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© 2003 American Society for Clinical Oncology Cervical Cancer Screening: From the Papanicolaou Smear to the Vaccine EraFrom the Division of Women’s and Perinatal Pathology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA. Address reprint requests to Christopher P. Crum, MD, Department of Pathology, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115; email: cpcrum{at}rics.bwh.harvard.edu.
In the next 20 years, cervical cancer screening will have evolved through four phases. The first was traditional screening, which has been associated with a two-thirds reduction in cancer incidence and death rates in the last 50 years and currently is ending. We are entering a second phase, human papillomavirus (HPV) testing, for managing cytologic abnormalities and possibly for primary screening. A third phase, new in development, proposes the use of host biomarkers (or combinations thereof) as either surrogates of HPV infection or, potentially, indicators to assess cancer risk and concentrate available resources on a subset of women. The fourth and, likely, final phase will be screening in an era of vaccines. If HPV vaccines are successful, the pool of at-risk individuals and the prevalence of papillomaviruses that place them at risk will gradually shrink. In this climate, screening strategies that target HPVs alone (as opposed to cytologic testing) may become more economical. If so, previous strategies may become obsolete as the balance of cervical cancer prevention shifts from traditional screening to primary prevention coupled with HPV testing.
HUMAN PAPILLOMAVIRUSES (HPVs) are the principal cause of cervical neoplasia and are ubiquitous in sexually active populations, where more than 80% of reproductive-age women are infected at some point. HPVs are also tightly linked with cervical preinvasive and invasive neoplasia. The association between HPV and these diseases has spawned a major effort directed at the application of viral testing to clinical and laboratory management, and this endeavor has been encouraged by both improvements in the sensitivity of the test and a clearer picture of its potential applications. This has been supported further by recent initiatives, such as the Atypical Squamous Cells of Undetermined Significance (ASCUS)/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS) trial and subsequent consensus conferences, to redesign the classification and clinical management of cervical cytologic abnormalities (http://bethesda2001.cancer.gov; http://www.asccp.org).1 These combined efforts of the participating medical societies and the National Cancer Institute represent a significant commitment to HPV testing. This commitment, combined with further advances in molecular testing, could herald the decline of the Papanicolaou smear (at least as we know it) as the central decision point in patient management and the emergence of a "molecular age" in cervical cancer prevention. As defined, this molecular age of cervical cancer prevention also promises the discovery of host genes that reflect HPV infection or its related neoplastic changes. Theoretically, host biomarkers might be specifically upregulated by the presence of high-risk HPVs. Emerging data supporting the existence of such reagents will be discussed herein. Finally, recent reports supporting the use of vaccines in cervical cancer prevention may alter the equation, balancing both screening resources and cancer risk.
HPV infection is now considered necessary for the development of most cervical neoplasms.2 Young women are most susceptible, and cervical samples from these individuals frequently score positive (as many as 40%) for HPV. However, infections are transient, often appearing and disappearing without cytologic abnormality.3 Persistent infection by the same HPV type increases the risk of a current or subsequent cervical neoplasm.4,5
More than 100 HPVs have been characterized; at least 25 of these are in the genital tract. At present, those HPVs with any association to cancer are termed high-risk HPV types. Table 1
Approximately 15% of reproductive-age women will score positive for high-risk HPVs. Most HPV infections are transient, and the risk of developing high-grade squamous intraepithelial lesions (HSIL) depends on the actual HPV type (such as type 16 v other HPV types), the duration of infection (transient v persistent), and the amount of virus present (viral load).11,12 Only a few cases score positive for the same HPV type on successive tests. Elfgren et al13 found that 92% of HPV-positive women cleared their infection during a 5-year period, but persistence of infection, particularly type 16, was associated with cervical intraepithelial neoplasia (CIN) development. Others have shown a higher risk of cervical neoplasia when the same type was repeatedly identified.14–17 Viral load is strongly associated with the risk of developing a biopsy-proven squamous intraepithelial lesion. However, even small amounts of virus may herald the presence of a preinvasive lesion, and setting too high a threshold for HPV detection will exclude some patients with coincident preinvasive disease.11 The interval from HPV exposure to a cytologic abnormality seems to be only a few months. Kreider et al18 found that the interval from experimental HPV 11 infection of mucosal epithelium to the development of a morphologically distinct lesion was approximately 4 months. Koutsky et al19 showed that the interval from HPV positivity to lesion detection (when lesions developed) ranged from 0 to 24 months.
The Papanicolaou smear is largely credited with the decline in cervical cancer incidence and death. In the United States, the incidence rate of cervical cancer has declined by two thirds since the advent of screening. Precisely what the contribution of Papanicolaou smear screening to this incidence rate is remains disputed. For example, a previously unscreened population will yield many symptomatic and asymptomatic patients with cancer once screening has begun, and the incidence rate will decline abruptly.20 From that point, the incidence rate should reflect a higher proportion of asymptomatic women detected by cytologic testing alone, a fact that supports the higher proportion of early-stage disease seen in screened populations. The current rate in developing countries is approximately 14 per 100,000 per year.21 The magnitude of expected reduction after screening a previously unscreened population varies considerably among cultures, raising questions about the degree of benefit in cancer prevention that can be expected from cytologic screening programs. Nevertheless, aggressive screening programs have reported up to 75% reductions in cancer incidence and reductions in death because of downstaging of disease.22 In the United States at present, approximately 14,000 women develop cervical cancer yearly, and 4,500 die as a result of their disease. Approximately half of these women have not had a Papanicolaou smear within 5 years.23 The remainder have been screened within that interval and can be divided into two general groups: those who had Papanicolaou smear abnormalities that were missed (false-negative results) and those who had Papanicolaou smear abnormalities detected but inappropriately managed. Some abnormalities, such as atypical glandular cells, are less easily detected by screening. As a consequence, adenocarcinomas are more difficult to prevent.23,24 Rapidly progressing cervical cancers are more commonly associated with HPV 18; however, there are no other distinguishing characteristics of populations in which these tumors suddenly appear. Thus, in most cases, unexpected cancers are the result of inefficient screening.25 Most of the improvements in conventional screening have centered on liquid-based methods, and most studies examining these methods have reported higher rates of sensitivity compared with conventional cytologic screening.26 However, the contribution of these higher sensitivities to reductions in cancer death rate is considered negligible.
Conceptual Basis for HPV Testing HPV testing combines high sensitivity and an objective measurement of cervical cancer or precursor risk.27 If an HPV test result is positive, the risk of an HSIL will vary further, depending on whether the smear result is normal (approximately 10%), the smear is a nondiagnostic abnormality (15% to 20%), or HPV is detected at more than one visit (up to 33%). A single positive Hybrid Capture II (Digene Corporation, Gaithersburg, MD) test result, particularly in young women, has less value.27 However, the high negative predictive value of this test, combined with a normal Papanicolaou smear result, almost ensures that the patient is or will be free of a cancer precursor at the time of testing or in the immediate future. Bory et al27 found that fewer than one per 1,000 HPV-negative women developed HSIL, in contrast to more than 20% of women who were persistently positive by Hybrid Capture II, amounting to a more than 300-fold increased risk. Goldie et al28 showed that self-testing for HPV was not as sensitive as clinic testing but was as sensitive as the Papanicolaou smear. HPV testing is now recommended for the management of nondiagnostic cytologic abnormalities (ASCUS).1 It is conceivable that some patients managed by this triage strategy will benefit from a reduced cancer risk. Approximately 15% of women with cancer have had prior abnormalities that might be more uniformly managed in a setting of HPV testing.23 However, the principal goal of HPV testing is to improve management of women with ASCUS. The cost-benefit ratio increases as a function of the resources devoted to screening. Goldie et al28 showed that in developing countries, the cost-benefit ratio for limited cytologic screening is only a few dollars per life-year saved, at the expense of reducing the cervical cancer rate by less than half. In the United States and Canada, where screening programs have reported significant reductions in cancer incidence, the cost per life-year saved of adding HPV testing is thousands of dollars per year of life saved.28,29 The likelihood of detecting HPV decreases progressively after the age of 30 years, suggesting that targeting specific populations may reduce the numbers of positive tests while increasing their clinical significance.30,31 However, a recent study using a sensitive assay for detecting HPV found two peaks of HPV DNA prevalence. The first peak, of 16.7%, is seen in the group younger than 25 years of age. HPV DNA prevalence declines to 3.7% in the age group of 35 to 44 years and then increases progressively to 23% among women ≥ 65 years of age.32 Although such disparate results in older women may reflect different testing protocols and populations under study, they indicate that caution should be exercised in interpreting HPV test results in older women. A second caveat pertains to the specificity of an HPV-positive result in women older than 30 years of age. Clavel et al12 found that the specificity of HPV testing for HSIL increased only a few percentage points in this group, implying that most HPV-positive women, irrespective of age, will not harbor HSIL. Nevertheless, HPV testing in conjunction with cytology might permit a longer screening interval in older women.33
Application to the Management of Abnormal Cytologic Test Results Data from the ALTS trial indicated that both HSIL and low-grade squamous intraepithelial lesions (LSILs) scored positive in more than 80% of cases with Hybrid Capture II, and triage of these entities with HPV testing was not considered cost-effective.36 Efforts to make ASCUS more informative initially centered on subclassifying ASCUS, resulting in marked differences in HSIL risk between "ASCUS favor reactive" and "ASCUS favor HSIL." Although this strategy provides information useful in triaging patients with ASCUS, the more recent approach, and one that is designed to incorporate HPV testing, has been to contract ASCUS to just two categories: ASCUS and ASC favor HSIL.37
At present, three approaches are recommended for management of ASCUS: Papanicolaou smear follow-up, immediate colposcopy, and concurrent direct-from-vial (reflex) HPV testing. These have been detailed in a summary of the American Society of Colposcopy and Cervical Pathology–sponsored consensus conference held in Bethesda, MD, in September 2001.37 In brief, Papanicolaou smear follow-up is considered effective but less sensitive and requires at least two successive negative smear results to exclude the presence of disease with the efficiency of a single HPV test. On the basis of the ALTS trial, differences in risk for additional cytologic screening versus HPV testing can be computed and are listed in Table 2
Triage of atypical glandular cells of uncertain significance (AGUS). Although studies are preliminary, the following are established facts: first, recognition and interpretation of glandular atypias in cytologic screening are difficult and reproducibility is poor, and second, most glandular neoplasms that occur in reproductive-age women are HPV related. The underlying abnormalities associated with AGUS may include either HSIL or adenocarcinoma. As a consequence, the positive predictive value of an HPV-positive AGUS may be higher than for ASCUS, justifying tissue studies even in the absence of a colposcopic abnormality. This conclusion will await further studies to clarify the sensitivity and predictive value of HPV testing.38,39 HPV testing after cone biopsy. There is compelling evidence that HPV is eventually eliminated after ablative therapy. Tate et al40 showed that HPV was uncommonly present in the mucosa adjacent to squamous intraepithelial lesions, implying that if these lesions were removed, the virus would not remain in normal mucosa. In general, if the HPV test result is negative, recurrences are rare. Conversely, recurrences are virtually always associated with HPV.41–43 However, most studies report that HPV may be present, at least initially, after successful ablation and may persist for a few months despite the absence of persistent disease. Strand et al44 found that only 10% were HPV positive at 6 to 12 months after cone biopsy or laser vaporization. Thus, provided that testing is delayed for 6 to 12 months, it may provide useful information regarding the risk of recurrence, particularly in women with abnormal cytologic test results after cone biopsy.
Caveats
The Hybrid Capture II system, currently the most widely used assay, comprises 13 of the most common high- and intermediate-risk types. This cocktail has been demonstrated to detect more than 95% of infections of these types. However, this sensitivity is achieved by the variable detection of a range of HPV types that do not fall within the high-risk group, including types 6, 11, 53, 54, and 66, among others.36 This is not a significant disadvantage if patients are properly counseled and do not equate Hybrid Capture with a cancer virus test. Other approaches use type-specific assays that are polymerase chain reaction–based (Fig 1
One of the more problematic aspects of HPV testing is its inappropriate use. It is conceivable that a positive HPV test result with broad-spectrum, high-risk probes may prompt unduly aggressive management. This caution applies if the test is used indiscriminately and if positive results increase the likelihood of cone biopsy or hysterectomy.
Infection with high-risk HPVs may produce at least three fundamental alterations in cell biology that are germane to tumorigenesis. These pathways are illustrated in Fig 2  . First, both the E6 and E7 viral oncoproteins produce alterations in cell cycle control, either through disturbances in p53 and Rb activity or by directly upregulating cyclin expression.2 Second, there is evidence that viral oncoprotein expression upregulates telomerase activity, which is reversed by viral gene product E2-mediated suppression of these oncogenes.48 Third, E6/E7 mediate centrosome duplication, one of several possible mechanisms by which genomic instability is initiated after high-risk HPV infection.49,50 Accumulation of allelic imbalance and other sequelae result in a myriad of genetic alterations, some of which may provide alternate pathways for telomerase amplification.51
Because HPV oncoproteins induce alterations in the cell cycle, cell cycle biomarkers may function as surrogate markers of HPV infection and can be used to facilitate the diagnosis of cervical neoplasia. The principal value of these markers is to distinguish nondiagnostic atypias from squamous intraepithelial lesions, rather than to assign a grade of CIN. Expression of a generic cell cycle proliferative marker (Ki-67) is typically confined to the suprabasal cells of the lower third of epithelial cells in normal mucosa. The presence of Ki-67–positive cells in the upper epithelial layers is characteristic of HPV infection, which induces cell cycle activity in these cells51,52 (Fig 3 ). Thus, Ki-67 staining may be helpful in distinguishing reactive epithelial changes from LSIL or atrophic mucosa from HSIL. Similarly, cyclin E, a nuclear protein upregulated by HPV 16 E7 and also linked to viral replication, is uncommonly expressed in noninfected epithelium and, when conspicuously present in nuclei, will usually discriminate HPV-related cervical neoplasia53 (Fig 4). p16ink4, a cyclin-dependent kinase inhibitor, is the most promising; it is expressed strongly in lesions associated with intermediate- and high-risk HPV types. Because high-risk HPVs are common in both LSIL and HSIL, p16ink4 will not discriminate between the two. However, staining for this marker, at least in the cervix, is highly associated with HPV infection54–56 (Fig 3). Thus, p16ink4 is useful in any situation in which a squamous intraepithelial lesion must be excluded.
Other markers, including telomerase and MN/CA9, have also been proposed. The limitations of telomerase include lack of sensitivity and specificity.57 MN/CA9 is a tumor protein that localizes to neoplastic glandular epithelium but may also highlight normal endocervical columnar cells. Carcinoembryonic antigen is also upregulated in cervical neoplasia, but only in a subset of squamous and glandular neoplasms.58
One goal of current research in cervical cancer screening is to simplify the process of risk assessment. At present, this involves cytologic interpretation coupled with HPV testing, a combination that still yields only a 20% positive predictive value (for HSIL) for either HPV-positive ASCUS or a persistently positive high-risk HPV test result. Ideally, both cytologic and HPV testing could be eliminated in favor of one or more host biomarkers that could be identified in Papanicolaou smears by immunohistochemical analysis or in liquid-based assays59,60 (Figs 4
HPV infection and, with it, cervical neoplasia, may be preventable by vaccines. The accumulated evidence strongly indicates that cervical neoplasia is preventable by vaccines. The leading candidates are the viral-like particle vaccines discovered more than 10 years ago.61–63 These vaccines induce an immune titer approximately 50-fold stronger than natural immunity and, in animal and preliminary human trials, seem successful at preventing infection.63 The strengths and weaknesses of these vaccines can be summarized as follows: First, viral-like particle–derived vaccines to HPV 16 prevent HPV 16–associated precursor development, persistent carriage of HPV 16, and in most cases, transient carriage of the virus. This implies that the vaccines prevent transmission as well as infection.63 Second, protection conferred by vaccines is highly type specific, based on laboratory studies.64 Third, although more than 20 different HPV types have been isolated from cervical carcinomas, a polyvalent vaccine containing up to five HPV types (such as types 16, 18, 31, 33, and 45) could, depending on the population, cover more than 80% of virus infections responsible for cervical neoplasia.7 Fourth, a polyvalent vaccine addressing the above-mentioned types may actually prevent a higher proportion of cancer deaths. Types 16, 18, and 45 are responsible for up to 95% of adenocarcinomas and virtually all small-cell neuroendocrine carcinomas. Studies also have also linked more aggressive tumor behavior to types 16 and 18 versus 31, 33, 35, and so on.65 The four stages of cervical cancer screening summarized herein reflect the advances in medical knowledge that have permitted an intimate portrait of HPV pathobiology. Like most advances of this type, translation to the clinical arena depends heavily on not only the elegance of the concepts but also the practicality of their application in day-to-day practice. The flaws of cytologic and HPV testing depend on the circumstances under which each is used. Cytologic testing is not the ideal screening technique because of its high false-negative rate relative to HPV testing. Moreover, nearly 50% of nondiagnostic squamous atypias are related to innocuous cellular changes. HPV testing, although it is the most sensitive, suffers from a low specificity and positive predictive value that peaks at 15% to 20%, which is similar for women with HPV-positive ASCUS or persistent HPV positivity. The disadvantages of HPV testing—chiefly the high rate of infection in the population—would be altered if a vaccine that prevented most cancer-associated HPV infections took its place in public health programs and was administered early in reproductive life. If the vaccines were successful and significant reductions in HPV infection resulted, screening programs might operate in reverse, beginning with HPV testing as a triage maneuver followed by cytologic confirmation. The proportion of the population scoring positive for HPV and, consequently, the number requiring cytologic evaluation would be reduced. Whether such scenarios would have room for sophisticated biomarker detection would depend heavily on the success with which vaccines reduced the index of HPV in the population. If this were to occur, the trade-off of lower specificity (such as with HPV testing) might be acceptable in view of the smaller number of women requiring further triage.
DR. CANNISTRA: Typically, how do you manage a positive HPV test within the setting of ASCUS? DR. DePRIEST: In the old days, we would repeat the PAP smears and do colposcopy intermittently. Now, we use the thin prep vial to do HPV testing. If it's positive for high-risk HPV, then that patient can be triaged directly to the colposcopic exam. DR. BEREK: Based on the ALTS trial [J Natl Cancer Inst 93:293, 2001], we would tend to triage the patients with HPV testing. We would follow the paradigm that seems to be most cost-effective; that is, if they're negative for HPV, we bring them back in a year. If they're positive, we bring them in for colposcopy and then we would evaluate and direct the management based on the colposcopically directed findings and biopsies. DR. McGUIRE: Basically, I don't do them, but our gynecologist followed the ALTS guidelines. DR. CANNISTRA: Do you think this is an important advance or do you think ultimately it may have an even bigger role as a simplified screening test? DR. CRUM: I think it depends on the country. In an underserved population with limited resources, a single HPV test might be more feasible, with the simplicity of the test outweighing the lack of specificity. In our population, the available resources encourage both cytologic screening and HPV testing. In terms of cancer prevention, the estimated number of lives saved by adding HPV testing in the US is very low. DR. CANNISTRA: Is it too expensive? DR. CRUM: That depends on the expectations. HPV triage is geared for a population that can afford both liquid-based cytology and HPV testing. In the US, the projected savings from the reduction in colposcopies and immediate follow-up visits (for the HPV negatives) theoretically will outweigh the additional costs of the tests. Whether this will be the case remains to be determined. In an underserved country, this approach would be much too expensive. DR. SKATES: To put things in perspective, could I get a sense of the various costs that we're talking about for the different tests? DR. CRUM: Liquid-based cytology costs from $8 to $10 for consumables and reimburses from $30 to $50. DR. SKATES: And HPV testing? DR. CRUM: Hybrid Capture (Digene) costs about $35 for consumables not including technician time and reimburses from $35 to $110, depending on the payer. DR. SKATES: When you say HPV testing may become economically viable, what are the steps that would need to occur for that to happen? DR. CRUM: Currently, if you screen women, on average 15% will score positive. The rate drops progressively in older women. Screening programs that include HPV testing are now being considered for women over age 30. In this group, the added sensitivity may make it possible to lengthen the screening interval, yet the number of anticipated positives would be low enough to minimize the proportion requiring closer follow-up. In a vaccine age where positive rates begin to decline, the gradual reduction in high-risk HPV positives in the population would further encourage the use of HPV testing as a screening strategy. DR. CANNISTRA: Liquid-based cytology is now widely used throughout the states. What's the distribution? DR. CRUM: Common in the northeast; less toward the south and west. It's working its way down there. DR. BEREK: Even though there's a problem in developing countries, we still have a huge public health problem in this country; that is, half the patients who are dying of cervical cancer have never had a PAP smear and up to two thirds haven't been screened in the past 5 years. It's more than just trying to find a more sophisticated test. If we applied a lot of the resources we use to practicing yuppie medicine and put it to public health screening, we probably would reduce the mortality of the illness. DR. SKATES: What is the recommendation for cervical screening in this country and does it differ from what it is in the UK? DR. BEREK: The college recommendation is at age 18 or when sexually active, whichever comes first, annually, and then after three successive negatives, this may be reduced to less frequently at the discretion of the practitioner. DR. SKATES: What is the recommendation in the UK? DR. RUSTIN: It's every 3 years.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
