Cervical Cancer and HPV

Infection with human papillomavirus (HPV) is common in the United States, with approximately 24.9 million women currently infected¹ and an estimated 6.2 million new infections diagnosed annually.² In recent years, it has become clear that oncogenic HPV is a necessary cause of cervical cancer; HPV is found in 99.7 percent of all cervical cancer cases.^3,4 An estimated 11,070 new cases of cervical cancer will have been diagnosed in the United States in 2008, and based on the number of deaths, it is estimated that one woman will die from the disease every 2.5 hours.⁵ Additionally, the burden of cervical disease in the United States extends to precancerous lesions, since a woman is diagnosed with a high-grade precancerous lesion every minute.⁶

HPV and Cervical Cancer

Fifteen oncogenic HPV types infect the genital mucosa; the most common types in the United States are HPV 16, 18, 31, 45 and 52.⁷ These HPV types are present in 85% of cervical cancers (Figure 1).⁷ HPV 16 (one of the A9 species of genetically related HPV types) shares 71 to 89 percent identity with types 31 and 52. Similarly, HPV 18 (one of the A7 species of genetically related HPV types) is genetically related to type 45.⁸

Squamous cell carcinoma is the most common type of cervical cancer^,7,9 and 55 percent of squamous cell carcinoma cases are due to infection with HPV 16 (Figure 2A).⁷ HPV 18 and 45 also are important because of their increased contribution to adenocarcinoma, an aggressive and difficult to detect type of cervical cancer comprising about 20 percent of cervical cancer cases.^7,9 HPV 18 accounts for approximately 37 percent of adenocarcinoma cases, while HPV 45 is found in another 7 percent of adenocarcinoma cases (Figure 2B).⁷

Women with persistent oncogenic virus infections--two consecutive positive HPV-DNA tests within six or 12 months--are at significantly increased risk for developing cervical precancerous lesions and cervical cancer.¹⁰ Women with evidence of a persistent infection with the same oncogenic HPV type over approximately 24 months are at an 800-fold greater risk of developing a high-grade cervical abnormality.¹¹

Precancerous lesions are diagnosed histologically by a pathologist as cervical intraepithelial neoplasia (CIN). CIN 1 is mild dysplasia, whereas CIN 2 and 3 refer to moderate and severe dysplasia, respectively.^12,13 CIN 2 often is used as a clinical marker for disease progression, because these lesions are typically therapeutic targets. Approximately 5 percent of CIN 2 lesions progress to invasive cancer.¹⁴

Since the implementation in 1949 of the conventional Papanicolaou (Pap) test, the primary screening method for precancerous lesions and cervical cancer, the incidence of cervical cancer and associated mortality has decreased by approximately 70 percent.⁶ Liquid-based Pap testing today is used by approximately 80 percent of physicians, and this method has been shown to have increased specificity and sensitivity for detecting precancerous lesions.^15-17 Adenocarcinoma precursor lesions are located high in the endocervix, making it difficult to obtain a specimen of exfoliated cells. Consequently, HPV-associated adenocarcinomas often are missed by routine screening.^18-20 Although vaccines for cervical cancer are expected to prevent at least 70 percent of cervical cancers, screening will continue to be essential as a secondary preventive measure; current recommendations remain unchanged despite the availability of vaccines.

In order to decrease the incidence of oncogenic HPV infection and cervical cancer, education of healthcare providers about the prevalence of HPV and the sequelae of oncogenic HPV infection is needed. PAs and other health care providers are instrumental in improving women's health through education and careful routine examinations. Additionally, increased knowledge among healthcare providers will lead to more-informed patients and an overall better understanding of oncogenic HPV and cervical cancer.

Epidemiology

Results from international studies have shown that women of any age can become infected with oncogenic HPV.²¹ In the United States, epidemiologic analysis has estimated that 80 percent of women will become infected with the virus by the age of 50.² The overall prevalence of infection with HPV among females aged 14 to 59 years is 26.8 percent; 15.2 percent of these infections are from an oncogenic HPV virus type. There is a 20.3 percent increase in the prevalence of HPV infection between females aged 14 to 19 (24.5 percent) and 20 to 24 (44.8 percent) years. HPV prevalence peaks in women aged 20 to 24 years and begins to decrease thereafter (Figure 3).¹ A study conducted by the Centers for Disease Control and Prevention (CDC) found that 45.7 percent of high school females have had sexual intercourse; 3.7 percent had sexual intercourse before age 13 (Figure 4).²² These data may reflect the high prevalence of HPV infection observed in females aged 14 to 19 years.

Although HPV prevalence is higher among younger women, women of all ages are at risk for acquiring HPV infection. Grainge and colleagues showed three-year acquisition rates for infection with HPV 16 and 18 were similar (3.0 to 3.7 percent and 2.5 to 5.3 percent, respectively) in women aged 21 to 51 years in the United Kingdom. This suggests that HPV-negative women older than 50 can acquire HPV.²³ It was postulated that these data may reflect new sexual contacts later in life, changes in sexual practices or the reemergence of latent HPV infections acquired earlier in life as a result of changes in the cervix from menopause or hormone replacement therapy.²³ The potential for infection with oncogenic HPV in older women suggests that all women should be considered candidates for vaccination against cervical cancer.

Burden of Disease

A substantial economic burden is associated with HPV infections and the occurrence of precancerous lesions and cervical cancer. In the United States, 65 million Pap tests are performed annually, of which approximately 3.7 million are abnormal.^24,25 An abnormal Pap test results in an estimated 3.5 physician follow-up visits over approximately 9.6 months.²⁶

In 2005, the estimated direct costs associated with cervical precancerous lesions were $1.5 billion; this includes costs attributed to genital warts, CIN 1, 2 and 3 lesions and cervical cancer but does not include the costs of other abnormal Pap test results or false-positives.²⁷ The estimated direct costs in 2001, when accounting for all cervical cancer screening abnormalities, were $3.9 billion.28,29 Importantly, more than 60 percent of the total economic burden of cancer is related to indirect costs associated with morbidity and mortality.³⁰ For example, as a result of mortality from cervical cancer, approximately $1.3 billion in productivity was lost in 2001.³¹

HPV infections also affect women's quality of life, including emotional, social and sexual functioning.^32,33 Abnormal screening results and/or a diagnosis of CIN or cervical cancer can have adverse effects such as stress and anxiety.^34,35 In addition, premature death related to cervical cancer affects women and their families, since these women lose approximately 26 years of life.³⁶

The incidence of cervical cancer is higher in certain underserved populations, such as Hispanics, African Americans and Asian Americans. These ethnic groups account for approximately 30% of the total U.S. population.^37,38 Studies show an increased incidence of cervical cancer risk within these populations.³⁶ By 2050, it is estimated that Hispanics, Africa percent Americans and Asian Americans will account for nearly 50 percent of the population,³⁸ thereby possibly increasing the burden of cervical cancer in the United States.