HPV and cervical cancer

In the low-resource countries of the world, 700 women die every day from cervical cancer, leaving behind families and communities that depended on them. Cervical cancer is the second most common cancer in women worldwide and the leading cause of cancer deaths in women in developing countries. With screening, vaccination, and political willpower, cervical cancer can be prevented.^1–5

The worldwide burden

• Nearly 500,000 women are diagnosed with invasive cervical cancer every year.
• 275,000 women die every year.
• 80% to 85% of deaths occur in developing countries.
• The highest incidence and mortality rates are in sub-Saharan Africa, Latin America, and South/Southeast Asia (Figure 1).
• Most cervical cancer in developing countries occurs in women who take care of children, provide income for families, and work in their communities.
• Poor women in industrialized countries have a higher incidence of cervical cancer than their wealthier neighbors.

The opportunities

• Cervical cancer is caused by human papillomaviruses (HPV).^6,7 Safe and effective vaccines have been developed against the HPV types responsible for most of the cancers.
• These vaccines are now available for girls and young women; HPV vaccine has also been approved for boys in some countries (see information about vaccinating boys in the Vaccination strategies section).
• Screening adult women for cancer or precancer continues to be a vital strategy.
• Developing countries need strong and persistent advocates for cervical cancer screening and vaccination programs.

Human papillomavirus (HPV), the cause of cervical cancer

In recent years, investigators have found that some viruses cause cancer. Among these are the hepatitis B and C viruses, which cause liver cancer, and the Epstein-Barr virus, which is responsible for several forms of lymphoma. In the early 1980s, certain HPV types were identified as the cause of cervical cancer by zur Hausen and colleagues. HPV is associated with virtually all cervical cancers.⁸

Prevalence of HPV

Papillomaviruses are easily transmissible, highly prevalent, tissue-specific DNA viruses. In fact, HPV is the most common sexually transmitted infection. There is no treatment once a person acquires an HPV infection, but recently approved vaccines can prevent infection if given before sexual activity begins.

About 630 million people worldwide are believed to be infected with HPV.^6,9 In the United States, about 40% of young women become infected with HPV within three years of sexual debut, and globally, 50% to 80% of sexually active women are infected by HPV at least once in their lives.^10,11 Fortunately, in most cases, these infections clear through natural immune responses. The vast majority of HPV infections are transient, becoming undetectable with molecular assays after a period of 4 to 18 months.^12-14

Usually women contract HPV between their late teenage years and early 30s, with the peak of infection coinciding with the onset of sexual activity. Most often, cervical cancer is found much later, usually after age 40 (Figure 2), with peak incidence around age 45 and peak mortality in the late 50s. Thus, there is typically a long delay between infection and invasive cancer.^13,15,16 This is the reason that screening programs can be so effective, as discussed in the Screening and treatment section.

HPV types

Human papillomaviruses comprise a large family of viruses, with more than 100 types known.¹⁷ Some types have a high potential for causing cancer (high-risk types), whereas others have a lower potential (low-risk types).

• High-risk types cause most anogenital cancers.
• Low-risk types cause genital warts, abnormal cervical cytology, recurrent respiratory papillomatosis, or, most commonly, infections that go unnoticed and eventually clear up.⁶
• HPV 16 and 18 are two types of high-risk HPV associated with about 70% of all cases of cervical cancer.^16,18
• At least 11 other HPV types are also high risk. Among these, HPV 45 and 31 account for about 4% of cases each.

While types 16 and 18 are the most common cancer-causing types worldwide, their prevalence varies slightly in different geographic areas. For example, the combined HPV 16/18 prevalence in cervical cancer lesions is slightly higher in Europe, North America, and Australia (74 to 77%) than in Africa, Asia, and South/Central America (65 to 70%). The next most common HPV types are the same on each continent, namely HPV 31, 33, 35, 45, 52, and 58, although their relative importance differs by region.^16,18

Progression from HPV infection to cervical cancer

Cervical cancer begins with HPV infection of the cervix (see short video, "Cervical Cancer, Cervical Dysplasia, Genital Warts"). The cervix is the lower portion of the uterus; it connects the uterus with the vagina (Figure 3). The vagina and the lower part of the cervix are lined with flat (squamous) cells, while the inner surface of the canal to the uterus consists of tall column-like cells. (During a Papanicolaou or "Pap" test, some of the squamous cells are scraped off the surface of the cervix and examined.)

The area where the flat and columnar cells meet is called the transformation zone, and this area is particularly vulnerable to attack by HPV viruses. Both pre-cancer and cancer usually arise in the transformation zone, which is larger during puberty.³ In older women, the transformation zone is deeper inside the canal, and the epithelium is not as susceptible to infection.

Normally, the surface layers of the cervix die and slough off, with a controlled stream of new cells constantly forming and pushing upward from below, in a manner similar to skin renewal. With persistent HPV infection, however, this process is disrupted; cells from the lower layer continue multiplying as they move toward the surface, rather than maturing and eventually dying. They first become abnormal (precancerous), and after a time, they develop cancerous properties. When they invade the deep muscle and fibrous tissue, and then the organs surrounding the uterus, the patient has invasive cancer.

Most HPV infections clear up spontaneously, but 5 to 10% of women who encounter high-risk types develop persistent infections, and this can lead to precancerous changes called lesions.^18,19 Neither incident nor persistent infections have symptoms, so women must be screened periodically to see if lesions have developed. Some lesions resolve spontaneously, but others can progress to invasive cervical cancer (Figure 4). See the Screening and treatment section for further information.

Because progression from HPV infection to invasive cancer is slow, usually taking decades, cancer is seen more frequently in women in their 40s and 50s.^2,20-22

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Risk factors for developing cervical cancer after HPV infection

Most women are infected with a high-risk type of HPV at some time in their lives, but, as mentioned above, only a small portion develop cancer. Risk factors that may affect whether or not an infected woman develops cancer include the following:^2,17,23

• Early age at first sexual intercourse.
• Early age at first delivery.
• High number of pregnancies.
• Smoking.
• Failure to be screened and treated for precancerous lesions.
• Long-term use of hormonal contraceptives.
• Many sexual partners; high-risk partners.
• Infection with human immunodeficiency virus (HIV) or other sexually transmitted infections (e.g., herpes virus or Chlamydia trachomatis).
• Immunosuppression due to HIV, other diseases, chemotherapy, or other causes.

Because HPV, like HIV, is sexually transmitted, people sometimes assume that interventions effective in preventing HIV infection—such as using condoms and reducing the number of sexual partners—work just as well for HPV prevention. But this is not true, because HPV resides in the skin, not in body fluids, and the virus can be present in genital regions not covered by a condom sheath. Even when used correctly with every act of sexual conduct, condoms are only about 70% effective in preventing HPV.²⁴

For both men and women, the risk of contracting HPV infection is affected primarily by sexual activity; their own or that of their partners. But while risk of HIV infection increases dramatically as the number of sexual partners increases, the situation with HPV is more complex. HPV viruses are so prevalent that a recent US study found that the chance that a woman would contract HPV after her first sexual partner was nearly 30% in her first year of sexual activity and 50% within three years.²⁵

Thus it is very difficult to avoid HPV infection. If a person has more than one partner (concurrently or serially), the risk goes up. Further, people who have had many sexual partners, have other sexually transmitted infections, or are immunosuppressed are more likely to have active HPV infections and to transmit them.

Best methods for preventing cervical cancer

Cervical cancer can be prevented either by avoiding HPV infection, or by periodic monitoring (screening) for infection and lesions.

Preventing HPV infection

• Avoid exposure to the virus through abstinence from sexual activity or through mutual monogamy forever, provided both partners are consistently monogamous and were not previously infected (but this is not considered practical for most people).

• Get the HPV vaccine before beginning sexual activity. The new vaccines are discussed in the Vaccines against HPV section. These vaccines do not protect against all HPV viruses that can cause cervical cancer, so screening is still necessary.
  

Preventing development of invasive cancer through screening and treatment

• The most familiar method of cervical cancer screening worldwide is the Pap test, but new alternatives have been shown to be as effective, or more effective, than Pap, often at a lower cost. Tests for HPV DNA have become available and may become a more common way of screening for infection. Screening options are discussed in the Screening and treatment section. Because cervical cancer develops slowly, over years, regular screening, along with removal of any lesions, is very effective in preventing invasive cancer.

Photo: PATH/Richard Lord