Periodic health examination, 1995 update: 1. Screening for human papillomavirus infection in asymptomatic women

Canadian Medical Association Journal 1995; 152: 483-493

Dr. Johnson is a research associate with the Department of Preventive Medicine and Biostatistics, University of Toronto, Toronto, Ont.

Copies of this and other task force reports are available from the Health Services Directorate, Health Services and Promotion Branch, Health Canada, Tunney's Pasture, Ottawa ON K1A 1B4.

© 1995 Canadian Medical Association

• Abstract
• Introduction
• Burden of suffering
• Screening for HPV infection
• Evidence linking HPV infection to cervical cancer
• Natural history of HPV infection
• Detection manoeuvre
• Effectiveness of early detection and treatment
• Adverse effects of HPV screening
• Recommendations
• Validation
• Research priorities
• References

Abstract

Options: Visual inspection, Papanicolaou testing, colposcopy or cervicography, use of HPV group-specific antigen, DNA hybridization, dot blot technique, Southern blot technique or polymerase chain reaction followed by physical or chemical therapeutic intervention.

Outcomes: Evidence for a link between HPV infection and cervical cancer, sensitivity and specificity of HPV screening techniques, effectiveness of treatments for HPV infection, and the social and economic costs incurred by screening.

Evidence: MEDLINE was searched for articles published between January 1966 to June 1993 with the use of the key words "papillomavirus," "cervix neoplasms," "mass screening," "prospective studies," "prevalence," "sensitivity," "specificity," "human" and "female."

Values: Proven cost-effective screening techniques that could lead to decreased morbidity or mortality were given a high value. The evidence-based methods and values of the Canadian Task Force on the Periodic Health Examination were used.

Benefits, harms and costs: Potential benefits are to prevent cervical cancer and eliminate HPV infection. Potential harmful effects include the creation of an unnecessary burden on the health care system and the labelling of otherwise healthy people as patients with a sexually transmitted disease for which therapy is generally ineffective. Potential costs would include expense of testing, increased use of colposcopy and treatment.

Recommendations: There is fair evidence to exclude HPV screening (beyond Papanicolaou testing for cervical cancer) in asymptomatic women (grade D recommendation).

Validation: The report was reviewed by members of the task force and three external reviewers who were selected to represent different areas of expertise.

Sponsors: These guidelines were developed and endorsed by the task force, which is funded by Health Canada and the National Health Research and Development Program. The principal author (K.J.) was supported in part by the National Health Research and Development Program through a National Health Fellowship (AIDS).

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A MEDLINE search of articles published from January 1966 to June 1993 was done with the use of the terms "papillomavirus," "cervix neoplasms," "mass screening," "prospective studies," "prevalence," "sensitivity," "specificity," "human" and "female." The methods established by the task force were used for evaluating and grading the evidence.(7) Studies were selected and evaluated to determine the epidemiologic features and natural history of HPV infection, the relation between HPV infection and cervical cancer, and the effectiveness of diagnostic and therapeutic intervention. High values were assigned to articles of proven cost-effective screening techniques that could lead to decreased morbidity and mortality.

The principal author (K.J.) conducted the literature review and provided an oral and written report to the task force members. The report was critically reviewed by the task force and later by three external experts.

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Burden of suffering

Many of the epidemiologic features of HPV infection remain to be determined, and precise estimates of the incidence, prevalence and natural history of this infection are unavailable. Cases of condylomata acuminata (proliferative HPV infection) are reportable in Britain, where it is the most frequently diagnosed viral sexually transmitted disease (STD).(17) Data from STD clinics in Britain(18) and Australia(19) indicate a prevalence of 4% to 13% among clinic attendees. These data, however, are based on visible condylomata and consequently underestimate the true prevalence of HPV infection, since this condition is commonly subclinical. It has been estimated that about 10% of people infected with HPV have visible lesions, 20% have lesions demonstrable with the use of colposcopy or a magnifying lens, and 70% have subclinical infection.(20) Subclinical infection can be detected only through clinical or laboratory testing, including Papanicolaou smears.

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Screening for HPV infection

Results from 10 recent surveys of HPV prevalence in various populations are presented in Table 1. The overall prevalence rates varied from 0.8%(22) to 88%(32) depending on the groups studied. As expected, since HPV infection is known to be an STD, rates among patients in STD clinics, sexually active adolescents and sexual contacts of women with HPV infection were higher than rates in other groups. Generally, although there were some exceptions,(26) the number of lifetime sexual partners has been a major factor in determining the risk of HPV infection. When it was possible to examine the effect of age, it was found that young women (adolescents and women in their 20s) were at significantly greater risk for HPV infection than older women.

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Evidence linking HPV infection to cervical cancer

The association between HPV infection and cervical cancer has been supported by evidence from animal studies,(34,35) molecular biology,(36-38) clinical case reports(39,40) and epidemiologic studies.(9-11,41-44) The earliest direct link between a papillomavirus infection and malignant transformation was reported in 1935, in rabbits with infectious papillomatosis (Shope papilloma).(34) A second example from animal studies is the malignant transformation of bovine papillomas under the influence of environmental factors in cattle.(35)

The development of DNA hybridization techniques in the late 1970s has allowed the identification of HPV DNA and the classification of these viruses into different types. Over 60 separate types of HPV have been identified to date, a new type having a genome homology of less than 50% in comparison with other known types.(45) Studies of HPV DNA in a variety of genital lesions have characterized the types of HPV that are most closely associated with risk for genital cancer.(36-38,46-48) The most important types in this regard are HPV types 16 and 18. In 1984 Gissmann and associates(36) reported finding one or both of these HPV types in 57.4% of cases of invasive cervical cancer. In a study from Scotland involving 30 women with different genital cancers HPV-16 DNA was found in 84% of the tumours and HPV-18 DNA in 8%.(37) Koutsky, Galloway and Holmes(20) combined and analysed the results of four studies(38,46-48) meeting predetermined criteria to examine the association between cancer and HPV types 16 and 18 relative to types 6 and 11 (usually considered to be associated with condylomata and low-grade cervical intraepithelial neoplasia [grade 1 CIN]). The latter two types of HPV had an inverse relation to increasing severity of histologically defined cervical lesions, whereas HPV-16 or HPV-18 was found in 20% of the patients with grade 1 CIN lesions, 51% of those with grade 2 or 3 CIN lesions and 63% of those with invasive cervical cancer which showed a strong positive association.

Epidemiologic studies, with or without viral typing, have confirmed the connection between HPV infection and cervical cancer.(8) Table 2 summarizes the findings of 11 such studies within the past decade that have demonstrated an association between HPV infection and cervical cancer, as well as the correlation between the presence of HPV infection and increasing grade of disease. Meisels and Morin(21) found evidence of HPV infection (koilocytosis) on Papanicolaou smears in 1.69% of over 234 000 women screened in Quebec and in 25.6% of those whose Papanicolaou smears showed signs of either dysplasia or neoplasia. The study by de Villiers and collaborators(24) involving 9295 women showed a prevalence of HPV infection of 5% to 10% among women whose Papanicolaou smears showed no abnormalities but one of 35% to 40% among those whose smears showed any degree of cytologic abnormality. A cohort of 241 women attending an STD clinic in the United States was followed prospectively for a mean of 25 months.(9) The outcome of interest was the time from a first positive HPV DNA test result (dot-blot hybridization) to the development of grade 2 or 3 CIN. The 2-year cumulative incidence of grade 2 or 3 CIN was 28% among women with a positive test result, as compared with 3% among those with a negative test result. Compared with women free of HPV infection, those with cervical HPV infection had a higher relative risk (RR = 11; attributable risk 78%) of having grade 2 or 3 CIN.

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Natural history of HPV infection

Most of the studies of the natural history of HPV infection involved the use of diagnostic cervical biopsies or other interventions and therefore may not accurately reflect the true course of HPV infection. Although the likelihood of progression is most consistently associated with the presence of HPV-16 and less so with other types of HPV(8,13,20) has not been universally demonstrated.(50) It is still uncertain how useful it would be to screen for HPV-16 or other HPV types.

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Detection manoeuvre

A recent study of the accuracy of Papanicolaou testing showed that among women with koilocytosis such testing had a sensitivity of only 15% in diagnosing HPV infection.(55) In a population-based screening program for cervical cancer the sensitivity of cytologic examination for HPV infection was estimated at 19%, the denominator being the expected number of cases of HPV infection taken from population estimates.(57) A small study (involving 21 women) in the United States attempted to determine the sensitivity and specificity of cytologic examination and colposcopy relative to DNA hybridization techniques in diagnosing HPV infection;(53) the sensitivity of Papanicolaou smears was 57% when equivocal smears were negative for HPV, with a specificity of 50%, but the sensitivity was 100% when equivocal smears were considered positive for HPV. Colposcopy had a sensitivity of 100% but a specificity of only 10% to 20%. Reid and colleagues(54) performed a prospective survey of 1012 women from either an STD clinic or private gynecologists' offices to assess cervical cytologic examination, cervicography and DNA hybridization for HPV as screening techniques for cervical cancer. Papanicolaou testing had a sensitivity of 52.2%. No single technique succeeded in identifying all of the abnormalities, but the best sensitivity (96%) was achieved through the retesting of only women with an initial high-grade cytologic abnormality or positive cervicography result. In the prospective cohort study of Koutsky and coworkers(9) 27 of the 28 women in whom grade 2 or 3 CIN developed had cytologic evidence of grade 2 or 3 CIN as well as a positive HPV DNA hybridization test result; the other woman had grade 1 CIN on cytologic examination before biopsy.

One major limitation of laboratory testing for HPV infection is the inability to grow these viruses in vitro in a laboratory setting. HPV group-specific antigen can be detected by means of immunohistochemical staining of cell or tissue samples; however, this method shows a lack of specificity, an inability to differentiate between HPV types and a poor correlation between presence of antigen and clinical outcome.(20,57)

Other laboratory approaches for diagnosing HPV infection rely on the identification of HPV DNA through hybridization techniques that use a known nucleic acid probe. These tests are in-situ hybridization, filter in-situ hybridization, the Southern blot technique and the dot blot technique.(11,20,53,58) In-situ hybridization involves the detection of HPV DNA in fixed or frozen tissue sections and is relatively less sensitive than the other techniques. The filter in-situ method involves hybridization against specific DNA probes after transfer of exfoliated cells to a filter; this technique has the advantages of being easy to perform and not requiring a biopsy specimen but may have a higher incidence of false-positive reactions. The Southern blot and dot blot techniques were designed to use biopsy material (although they may now be performed with material collected from "noninvasive" cervical or vaginal scrapes); they involve the identification of viral DNA separated from cellular DNA through gel electrophoresis.

Most research settings tend to use the Southern blot technique as their gold standard, but it is not well-suited as a widespread screening technique because it is time consuming, labour intensive and, consequently, expensive. The hybridization assays are relatively new methods for detecting HPV and are limited by as-yet poorly defined sensitivity and specificity and problems of interpretation, at least in part because of the adequacy of the sampling technique.

The polymerase chain reaction is a recently developed technique in which target DNA sequences are amplified in vitro to levels that greatly enhance their detection by conventional techniques of dot blot hybridization. This procedure is extremely sensitive but may have a significant false-positive rate. It is yet unclear how useful this method may be in screening for HPV infection.

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Effectiveness of early detection and treatment

Two therapeutic approaches that have had somewhat better results are interferon therapy and carbon dioxide laser vaporization.(62-69) A summary of recent trials of these treatments is presented in Table 4. The study by Carmichael and Maskens,(12) in which no treatment was given, is included for comparison. Although the "cure" rates were generally better than usually seen with the older therapies, the recurrence rate was still high in most studies (35% to 90% depending on the length of follow-up); also, the cure rate was good in the group of untreated subjects, which suggests that no treatment is a reasonable approach in many circumstances.

The goal of treatment may vary. Complete or permanent elimination of visible condylomata is one goal. Cancer detection and prevention are others. Older chemical treatments may be more acceptable to some patients than the newer, more invasive and expensive techniques such as laser vaporization. No therapy exists for nonvisible HPV infection, thus there is little value in screening for such latency.

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Adverse effects of HPV screening

• Morbidity of testing and treatment. Although Papanicolaou testing alone has few adverse effects apart from usually minor discomfort, the need for repeat testing, colposcopy, various destructive therapies and possible surgery may have a negative impact on the individual.
• A significant increase in the number of Papanicolaou smears and referrals for colposcopy (on a population basis) would result in large financial and other costs to society, including the increased depletion of resources to deal with the necessary testing and treatment.
• Most people with HPV infection are probably asymptomatic, and diagnosis of HPV infection may produce a significant labelling effect in many individuals. Of major importance is the knowledge that HPV infection is sexually transmissible. Although it may be in a dormant state for many months or years, considerable distress may follow once an otherwise healthy person becomes a "patient."

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Recommendations (Table 5)

The present screening recommendations for cervical cancer do not include specific testing for HPV infection beyond the recommendations for Papanicolaou testing. In the event of an abnormal result further testing (e.g., repeat Papanicolaou testing, colposcopy and biopsy) is at the discretion of the attending physician, often guided by the advice of the testing laboratory. Mass repeat testing of all atypical smears may add too great a burden on existing facilities. Current criteria for recall testing are appropriate for balancing false-negative and false-positive rates for Papanicolaou testing alone as a screening procedure, and the addition of further diagnostic tests to the present routine would add little to the effort to reduce the incidence of cervical cancer. In addition, further testing would considerably increase monetary costs, stretch the existing system beyond its capacity (especially with a rapid increase in the number of referrals for colposcopy) and likely increase morbidity considerably in terms of quality of life for many people, without adding established benefit.

Future research into HPV infection (see Research priorities) should be encouraged, since the ultimate aim of HPV screening -- the reduction in the incidence of cervical cancer -- continues to be a major research priority. Ultimately, any recommendations regarding HPV screening must be re-examined in the light of findings from further research, since so many current issues remain unresolved.

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Validation

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Research priorities

1. Refining a diagnostic method that will be sensitive, specific, noninvasive and appropriate for large-scale screening purposes to identify the type of HPV present or to predict which lesions are likely to progress to cervical cancer.
2. Defining precisely the incidence of HPV infection in the general population.
3. Assessing the risks associated with specific HPV genotypes for progression to cervical cancer.
4. Identifying cofactors that influence HPV transmission and that may promote carcinomatous changes in cervical lesions.
5. Finding effective treatments for people with HPV infection for whom it can be determined that treatment will produce a net benefit.
6. Developing immunologic therapies, especially a possible vaccine, for HPV infection.
7. Determining the efficacy and cost-effectiveness of screening for HPV infection.

We thank Drs. George H. Anderson, head of the Cytology Laboratories, British Columbia Cancer Agency, Vancouver, Máire A. Duggan, Foothills Provincial General Hospital, Calgary, and Paul R. Gully, chief, Sexually Transmitted Disease Control Division, Laboratory Centre for Disease Control, Ottawa, for reviewing the draft report. The views expressed in this report are those of the task force and do not necessarily reflect the positions of the reviewers.

The task force is funded by Health Canada and by the National Health Resear1ch and Development Program (grants 6605-2702-57X and 6603-1375-57X). Dr. Johnson was supported in part by the National Health Research and Development Program through a National Health Fellowship (AIDS).

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Members of the Canadian Task Force on the Periodic Health Examination:

Chairman: Dr. Richard Goldbloom, professor, Department of Pediatrics, Dalhousie University, Halifax, NS. Vice-chairman: Dr. Renaldo N. Battista, director, Division of Clinical Epidemiology, Montreal General Hospital, Montreal, Que. Members: Drs. Geoffrey Anderson, assistant professor, Department of Health Services Research and Development, University of British Columbia, Vancouver, BC; Marie-Dominique Beaulieu, associate professor, Department of Family Medicine, University of Montreal, Montreal, Que.; R. Wayne Elford, professor and chairman of research, Department of Family Medicine, University of Calgary, Calgary, Alta.; John W. Feightner, professor and research director, Department of Family Medicine, McMaster University, Hamilton, Ont.; William Feldman, professor of pediatrics, University of Toronto, and head, Division of General Pediatrics, Hospital for Sick Children, Toronto, Ont.; Alexander G. Logan, professor, Faculty of Medicine, University of Toronto, Toronto, Ont.; Brenda Morrison, professor, Department of Health Care and Epidemiology, University of British Columbia, Vancouver, BC; David Offord, professor, Department of Psychiatry, McMaster University, Hamilton, Ont.; Christopher Patterson, professor and head, Division of Geriatric Medicine, McMaster University, Hamilton, Ont.; Walter O. Spitzer, professor and chairman, Department of Epidemiology and Biostatistics, McGill University, Montreal, Que.; and Elaine Wang, assistant professor, Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Ont. Resource people: Dr. Phillip Mickelson, medical consultant, health standards, Health Services Directorate, Health Canada, Ottawa, Ont.; and Ms. Jennifer Dingle, coordinator, Canadian Task Force on the Periodic Health Examination, Department of Pediatrics, Dalhousie University, Halifax, NS

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