Key Points ALTS (ASCUS/LSIL Triage Study for Cervical Cancer) and Portland Kaiser Permanente studies allowed researchers to examine whether testing for specific human papillomavirus (HPV) types -- HPV16 and HPV18 -- was more effective at predicting risk for precancerous conditions or cervical cancer than testing for a broad pool of cancer-causing, or oncogenic, HPV types (Question 5). The study authors found that women who tested positive for HPV16 or HPV18 had an increased risk for precancerous conditions and cervical cancer compared to those women who tested positive for another oncogenic HPV type and to those who tested negative for HPV (Question 6). Future research will help to demonstrate whether women who test negative for HPV16 and HPV18 can be followed and treated less aggressively than women who test positive for these HPV types (Question 9).

Background

Cervical infections due to a group of about 15 oncogenic, or cancer-causing, human papillomavirus (HPV) types cause virtually all cervical cancers. They also are the cause of their immediate precursor, cervical intraepithelial neoplasia grade 3 (CIN3), a precancerous condition. Overall, about 10 percent of women at any one time have an oncogenic HPV infection, and they are more common in young women than in older women. Most cervical infections by even oncogenic HPV types go away on their own and do not cause cancer. In some women, oncogenic HPV infections persist and can progress over several years to CIN3, and may even progress to invasive cervical cancer. Most women, however do not progress to the precancer stage. Cervical cancer itself is extremely rare in the United States; there are about 11,000 new cases diagnosed and about 4,000 related deaths reported annually.

Understanding Pap Smears and Other Cervical Cancer Screening and Management Techniques

1. What is a Pap smear? What is a colposcopy?

A Pap smear is a procedure in which cells are scraped from the cervix (the lower, narrow end of the uterus that serves as a channel between the uterus and the vagina) and examined under a microscope. A Pap smear is used to detect cancer and cellular changes that may lead to cancer, as well as non-cancerous conditions like infection or inflammation.

A colposcopy is a procedure in which the vagina and cervix are examined using a lighted magnifying instrument called a colposcope. The vagina and cervix may be biopsied during a colposcopy so that tissue samples can be examined under a microscope for abnormal cells. A colposcopy may be prescribed if a Pap smear detects certain abnormal cellular conditions.

2. What is human papillomavirus (HPV)?

There are more than 100 types of human papillomaviruses (HPV). HPV is one of the most common sexually transmitted diseases (STDs), and more than 30 of the different types of HPV can be transmitted through sexual contact. While some types of HPV may cause warts to appear around the genitals, HPV infections also may occur without any obvious symptoms.

The U.S. Food and Drug Administration (FDA) has approved the use of a test for HPV as a screening tool for cervical cancer in conjunction with a Pap smear or cytology. Oncogenic HPV DNA testing (or "triage") for patients with ASCUS has proven to be a useful alternative to referring patients for immediate colposcopy to detect CIN3 and cancer (greater or equal to CIN3). A 2004 conference of the International Agency for Research on Cancer concluded that there was sufficient evidence that HPV DNA testing could be used as a primary screening test in women age 30 and older.

3. Why are HPV16 and HPV18 important?

Of the types of HPV that increase risk for certain types of cancer, HPV16 is the most common among women in the general population. Large case studies have shown that approximately 50 percent of women with CIN3 or cervical cancer are infected with HPV16. Additional research suggests that 60 percent to 70 percent of cervical cancer cases worldwide are caused by either HPV16 or HPV18. Virtually all remaining cases of cervical cancer are caused by other oncogenic HPV types.

4. What are ASCUS and LSIL?

ASCUS and LSIL are acronyms for two mild abnormalities detected by Pap tests. ASCUS stands for "Atypical Squamous Cells of Undetermined Significance", and LSIL stands for "Low-grade Squamous Intraepithelial Lesion".

A diagnosis of ASCUS means that the nature of the abnormality is uncertain or equivocal. A diagnosis of LSIL means that there is a more definite, but still mild, abnormality.

Study Findings

5. What were the goals of the ALTS and the Portland Kaiser Permanente studies?

The National Cancer Institute (NCI) organized and funded ALTS (the ASCUS/LSIL Triage Study for Cervical Cancer) to help resolve the controversy over what physicians and women should do about ASCUS (equivocal) and LSIL (mildly abnormal) Pap test results*. Most of these abnormalities will go away without treatment, but some may lead to a precancerous condition or cancer. This analysis of the ALTS data provided the opportunity for researchers to determine whether women with equivocal Pap smear results, who also tested positive for HPV16, had a greater risk for CIN3 or cervical cancer than women with equivocal Pap smear results who tested positive for other oncogenic types of HPV.

The Portland study was designed to examine the natural history of HPV infection and cervical neoplasia (abnormal and uncontrolled cell growth)**. Additionally, this study allowed analysis of whether testing specifically for HPV16 and HPV18, in addition to overall testing for all HPV oncogenic types, might help identify women at particularly high risk for CIN3 or cervical cancer.

6. What were the results of these studies?

In their analysis of ALTS data, Castle et al. found that 542 women in the study group developed CIN3 or cervical cancer. Those who tested positive for HPV16 had 38 times the risk for CIN3 or cervical cancer than women in the study who were HPV negative. Women who tested positive for other oncogenic HPV types had seven times the risk for these conditions than women who tested HPV negative. The authors concluded that patients with a positive HPV16 diagnosis may require more aggressive management than those who test positive for another oncogenic HPV type or who are HPV negative.

Khan et al. found that women in the Portland study who tested positive for HPV16 or HPV18 were diagnosed with CIN3 or cervical cancer more often than women who tested positive for another oncogenic HPV type, or women who tested negative for HPV. Additional analysis of women with normal Pap smear results at study enrollment provided further evidence for the observed risk differences. The authors concluded that screening for HPV16 and HPV18 separately from other oncogenic HPV types may identify women at the greatest risk of CIN3 and cervical cancer, while allowing for less aggressive management of cases of other oncogenic HPV infections.

The authors note that an elevated risk for HPV16 also was observed in a natural history study in Guanacaste, Costa Rica (Schiffman, Virology, 2005)***.

7. How were these studies performed?

The ALTS study compared three different management strategies for 5,060 women with Pap tests that either showed ambiguous cytologic abnormalities (ASCUS, 3,488 women), or low-grade squamous intraepithelial lesions (LSIL, 1,572 women). The study referred one-third of the women to an immediate colposcopy, regardless of their Pap test results; one-third to colposcopy if their initial HPV test was positive or if their Pap test showed high-grade squamous intraepithelilal lesions (HSIL); and one-third to colposcopy if their Pap test showed HSIL at their enrollment in the study or during follow-up. All three groups received additional tests every six months for two years of follow-up and a colposcopy at the end of the trial. Women whose test results showed cervical intraepithelial neoplasia grade 2 (CIN2) or higher received treatment for the condition.

The Portland study examined data on 20,514 women who received routine cytologic screening through a prepaid health plan in Oregon. Women included in this analysis had negative, equivocal, or mildly abnormal baseline cervical Pap smears; suitable samples for HPV testing; and type-specific HPV test results. Study participants received regular follow-up cytology testing for up to 10 years following their enrollment. Practice guidelines at the time of the study mandated treatment for women whose Pap smears showed CIN2 or higher, but some physicians also treated some patients with cervical intraepithelial neoplasia grade 1 (CIN1).

8. What were the limitations of these studies?

ALTS was a clinical trial and, consequently, the participants in the trial may have been screened more regularly than patients in everyday clinical management. Additionally, the women in this study were relatively young, with a median age of 25. A population of older women might lead to different results.

Women with cellular abnormalities in the Portland study received very aggressive treatment -- more than was mandated by clinical standards at the time or today. Thus, results in this study may actually underestimate the risk attributable to HPV16 and to HPV18 because of over-treatment. Additionally, there were relatively few cases to analyze despite the study size, possibly leading to some imprecise estimates of risk.

9. What are the next steps in this area of research?

Twenty organizations - including the American Society for Colposcopy and Cervical Pathology (ASCCP), the American Cancer Society, and the National Cancer Institute (NCI) - will participate in a conference in September 2005 to discuss the use of HPV DNA testing for screening and for triage of equivocal (ASCUS) Pap smears. One of the topics of discussion is likely to be the utility of HPV genotype detection in screening and clinical management.

The data from these recent two studies should be confirmed in other larger studies and in other populations, perhaps even in some of the clinical trials that are evaluating HPV DNA tests to develop more precise estimates of risk. Also, subsequent evaluations will need to examine this question in women who are newly infected.

To perform HPV genotyping, a reliable, FDA-approved test to distinguish these specific HPV types will need to be developed and validated. When FDA-approved tests that provide genotype information become available, researchers will be better able to identify women with persistent infection, an important risk factor for the development of precancer and cancer. Understanding the risks associated with a persistent HPV infection and the appropriate clinical management of these women is critical to preventing cervical cancer.

Future research will help to demonstrate whether women who test negative for HPV16 and HPV18 can be followed and treated less aggressively than women who test positive for these HPV types, thereby reducing the number of clinical visits, potential over-treatment of these women, and increasing the cost effectiveness of such testing.

For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

*Castle PE, Solomon D, Schiffman M, Wheeler CM for the ALTS Group. Human papillomavirus type 16 infections and 2-year absolute risk of cervical precancer in women with equivocal or mild cytologic abnormalities." Journal of the National Cancer Institute, Vol 97, No. 14, July 20, 2005.

**Kahn MJ, Castle PE, Lorincz AT, Wacholder S, Sherman ME, Scott DR, Bush BB, Glass AG, Schiffman M. The elevated 10-year risk of cervical neoplasia in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice." Journal of the National Cancer Institute, Vol. 97, No. 14, July 20, 2005.

*** Schiffman M, Herrero R, DeSalle R, Hildesheim A, Wacholder S, Rodriguez AC, Bratti MC, Sherman ME, Morales J, Guillen D, Alfaro M, Hutchinson M, Wright TC, Solomon D, Zigui C, Schussler J, Castle PE, Burk RD. The carcinogenicity of human papillomavirus types reflects viral evolution. Virology, Vol. 337, 2005.

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