Cervical cancer is the third most prevalent cancer in women around the world, and the fourth highest cause of women's cancer-related deaths.1 In the U.S., the advent of Pap testing has had a tremendous impact on cervical cancer rates—dropping it from the number 1 cause of death in women to number 14.2 Still, 4,220 women in the U.S. die of cervical cancer each year,2 even though it is a theoretically preventable disease.
The link between cervical cancer and human papillomavirus (HPV) has become clear over the past few decades—today we know that persistent infection with specific types of HPV account for nearly all cases of cervical cancer.2
Because cervical cancer rarely causes overt symptoms in its early stages—when treatment is most effective—screening for HPV infections at the greatest risk of progressing to cervical pre-cancer and cancer is imperative.
What Is HPV?
The most commonly diagnosed sexually transmitted infection in the United States, HPV is most often spread through sexual intercourse, although it can be transmitted via nonpenetrative sexual activity as well.3
HPV is a small, double-stranded DNA virus that affects epithelial cells such as skin and mucous membranes. There are more than 100 HPV genotypes, about 30 of which are sexually transmitted. Most HPV strains are harmless, at worst causing warts on the hands, feet and other parts of the body. A handful of high-risk types, however, cause infections that can develop into cervical cancer.
Incidence of HPV
Approximately 42% of women between the ages of 14 and 59 in the U.S. are likely to be infected with HPV at any time, with higher rates for women under 25, minorities and those with multiple partners.4 HPV infection is also common among men—studies show prevalence greater than 20% in heterosexual men.3 Estimates suggest that 20 million people in the U.S. are currently infected, with 6.2 million new cases occurring each year.3
It's important to note that while HPV incidence is high, most infections resolve spontaneously.3 Only 10% of women who are infected with HPV develop a persistent infection.5
Low-Risk and High-Risk HPV Genotypes
HPV types have been categorized as high- or low-risk, based on whether they are associated with cervical cancer.
Of more than 100 known types, most HPV types have been categorized as low-risk and are rarely associated with cervical cancer.6 Low-risk types 6 and 11, for example, cause 90% of genital warts and have not been associated with the development of cervical cancer.3
However, 14 high-risk HPV types are detected in nearly 100% of cervical cancers.2,3 Of these, two types are associated with 70% of cervical cancers.3 Type 16 causes approximately 55% to 60% of cervical cancer cases, and type 18 accounts for 10% to 15%.2 What's more, type 16 accounts for a disproportionately high 10% of HPV infections.3
Progression to Cervical Cancer
While most HPV infections resolve on their own, some infections with high-risk HPV types can progress to low-grade cervical intraepithelial neoplasia (CIN1) within a few years of infection. Some persistent HPV infections can progress directly to high-grade CIN2, in which moderately abnormal cells are found within the cervical epithelium, or CIN3 – the immediate precursor for cervical cancer – in which abnormal cells are found throughout all layers of the cervical epithelium. It is important to note that it is possible for lesions to resolve and the infection to clear at all stages of CIN, although higher-grade CIN cases are less likely to regress.3
If left untreated, CIN2 or CIN3 can progress to cervical cancer years or decades after the initial infection. 6
Squamous cell carcinoma accounts for about 76% of cervical cancers, and is found along the thin, flat squamous cells that form the basal layer of the cervical epithelium. Most squamous cell carcinomas occur in the transformation zone where squamous and glandular cells meet.8 The remaining 24% of cervical cancers include adenocarcinomas, which occur in the glandular cells that line the endocervical canal, and adenosquamouscarcinomas, which affect both squamous and glandular cells.9
HPV16 and HPV18 are the two most common genotypes associated with both squamous cell carcinomas and adenocarcinomas, although HPV18 may have a stronger associated with the latter. 10
Examining incidence of cervical cancer over time has shown that only squamous cell carcinoma is decreasing. Because adenocarcinoma occurs primarily in the glandular cells which are not routinely sampled in Pap testing, cytology has been relatively ineffective in decreasing the incidence of adenocarcinoma.2
Effectiveness of Cancer Screening
Audits of the U.S. and Swedish cervical screening programs found that the majority of women diagnosed with cervical cancer had not been screened within the previous 10 years.11,12 This clearly highlights the need for increased participation in screening programs. Additionally, 7% to 13% of cervical cancer cases can be attributed to inadequate follow-up after an abnormal cytology result, demonstrating the need for physician education on guidelines and patient management.11,12
However, in the U.S. study, 32% of women diagnosed with cervical cancer had a recent cytology screen, which had been reported as negative.11 In the Swedish study, 24% of women diagnosed with cervical cancer had recent negative cytology results.12
Other estimates suggest that cytology alone can miss precancerous cervical cells in approximately 50% of women in a single round of screening.13 Due to this limitation, screening with Pap cytology alone relies on frequent testing.
Early treatment at the precancer stage is critical because in this stage, high-grade lesions and cervical cancers confined to the cervix can be completely excised, and the cure rate reaches as high as 98%.8 If cervical cancer is detected and treated before it has spread, the 5-year survival rate is approximately 90%. However, if cancer has spread to the regional lymphnodes, the survival rate drops to about 57%. Once cervical cancer has extended beyond the cervix to distant organs, only about 16% of women survive beyond 5 years.15
Because cytology is known to have limited sensitivity6 and relies on subjective classifying borderline cytological abnormalities, it is possible that some women at risk of having or developing cervical pre-cancer may be overlooked for further testing and early intervention.
Value of HPV DNA testing in Preventing Cervical Cancer
The adoption of testing for high-risk HPV types has allowed clinicians to identify women at highest risk of cervical cancer more accurately and earlier in the progression of the disease.
Cytology, while valuable, merely detects abnormal cellular changes which may be the consequences of HPV infection or possibly inflammation.6 HPV DNA testing is less subjective and more sensitive in detecting precancerous lesions than cytology alone, particularly for the detection of adenocarcinoma precursors.
In a systematic evidence review of randomized studies conducted for the U.S. Preventive Services Task Force, HPV DNA testing was found to demonstrate an average of 35.7% greater sensitivity than cytology in the detection of CIN2 or CIN3.14
Based on these data, it should come as no surprise that the potential benefits of HPV DNA testing have been recognized in the U.S. guidelines, to help clinicians identify and triage women at the highest immediate risk of high-grade cervical disease. Current guidelines recommend that all women 21 years and older with ASC-US cytology be tested for high-risk HPV, and that only those women with ASC-US who are high-risk HPV positive be referred to colposcopy. Also, in women 30-65 years old, co-testing using the combination of Pap cytology plus HPV DNA testing is the preferred cervical cancer screening method.
As the fundamental goal of cervical cancer screening is to prevent morbidity and mortality from cervical cancer, the ideal screening strategy should be to identify cervical cancer precursors likely to progress to invasive cancers, while minimizing unnecessary treatment for low-risk types. Today's guidelines aim to do that, while balancing varying levels of risk for women of different ages and encouraging clinicians to make recommendations based on individual patient histories.
1. HPV and Cervical Cancer in the World—2007 Report. Vaccine. 2007;25(3): 147-172. Available at: http://www.who.int/hpvcentre/publications/HPVReport2007.pdf. Accessed September 6, 2012.
2. 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. CA: A Cancer Journal for Clinicians. 2012;62(3): 147-172. Available at: http://onlinelibrary.wiley.com/doi/10.3322/caac.21139/full. Accessed September 6, 2012.
3. Centers for Disease Control and Prevention. Human papillomavirus: Epidemiology and prevention of vaccine-preventable diseases. Available at: http://www.cdc.gov/vaccines/pubs/pinkbook/hpv.html. Accessed September 7, 2012.
4. Hariri S, Unger ER, Sternberg M, et al. Prevalence of genital human papillomavirus among females in the United States, the National Health and Nutrition Examination Survey, 2003–2006. J Infect Dis. 2011; 204(4):566-73. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21791659. Accessed September 6, 2012.
5. Wright T. Natural history of HPV infections. J Fam Pract. 2009. Available at: http://www.jfponline.com/Pages.asp?AID=7892. Accessed September 7, 2012.
6. Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. J Clin Sci. 2006; 110:525-41. Available at: http://www.clinsci.org/cs/110/0525/1100525.pdf. Accessed September 7, 2012.
7. Munoz N, Bosch FX, Castellsague X, et al. Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer. 2004; 111:278-85. Available at: http://www-lab.biomedicas.unam.mx/smpv/international%20journal%20cancer.pdf. Accessed September 7, 2012.
8. Burd E. Human papillomavirus and cervical cancer. Clin Microbiol Rev. 2003; 16(1):1-17. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC145302/. Accessed September 7, 2012.
9. Herbert A, Anshu, Gregory M, Gupta SS, Singha N. Invasive cervical cancer audit: a relative increase in interval cancers while coverage increased and incidence declined. BJOG. 2009; 115(6):845-53. Available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1471-0528.2008.01990.x/pdf. Accessed September 7, 2012.
10. Bosch FX, Sanjose S. Chapter 1: Human papillomavirus and cervical cancer—burden and assessment of causality. JNCI Monographs. 2003; 2003(31):3-13. Available at: http://jncimono.oxfordjournals.org/content/2003/31/3.full. Accessed September 7, 2012.
11. Leyden W, 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; 97:675-83. Available at: http://jnci.oxfordjournals.org/content/97/9/675.full. Accessed September 7, 2012.
12. Adrae B, Kemetli L, Sparen P, et al. Screening-preventable cervical cancer risks: evidence from a nationwide audit in Sweden. J Natl Cancer Inst. 2008; 100:622-29. Available at: http://jnci.oxfordjournals.org/content/100/9/622.full. Accessed September 7, 2012.
13. Sasieni PD, Cuzick J, Lynch-Farmery E; The National Coordinating Network for Cervical Screening Working Group. Estimating the efficacy of screening by auditing smear histories of women with and without cervical cancer. Br J Cancer. 1996;73:1001-1005. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2075813/pdf/brjcancer00036-0131.pdf. Accessed September 8, 2012.
14. Whitlock EP, Vesco KK, Eder M, Lin JS, Senger CA, Burda BU. Liquid-based cytology and human papillomavirus testing to screen for cervical cancer: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155(10):687-697. Available at: http://www.uspreventiveservicestaskforce.org/uspstf11/cervcancer/cervcancerupd.htm. Accessed September 8, 2012.
15. National Cancer Institute. SEER stat fact sheets: cervix uteri. Available at: http://seer.cancer.gov/statfacts/html/cervix.html. Accessed September 8, 2012.