SEARCH

SEARCH BY CITATION

Keywords:

  • cervical abnormalities;
  • colposcopy-guided biopsy;
  • oncogenic human papillomavirus testing;
  • positive predictive value;
  • prevention;
  • screening;
  • viral-like particle vaccines

Abstract

  1. Top of page
  2. Abstract
  3. Screening Test Performance
  4. Triage of Equivocal Screening Results
  5. Diagnosis and Treatment Decisions
  6. Cost-effectiveness
  7. Screening Recommendations: Current and Future
  8. REFERENCES

The development of a prophylactic human papillomavirus (HPV) vaccine that potentially may eliminate a majority of cervical cancers is a landmark in cancer prevention. Cervical screening, however, will continue to play an important role for the foreseeable future. Maintaining screening at the same intensity and simply adding on the expense of vaccination would result in redundancy of prevention efforts at enormously increased costs without necessarily further reducing cervical cancer mortality. Effectively integrating vaccination and screening efforts will be a critical and evolving challenge over the next decade; this will require understanding not only the impact of vaccination on reducing cervical abnormalities but also the influence of vaccination on screening test performance. Cancer 2008;113:(10 suppl):3031–5. Published 2008 by the American Cancer Society.

Prophylactic viral-like particle (VLP) vaccines that target oncogenic HPV types 16 and 18 (HPV-16 and HPV-18) prevent infections and cell abnormalities caused by these HPV types in previously unexposed girls and women. Preventing these infections eventually could eliminate approximately 70% of cervical cancer cases worldwide.1 In the excellent overview by Dunne et al2 in this Supplement, the authors emphasize that, even with successful vaccination, cervical cancer screening will remain an essential component of cancer prevention, probably for several decades, for the following reasons: 1) Approximately 15 types of HPV can cause cervical cancer. Currently, VLP vaccines primarily protect against oncogenic HPV-16 and HPV-18, which, together, account for approximately 70% of cervical cancers worldwide, with minor regional variation in this percentage.1 Although there is evidence for some degree of cross-protection for a few closely related types, we will need to continue screening for cervical abnormalities caused by non-16/18 oncogenic HPV types. 2) The VLP vaccines are effective in preventing infection in females previously unexposed to the targeted HPV types. However, the vaccine does not treat pre-existing infections.3–5 Women who are infected before vaccination remain at risk for abnormalities. 3) Current vaccination recommendations6, 7 appropriately emphasize the targeting of young girls before their beginning sexual activity; the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices includes ‘catch-up’ for women up to age 26 years. Vaccination is not recommended for women aged >26 years as of this writing, and there is no evidence of a significant burden of precancer or cancer because of incident infection in this population.

Although it will take decades for vaccination programs to reduce cervical cancer incidence and mortality substantially, the impact on precursor lesions will be evident much more quickly. Currently, we spend billions of dollars on cervical screening, diagnosis, management—and treatment of cervical abnormalities—the majority of which never will progress to cancer. Changes in the relative rates of different grades of cervical abnormalities already are appreciable among women who are being followed as participants in HPV vaccine clinical trials.4, 5 Therefore, now is the time to consider the soon-to-be altered role and nature of secondary prevention efforts as vaccine coverage increases.

To summarize what is detailed below, vaccination will decrease the incidence of conditions that are targeted for secondary prevention efforts, precancer (cervical intraepithelial neoplasia grade 3 [CIN-3]) and cancer, and, thus, will decrease the efficiency of screening tests and diagnostic methods in vaccinated populations. Specifically, the elimination of histologic CIN-3 lesions caused by HPV-16 and HPV-18 infections will be welcome, but this also will translate into lower positive predictive values for abnormal screening tests and diagnostic results.8

The discussion below is organized by the chronologic steps that comprise cervical cancer secondary prevention programs. These include screening of women in the general population without known disease, triage of equivocal results, diagnosis of women with screening abnormalities, decisions on treatment, cost-effectiveness, and screening recommendations.

Screening Test Performance

  1. Top of page
  2. Abstract
  3. Screening Test Performance
  4. Triage of Equivocal Screening Results
  5. Diagnosis and Treatment Decisions
  6. Cost-effectiveness
  7. Screening Recommendations: Current and Future
  8. REFERENCES

For cervical cytology screening, vaccination will have an additional effect of preferentially reducing high-grade cytologic findings compared with equivocal and low-grade changes. To understand this, we need to review aspects of HPV natural history. Low-grade cytologic changes may be caused by any 1 of 40 or so anogenital HPV types (only ≈15 of which are considered oncogenic). High-grade cytologic abnormalities are caused largely by oncogenic HPV types, most commonly HPV-16.9 In a vaccinated cohort, the elimination of HPV-16/HPV-18-associated cytologic abnormalities will reduce the number of high-grade results disproportionately to the reduction of lesser abnormalities. This already can be seen in the early data from Merck (West Point, PA) and GlaxoSmithKline (Rixensart, Belgium) vaccine trial populations.4, 5, 10 Therefore, not only will the overall number of abnormal results decrease, but the distribution of cytologic abnormalities will be shifted to relatively more equivocal and low-grade findings and fewer high-grade lesions. Currently, high-grade cytologic abnormalities comprise less than 1% of screening interpretations.11 It is not known how such shifts may affect cytotechnologists' screening performance, especially if they encounter high-grade lesions even less often.

Removing HPV-16 and HPV-18 (and an unknown fraction of HPV-31 and HPV-45 because of cross-protection) also will decrease the positive predictive value of HPV testing using pooled genotype formats that probe for all oncogenic HPV types. Increasingly, oncogenic HPV DNA testing is being used in conjunction with cytology among women aged ≥30 years to provide increased sensitivity and better risk prediction with the possibility of fewer cycles of screening.8 The predictive power of oncogenic HPV testing derives in large part from the detection of HPV-16 and HPV-18.12 However, the elimination of these HPV genotypes through vaccination would make cervical precancer and cancer much rarer while reducing the overall number of women testing positive by only ≈10%, thereby diminishing the predictive value of a positive HPV test result.

HPV infections typically are transient: Most infections, especially non-HPV-16 infections, resolve within 1 year, and approximately 90% are no longer detectable by 2 years.13, 14 The longer HPV infections persist, the more likely they are to continue to persist13, 14; and they increasingly are more likely to be associated with a precancerous lesion. Given the central role of HPV persistence in the development of cervical precancer and cancer, HPV testing specificity could be increased if evidence of viral persistence was the trigger for additional follow-up.

There is some evidence to support a minimum 1-year threshold for clinically meaningful persistence. Follow-up research studies with repeat genotype-specific measurements over 1 year or 2 years begin to distinguish persistent infections and associated lesions that pose greater risk from transient infections that pose a lower risk. However, the current US Food and Drug Administration (FDA)-approved HPV test does not identify specific HPV genotypes; positive results only indicate the presence of 1 or more of the oncogenic genotypes included in the pooled probe. A screening strategy based on determination of HPV genotype-specific persistence, providing high predictive value for precancer over the subsequent 5 to 10 years. This strategy must necessarily await widespread availability of validated partial or full HPV genotyping assays.15 In the interim, consecutive positive tests using the current FDA-approved HPV test will serve as a useful surrogate for HPV persistence, especially for older women, whose prevalent infections are more likely to persist and who are less likely to acquire new infections.

Triage of Equivocal Screening Results

  1. Top of page
  2. Abstract
  3. Screening Test Performance
  4. Triage of Equivocal Screening Results
  5. Diagnosis and Treatment Decisions
  6. Cost-effectiveness
  7. Screening Recommendations: Current and Future
  8. REFERENCES

HPV testing is now used widely to triage equivocal cytology (atypical squamous cells of undetermined significance [ASC-US]).16 The negative predictive value of HPV testing for this application will remain high among vaccinated cohorts, because a negative test still will predict extremely low risk. However, the positive predictive among women with HPV-positive ASC-US will be lower than it is now. Therefore, the clarity of risk stratification afforded by triage with a HPV-positive ASC-US single ‘reflex’ HPV test will be reduced; in effect, all women will be at lower risk. Therefore, in the context of triage (as well as screening), requiring consecutive positive HPV tests to trigger colposcopy could improve risk prediction and positive predictive values for test results.

Diagnosis and Treatment Decisions

  1. Top of page
  2. Abstract
  3. Screening Test Performance
  4. Triage of Equivocal Screening Results
  5. Diagnosis and Treatment Decisions
  6. Cost-effectiveness
  7. Screening Recommendations: Current and Future
  8. REFERENCES

Little attention has been paid to the impact of vaccination on the performance of the current reference standard of diagnosis—colposcopy-guided biopsy. Colposcopy serves 2 purposes: to rule out invasive cancer and to guide the clinician in identifying the worst lesion for taking biopsies. The art of colposcopy, which already is challenged by the very small CIN-3 lesions that are present in young women in well screened cohorts, will become even more difficult when vaccination is added to screening. Colposcopy was designed to detect large CIN-3 lesions and cancers. Colposcopic impression is not reproducible for the delineation of metaplasia, acute HPV infection, or low-grade lesions.16 Even CIN-3 lesions, if they are small, are easy to miss. However, HPV-16 produces the most clearly identifiable abnormal lesions. When HPV-16 is less prevalent because of vaccination, the remaining clinically relevant lesions will be very difficult to distinguish from minor changes and abnormalities of the cervical epithelia and will be difficult to target successfully by biopsy.

It is becoming evident that HPV-16 and HPV-18 cause the most threatening cases of cervical neoplasia.12 In particular, HPV-16 and HPV-18 associated precancers may progress to cancer faster than other HPV types, and HPV-18 is associated with invasive cases that are difficult-to-detect in the precancerous stage.17, 18 If HPV-16- and HPV-18-associated high-grade lesions are eliminated, then the decision to treat remaining CIN-2, an equivocal precancer,19 may need to be reconsidered to avoid over-treatment and its consequences.20

Cost-effectiveness

  1. Top of page
  2. Abstract
  3. Screening Test Performance
  4. Triage of Equivocal Screening Results
  5. Diagnosis and Treatment Decisions
  6. Cost-effectiveness
  7. Screening Recommendations: Current and Future
  8. REFERENCES

Primary prevention of a proportion of cervical cancer through vaccination will be a tremendous achievement. However, effectively integrating vaccination and screening efforts will be a critical and evolving challenge over the next decade. It has been estimated that the current cervical cancer prevention effort in the United States may cost billions of dollars per year. HPV vaccines are expensive, and implementation may cost billions more. At least for the public sector, health resources are limited and competitive. Maintaining screening at the same intensity and simply adding on the expense of vaccination would result in redundancy of prevention efforts at enormously increased costs without necessarily further reducing cervical cancer mortality.

To determine the impact of successful vaccination efforts on the performance of screening, triage and management will require 5 to 10 years for a cohort of young vaccinated adolescents to become sexually active and reach the ages of peak prevalence of HPV-associated lesions. HPV infection and associated equivocal and low-grade cytologic abnormalities quickly follow the initiation of sexual activity. The average age of CIN-3 lesions forms a bell-shaped curve, with a peak incidence in highly screened populations approximately 10 years after the average age at first sexual intercourse. Therefore, it will not take very long to be able to see the effect of HPV vaccination. Public health experts and the cervical cancer prevention community should begin planning studies now to assess these effects and to consider strategies for integrating vaccination and screening. The commentary in this Supplement by Saraiya et al21 discusses how cancer registries may play a role in monitoring the impact of vaccination.

Screening Recommendations: Current and Future

  1. Top of page
  2. Abstract
  3. Screening Test Performance
  4. Triage of Equivocal Screening Results
  5. Diagnosis and Treatment Decisions
  6. Cost-effectiveness
  7. Screening Recommendations: Current and Future
  8. REFERENCES

In anticipating how screening recommendations may be modified in the next decade, several possibilities have been proposed: delaying the age of initiation of screening; extending the interval between screenings; and/or using different screening modalities.22 Current recommendations call for screening approximately 3 years after the onset of sexual activity, or by age 21 years.23, 24 Waiting for 3 years allows many transient HPV infections that are acquired soon after initiation of sexual activity to clear before screening. Cervical cancer is extraordinarily rare in women aged <25 years and may be caused disproportionately by HPV-16 or HPV-18. Therefore, vaccination should result in an even greater reduction in the risk for precancer and cancer in this age group and may allow a delay in the age of initiation of screening until women are in their middle 20s. Screening 5 years after beginning sexual activity, or by age 25 years, would avoid even more of the peak in benign HPV infections and associated cytologic abnormalities, the vast majority of which clear within 2 years. Consequently, there should be a reduction in unnecessary follow-up and treatment of equivocal disease.

In addition to increasing the age of initiation of screening, the reduced risk for precancer and cancer in vaccinated cohorts may allow an extension of the interval between screenings. This is especially true if a more sensitive screening test is used. Computer-based, location-guided screening25 and/or ancillary use of molecular markers26 potentially may increase the sensitivity of cytology without a loss of specificity.

Several studies have demonstrated increased sensitivity of HPV testing compared with cytology alone for cervical screening in women aged ≥30 years.27–31 Current recommendations include the option of screening with both cytology and HPV testing in this age group. In fact, concurrently performed cytology adds little to the sensitivity or negative predictive value of oncogenic HPV testing. Modeling has been used to demonstrate that dual testing is extremely cost-inefficient compared with HPV testing followed by cytology triage of HPV-positive results.22 In the latter scenario, women who are HPV-positive and cytology-positive would be referred for colposcopy, whereas HPV-positive but cytology-negative women would have repeat HPV testing in 12 months. If validated HPV genotyping tests become available, then management may depend on the HPV type identified: The presence of HPV-16 or HPV-18 would trigger colposcopy, whereas women with other carcinogenic HPV types would be followed with repeat testing.12 Increasing the numbers of biopsies taken at colposcopy probably would increase the sensitivity of the procedure.31

Thoughtful integration of vaccination and screening will reduce not only cervical cancer risk, but also overtreatment for abnormalities destined to resolve. Clinical studies and cost-effectiveness analyses will provide the basis for deciding which prevention strategies are best for specific regions, resulting in strategies that are tailored to their resources and societal priorities. The important task will be to make sure that all women have access to excellent strategies based on the latest knowledge and reliable prevention tools.

REFERENCES

  1. Top of page
  2. Abstract
  3. Screening Test Performance
  4. Triage of Equivocal Screening Results
  5. Diagnosis and Treatment Decisions
  6. Cost-effectiveness
  7. Screening Recommendations: Current and Future
  8. REFERENCES
  • 1
    Munoz N,Bosch FX,Castellsague X, et al. Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer. 2004; 20:111: 278285.
  • 2
    Dunne EF,Datta SD,Markowitz L. A review of prophylactic human papillomavirus vaccines: recommendations and monitoring in the United States. Cancer. 2008; 113( 10 suppl): 29953003.
  • 3
    Hildesheim A,Herrero R,Wacholder S, et al. Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. JAMA. 2007; 298: 743753.
  • 4
    FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007; 356: 19151927.
  • 5
    Garland SM,Hernandez-Avila M,Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007; 356: 19281943.
  • 6
    Saslow D,Castle PE,Cox JT, et al. American Cancer Society guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin. 2007; 57: 728.
  • 7
    Markowitz LE,Dunne EF,Saraiya M,Lawson HW,Chesson H,Unger ER. Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007; 56: 124.
  • 8
    Schiffman M. Integration of human papillomavirus vaccination, cytology, and human papillomavirus testing. Cancer. 2007; 111: 145153.
  • 9
    Kovacic MB,Castle PE,Herrero R, et al. Relationships of human papillomavirus type, qualitative viral load, and age with cytologic abnormality. Cancer Res. 2006; 66: 1011210119.
  • 10
    Paavonen J,Jenkins D,Bosch FX, et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet. 2007; 369: 21612170.
  • 11
    Davey DD,Neal MH,Wilbur DC,Colgan TJ,Styer PE,Mody DR. Bethesda 2001 implementation and reporting rates: 2003 practices of participants in the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology. Arch Pathol Lab Med. 2004; 128: 1224129.
  • 12
    Khan MJ,Castle PE,Lorincz AT, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2005; 20:97: 1072109.
  • 13
    Plummer M,Schiffman M,Castle PE,Maucort-Boulch D,Wheeler CM. A 2-year prospective study of human papillomavirus persistence among women with a cytological diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion. J Infect Dis. 2007; 195: 1582159.
  • 14
    Rodriguez AC,Schiffman M,Herrero R, et al; Proyecto Epidemiologico Guanacastle Group. Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. J Natl Cancer Inst. 2008: 100: 513517.
  • 15
    Stoler MH,Castle PE,Solomon D,Schiffman M. The expanded use of HPV testing in gynecologic practice per ASCCP-guided management requires the use of well-validated assays. Am J Clin Pathol. 2007; 127: 13.
  • 16
    Jeronimo J,Massad LS,Schiffman M. Visual appearance of the uterine cervix: correlation with human papillomavirus detection and type. Am J Obstet Gynecol. 2007; 197: 4748.
  • 17
    Lorincz AT,Reid R,Jenson AB,Greenberg MD,Lancaster W,Kurman RJ. Human papillomavirus infection of the cervix: relative risk associations of 15 common anogenital types. Obstet Gynecol. 1992; 79: 328337.
  • 18
    Smith JS,Lindsay L,Hoots B, et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer. 2007; 121: 621632.
  • 19
    Castle PE,Stoler MH,Solomon D,Schiffman M. The relationship of community biopsy-diagnosed cervical intraepithelial neoplasia grade 2 to the quality control pathology-reviewed diagnoses: an ALTS report. Am J Clin Pathol. 2007; 127: 805815.
  • 20
    Kyrgiou M,Koliopoulos G,Martin-Hirsch P,Arbyn M,Prendiville W,Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet. 2006; 367: 489498.
  • 21
    Saraiya M,Goodman MT,Datta SD,Chen VW,Wingo PA. Cancer registries and monitoring the impact of prophylactic human papillomavirus vaccines: the potential role [commentary]. Cancer. 2008; 113( 10 suppl): 30473057.
  • 22
    Goldhaber-Fiebert JD,Stout NK,Salomon JA,Kuntz KM,Goldie SJ. Cost-effectiveness of cervical cancer screening with human papillomavirus DNA testing and HPV-16,18 vaccination. J Natl Cancer Inst. 2008; 100: 308320.
  • 23
    Saslow D,Runowicz CD,Solomon D, et al. American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin. 2002; 52: 342362.
  • 24
    Wright TCJr,Massad LS,Dunton CJ,Spitzer M,Wilkinson EJ,Solomon D. 2006 Consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol. 2007; 197: 346355.
  • 25
    Davey E,d'Assuncao J,Irwig L, et al. Accuracy of reading liquid based cytology slides using the ThinPrep Imager compared with conventional cytology: prospective study. BMJ. 2007; 335: 3131.
  • 26
    Wentzensen N,von Knebel DM. Biomarkers in cervical cancer screening. Dis Markers. 2007; 23: 315330.
  • 27
    Naucler P,Ryd W,Tornberg S, et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med. 2007; 357: 15891597.
  • 28
    Mayrand MH,Duarte-Franco E,Rodrigues I, et al. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med. 2007; 357: 15791588.
  • 29
    Ronco G,Giorgi-Rossi P,Carozzi F, et al. Human papillomavirus testing and liquid-based cytology in primary screening of women younger than 35 years: results at recruitment fora randomised controlled trial. Lancet Oncol. 2006; 7: 547555.
  • 30
    Bulkmans NW,Berkhof J,Rozendaal L, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet. 2007; 370: 17641772.
  • 31
    Ronco G,Segnan N,Giorgi-Rossi P, et al. Human papillomavirus testing and liquid-based cytology: results at recruitment from the new technologies for cervical cancer randomized controlled trial. J Natl Cancer Inst. 2006; 98: 765774.