HPV testing as for cytology, and therefore self-collection by vaginal swab may become an option in the foreseeable future to determine who needs further evaluation.²⁶

Current guidelines call for the triage of positive primary HPV results by reflex cytology testing; the paired results inform management decisions.^27-29 Reflex testing with more precise technology for predicting the presence of CIN 3+ risk may replace cytology triage using candidates such as p16/Ki67 dual staining.^30-32

HPV: Evidence behind the evolution

Findings from numerous large, randomized, controlled trials have established that HPV-based testing improves screening sensitivity compared with cytology, increasing the detection of CIN 3+ in the first round of screening by a factor of 2 to 3.³³

The absence of high-risk HPV is associated with lower risks of developing CIN 3+ over longer intervals than is negative cytology screening.^18,19,34-36

A large, randomized US trial compared the 3 current screening strategies in women 25 years and older. The sensitivities for the detection of CIN 3+ were cytology, 48%; cytology changing to cotesting at age 30, 62%; and primary HPV testing, 76%.²⁵

This increased sensitivity of HPV-based testing comes at the cost of decreased specificity and increased referrals for colposcopy. Also, over-referral can lead to treatment of mild and moderate severity lesions that may regress spontaneously. It is important to manage abnormal results according to risk-based management guidelines that seek to avoid overtreatment.²⁸

Another argument in support of HPV-based testing is the relative and absolute increase in cervical adenocarcinoma incidence in the United States and elsewhere over recent decades, despite cervical cancer screening.^37,38 Adenocarcinomas now make up 20% to 30% of cervical cancers.⁵

This implies that cytology screening identifies squamous lesions vs glandular ones with greater sensitivity and perhaps that identification of squamous precursors is more effective in cancer prevention than the identification of adenocarcinomas in situ. It is hoped that HPV-based screening will be more sensitive than cytology for identifying cervical adenocarcinoma in situ and adenocarcinomas.

Although evidence shows that HPV-based testing offers advantages over cytology-based screening, there is debate as to whether cotesting is preferable to primary HPV testing; the basis of debate is over sensitivity.³⁹ The concept of cervical cancer screening without cytology can be unfamiliar and unsettling to patients and providers alike.

However, the incidence of HPV-negative but cytology-abnormal tests preceding cervical precancer and cancer is a relatively rare event; it is estimated the cytology component of cotesting would prevent 5 cervical cancers per 1 million women per year.⁴⁰

This small gain comes at a considerable cost, doubling the number of tests performed and adding considerable expense and resource utilization, not to mention leading to the diagnosis and overtreatment of lesser lesions.

No screening program is expected to diagnose or prevent every case of the target disease, and attempting do so, particularly in the case of cervical cancer, would be cost-prohibitive
and misguided.⁴¹

It should be remembered that HPV vaccination will continue to decrease the prevalence of vaccine-type oncogenic HPVs in the general population over time. As precursor lesions and cervical cancers become rarer, false-positive cytologic abnormalities will become more common and cytology screening will become even less efficient.

Current guidelines

The most recent cervical cancer screening guidelines come from the United States Preventive Services Task Force (USPSTF)¹⁴ and the American Cancer Society (ACS).³ The American College of Obstetricians and Gynecologists, on behalf of other stakeholder organizations, has issued a statement endorsing the USPSTF guidelines (Table 2).¹⁵

Both major guidelines endorse all 3 screening options (cytology, cotesting, and primary HPV testing) for individuals 30 years and older. There are 2 major differences between them, however.

First, the USPSTF continues to recommend that screening start at age 21, whereas the ACS now recommends delaying the initiation of screening to age 25, beacuase of the rarity of cervical cancer below this age and the potential for overtreatment of lesions destined to spontaneously regress.

Second, the USPSTF recommends that individuals aged 21 to 29 years be screened with cytology every 3 years because of the higher rate of HPV positivity in this age group; thereafter, any of the 3 screening modalities can be used, with shared decision-making encouraged.

The ACS recommends primary HPV testing every 5 years as the preferred screening modality from age 25 on; if primary HPV testing is not yet clinically available, screening with cotesting every 5 years or cytology every 3 years is acceptable.

The ACS recommends phasing out cytology and cotesting as soon as primary HPV testing can be implemented. The rationale for primary HPV testing supplanting cytology is its greater sensitivity for detecting current CIN 3+ and superior reassurance that CIN 3+ will not develop over the next 5 years compared with a negative cytology.

The ACS acknowledges that very few settings are ready for this transition in terms of laboratory infrastructure.

Conclusion

Preventing cervical cancer is a process. Primary prevention with HPV vaccination and secondary prevention with effective screening remain the priorities. As vaccine uptake increases, cytology screening is expected to become less efficient. Cervical cancer screening will continue to evolve along with our understanding of HPV biology and technological advances.

Ultimately, a highly accurate and cost-effective test with streamlined triage and management of abnormal results will translate into the best outcomes for most individuals. Clinical guidelines are shifting from cytology to HPV-based testing, with primary HPV testing presenting the most advantageous balance between sensitivity, specificity, and cost.

During this time of transition, it should be remembered that the best strategy is to screen as many women as possible using any of the 3 strategies approved by current clinical guidelines.

References

1. Koss LG. The Papanicolaou test for cervical cancer detection: a triumph and a tragedy. JAMA. 1989;261(5):737-743. doi:10.1001/jama.1989.03420050087046
2. zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer. 2002;2(5):342-350. doi:10.1038/nrc798
3. Fontham ETH, Wolf AMD, Church TR, et al. Cervical cancer screening for individuals at average risk: 2020 guideline update from the American Cancer Society. CA Cancer J Clin. 2020;70(5):321-346. doi:10.3322/caac.21628
4. Meites E, Szilagyi PG, Chesson HW, Unger ER, Romero JR, Markowitz LE. Human papillomavirus vaccination for adults: updated recommendations of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep. 2019;68(32):698-702. doi:10.15585/mmwr.mm6832a3
5. 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. doi:10.1093/jnci/dji115
6. Pruitt SL, Werner CL, Borton EK, et al. Cervical cancer burden and opportunities for prevention in a safety-net healthcare system. Cancer Epidemiol Biomarkers Prev. 2018;27(12):1398-1406. doi:10.1158/1055-9965.EPI-17-0912
7. Singh GK, Jemal A. Socioeconomic and racial/ethnic disparities in cancer mortality, incidence, and survival in the United States, 1950-2014: over six decades of changing patterns and widening inequalities. J Environ Public Health. 2017;2017:e2819372. doi:10.1155/2017/2819372
8. Yu L. Rural–urban and racial/ethnic disparities in invasive cervical cancer incidence in the United States, 2010–2014. Prev Chronic Dis. 2019;16:E70. doi:10.5888/pcd16.180447
9. Arbyn M, Bergeron C, Klinkhamer P, Martin-Hirsch P, Siebers AG, Bulten J. Liquid compared with conventional cervical cytology: a systematic review and meta-analysis. Obstet Gynecol. 2008;111(1):167-177. doi:10.1097/01.AOG.0000296488.85807.b3
10. Siebers AG, Klinkhamer PJJ, Grefte JMM, et al. Comparison of liquid-based cytology with conventional cytology for detection of cervical cancer precursors: a randomized controlled trial. JAMA. 2009;302(16):1757-1764. doi:10.1001/jama.2009.1569
11. de Sanjose S, Quint WG, Alemany L, et al; Retrospective International Survey and HPV Time Trends Study Group. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 2010;11(11):1048-1056. doi:10.1016/S1470-2045(10)70230-8
12. Bosch FX, de Sanjosé S. Human papillomavirus in cervical cancer. Curr Oncol Rep. 2002;4(2):175-183. doi:10.1007/s11912-002-0079-y
13. Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2005;97(14):1072-1079. doi:10.1093/jnci/dji187
14. US Preventive Services Task Force, Curry SJ, Krist AH, et al. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;320(7):674-686. doi:10.1001/jama.2018.10897
15. Updated cervical cancer screening guidelines. American College of Obstetricians and Gynecologists. April 2021. Accessed November 1, 2021. https://www.acog.org/en/clinical/clinical-guidance/practice-advisory/articles/2021/04/updated-cervical-cancer-screening-guidelines
16. Sawaya GF, Smith-McCune K, Kuppermann M. Cervical cancer screening: more choices in 2019. JAMA. 2019;321(20):2018-2019. doi:10.1001/jama.2019.4595
17. Sawaya GF, Sanstead E, Alarid-Escudero F, et al. Estimated quality of life and economic outcomes associated with 12 cervical cancer screening strategies: a cost-effectiveness analysis. JAMA Intern Med. 2019;179(7):867-878. doi:10.1001/jamainternmed.2019.0299
18. 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):dju153. doi:10.1093/jnci/dju153
19. Dillner J. Primary human papillomavirus testing in organized cervical screening. Curr Opin Obstet Gynecol. 2013;25(1):11-16. doi:10.1097/GCO.0b013e32835c5d10
20. Dijkstra MG, van Zummeren M, Rozendaal L, et al. Safety of extending screening intervals beyond five years in cervical screening programmes with testing for high risk human papillomavirus: 14 year follow-up of population based randomised cohort in the Netherlands. BMJ. 2016;355:i4924. doi:10.1136/bmj.i4924
21. Elfström KM, Smelov V, Johansson ALV, et al. Long term duration of protective effect for HPV negative women: follow-up of primary HPV screening randomised controlled trial. BMJ. 2014;348:g130. doi:10.1136/bmj.g130
22. Ogilvie GS, van Niekerk D, Krajden M, et al. Effect of screening with primary cervical HPV testing vs cytology testing on high-grade cervical intraepithelial neoplasia at 48 months: the HPV focal randomized clinical trial. JAMA. 2018;320(1):43-52. doi:10.1001/jama.2018.7464
23. Saslow D, Solomon D, Lawson HW, et al; 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(3):147-172. doi:10.3322/caac.21139
24. Practice Bulletin No. 168: cervical cancer screening and prevention. Obstet Gynecol. 2016;128(4):e111-e130. doi:10.1097/AOG.0000000000001708
25. 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):189-197. doi:10.1016/j.ygyno.2014.11.076
26. Arbyn M, Smith SB, Temin S, Sultana F, Castle P; Collaboration on Self-Sampling and HPV Testing. Detecting cervical precancer and reaching underscreened women by using HPV testing on self samples: updated meta-analyses. BMJ. 2018;363:k4823. doi:10.1136/bmj.k4823
27. Huh WK, Ault KA, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Obstet Gynecol. 2015;125(2):330-337. doi:10.1097/AOG.0000000000000669
28. Perkins RB, Guido RS, Castle PE, et al; 2019 ASCCP Risk-Based Management Consensus Guidelines Committee. 2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2020;24(2):102-131. doi:10.1097/LGT.0000000000000525
29. Updated guidelines for management of cervical cancer screening abnormalities. American College of Obstetricians and Gynecologists. October 2020. Accessed November 1, 2021. https://www.acog.org/en/clinical/clinical-guidance/practice-advisory/articles/2020/10/updated-guidelines-for-management-of-cervical-cancer-screening-abnormalities
30. Wentzensen N, Schiffman M, Palmer T, Arbyn M. Triage of HPV positive women in cervical cancer screening. J Clin Virol. 2016;76(suppl 1):S49-S55. doi:10.1016/j.jcv.2015.11.015
31. Clarke MA, Cheung LC, Castle PE, et al. Five-year risk of cervical precancer following p16/Ki-67 dual-stain triage of HPV-positive women. JAMA Oncol. 2019;5(2):181-186. doi:10.1001/jamaoncol.2018.4270
32. Stoler MH, Baker E, Boyle S, et al. Approaches to triage optimization in HPV primary screening: extended genotyping and p16/Ki‐67 dual‐stained cytology—retrospective insights from ATHENA. Int J Cancer. 2020;146(9):2599-2607. doi:10.1002/ijc.32669
33. Melnikow J, Henderson JT, Burda BU, Senger CA, Durbin S, Weyrich MS. Screening for cervical cancer with high-risk human papillomavirus testing: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2018;320(7):687-705. doi:10.1001/jama.2018.10400
34. Gilham C, Sargent A, Kitchener HC, Peto J. HPV testing compared with routine cytology in cervical screening: long-term follow-up of ARTISTIC RCT. Health Technol Assess. 2019;23(28):1-44. doi:10.3310/hta23280
35. Ronco G, Giorgi-Rossi P, Carozzi F, et al; New Technologies for Cervical Cancer screening Working Group. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncol. 2010;11(3):249-257. doi:10.1016/S1470-2045(09)70360-2
36. Ogilvie GS, Krajden M, van Niekerk D, et al. HPV for cervical cancer screening (HPV FOCAL): complete round 1 results of a randomized trial comparing HPV-based primary screening to liquid-based cytology for cervical cancer. Intl J Cancer. 2017;140(2):440-448. doi:10.1002/ijc.30454
37. Sherman ME, Wang SS, Carreon J, Devesa SS. Mortality trends for cervical squamous and adenocarcinoma in the United States: relation to incidence and survival. Cancer. 2005;103(6):1258-1264. doi:10.1002/cncr.20877
38. Smith HO, Tiffany MF, Qualls CR, Key CR. The rising incidence of adenocarcinoma relative to squamous cell carcinoma of the uterine cervix in the United States--a 24-year population-based study. Gynecol Oncol. 2000;78(2):97-105. doi:10.1006/gyno.2000.5826
39. Perkins RB, Austin RM, Zhao C, Saslow D, Massad LS. What role should cytology play in cervical cancer screening? J Low Genit Tract Dis. 2019;23(3):205-209. doi:10.1097/LGT.0000000000000479
40. Schiffman M, Kinney WK, Cheung LC, et al. Relative performance of HPV and cytology components of cotesting in cervical screening. J Natl Cancer Inst. 2018;110(5):501-508. doi:10.1093/jnci/djx225
41. Castle PE. When less is more. J Natl Cancer Inst. 2016;109(2):djw240. doi:10.1093/jnci/djw240