Cervical Cancer Prevention: Liquid-Based Cytology and hr-HPV Co-testing Remain the Most Effective Cervical Cancer Screening Method

Cervical cancer is a preventable high risk human papilloma virus (hr-HPV)-associated disease. Its incidence has markedly plummeted since the introduction of the exfoliative cytology method also known as Pap Smear by Dr. George Papanicolaou in the 1940s. The introductions of ThinPrep liquid based cytology in the 1980s, and subsequently of testing for hr-HPV have contributed to this decline.  However, in the United States there are still approximately 12,000 women who develop cervical cancer every year and about one third of them succumb to the disease ¹. About half of all cervical cancers occur in women who have never been screened. Another 10% occur in women who haven’t been screened in the last 5 years². Thus, more work is needed to encourage preventive screening for cervical cancer.Guidelines have been promulgated by professional societies such as the American College of Obstetrics and Gynecology (ACOG) and the American Society of Colposcopy and Cervical Pathology (ASCCP),  and by the United States Preventive Services Task Force (USPSTF) for the method and frequency of screening for cervical cancer. The guidelines by ACOG³ are summarized in Table 1. Other guidelines are similar.Table 1: ACOG 2016 Cervical Cancer Screening Guidelines

Age (years)	Recommended Screening
<21	No screening
21 to 29	Pap test every 3 years
30 to 65	Pap test + hr-HPV co-testing every 5 years (preferred)or Pap test every 3 years
>65	No screening (if low cancer risk)a

^a 3 consecutive negative Pap tests or 2 consecutive negative co-tests within the last 10 years, with the most recent test within the past 5 years.From the above table, screening is not recommended for women who are younger than 21 in age and for those who are older than 65 and have had negative results for the last 10 years. In addition, co-testing with hr-HPV is not recommended in women who are younger than 30 years in age due to the fact that most HPV infections will spontaneously clear in this age group⁴.It is also recommended by guidelines⁵ that for women 21-29 years in age reflex testing for hr-HPV  should be performed if cytology screening indicates the presence of Atypical Squamous Cells of Undetermined Significance (ASCUS). If hr-HPV is present then referral to colposcopy is recommended; a negative result would indicate the need for repeat testing in 6-12 months.Recently, USPSTF, whose own guidelines have been similar to the ones above, has solicited input about a draft recommendation that permits screening in women 30 years or older with hr-HPV testing alone. This came on the heels of approval by FDA of one stand-alone method for this use. Input from Quest Diagnostics was submitted to discourage this suggestion pending further research. The USPSTF draft recommendation relied heavily on research from Europe and Canada with scant data from US population.  In our opinion, the best evidence still supports screening with Pap and hr-HPV together to provide the best protection against cervical cancer for women ages 30 to 65.  A recent study conducted by Quest Diagnostics⁶ by  retrospective review of  results from over 256,648 women in whom a biopsy was preceded by a Papanicolaou test and HPV test, HPV‐only testing missed 98 of 526 cervical cancers (18.6%), which is significantly more than what was missed by co-testing (29 cancers; 5.5%) (P <.0001).  This study supports co-testing as the most effective cervical cancer screening method for women aged 30 to 65 years as it is in the present guidelines.

1. https://www.cdc.gov/cancer/hpv/statistics/cervical.htm
2. The American College of Obstetricians and Gynecologists. Practice bulletin no. 140: management of abnormal cervical cancer screening test results and cervical cancer precursors. Obstet Gynecol. 2013;122:1338-1367.
3. The American College of Obstetricians and Gynecologists. Practice bulletin no. 168: cervical cancer screening and prevention. Obstet Gynecol. 2016;128:e111-e130.
4. Rodríguez AC, Schiffman M, Herrero R, et al. Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. J Natl Cancer Inst. 2008;100:513-517.
5. Massad, LS, Einstein MH, Huh WK, et al. 2012 Updated Consensus Guidelines for the Management of Abnormal Cervical Cancer Screening Tests and Cancer Precursors. Journal of Lower Genital Tract Disease. 2013: 17(5): S1-S27
6. 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 Cytopathol. 2015;123(5):282-288