HPV and Cervical Cancer
The Human Papilloma Virus
The Human Papilloma Virus (HPV) is one of the most common sexually transmitted infections (STI) in the world. It is estimated that 5.5 million people worldwide are infected annually. Sexually active individuals have an 80 to 85% chance of being infected at some time in their life.
The virus invades human epithelial cells (a type of skin cell), including the oral mucosa, esophagus (throat), larynx (voice box), trachea (airway), conjunctiva of the eye, and the anal and genital areas. The time between exposure to the virus and having any symptoms can be 3 to 4 months, yet the virus can be transmitted to someone else during this time (unbeknownst to either person). Although HPV is considered a sexually transmitted infection, this can be misleading. It is transmitted by skin to skin contact, therefore traditional methods of protecting oneself against an STI, such as condoms can reduce, but not eliminate the risk of HPV infection. Infection can occur through skin to skin genital contact without intercourse.
Persons at higher risk for HPV infection include those with numerous lifetime sexual partners (the higher the number, the higher the risk), early age of first intercourse, history of other STIs, alcohol and drug use related to sexual behaviors, and partner's number of sexual partners.
The infection is most prevalent in women in the 20-24 year old age group, with 15-19 year olds being the second largest group. Prevalence decreases with age, dropping significantly after age 30. It is thought that the younger, developing cervix is more likely to be infected, but these infections tend to be short-lived and are usually cleared by the immune system. Cases of cervical cancer are extremely rare under age 30.
Researchers have identified 100 different strains of HPV, 40 of which can infect the anal and genital areas. These strains have been further divided into low and high risk strains, which we will address later. Many people think of HPV as the virus that causes genital warts, yet only a few of the 100 strains actually cause warts.
There is no treatment to rid the body of HPV, but 80% of infections are cleared by the body's immune system. For the 20% who develop chronic infection with HPV, the risk of cervical cancer is higher. If the HPV strain is one that causes genital warts, they can be treated by topical methods such as freezing, acid application or imiquimod (a medication used to boost local immune response). Surgical treatments include laser, excision, or CUSA (ultrasound).
Cervical Cancer and the Pap test
Cervical cancer is the second most common cancer in women worldwide. Approximately 500,000 new cases are diagnosed annually worldwide, 83% of which will be in developing countries (estimated 10,370 new cases in the US in 2005). There will be an estimated 273,000 deaths due to the disease annually, three-fourths of these in developing countries. Higher income nations have the Papanicolaou (pap) test to thank for a 75% decrease in cervical cancer cases over the past 50 years. Unfortunately, this test has not been successful in lower income nations due to cost, ability to get the test to women and once available, to get the results back to them. The Pap test has made great strides in catching cervical changes early, but it is not without problems. The traditional Pap test is not very sensitive (55-60% sensitivity), which means that up to 40-45% of the time that the test is read as normal, there is actually cervical dysplasia (abnormality) present. By performing the test annually, along with a manual exam, we increase the chance of detecting a cancer. Newer liquid based cytology tests, called Thin Prep ® and Sure Path ® , reportedly have a sensitivity of 84%, which is better, but still not great.
Cervical cancer is further broken down into 3 types: squamous cell carcinoma (about 75% of cases), adenocarcinoma (15-25% of cases), and rarely, adenosquamous (a combination of the two). It is recommended that women start screening with Pap smears within 3 years of becoming sexually active, but no later than 21 years old. Then annual testing with traditional Pap methods, or every 2 years with the liquid based cytology. Women who have had a hysterectomy should clarify with their surgeon whether or not they still have a cervix and whether they should continue screening.
Pap Test Results
Several different classification schemes have evolved over the years for characterizing Pap test results. Unfortunately, this is a continuing source of confusion. The most commonly used classification scheme is the Bethesda System. Learn more about interpreting pap test results.
HPV Causing Cervical Cancer
Researchers have determined that HPV is found in almost 100% of cervical cancers worldwide. This is unique to cervical cancer, no other cancer has been found to have one central cause. Even the tie between smoking and lung cancer is not as strong, with only 80 to 85% of cases caused by smoking. Although HPV is necessary to the development of cervical cancer, it alone is not enough. About 80% of HPV infections are transient and resolve without treatment because the immune system is able to fight them off. Some factors that appear to increase the risk of HPV infection not clearing and possibly progressing to cancer include: cigarette smoking, oral contraceptive use for more than 5 years, multiple births, and poor nutrition. Studies have found smokers to be 2-3 times more likely to develop cervical dysplasia or cancer than nonsmokers. Several studies have showed a dose intensity relationship, the more tobacco smoked, the higher the risk. In addition, researchers have found that nicotine is present in the cervical cells of smokers.
There are 40 strains of HPV that can affect the anal and genital tracts and these are further divided into low risk and high risk strains. Thirteen strains are considered high risk, or more likely to progress to high grade lesions (HSIL, CIN 2 or 3) and possibly cancer, if not cleared by the immune system. These strains are: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. Strains 16 and 18 are by far the most common types, and one or both are present in approximately 70% of cervical cancers worldwide. Despite this strong link, only a very small percentage of high risk HPV infections will ever become invasive cancer (estimated at 2%). The time between initial exposure and the development of cancer can vary from months to years, but the average time is thought to be 15 years. Unfortunately, the high risk HPV strains do not usually cause any symptoms to alert someone that they have the infection. The low risk strains are not considered a risk for cervical cancer, but they can cause low grade lesions (CIN 1) and several of these strains can cause genital warts.
Testing for HPV
Several years ago, a test was developed to identify high risk strains of HPV. The test is done on the same cells that are used in a Pap test. Studies have found the Hybrid Capture II test to detect the presence of high risk HPV in 83-100% (depending on the study) of high grade lesions (CIN 2 or 3, HSIL) or invasive cervical cancer.
In women over the age of 30, when both Pap test and high risk HPV tests are negative, the woman can wait 3 years for the next screening (though they should have an annual manual exam to check other areas of the woman's reproductive organs).
With a Pap result of atypical squamous cells of undetermined significance (ASCUS), women have the option to repeat the Pap in 6 months and if the result is the same, proceed to colposcopy for further evaluation. Alternatively, the cervical cells can be tested for high risk HPV strains. A Pap result of ASCUS, in conjunction with a negative HPV test, can be followed with a repeat Pap in 6 to 12 months. If either test is positive at that time, colposcopy should be performed. If the initial HPV is positive with an ASCUS Pap, colposcopy is warranted.
The test costs between $50 and $200, depending on the lab used. Many insurance companies cover the cost of the test if it is being used as screening for women over 30 (as this is recommended by several medical organizations). Some companies will cover the cost of HPV testing for women under 30 with an inconclusive or abnormal Pap test result. But many experts agree that abnormalities in young women are a result of transient infections and can be followed by repeat Pap testing in 6 to 12 months.
One thing to keep in mind, almost all women will have an HPV infection at some time in their life. The Hybrid Capture test does not have the ability to tell what HPV strain the person has, just whether or not they have any high risk strain. Multiple positive results over years could be different transient infections and cannot be assumed to be a persistent infection with one strain.
There has been a lot of talk about vaccines for HPV, but they are all still in development or in clinical trials. Merck and Glaxo SmithKline appear to be the first companies ready to apply for FDA approval (applying in early 2006 and 2007 respectively). Their vaccines are targeting the two most common HPV high risk strains, 16 and 18, which are responsible for 70% of cervical cancers worldwide. An important piece of patient education regarding these vaccines, is that they will still need to have Pap tests, as there are still eleven other HPV high risk strains that can lead to cervical dysplasia or cancer. The pharmaceutical companies have found that the vaccine is less effective if they add more strains to it, therefore they feel targeting the 2 most common types is best. Information available from ongoing trials report the vaccine to be about 90% effective in preventing HPV infection. Researchers feel the vaccine would be best given to adolescents ages 9-12, who have not yet been exposed to the virus. Early trials did not include these age groups, but are currently ongoing. In addition, it is not yet known how long the vaccine will protect women from HPV. Regardless of these issues, it is clear that this could be a major step in decreasing cervical cancer mortality in lower income countries.
What About the Men?
Researchers have historically been looking at women and HPV because of the cervical cancer link, but men are getting a closer look. Obviously, men are a large part of the issue of HPV rates, so it makes sense to target them as well. Vaccines are only now being tested in men and adolescent boys.
Anal cancer rates have increased 160% in men from 1973 to 2000, which is very concerning to researchers (rates in women have increased 78%). One study found 88% of anal tumors studied contained HPV, suggesting it may be a causative factor. Several other factors also increased the risk: >14 lifetime sexual partners, receptive anal intercourse, and smokers were almost 4 times as likely to develop anal cancer. HPV has also been linked to penile cancer in men and head and neck cancers in both sexes.
Most men, like women, have no symptoms, unless they develop genital warts. Currently, aside from treating genital warts, there is no treatment for HPV in men. It is known that anal warts can be a precursor to anal cancer and these warts can be tested for high risk HPV strains. This can allow for surgical intervention for the patients at highest risk for developing anal cancer.
Knowledge about Human Papilloma Virus has grown tremendously in the last 10 years and is certain to continue. Healthcare providers and consumers will need to keep abreast with changes in practice in order to achieve improved health outcomes for women. Look to OncoLink for periodic updates!
- Abeloff, M., Armitage, J., Niederhuber, J., Kastan, M. & McKenna, G. (Eds.): Clinical Oncology (2004). Elsevier, Philadelphia , PA.
- The American Cancer Society. Facts and Figures 2005 . www.cancer.org
- Arbyn, Mark et al. Virologic Versus Cytologic Triage of Women With Equivocal Pap Smears: A Meta-analysis of the Accuracy To Detect High-Grade Intraepithelial Neoplasia. Journal of the National Cancer Institute , 2004; 96(4):280-293.
- Castellsague X, Bosch FX, Munoz N. Environmental co-factors in HPV carcinogenesis. Virus Res 2002;89:191-9.
- Daling JR, Madeleine MM, Johnson LG et al. Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer. Cancer 2004;101:270-80.
- Damasus-Awatai G, Freeman-Wang T. Human papilloma virus and cervical screening. Curr Opin Obstet Gynecol 2003;15:473-7.
- Fey MC, Beal MW. Role of human papilloma virus testing in cervical cancer prevention. J Midwifery Womens Health 2004;49:4-13.
- Franco EL, Harper DM. Vaccination against human papillomavirus infection: a new paradigm in cervical cancer control. Vaccine 2005;23:2388-94.
- Goldie SJ, Kohli M, Grima D et al. Projected clinical benefits and cost-effectiveness of a human papillomavirus 16/18 vaccine. J Natl Cancer Inst 2004;96:604-15.
- Munoz N, Bosch FX, de Sanjose S et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518-27.
- Papaconstantinou HT, Lee AJ, Simmang CL et al. Screening methods for high-grade dysplasia in patients with anal condyloma. J Surg Res 2005;127:8-13.
- Raley JC, Followwill KA, Zimet GD, Ault KA. Gynecologists' attitudes regarding human papilloma virus vaccination: a survey of Fellows of the American College of Obstetricians and Gynecologists. Infect Dis Obstet Gynecol 2004;12:127-33.
- Sankaranarayanan R, Chatterji R, Shastri SS et al. Accuracy of human papillomavirus testing in primary screening of cervical neoplasia: results from a multicenter study in India . Int J Cancer 2004;112:341-7.
- Washam C. Targeting teens and adolescents for HPV vaccine could draw fire. J Natl Cancer Inst 2005;97:1030-1.
- Washam C. Two HPV vaccines yielding similar success. J Natl Cancer Inst 2005;97:1030.
- Wright TC, Jr., Schiffman M, Solomon D et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol 2004;103:304-9.