by Dr. C.H. Weaver M.D. updated 7/2019
The Hybrid Capture II test for the human papillomavirus (HPV) is a valuable diagnostic tool in women whose Pap smear results are classified as atypical squamous cells of undetermined significance (ASCUS), according to the results of a study recently published in the Journal of the National Cancer Institute.
The HPV is a sexually transmitted disease that is the primary cause of cervical cancer. HPV is present in virtually all cases of invasive cervical cancer. The Hybrid Capture II HPV test is a new DNA-based test designed to detect the 13 types of HPV that are associated with cervical cancer, a function that the Pap smear does not provide.
The Pap smear is an annual screening procedure during which a physician scrapes cells from the cervix for examination under a microscope. The results of the Pap smear are then classified into five categories: negative or within normal limits (normal); atypical squamous cells of undetermined significance (ASCUS); low-grade squamous intraepithelial lesions (abnormal); high-grade squamous intraepithelial lesions (abnormal); or carcinoma (cancer).
Every year, more than 2 million women in the United States receive an ASCUS diagnosis from their Pap smear results. Currently, there is no consensus as to the appropriate management strategy for women with ASCUS results. Because an ASCUS result does not provide much information, women with these results are often referred to undergo more invasive screening procedures, such as colposcopy. Effective management strategies for ASCUS results are needed in order to identify women who may have significant disease while sparing others from excessive and unnecessary follow-up. The National Cancer Institute recently sponsored a multi-center clinical trial to compare three management strategies following an ASCUS diagnosis.
The study involved 3,488 women who had a recent diagnosis of ASCUS. The women were randomized to receive one of three follow-up options: immediate colposcopy, Hybrid Capture II HPV test, or a follow-up Pap smear. If the follow-up Pap smear indicated high-grade squamous intraepithelial lesions or the results of the HPV test were positive, then these women were referred to colposcopy.
The results indicated that the HPV test was an effective next-step following an ASCUS diagnosis. In this study, 55% of women with ASCUS tested positive for HPV and would be referred to colposcopy using this management strategy. About 5% of the women in the trial were diagnosed with cervical intraepithelial neoplasia grade 3 (CIN3), which is a lesion at high risk of progressing to invasive cancer. Of these women, 96.3% tested positive for HPV. The results also indicated that the HPV test in women with ASCUS results has a negative predictive value of 99.5%, so the 45% of women who were HPV-negative are highly unlikely to have a significant abnormality.
It is recommended that women with ASCUS Pap results should undergo immediate HPV testing. Women who are positive for HPV can then undergo appropriate follow-up, while women who are negative for HPV can be assured that they do not have the virus and may be spared from excessive follow-up procedures. (2) HPV testing as an intermediate step following an ASCUS diagnosis, but prior to performing a colposcopy will reduce the number of women referred to colposcopy, and could help to reduce the medical costs of performing more invasive procedures and spare healthy women from undergoing unnecessary procedures.
Can the PAP Smear be Replaced by the HPV Test?
Researchers from the United Kingdom recently conducted a clinical trial to evaluate the effectiveness of HPV testing as initial screening for cervical cancer. The researchers also sought to determine the optimal strategy of the management of women who tested positive for HPV, but had borderline or negative cytology. This trial included over 11,000 women between the ages of 30 and 60. Overall, HPV testing detected 97% of cervical intraepithelial neoplasia (CIN), which is a pre-cancerous condition that can lead to cancer, compared with a detection rate of 77% of CIN with cytology. A subgroup of 895 women had either borderline cytology (these patients could be HPV positive or negative), or had tested positive for HPV with negative cytology. Of these women, half were treated with an immediate colposcopy, and the other half waited for 12 months to undergo repeat HPV and Pap tests, as well as a colposcopy (surveillance group). In the group of women who initially had a positive HPV test and underwent surveillance, 45% of those with negative cytology and 35% of those with borderline cytology were HPV negative at 6-12 months. None of these patients developed CIN. In addition, no cases of CIN occurred in the group of women in the surveillance group who initially tested HPV negative with borderline cytology.
The researchers concluded that an initial HPV test appears to detect more CIN than standard cytology. The authors state that HPV positive test results should be followed with a standard cytology test. If a borderline cytology test is found in these women, repeat testing 12 months after initial testing does not appear to increase the incidence of CIN compared with immediate testing, and may result in fewer colposcopies. In addition, women who are initially HPV negative with borderline cytology may also safely be managed with repeat testing at 12 months. Women over the age of 30 may wish to speak with their physician about the risks and benefits of initial testing for HPV in place of standard cytology, and appropriate management according to their individual results.
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HPV Test Identifies a Majority of Women with High-Grade CIN
An analysis of several previously published studies concludes that a test for high-risk types HPV identifies a large majority of women with high-grade cervical intraepithelial neoplasia (CIN). These results were published in the International Journal of Cancer.
Effective screening programs for cervical cancer have decreased the frequency of cervical cancer in the U.S. Screening can detect precancerous changes to the cervix, known as cervical intraepithelial neoplasia (CIN). The severity of CIN is classified on a scale of 1 to 3, with 3 being the most severe. Because the more severe types of CIN may progress to cervical cancer, removal of these lesions reduces the risk of cancer.
Cervical cancer screening has traditionally relied on the Pap test. During a Pap test, a sample of cells is removed from the cervix using a small wooden spatula or a brush. The cells are examined by a laboratory and results are then classified into five categories: normal; atypical squamous cells of undetermined significance (ASCUS); low-grade squamous intraepithelial lesions (LSIL); high-grade squamous intraepithelial lesions (HSIL); or cancer.
More recently, researchers have evaluated the role of HPV testing in cervical cancer screening. HPV is a sexually transmitted infection that is the primary cause of cervical cancer. Different types of HPV are classified as “low-risk” or “high-risk” based on how likely they are to cause cervical cancer. Screening women for high-risk types of HPV may identify women who are most likely to have precancerous changes to the cervix.
To compare the Pap test and the HPV test as cervical cancer screening tools, researchers assessed the results of several previously published studies. The studies were conducted in North American and Europe and enrolled more than 60,000 women.
- The HPV test identified a higher proportion of the women with high-grade CIN (CIN 2 or CIN 3) than the Pap test. HPV testing identified 96% of these women and the Pap test identified 53%.
- The ability of the HPV test to identify women with high-grade CIN did not vary by age. The ability of the Pap test to identify women with high-grade CIN was greatest in women over the age of 50.
- The HPV test was less accurate than the Pap test at correctly classifying women without high-grade CIN. Among women without high-grade CIN, the HPV test correctly classified 91% of the women and the Pap test correctly classified 96% of the women.
- Among women with a positive HPV test, 16% were found to have high-grade CIN. Among women with a positive Pap test, 20% were found to have high-grade CIN.
Although questions remain about the most appropriate use of HPV testing, the researchers suggest that a strategy of initial HPV testing, followed by a Pap test for those with positive HPV results, may improve the accuracy of cervical cancer screening.(4)
- Journal of the National Cancer Institute, Vol 93, No. 4, pp. 293-299, 2001.
- Wright T, Cox J, Massad L, et al. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. Journal of the American Medical Association. 2002;287:2120-2129.
- Cuzick J, Szarewski A, Cubie H, et al. Management of women who test positive for high-risk types of human papillomavirus: the HART study. The Lancet. 2003;362:1871-1876.
- Cuzick J, Clavel C, Petry K-U et al. Overview of the European and North American Studies on HPV Testing in Primary Cervical Cancer Screening. International Journal of Cancer. Early online publication April 3, 2006.