COMMENTARY Recent Progress in Defining the Epidemiology of Human Papillomavirus Infection and Cervical Neoplasia Mark H. Schiffinan*
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development, recurrence, or pathologic progression of cervical neoplasia (15,16). These efforts have proven more difficult than anticipated, partly because of methodologic problems with HPV assays, which generally depend on the detection of HPV-specific DNA in samples of cervical tissue. The results have proven to be strikingly dependent on methods of cervical tissue sampling and DNA detection. At present, at least four different techniques of collecting exfoliated cervical cells for HPV testing are in common use: swab, scrape, cytobrush, and lavage. Test sensitivity has been shown to vary by collection method (17). Once cervical samples are collected, multiple methods of DNA-DNA or RNA-DNA hybridization are used for HPV detection and typing. Most epidemiologists have used either a commercially available RNA-DNA dot blot system (18) or polymerase chain reaction (PCR) techniques developed to amplify DNA sequences shared by many of the 20 or so different types of genital HPVs (19). However, no "gold standard" has yet been established. An informal survey at a recent HPV meeting revealed over 20 discrete techniques in current use, and the noncomparability of the many methods was the topic of several recent reports (19-22). It is not surprising, therefore, that early epidemiologic studies of HPV and cervical neoplasia, using new and imperfectly validated methods, failed to find several expected associations [discussed in (23)]. Although most investigators have observed an elevated prevalence of HPV in women with existing cervical neoplasia compared with control women, the estimated magnitude of the increase has varied substantially, primarily because the prevalence of HPV among cytologically normal women has
Received November 27. 1991: revised January 16, 1992; accepted January 21, 1992. I thank Tom Rohan for expert review and Susan Devesa. Allan Hildesheim, Louise Brinton, Mary Hagerty, and Kathy Amidon for help in preparing this commentary. *Correspondence to: Mark H. Schiffman, M.D., M.P.H. Environmental Epidemiology Branch, Division of Cancer Etiology. National Cancer Institute, Executive Plaza North, Rm. 443, Bethesda, MD 20892.
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This commentary describes recent epidemiologic advances in understanding the natural history of cervical neoplasia which have confirmed the central etiologic role of human papillomavirus (HPV) infection. Epidemiologic data have long suggested that a venereally transmitted infectious agent causes cervical neoplasia (a term used to include invasive cervical cancer and its intraepithelial precursor lesions). In particular, numerous studies have established that the risk of cervical neoplasia is increased among women who initiate sexual intercourse at earlier ages and who have greater numbers of sexual partners (/). In the mid-1980s, case series assembled by laboratory scientists demonstrated that biopsy specimens of cervical cancer contain HPV DNA sequences (2). Subsequently, laboratory evidence supporting a causal role for HPV infection in the etiology of cervical neoplasia has strengthened considerably. Repeated studies have demonstrated that the majority of cervical intraepithelial lesions, cervical cancers, and derived cell lines contain HPV DNA {3-5). The transforming activities of proteins encoded by the E6 and E7 regions of the HPV genome strongly suggest that HPV is not merely a "passenger virus" with a predilection for neoplastic cervical cells (6). Recent studies (7,8), demonstrating that these transforming proteins bind to tumor suppressor gene products, provide a plausible mechanism for HPV-induced cervical neoplasia. To corroborate these laboratory findings, epidemiologists have attempted, from their perspective, to confirm that HPV infection is the long-sought, venereally transmissible cause of cervical neoplasia. Most epidemiologic research has focused on a few key points. Epidemiologists have studied the prevalence of HPV infection among cytologically normal women (9-11) and made the case-control comparisons needed for the interpretation of a high prevalence of HPV positivity among women with cervical neoplasia (12). They have investigated the risk factors for HPV infection, reasoning that HPV should share many of the same risk factors as cervical neoplasia if the virus causes the disease (10,12-14). Finally, they have established prospective investigations to examine whether HPV infection predicts the
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As improved HPV assays are used, expected associations are being observed with regard to the correlation between HPV infection and known risk factors for cervical neoplasia. A recent investigation of the correlates of HPV infection among 400 cytologically normal women attending a student health clinic in Berkeley, Calif., demonstrated convincingly that women with multiple sexual partners are at increased risk of HPV infection (14). A strong and stepwise gradient of risk of infection with number of partners was observed. In this same investigation, other well-known risk factors for cervical neoplasia were also found to be associated with HPV positivity, including age at first intercourse, oral contraceptive use, and race (Black). Many of these correlations have also been observed in other recent studies [(30-33); Bauer HM, Schiffman MH, Manos MM, et al.: unpublished data]. Thus, HPV infection "fits" as an intermediate end point that could logically explain many traditional epidemiologic risk factors for cervical neoplasia. The largest cohort studies of HPV infection among cytologically normal women have not yet published their earliest results. However, unpublished data from the three prospective studies with the longest follow-up of HPV-infected women all show an elevated risk of progression to overt cervical intraepithelial neoplasia within a few years of follow-up [(16); Paavonen J, Nieminen P, Aho M, et al.: unpublished data; Schiffman MH, Manos MM, Glass AG, et al.: unpublished data]. Additionally, two follow-up studies of women with low-grade lesions have observed that the HPV type influences the risk of disease progression (15 J4), and several small follow-up studies of women with invasive cancer have suggested that the presence and/or type of HPV might predict prognosis (35-38). As a whole, the current epidemiologic data support a central, causal role for HPV infection in the etiology of cervical neoplasia. Nonetheless, genital HPV infection is very common among young, cytologically normal women (11), leading some investigators to question the risk posed by infection in the absence of still-to-be-defined host factors and/or cofactors. The disproportionately high prevalence of HPV in young women, compared with the much lower incidence of cervical neoplasia in older women, may be partly a consequence of transient versus persistent infection. In several population studies reported recently, HPV "point" prevalence among cytologically normal women (based on a single measurement for each woman) was observed to peak among sexually active women in their early twenties and then to decrease substantially with age (Fig. 1) (28,39,40). In contrast, HPV positivity among women with apparent neoplasia remains very high regardless of age. The agerelated decrease in HPV detection among cytologically normal women is quite important, because the strongest predictor of HPV positivity, lifetime number of sexual partners, tends to increase with age. The decline in HPV positivity despite an increased cumulative number of partners suggests that many HPV infections are transient, due to suppression of genital HPV infection and cessation of detectable viral shedding. The decreasing age trend in HPV prevalence could also theoretically be attributable in part to an international "cohort effect" of increasing HPV infection in younger women. There is evidence that venereal warts, caused by HPV types 6 and 11, are increasing in prevalence (41). Similar data regarding time trends in the
COMMENTARY 395
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ranged unbelievably from under 5% (24) to 80% (25). HPV prevalence has not been observed to be elevated consistently in populations at known high risk of cervical neoplasia (9,26). Moreover, several early studies found few correlations between HPV positivity and the established epidemiologic risk factors for cervical neoplasia (10,12,13). In particular, the early investigations observed no relationship between HPV infection and the measures of lifetime sexual behavior known to influence greatly the risk of cervical neoplasia. Few prospective studies of HPV natural history have been published because of the time required to establish and follow sufficiently large cohorts of HPVtested women. It is encouraging that, in the past year, epidemiologic data have been reported that parallel the optimistic and convincing laboratory work demonstrating HPV oncogenicity. The new studies have used HPV assays that were better validated than earlier epidemiologic investigations, reinforcing the impression that misclassification of HPV status may have limited the first generation of epidemiologic studies (27). Recent case-control data have firmly established that the great majority of women with existent cervical neoplasia concurrently have detectable HPV DNA, compared with a much lower percentage of control women. In several carefully performed casecontrol studies using good HPV assay methods, HPV detection has been associated with a 10-fold or greater risk of cervical neoplasia [(25); Schiffman MH, Manos MM, Glass AG, et al.: unpublished data; Munoz N, Bosch FX, Shah K, et al.: unpublished data]. In one investigation of high-grade intraepithelial neoplasia (including moderate dysplasia, severe dysplasia, and carcinoma in situ), the relative risk of neoplasia associated with HPV was 40, with a lower 95% confidence bound of 15 (Schiffman MH, Manos MM, Glass AG, et al.: unpublished data). The proportion of intraepithelial neoplasia apparently attributable to HPV infection approached 90%. Relative risks and attributable proportions of this strength and consistency are so rare in cancer epidemiology that the statistical association of HPV and cervical neoplasia is virtually beyond question. The association of specific HPV types with higher grade cervical neoplasia is also virtually certain. Although the number of known genital HPV types now exceeds 20, with no end in sight to the discovery of new types, certain ones (notably 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, and 58) account for about 90% of infections in cases of high-grade intraepithelial neoplasia and cancer (29). Type 16 appears to be the single most common cancer-associated HPV type in all geographic areas surveyed (5£9) and is the most common HPV type in the cytologically normal female population as well (11). In aggregate, however, cancer-associated HPV types account for only about half of the genital infections detected among women with normal cytologic diagnoses or low-grade cervical dysplasia, when detection methods capable of capturing most HPV types are used [(5); Manos MM, Zhang T, Bauer HM, et al.: unpublished data]. The type-specific prevalence estimates corroborate parallel laboratory evidence suggesting that many genital types of HPV can cause the appearance of low-grade intraepithelial lesions but that fewer types are likely to cause high-grade lesions.
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Age Group Fig. 1. Age-specific patterns of HPV infection and cervical neoplasia. Point prevalence of HPV DNA in cytologically normal women decreases with age, based on data from 463 women screened in 1989-1990 at Kaiser-Permanente in Portland, Ore. ( • ) . Point prevalence of the early cytopathologic effects of HPV infection, called condylomatous atypia, also declines with age, based on data from 19 571 women who obtained Pap smears in 1989-1990 at the same KaiserPermanente gynecology and obstetrics clinics (•). In contrast, the incidence of cervical intraepithelial neoplasia 3 among White women in the United States (A) increases with age to a peak at ages 25-29 years, then declines, perhaps due in pan to a decrease in Pap smear screening. The incidence of invasive cervical cancer rises to a plateau around ages 35-39 years in White women in the United States ( O ) but continues to rise at later'ages in Black women (data not shown). The incidence data for cervical intraepithelial neoplasia 3 and invasive cancer are derived from the National Cancer Institute Surveillance, Epidemiology, and End Results Program cancer registries for the years 1984-1988 and are restricted to White women for comparability with the Portland data.
prevalence of cervical cytologic abnormalities have been reported (41,42) but are more difficult to collect because time trends in Pap smear diagnoses can be confounded by the increasing recognition by cytopathologists of minor HPVassociated changes. Whether or not HPV infection is increasing in prevalence, preliminary data from natural history studies support the interpretation that most HPV infections found in young women are detectable only transiently. When cytologically normal women are measured repeatedly, most HPV-infected women do not have persistent infection—defined as continued detection of the same viral type or types (Burk RB, Rosenthal WD, Rose E, et al.: unpublished data; Schneider A, Gissmann L, Kirchhoff T, et al.: unpublished data; Schiffman MH, Manos MM, Glass AG, et al.: unpublished data). These data are consistent with earlier studies demonstrating that repeated HPV testing tends to detect virus at least once in a high proportion of apparently cytologically normal women (43). Overall, the occasional detection of 396
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0 . 1 O)
HPV in young and sexually active women may be common and not clinically important. If HPV infection is commonly suppressed, the resultant state of the virus is unknown, and it is not yet clear whether genital HPV infections are entirely eliminated or merely become latent. A series of small studies of HIV-infected women have reported extremely high prevalences of both HPV DNA detection and overt intraepithelial neoplasia associated with immunosuppression, supporting the possibility of latent, potentially re-emergent infections (44,45). In summary, recent epidemiologic results are encouraging because they suggest a coherent (though admittedly still hypothetical) natural history schema of HPV infection and cervical neoplasia. The schema, supported by the cross-sectional data shown in Fig. 1, can be stated as follows. As women initiate sexual intercourse in their teens and twenties, transient genital HPV infection is a common result. Many women develop no obvious clinical evidence of disease and eventually suppress or lose the infection. Others exhibit low-grade cervical lesions that may regress spontaneously as a result of poorly understood host defense mechanisms. A minority of women exposed to HPV develop persistent infection, perhaps as a result of an inadequate immune response. Some of those persistent infections of certain high-risk HPV types progress to high-grade intraepithelial lesions, which peak in diagnosis at around 25-29 years of age. Cofactors, including smoking, oral contraceptive use, or infection with other sexually transmitted diseases, may have a role in this progression. The same cofactors or other factors influencing the integration of HPV DNA into the human genome may cause in some women the subsequent progression to invasive disease, the incidence of which reaches a plateau in the White U.S. female population at around 35-39 years of age. The next generation of epidemiologic studies of HPV will undoubtedly focus on testing this hypothetical schema or on alternative views of the natural history of infection related to cervical neoplasia. A few especially important questions can be identified already. 1) Is HPV infection transmitted almost entirely by sexual intercourse, or are other routes of transmission also important? Serologic measures of exposure to HPV are not yet trustworthy, but early results suggest that many young children may already have been exposed to genital types of HPV (46,47). Using the more reliable DNA assays, very few researchers have been able to assess directly the frequency of cervical HPV infection in virginal women. The scant data that exist suggest that virtually no virgins have cervical HPV infections detectable by consensus PCR or standard blot methods (Gutman LT: unpublished data; Manos MM, Bauer HM, Schiffman MH, et al.: unpublished data). Nevertheless, the possibility of early, nonsexual, and nearly ubiquitous latent infection detectable only by ultrasensitive PCR technology has been raised (25). Nonsexual routes of transmission remain to be identified. The few recent studies of mothers and infants that have been reported disagree as to the importance of perinatal transmission of HPV [(48); Smith EM, Turch LP, Johnson SR, et al.: unpublished data]. Some studies indicating a possibility of fomite transmission have been reported but are not conclusive (49). In summary, the epidemi-
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sible that unknown HPV types may account for these tumors, but recent molecular studies suggest that HPV-negative cancers may be an etiologically distinct group, associated with somatic mutations in tumor suppressor genes, p53 and Rb (57). Three small studies have suggested, moreover, that HPV-negative cervical cancer might carry a worse prognosis [(37,38); de Britton RC, Hildesheim A, de Lao SL, et al.: unpublished data]. If cervical cancer can arise, albeit rarely, from precursor lesions not associated with HPV infection, the morphologic appearance and natural history of those precursor lesions must be defined. For example, HPV-negative cancers could arise from HPV-negative intraepithelial lesions, perhaps already containing mutations in tumor suppressor genes. If so, the 10%-20% of unambiguous but early lesions found not to have detectable HPV DNA might have a high risk of progression. Additional interesting questions regarding the epidemiology of HPV infection were raised in a recent editorial in the Journal (52). It is clear that a host of HPV-related hypotheses, fully spanning the pathogenesis of cervical cancer, can now be tested using existent measurement techniques. There are few other areas of cancer research offering such immediate and obvious opportunities for fruitful collaboration among laboratory scientists, clinicians, pathologists, and epidemiologists.
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tion and cervical cancer in Latin America. N Engl J Med 320:1436-1441, 1989 (13) KJAER SK, ENGHOLM G, TEISEN C, ET AL: Risk factors for cervical human papillomavirus and herpes simplex virus infections in Greenland and Denmark: A population-based study. Am J Epidemiol 131:669-682, 1990 (14) LEY C, BAUER HM, REINGOLD A, ET AL: Determinants of genital human papillomavirus infection in young women. J Natl Cancer Inst 83:9971003, 1991
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ologic study of HPV transmission is clearly in its infancy, and progress will require the continuing development of HPV DNA and serologic assays to permit the distinction between levels of infection (e.g., viral exposure, latent infection, overt infection, or past infection). 2) What do the age trends in Fig. 1 imply about the physical state of HPV infection in the natural history of cervical cancer? In the United States, the prevalences of HPV DNA and related low-grade cytologic abnormalities appear to peak among women as they initiate sexual intercourse in their teens and early twenties. However, high-grade intraepithelial precursor lesions are most common 5-10 years later, and the incidence of invasive cancer plateaus another decade later. What is the intervening state of the virus in women with progressive disease? Is transcriptionally active viral persistence the key variable, or can other molecular end points better predict more serious infection (e.g., patterns of RNA transcription, production of specific viral proteins, and patterns of interaction of viral proteins with tumor suppressor gene products)? The success of Pap smear screening programs suggests that most invasive cervical cancers do not arise from undetectable, latent HPV infection. Rather, most appear to arise slowly from intraepithelial lesions, which are nearly all HPV positive. Perhaps HPV screening at older ages could be used to supplement Pap smears as a means of identifying women at high risk. 3) How do other well-established demographic and behavioral risk factors for cervical neoplasia fit into a natural history schema that accepts HPV as the central causal agent? It makes sense that sexual factors leading to HPV infection would, in turn, be risk factors for the entire spectrum of cervical neoplasia, including the earliest low-grade lesions. However, other epidemiologic risk factors, e.g., smoking and herpes simplex type 2 infection, might be unimportant for the appearance of low-grade disease, exerting their influence only at the stage of progression to high-grade intraepithelial or invasive lesions. It might be useful, in this regard, to know more about the clonality of low-grade and high-grade cervical intraepithelial lesions, because the natural history stage at which lesions become predominantly monoclonal might be the best stage to search for genotoxic cofactors. We assume that most invasive cervical cancers are monoclonal, based most recently on studies of viral integration patterns (50), but the clonality of preinvasive cervical lesions is poorly understood. The search for important HPV cofactors is likely to dominate the next phase of epidemiologic research on the etiology of cervical cancer. Although HPV infection explains much of what decades of epidemiologic research discovered about risk factors for cervical neoplasia, particularly its venereal transmission, we know very little about potential cofactors. Therefore, even if HPV infection is the unifying, central risk factor for cervical neoplasia throughout the world, it is worth considering that the necessary cofactors could vary considerably among different geographic regions. Smoking, for example, might be an important cofactor in the United States, but it is unlikely to explain the occurrence of cervical cancer in parts of the world where smoking among women is rare. 4) What causes the small minority (10%-15% or less) of cervical cancers that do not contain HPV-related DNA? It is pos-
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Cytobrush and cervicovaginal lavage sampling methods for the detection of genital human papillomavirus. Am J Obstet Gynecol 161:1669-1672, 1989 (18) KIVIAT NB, KOUTSKY LA, CRITCHLOW CW, ET AL: Comparison of Southern
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cially available nucleic acid hybridization assays for the detection and typing of human papillomavirus in clinical specimens. Am J Clin Parhol 95:21-29,1991
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development, recurrence, or pathologic progression of cervical neoplasia (15,16). These efforts have proven more difficult than anticipated, partly because of methodologic problems with HPV assays, which generally depend on the detection of HPV-specific DNA in samples of cervical tissue. The results have proven to be strikingly dependent on methods of cervical tissue sampling and DNA detection. At present, at least four different techniques of collecting exfoliated cervical cells for HPV testing are in common use: swab, scrape, cytobrush, and lavage. Test sensitivity has been shown to vary by collection method (17). Once cervical samples are collected, multiple methods of DNA-DNA or RNA-DNA hybridization are used for HPV detection and typing. Most epidemiologists have used either a commercially available RNA-DNA dot blot system (18) or polymerase chain reaction (PCR) techniques developed to amplify DNA sequences shared by many of the 20 or so different types of genital HPVs (19). However, no "gold standard" has yet been established. An informal survey at a recent HPV meeting revealed over 20 discrete techniques in current use, and the noncomparability of the many methods was the topic of several recent reports (19-22). It is not surprising, therefore, that early epidemiologic studies of HPV and cervical neoplasia, using new and imperfectly validated methods, failed to find several expected associations [discussed in (23)]. Although most investigators have observed an elevated prevalence of HPV in women with existing cervical neoplasia compared with control women, the estimated magnitude of the increase has varied substantially, primarily because the prevalence of HPV among cytologically normal women has
Received November 27. 1991: revised January 16, 1992; accepted January 21, 1992. I thank Tom Rohan for expert review and Susan Devesa. Allan Hildesheim, Louise Brinton, Mary Hagerty, and Kathy Amidon for help in preparing this commentary. *Correspondence to: Mark H. Schiffman, M.D., M.P.H. Environmental Epidemiology Branch, Division of Cancer Etiology. National Cancer Institute, Executive Plaza North, Rm. 443, Bethesda, MD 20892.
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This commentary describes recent epidemiologic advances in understanding the natural history of cervical neoplasia which have confirmed the central etiologic role of human papillomavirus (HPV) infection. Epidemiologic data have long suggested that a venereally transmitted infectious agent causes cervical neoplasia (a term used to include invasive cervical cancer and its intraepithelial precursor lesions). In particular, numerous studies have established that the risk of cervical neoplasia is increased among women who initiate sexual intercourse at earlier ages and who have greater numbers of sexual partners (/). In the mid-1980s, case series assembled by laboratory scientists demonstrated that biopsy specimens of cervical cancer contain HPV DNA sequences (2). Subsequently, laboratory evidence supporting a causal role for HPV infection in the etiology of cervical neoplasia has strengthened considerably. Repeated studies have demonstrated that the majority of cervical intraepithelial lesions, cervical cancers, and derived cell lines contain HPV DNA {3-5). The transforming activities of proteins encoded by the E6 and E7 regions of the HPV genome strongly suggest that HPV is not merely a "passenger virus" with a predilection for neoplastic cervical cells (6). Recent studies (7,8), demonstrating that these transforming proteins bind to tumor suppressor gene products, provide a plausible mechanism for HPV-induced cervical neoplasia. To corroborate these laboratory findings, epidemiologists have attempted, from their perspective, to confirm that HPV infection is the long-sought, venereally transmissible cause of cervical neoplasia. Most epidemiologic research has focused on a few key points. Epidemiologists have studied the prevalence of HPV infection among cytologically normal women (9-11) and made the case-control comparisons needed for the interpretation of a high prevalence of HPV positivity among women with cervical neoplasia (12). They have investigated the risk factors for HPV infection, reasoning that HPV should share many of the same risk factors as cervical neoplasia if the virus causes the disease (10,12-14). Finally, they have established prospective investigations to examine whether HPV infection predicts the
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As improved HPV assays are used, expected associations are being observed with regard to the correlation between HPV infection and known risk factors for cervical neoplasia. A recent investigation of the correlates of HPV infection among 400 cytologically normal women attending a student health clinic in Berkeley, Calif., demonstrated convincingly that women with multiple sexual partners are at increased risk of HPV infection (14). A strong and stepwise gradient of risk of infection with number of partners was observed. In this same investigation, other well-known risk factors for cervical neoplasia were also found to be associated with HPV positivity, including age at first intercourse, oral contraceptive use, and race (Black). Many of these correlations have also been observed in other recent studies [(30-33); Bauer HM, Schiffman MH, Manos MM, et al.: unpublished data]. Thus, HPV infection "fits" as an intermediate end point that could logically explain many traditional epidemiologic risk factors for cervical neoplasia. The largest cohort studies of HPV infection among cytologically normal women have not yet published their earliest results. However, unpublished data from the three prospective studies with the longest follow-up of HPV-infected women all show an elevated risk of progression to overt cervical intraepithelial neoplasia within a few years of follow-up [(16); Paavonen J, Nieminen P, Aho M, et al.: unpublished data; Schiffman MH, Manos MM, Glass AG, et al.: unpublished data]. Additionally, two follow-up studies of women with low-grade lesions have observed that the HPV type influences the risk of disease progression (15 J4), and several small follow-up studies of women with invasive cancer have suggested that the presence and/or type of HPV might predict prognosis (35-38). As a whole, the current epidemiologic data support a central, causal role for HPV infection in the etiology of cervical neoplasia. Nonetheless, genital HPV infection is very common among young, cytologically normal women (11), leading some investigators to question the risk posed by infection in the absence of still-to-be-defined host factors and/or cofactors. The disproportionately high prevalence of HPV in young women, compared with the much lower incidence of cervical neoplasia in older women, may be partly a consequence of transient versus persistent infection. In several population studies reported recently, HPV "point" prevalence among cytologically normal women (based on a single measurement for each woman) was observed to peak among sexually active women in their early twenties and then to decrease substantially with age (Fig. 1) (28,39,40). In contrast, HPV positivity among women with apparent neoplasia remains very high regardless of age. The agerelated decrease in HPV detection among cytologically normal women is quite important, because the strongest predictor of HPV positivity, lifetime number of sexual partners, tends to increase with age. The decline in HPV positivity despite an increased cumulative number of partners suggests that many HPV infections are transient, due to suppression of genital HPV infection and cessation of detectable viral shedding. The decreasing age trend in HPV prevalence could also theoretically be attributable in part to an international "cohort effect" of increasing HPV infection in younger women. There is evidence that venereal warts, caused by HPV types 6 and 11, are increasing in prevalence (41). Similar data regarding time trends in the
COMMENTARY 395
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ranged unbelievably from under 5% (24) to 80% (25). HPV prevalence has not been observed to be elevated consistently in populations at known high risk of cervical neoplasia (9,26). Moreover, several early studies found few correlations between HPV positivity and the established epidemiologic risk factors for cervical neoplasia (10,12,13). In particular, the early investigations observed no relationship between HPV infection and the measures of lifetime sexual behavior known to influence greatly the risk of cervical neoplasia. Few prospective studies of HPV natural history have been published because of the time required to establish and follow sufficiently large cohorts of HPVtested women. It is encouraging that, in the past year, epidemiologic data have been reported that parallel the optimistic and convincing laboratory work demonstrating HPV oncogenicity. The new studies have used HPV assays that were better validated than earlier epidemiologic investigations, reinforcing the impression that misclassification of HPV status may have limited the first generation of epidemiologic studies (27). Recent case-control data have firmly established that the great majority of women with existent cervical neoplasia concurrently have detectable HPV DNA, compared with a much lower percentage of control women. In several carefully performed casecontrol studies using good HPV assay methods, HPV detection has been associated with a 10-fold or greater risk of cervical neoplasia [(25); Schiffman MH, Manos MM, Glass AG, et al.: unpublished data; Munoz N, Bosch FX, Shah K, et al.: unpublished data]. In one investigation of high-grade intraepithelial neoplasia (including moderate dysplasia, severe dysplasia, and carcinoma in situ), the relative risk of neoplasia associated with HPV was 40, with a lower 95% confidence bound of 15 (Schiffman MH, Manos MM, Glass AG, et al.: unpublished data). The proportion of intraepithelial neoplasia apparently attributable to HPV infection approached 90%. Relative risks and attributable proportions of this strength and consistency are so rare in cancer epidemiology that the statistical association of HPV and cervical neoplasia is virtually beyond question. The association of specific HPV types with higher grade cervical neoplasia is also virtually certain. Although the number of known genital HPV types now exceeds 20, with no end in sight to the discovery of new types, certain ones (notably 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, and 58) account for about 90% of infections in cases of high-grade intraepithelial neoplasia and cancer (29). Type 16 appears to be the single most common cancer-associated HPV type in all geographic areas surveyed (5£9) and is the most common HPV type in the cytologically normal female population as well (11). In aggregate, however, cancer-associated HPV types account for only about half of the genital infections detected among women with normal cytologic diagnoses or low-grade cervical dysplasia, when detection methods capable of capturing most HPV types are used [(5); Manos MM, Zhang T, Bauer HM, et al.: unpublished data]. The type-specific prevalence estimates corroborate parallel laboratory evidence suggesting that many genital types of HPV can cause the appearance of low-grade intraepithelial lesions but that fewer types are likely to cause high-grade lesions.
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Age Group Fig. 1. Age-specific patterns of HPV infection and cervical neoplasia. Point prevalence of HPV DNA in cytologically normal women decreases with age, based on data from 463 women screened in 1989-1990 at Kaiser-Permanente in Portland, Ore. ( • ) . Point prevalence of the early cytopathologic effects of HPV infection, called condylomatous atypia, also declines with age, based on data from 19 571 women who obtained Pap smears in 1989-1990 at the same KaiserPermanente gynecology and obstetrics clinics (•). In contrast, the incidence of cervical intraepithelial neoplasia 3 among White women in the United States (A) increases with age to a peak at ages 25-29 years, then declines, perhaps due in pan to a decrease in Pap smear screening. The incidence of invasive cervical cancer rises to a plateau around ages 35-39 years in White women in the United States ( O ) but continues to rise at later'ages in Black women (data not shown). The incidence data for cervical intraepithelial neoplasia 3 and invasive cancer are derived from the National Cancer Institute Surveillance, Epidemiology, and End Results Program cancer registries for the years 1984-1988 and are restricted to White women for comparability with the Portland data.
prevalence of cervical cytologic abnormalities have been reported (41,42) but are more difficult to collect because time trends in Pap smear diagnoses can be confounded by the increasing recognition by cytopathologists of minor HPVassociated changes. Whether or not HPV infection is increasing in prevalence, preliminary data from natural history studies support the interpretation that most HPV infections found in young women are detectable only transiently. When cytologically normal women are measured repeatedly, most HPV-infected women do not have persistent infection—defined as continued detection of the same viral type or types (Burk RB, Rosenthal WD, Rose E, et al.: unpublished data; Schneider A, Gissmann L, Kirchhoff T, et al.: unpublished data; Schiffman MH, Manos MM, Glass AG, et al.: unpublished data). These data are consistent with earlier studies demonstrating that repeated HPV testing tends to detect virus at least once in a high proportion of apparently cytologically normal women (43). Overall, the occasional detection of 396
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0 . 1 O)
HPV in young and sexually active women may be common and not clinically important. If HPV infection is commonly suppressed, the resultant state of the virus is unknown, and it is not yet clear whether genital HPV infections are entirely eliminated or merely become latent. A series of small studies of HIV-infected women have reported extremely high prevalences of both HPV DNA detection and overt intraepithelial neoplasia associated with immunosuppression, supporting the possibility of latent, potentially re-emergent infections (44,45). In summary, recent epidemiologic results are encouraging because they suggest a coherent (though admittedly still hypothetical) natural history schema of HPV infection and cervical neoplasia. The schema, supported by the cross-sectional data shown in Fig. 1, can be stated as follows. As women initiate sexual intercourse in their teens and twenties, transient genital HPV infection is a common result. Many women develop no obvious clinical evidence of disease and eventually suppress or lose the infection. Others exhibit low-grade cervical lesions that may regress spontaneously as a result of poorly understood host defense mechanisms. A minority of women exposed to HPV develop persistent infection, perhaps as a result of an inadequate immune response. Some of those persistent infections of certain high-risk HPV types progress to high-grade intraepithelial lesions, which peak in diagnosis at around 25-29 years of age. Cofactors, including smoking, oral contraceptive use, or infection with other sexually transmitted diseases, may have a role in this progression. The same cofactors or other factors influencing the integration of HPV DNA into the human genome may cause in some women the subsequent progression to invasive disease, the incidence of which reaches a plateau in the White U.S. female population at around 35-39 years of age. The next generation of epidemiologic studies of HPV will undoubtedly focus on testing this hypothetical schema or on alternative views of the natural history of infection related to cervical neoplasia. A few especially important questions can be identified already. 1) Is HPV infection transmitted almost entirely by sexual intercourse, or are other routes of transmission also important? Serologic measures of exposure to HPV are not yet trustworthy, but early results suggest that many young children may already have been exposed to genital types of HPV (46,47). Using the more reliable DNA assays, very few researchers have been able to assess directly the frequency of cervical HPV infection in virginal women. The scant data that exist suggest that virtually no virgins have cervical HPV infections detectable by consensus PCR or standard blot methods (Gutman LT: unpublished data; Manos MM, Bauer HM, Schiffman MH, et al.: unpublished data). Nevertheless, the possibility of early, nonsexual, and nearly ubiquitous latent infection detectable only by ultrasensitive PCR technology has been raised (25). Nonsexual routes of transmission remain to be identified. The few recent studies of mothers and infants that have been reported disagree as to the importance of perinatal transmission of HPV [(48); Smith EM, Turch LP, Johnson SR, et al.: unpublished data]. Some studies indicating a possibility of fomite transmission have been reported but are not conclusive (49). In summary, the epidemi-
Vol. 84, No. 6, March 18, 1992
sible that unknown HPV types may account for these tumors, but recent molecular studies suggest that HPV-negative cancers may be an etiologically distinct group, associated with somatic mutations in tumor suppressor genes, p53 and Rb (57). Three small studies have suggested, moreover, that HPV-negative cervical cancer might carry a worse prognosis [(37,38); de Britton RC, Hildesheim A, de Lao SL, et al.: unpublished data]. If cervical cancer can arise, albeit rarely, from precursor lesions not associated with HPV infection, the morphologic appearance and natural history of those precursor lesions must be defined. For example, HPV-negative cancers could arise from HPV-negative intraepithelial lesions, perhaps already containing mutations in tumor suppressor genes. If so, the 10%-20% of unambiguous but early lesions found not to have detectable HPV DNA might have a high risk of progression. Additional interesting questions regarding the epidemiology of HPV infection were raised in a recent editorial in the Journal (52). It is clear that a host of HPV-related hypotheses, fully spanning the pathogenesis of cervical cancer, can now be tested using existent measurement techniques. There are few other areas of cancer research offering such immediate and obvious opportunities for fruitful collaboration among laboratory scientists, clinicians, pathologists, and epidemiologists.
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ologic study of HPV transmission is clearly in its infancy, and progress will require the continuing development of HPV DNA and serologic assays to permit the distinction between levels of infection (e.g., viral exposure, latent infection, overt infection, or past infection). 2) What do the age trends in Fig. 1 imply about the physical state of HPV infection in the natural history of cervical cancer? In the United States, the prevalences of HPV DNA and related low-grade cytologic abnormalities appear to peak among women as they initiate sexual intercourse in their teens and early twenties. However, high-grade intraepithelial precursor lesions are most common 5-10 years later, and the incidence of invasive cancer plateaus another decade later. What is the intervening state of the virus in women with progressive disease? Is transcriptionally active viral persistence the key variable, or can other molecular end points better predict more serious infection (e.g., patterns of RNA transcription, production of specific viral proteins, and patterns of interaction of viral proteins with tumor suppressor gene products)? The success of Pap smear screening programs suggests that most invasive cervical cancers do not arise from undetectable, latent HPV infection. Rather, most appear to arise slowly from intraepithelial lesions, which are nearly all HPV positive. Perhaps HPV screening at older ages could be used to supplement Pap smears as a means of identifying women at high risk. 3) How do other well-established demographic and behavioral risk factors for cervical neoplasia fit into a natural history schema that accepts HPV as the central causal agent? It makes sense that sexual factors leading to HPV infection would, in turn, be risk factors for the entire spectrum of cervical neoplasia, including the earliest low-grade lesions. However, other epidemiologic risk factors, e.g., smoking and herpes simplex type 2 infection, might be unimportant for the appearance of low-grade disease, exerting their influence only at the stage of progression to high-grade intraepithelial or invasive lesions. It might be useful, in this regard, to know more about the clonality of low-grade and high-grade cervical intraepithelial lesions, because the natural history stage at which lesions become predominantly monoclonal might be the best stage to search for genotoxic cofactors. We assume that most invasive cervical cancers are monoclonal, based most recently on studies of viral integration patterns (50), but the clonality of preinvasive cervical lesions is poorly understood. The search for important HPV cofactors is likely to dominate the next phase of epidemiologic research on the etiology of cervical cancer. Although HPV infection explains much of what decades of epidemiologic research discovered about risk factors for cervical neoplasia, particularly its venereal transmission, we know very little about potential cofactors. Therefore, even if HPV infection is the unifying, central risk factor for cervical neoplasia throughout the world, it is worth considering that the necessary cofactors could vary considerably among different geographic regions. Smoking, for example, might be an important cofactor in the United States, but it is unlikely to explain the occurrence of cervical cancer in parts of the world where smoking among women is rare. 4) What causes the small minority (10%-15% or less) of cervical cancers that do not contain HPV-related DNA? It is pos-
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cially available nucleic acid hybridization assays for the detection and typing of human papillomavirus in clinical specimens. Am J Clin Parhol 95:21-29,1991
