Vaccination against the human papillomavirus (HPV) strains that increase cervical cancer risk are expected to reduce cervical cancer rates in decades to come. For the time being, screening and early detection remain crucial fronts in cancer control.
Early detection with Pap tests and liquid-based cytology has dramatically reduced mortality rates, and newer HPV DNA testing for high-risk lesions promises to lower those rates even further. The past year has seen the release of new research and screening guidelines for cervical cancer, as well as emerging screening technologies and strategies.
Less than a decade after widespread HPV vaccination began in the United States, and despite relatively low vaccination rates (eg, 23% among women aged 18 to 26)1, a new study suggests public health benefits might already be discernable.2 The study reports significant trends toward declining rates of high-grade cervical lesions and adenocarcinoma in situ among women between the ages of 21 and 39 since the initiation of vaccination efforts.2
The full benefits of HPV vaccination against high-risk HPV subtypes aren’t expected to fully materialize for several years; however, a wave of new revisions to cervical cancer screening guidelines since the vaccines’ approval represents an important evolution in cervical cancer control efforts.
In the past year and a half alone, the Cochrane Gynaecological Cancer Group has published a new meta-analysis of HPV testing versus repeat cytology, and the United States Preventive Services Task Force (USPSTF), American Congress of Obstetricians and Gynecologists (ACOG), the American Cancer Society (ACS), and other organizations have all revised their screening guidelines.3-8
These new guidelines include a reduced reliance on Pap results and increased reliance on Pap and HPV DNA testing (“co-testing”), among other important changes. The changes might well improve patient participation rates, thanks to reduced recommended number and frequency of screenings, as well as increased patient convenience.9
• Girls and women younger than 21 years of age should not undergo cervical cancer screening.
• Except for immunocompromised women, no woman, regardless of age, should undergo annual screening, either with Pap tests or HPV DNA tests.
• Cervical cancer screening should begin at age 21, regardless of risk factors, with women age 21 to 29 undergoing cytology (conventional Pap smears or liquid-based cytology) every 3 years.
• HPV DNA testing should not be used among women younger than 30 years of age.
• Women between the ages of 30 and 65 should undergo screening every 5 years with cytology plus HPV testing (“co-testing”), but can also continue cytology-only screening every 3 years if they so choose.
• Women greater than 65 years of age, who have had three consecutive negative cytology tests or two consecutive 5-year cytology plus HPV DNA co-tests, and with the most recent test no more than 5 years before age 65, should stop undergoing screenings.
• No screening is indicated for women who have had the cervix or entire uterus removed and who do not have any history of cervical intraepithelial neoplasia 2 (CIN2) or more severe diagnosis.
• Women with a history of CIN2 or more severe should undergo screening for at least 20 years, even beyond 65 years of age.
• Immunocompromised women (eg, those undergoing cancer chemotherapy, organ transplantation, or who are HIV-positive) should undergo screening twice during the first year after diagnosis, and then annually.
The ACS consensus recommendations, which were released jointly with those of the American Society of Colposcopy and Cervical Pathology and the American Society of Clinical Pathologists, include HPV DNA testing and extend testing intervals for many women.7,9
The joint-consensus ACS screening guidelines, however, make different recommendations for women based on their age and potential risk factors (summarized in the box below).
On the other hand, the USPSTF recommendations are similar to the ACS guidelines. USPSTF recommends Pap-test cervical cancer screening among women between the ages of 21 and 65 every 3 years or every 5 years alongside HPV DNA testing for women age 30 to 65 years.6
The USPSTF recommendations discourage screening among women younger than 21 years of age; women who have had hysterectomies with cervix removal and who have no history of high-grade precancerous lesions or cervical cancer; or women aged greater than 65 years who “had adequate prior screening and are not otherwise at high risk for cervical cancer.”6
New and Emerging Screening Technologies
Despite its higher sensitivity, one criticism of HPV DNA testing has been that such testing has appeared to have lower specificity than older screening modalities because it fails to distinguish transient from chronic infections.10 Transient HPV infections are not associated with cancer risk.10
A systematic review published in March 2013 by the Cochrane Gynaecological Cancer Group found that HPV (hybrid capture 2, HC2) assay testing with women who exhibit atypical squamous cells of undetermined significance can be recommended because it has higher sensitivity and “similar specificity” compared with repeat cytology.5 Yet, among women with low-grade squamous intraepithelial lesions (LSILs), the authors found that HC2 testing specificity was significantly lower than that seen for repeat cytology.5
“If HPV testing is to reach its full potential, new approaches with better specificity are needed,” said Jack Cuzick, PhD, at Queen Mary University of London, United Kingdom, and colleagues.
Direct detection tests for HPV E6 and E7 proteins are under development, Dr. Cuzick and colleagues note.10 They also report that other surrogate biomarkers, such as the overexpression of cyclin-dependent kinase inhibitor p16INK4a, reveal oncoprotein transformations seen in the early stages of carcinogenesis and represent a promising diagnostic tool.10 Also anticipated are epigenetic (methylation) tests, which will allow detection of HPV methylation of host cell DNA or the methylation of the viral genome itself.10
Barriers to participation in cervical cancer screening programs also need to be addressed: the inability of working women to get time off for doctor visits, emotional issues and physical discomfort, and the lack of available female clinicians. 10 All of these factors may discourage women from obtaining the necessary cervical cancer screening.10While pamphlet- or instruction-aided patient self-sampling with a swab or tampon might improve participation rates in screening—and research suggests many women prefer self-sampling to clinician screening—such tests have not yet been formally approved for use.10,11
Vinegar As an Alternative to Pap and HPV DNA Screening
Indian researchers have identified a low-cost and surprisingly effective alternative: inspection by trained health workers, using a 4% acetic acid (vinegar) solution.12,13 This “naked-eye” visual-inspection technique is particularly useful in developing countries, where widespread implementation of Pap and HPV DNA testing is not economically feasible and where cervical cancer is the most frequently diagnosed cancer. This method could curb cervical cancer mortality by 31% in 15 years, concluded authors of the randomized study of 150,000 women in India during their plenary presentation at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL.12,13
The investigators randomly assigned women age 35 to 64 years with no cancer history to receive biennial visual inspections using 4% vinegar applied to the cervix or no screening. They found that despite similar incidence rates between the two groups, vinegar-screened women experienced a 31% reduction in cervical cancer-specific mortality (11.1 vs 16.2 per 100,000 women; mortality rate ratio [RR], 0.69; 95% CI: 0.54-0.88; P=0.003).12,13
This 1-minute screening method reliably identifies precancerous lesions and could prevent as many as 73,000 cervical cancer deaths worldwide each year, particularly in low-income countries, reported senior author Surendra Shastri, MD, of the Tata Memorial Center in Mumbai, India.12,13
Alongside improved visual detection strategies for medically under-served countries, vaccination and evolving molecular testing are poised to reduce the future global burden of cervical cancer. Clinical guidelines for screening will likely undergo regular revisions in the years to come, to keep pace with changes in diagnostic technologies.
1. Williams WW, Lu PJ, Saraiya M, et al. Factors associated with human papillomavirus vaccination among young adult women in the United States. Vaccine. 2013;31:2937-2946.
2. Niccolai LM, Julian PJ, Meek JI, et al. Declining rates of high-grade cervical lesions in young women in Connecticut, 2008-2011. Cancer Epidemiol Biomarkers Prev. 2013;22(8):1446-1450.
3. Karjane N, Chelmow D. New cervical cancer screening guidelines, again. Obstet Gynecol Clin N Am. 2013;40:211-223.
4. Hong JH, Lee JK. Updates on the current screening guidelines for the early detection of cervical cancer. J Gynecol Oncol. 2013; 24(3):212-214.
5. Arbyn M, Roelens J, Simoens C, et al. Human papillomavirus testing versus repeat cytology for triage of minor cytological cervical lesions. Cochrane Database Syst Rev. 2013;3:CD008054.
6. US Preventive Services Task Force (USPSTF). Clinical guideline: screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;156(112):880-891.
7. Smith RA, Brooks D, Cokkinides V, et al. Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervical cancer screening and lung cancer screening. CA: Cancer J Clin. 2013;63(2):87-105.
8. Saslow D, Solomon D, Lawson HW, et al. 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. J Lower Genit Tr Dis. 2012;16(3):1-29..
9. Chelmow D, Waxman A, Cain JM, Lawrence HC. The evolution of cervical screening and the specialty of obstetrics and gynecology. Obstet Gynecol. 2012;119(4):695-699.
10. Cuzick J, Bergeron C, Doeberitz MVK, et al. New technologies and procedures for cervical cancer screening. Vaccine. 2012;30(S):F107-F116.
11. Waller J, McCaffery K, Szarewski A, et al. Acceptability of unsupervised HPV testing by self-sampling using only written instructions. J Med Screen. 2006;16:193-198.
12. Shastri SS, Mittra I, Mishra G, et al. Effect of visual inspection with acetic acid (VIA) screening by primary health workers on cervical cancer mortality: A cluster randomized controlled trial in Mumbai, India. J Clin Oncol. 2013; 31(suppl; abstr 2)
13. Kay M. Screening with acetic acid could prevent 22,000 deaths from cervical cancer in India every year. BMJ. 2013;346:f3935.