- Email: [email protected]
Natural history of cervical human papillomavirus infections
COMMENTARY
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levonorgestrel implant, intrauterine device, and sterilization. Obstet Gynecol 2001; 97: 539–47. Sivin I, Viegas O, Campodonico I, et al. Clinical performance of a new two-rod levonorgestrel contraceptive implant: a three-year randomized study with Norplant implants as controls. Contraception 1997; 55: 73–80. Sivin I, Mishell DR, Darney P, Wan L, Christ M. Levonorgestrel capsule implants in the United States: a 5-year study. Obstet Gynecol 1998; 92: 337–44. Du MK, Chow LP, Zheng HM, Chen CHC. A 10-year follow-up study of contraceptive Norplant implants. Int J Gynecol Obstet 2000; 68: 249–56.
Natural history of cervical human papillomavirus infections See page 1831 One of the general principles governing the introduction of screening is that the natural history of the disorder should be known. A major difficulty with such a principle is that until screening is initiated, the natural history of the disorder is not known. The reason for this lack of knowledge is that the abnormality discovered by screening has not been recognised before in that particular phase of the disease’s natural history. So the proportion of individuals that progress to clinically recognised disease and the rate of such progression will not have been described. Although some similar abnormalities may have been discovered serendipitously, these do not represent the full range discovered by screening a large population. There is an additional difficulty in that the introduction of highly sensitive screening tests may reveal disease that might never have been detected in the absence of screening. This point has been recognised as probably true for prostate cancer and recently for lung cancer.1 It is also true for cervical cancer, because lowgrade cervical intraepithelial neoplastic (CIN) lesions rarely become invasive.2,3 In this issue of The Lancet, Ciaran Woodman and his colleagues report the results of an elegant study designed to determine the natural history of human papillomavirus (HPV) infections. 1075 young women agreed to participate in an intensive cervical-screening programme. Smears were taken about every 7 months and analysed for the presence of HPV and cytological abnormalities. This frequency enabled Woodman and co-workers to determine more accurately than had been done in a large US cohort followed passively4 the timing of HPV infections, and the development of high-grade CIN that followed some of these infections. Somewhat surprisingly, of the 246 women who had an abnormal smear, 40% tested negative for HPV and another 33% tested HPV positive for the first time only at the same visit as the abnormal smear. Thus for only 21% of women was a positive HPV test predictive of abnormal cytology at a subsequent visit, and the cumulative risk at 3 years was 33%. However, of the 28 women who developed high-grade CIN during follow-up, 82% had become HPV positive. The risk of a moderate or severe dyskaryosis was substantially greater in those who tested HPV positive; it was maximum at 6 months after the first positive HPV test, but declined rapidly thereafter. So in this study, persistence of HPV infection did not confer the largest risk of an abnormal smear. This finding differs from the US cohort,4 among whom persistence of HPV infection was associated with increased risk of squamous intraepithelial lesions.5 However, the US study was smaller and fewer lesions were detected than in the study of Woodman and colleagues. Thus, Woodman and co-workers have confirmed the 1816
transitory nature of most HPV infections. They also quantified the risk associated with HPV 16 and have shown that cytology may identify dyskaryosis very soon after the first evidence of HPV infection. These data also show that the development of CIN in a woman who has a positive HPV test may be due more to the play of chance than most investigators have assumed. The implications of this study go beyond those the researchers tentatively discuss. In the past few years cervical smears have been shown to have a “low sensitivity” when compared with HPV tests in the same woman. This finding is almost certainly due to the detection of non-progressive disease. A positive HPV test especially in young women, rarely represents disease that could, if unrecognised, progress to cervical cancer. Although more “disease” is being recognised as a result of HPV testing,6,7 the low sensitivity of the corresponding cervical smear is largely spurious. So the use of HPV testing risks the overtreatment of more non-progressive disease than does the cervical smear. The successful population programmes for cervical screening in North America and Europe have all been based on cytology, and estimates of the sensitivity of such programmes range from 40% to 90%.8 Knowing more about the natural history of HPV infection, especially in young women, reinforces the view that such testing should not be carried out among women under the age of 35.9 It also suggests that a radically new approach to screening is needed which recognises that most cervical cancers are caused by specific subtypes of HPV.10 Screening for HPV infection, if done at the right age, may identify women with a low risk of cervical cancer if they test negative, but cannot help identify the minority who have a high risk of progression. To achieve this latter aim, a test is needed that indicates the virus will exert its oncogenic potential in that woman—which probably means that attention should be transferred from the agent to the host. Anthony B Miller Division of Clinical Epidemiology, Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany (e-mail: [email protected].) 1
Black WC. Overdiagnosis: an unrecognized cause of confusion and harm in cancer screening. J Natl Cancer Inst 2000; 92: 128–02. 2 Ostor AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol 1993; 12: 186–92. 3 Holowaty P, Miller AB, Rohan T, To T. The natural history of dysplasia of the uterine cervix. J Natl Cancer Inst 1999; 91: 252–58. 4 Liaw K, Glass G, Manos M, et al. Detection of human papillomavirus DNA in cytologically normal women and subsequent cervical squamous intraepithelial lesions. J Natl Cancer Inst 1999; 91: 954–60. 5 Ho GY, Bierman R, Beardsley L, Chang CC, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998; 338: 423–28. 6 Blumenthal PD, Gaffikin L, Chirenje ZM, McGrath J, Womack S, Shah K. Adjunctive testing for cervical cancer in low resource settings with visual inspection, HPV, and the Pap smear. Int J Gynec Obstr 2001; 72: 47–53. 7 Cuzick J, Beverley E, Terry G, et al. HPV testing in primary screening of older women. Br J Cancer 1999; 81: 554–58. 8 IARC Working Group on Cervical Cancer Screening. Summary Chapter. In: Hakama M, Miller AB, Day NE, (eds). Screening for cancer of the uterine cervix. IARC Scientific Publications No. 76. Lyon, International Agency for Research on Cancer, 1986: 133–42. 9 Miller AB, Nazeer S, Fonn S, et al. Report on consensus conference on cervical cancer screening and management. Int J Cancer 2000; 86: 440–47. 10 Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189: 12–19.
THE LANCET • Vol 357 • June 9, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
7
8
9
levonorgestrel implant, intrauterine device, and sterilization. Obstet Gynecol 2001; 97: 539–47. Sivin I, Viegas O, Campodonico I, et al. Clinical performance of a new two-rod levonorgestrel contraceptive implant: a three-year randomized study with Norplant implants as controls. Contraception 1997; 55: 73–80. Sivin I, Mishell DR, Darney P, Wan L, Christ M. Levonorgestrel capsule implants in the United States: a 5-year study. Obstet Gynecol 1998; 92: 337–44. Du MK, Chow LP, Zheng HM, Chen CHC. A 10-year follow-up study of contraceptive Norplant implants. Int J Gynecol Obstet 2000; 68: 249–56.
Natural history of cervical human papillomavirus infections See page 1831 One of the general principles governing the introduction of screening is that the natural history of the disorder should be known. A major difficulty with such a principle is that until screening is initiated, the natural history of the disorder is not known. The reason for this lack of knowledge is that the abnormality discovered by screening has not been recognised before in that particular phase of the disease’s natural history. So the proportion of individuals that progress to clinically recognised disease and the rate of such progression will not have been described. Although some similar abnormalities may have been discovered serendipitously, these do not represent the full range discovered by screening a large population. There is an additional difficulty in that the introduction of highly sensitive screening tests may reveal disease that might never have been detected in the absence of screening. This point has been recognised as probably true for prostate cancer and recently for lung cancer.1 It is also true for cervical cancer, because lowgrade cervical intraepithelial neoplastic (CIN) lesions rarely become invasive.2,3 In this issue of The Lancet, Ciaran Woodman and his colleagues report the results of an elegant study designed to determine the natural history of human papillomavirus (HPV) infections. 1075 young women agreed to participate in an intensive cervical-screening programme. Smears were taken about every 7 months and analysed for the presence of HPV and cytological abnormalities. This frequency enabled Woodman and co-workers to determine more accurately than had been done in a large US cohort followed passively4 the timing of HPV infections, and the development of high-grade CIN that followed some of these infections. Somewhat surprisingly, of the 246 women who had an abnormal smear, 40% tested negative for HPV and another 33% tested HPV positive for the first time only at the same visit as the abnormal smear. Thus for only 21% of women was a positive HPV test predictive of abnormal cytology at a subsequent visit, and the cumulative risk at 3 years was 33%. However, of the 28 women who developed high-grade CIN during follow-up, 82% had become HPV positive. The risk of a moderate or severe dyskaryosis was substantially greater in those who tested HPV positive; it was maximum at 6 months after the first positive HPV test, but declined rapidly thereafter. So in this study, persistence of HPV infection did not confer the largest risk of an abnormal smear. This finding differs from the US cohort,4 among whom persistence of HPV infection was associated with increased risk of squamous intraepithelial lesions.5 However, the US study was smaller and fewer lesions were detected than in the study of Woodman and colleagues. Thus, Woodman and co-workers have confirmed the 1816
transitory nature of most HPV infections. They also quantified the risk associated with HPV 16 and have shown that cytology may identify dyskaryosis very soon after the first evidence of HPV infection. These data also show that the development of CIN in a woman who has a positive HPV test may be due more to the play of chance than most investigators have assumed. The implications of this study go beyond those the researchers tentatively discuss. In the past few years cervical smears have been shown to have a “low sensitivity” when compared with HPV tests in the same woman. This finding is almost certainly due to the detection of non-progressive disease. A positive HPV test especially in young women, rarely represents disease that could, if unrecognised, progress to cervical cancer. Although more “disease” is being recognised as a result of HPV testing,6,7 the low sensitivity of the corresponding cervical smear is largely spurious. So the use of HPV testing risks the overtreatment of more non-progressive disease than does the cervical smear. The successful population programmes for cervical screening in North America and Europe have all been based on cytology, and estimates of the sensitivity of such programmes range from 40% to 90%.8 Knowing more about the natural history of HPV infection, especially in young women, reinforces the view that such testing should not be carried out among women under the age of 35.9 It also suggests that a radically new approach to screening is needed which recognises that most cervical cancers are caused by specific subtypes of HPV.10 Screening for HPV infection, if done at the right age, may identify women with a low risk of cervical cancer if they test negative, but cannot help identify the minority who have a high risk of progression. To achieve this latter aim, a test is needed that indicates the virus will exert its oncogenic potential in that woman—which probably means that attention should be transferred from the agent to the host. Anthony B Miller Division of Clinical Epidemiology, Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany (e-mail: [email protected].) 1
Black WC. Overdiagnosis: an unrecognized cause of confusion and harm in cancer screening. J Natl Cancer Inst 2000; 92: 128–02. 2 Ostor AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol 1993; 12: 186–92. 3 Holowaty P, Miller AB, Rohan T, To T. The natural history of dysplasia of the uterine cervix. J Natl Cancer Inst 1999; 91: 252–58. 4 Liaw K, Glass G, Manos M, et al. Detection of human papillomavirus DNA in cytologically normal women and subsequent cervical squamous intraepithelial lesions. J Natl Cancer Inst 1999; 91: 954–60. 5 Ho GY, Bierman R, Beardsley L, Chang CC, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998; 338: 423–28. 6 Blumenthal PD, Gaffikin L, Chirenje ZM, McGrath J, Womack S, Shah K. Adjunctive testing for cervical cancer in low resource settings with visual inspection, HPV, and the Pap smear. Int J Gynec Obstr 2001; 72: 47–53. 7 Cuzick J, Beverley E, Terry G, et al. HPV testing in primary screening of older women. Br J Cancer 1999; 81: 554–58. 8 IARC Working Group on Cervical Cancer Screening. Summary Chapter. In: Hakama M, Miller AB, Day NE, (eds). Screening for cancer of the uterine cervix. IARC Scientific Publications No. 76. Lyon, International Agency for Research on Cancer, 1986: 133–42. 9 Miller AB, Nazeer S, Fonn S, et al. Report on consensus conference on cervical cancer screening and management. Int J Cancer 2000; 86: 440–47. 10 Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189: 12–19.
THE LANCET • Vol 357 • June 9, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.