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Keywords:

  • vulva;
  • vagina;
  • anus;
  • carcinoma;
  • human papillomavirus;
  • human immunodeficiency virus;
  • meta-analysis

Abstract

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix

This meta-analysis investigated human papillomavirus (HPV) prevalence in vulvar, vaginal and anal intraepithelial neoplasia (VIN, VAIN, AIN) grades 1–3 and carcinoma from 93 studies conducted in 4 continents and using PCR assays. Overall HPV prevalence was 67.8%, 85.3% and 40.4% among 90 VIN1, 1,061 VIN2/3 and 1,873 vulvar carcinomas; 100%, 90.1% and 69.9% among 107 VAIN1, 191 VAIN2/3 and 136 vaginal carcinomas; and 91.5%, 93.9% and 84.3% among 671 AIN1, 609 AIN2/3 and 955 anal carcinomas, respectively. HPV16 was found more frequently (>75%) and HPV18 less frequently (<10%) in HPV-positive vulvar, vaginal and anal carcinomas than in cervical carcinoma. HPV6 and 11 were common in VIN1 and AIN1, but not in VAIN1. HPV prevalence in vulvar carcinoma varied most by histological type (69.4% in warty-basaloid and 13.2% in keratinized type) and was also higher in women 60 years or younger and in studies carried out in North America. HPV prevalence in anal carcinoma was higher among women (90.8%) than men (74.9%), but no difference by gender emerged in North America. The majority of AIN2/3 derived from studies of HIV-positive individuals and/or men who have sex with men. Among AIN2/3, HIV infection was associated with higher HPV prevalence, more multiple-type infections and a relative under-representation of HPV16. In conclusion, ∼40% of vulvar, 60% of vaginal and 80% of anal carcinoma may be avoided by prophylactic vaccines against HPV16/18. This proportion would be similar for the corresponding high-grade lesions of the vagina and anus, but higher for VIN2/3 (75%) than for vulvar carcinoma. © 2008 Wiley-Liss, Inc.

Anogenital carcinomas other than cervical carcinoma are relatively rare. Only a few areas of the United States show age-standardized incidence rates for vulvar carcinoma in women, or anal carcinoma in men, greater than 2 per 100,000, and those for vaginal cancer in all parts of the world are below 1 per 100,000.1 Anogenital carcinomas share many risk factors with cervical carcinoma, namely those relating to sexual behavior and smoking,2–6 and immunosuppression.7, 8 Increases in their incidence have been reported in the last decades in some high-resource countries, notably in women and men below age 50 years.9–13

In 2005, an expert working group convened by the International Agency for Research on Cancer established a causal role for human papillomavirus (HPV) 16 in a subset of vulvar, vaginal and anal carcinoma.14 A similar role for types other than HPV16 could not be established due to the limited number and size of the reviewed studies.

Also strongly related to HPV are vulvar, vaginal and anal intraepithelial neoplasia (VIN, VAIN, AIN) grades 1–3, which are considered precursor lesions of carcinoma in the corresponding sites. However, scant data are available on the HPV types that contribute to intraepithelial neoplasia, as well as their potential to progress to carcinoma in the anogenital tract.14

Current prophylactic HPV vaccines against HPV types 16/18, or 6/11/16/18, are thus expected to offer protection against anogenital carcinomas14 and their precursor lesions.15 To estimate the fraction of cancerous and precancerous lesions of the anogenital tract that may be prevented by HPV vaccines, we collated all relevant data published from 4 continents on the prevalence of HPV overall, and of individual HPV types.

Material and methods

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix

Search strategy and selection criteria

MEDLINE and regional databases (MedCarib, LILACS, African Index Medicus, IndMed and IMSEAR) were used to search for articles published between January 1986 and March 2008, regardless of language of publication. Combinations of the MeSH terms: “papillomavirus,” “papillomavirus infections,” “vulva neoplasms,” “vagina neoplasms” and “anal neoplasms” were used. References cited in selected articles were also investigated. Eligibility criteria included the report of HPV DNA detection by means of PCR in a minimum of 4 cases. Studies had to provide a clear description of PCR primers and methods used for HPV typing, and DNA prevalence had to be reported for carcinoma and intraepithelial neoplasia separately. Careful checks were made to avoid including overlapping data. Where study methods suggested that additional data were available, these data were requested and provided by some investigators.2–4, 16–20

A total of 63 studies on vulvar lesions, 14 on vaginal lesions and 29 on anal lesions identified from MEDLINE were included in the present meta-analysis (no additional studies were retrieved from regional databases). Detailed information on each of the 93 included studies (some dealing with more than 1 anogenital site) is listed in Tables AI–AVI.

Data extraction

For each study, information on country, sample size, age group, gender (when applicable), type of specimen, PCR primers used to detect the presence of HPV DNA, and overall and type-specific HPV prevalence was extracted. HIV infection status was available only for AIN as none of the identified studies on vulvar and vaginal lesions, or anal carcinoma, explicitly included HIV-positive individuals.

Where possible, HPV findings were stratified by histological type of carcinoma (e.g., warty/basaloid or keratinizing),21, 22 grade of intraepithelial neoplasia (grades 1, 2 and 3)21 with in situ carcinoma included as grade 3, age group, geographical region and HIV status. Thirty reported cases of differentiated VIN, which are often associated with lichen sclerosus or other dermatoses, and 32 cases of anal warts were not included in this report.

Estimation of HPV prevalence

Type-specific prevalence is presented for (i) 15 high-risk HPV types, namely 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73 and 82; and (ii) low-risk HPV Types 6 and 11.23 No other type was found in more than 0.5% of any anogenital carcinomas.

Methods for estimation of type-specific HPV prevalence have been described in detail previously.24 Whereas most studies did report the prevalence of HPV16, the prevalence of other types was less frequently reported. Thus, the prevalence of an individual HPV type was based only on studies testing for the genotype in question, and includes the prevalence in single- and multiple-type infections. HPV type-distribution is expressed either as a proportion of all cases tested for the given HPV type, or as a proportion of HPV-positive women.

Statistical analysis

Odds ratios (ORs) for HPV positivity and corresponding 95% confidence intervals (CIs) in the 2 largest groups of carcinoma (i.e., vulvar and anal) were estimated by unconditional logistic regression including terms for PCR primers (MY09/11 and/or GP5+/6+, other), geographical region (North America, elsewhere), major histological types (keratinized, warty, basaloid, large-cell and unspecified) and variables that were known or suspected to be possible sources of heterogeneity in HPV prevalence, i.e., age group (≤60; 61–70; ≥71 years) for vulvar carcinoma, and gender for anal carcinoma. Upon review, studies of AIN2/3 in which HIV status was not reported were considered on the basis of geographical region, age distribution and case sources, as unlikely to be HIV-positive and were therefore combined with the HIV-negative subjects. Crude ORs by HIV status (negative/not reported, positive) were computed for AIN2/3.

Results

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix

Prevalence of HPV

Table I shows the number and location of studies included in the present meta-analysis and overall HPV prevalence separately for intraepithelial neoplasia and carcinoma. For all 3 anatomic sites considered, the majority of studies were from Europe and North America. The vast majority of information on HPV in AIN derived from studies of HIV-positive individuals or men who have sex with men (MSM).

Table I. Human Papillomavirus (HPV) Prevalence in Intraepithelial Neoplasia and Carcinoma of the Vulva, Vagina and Anus, by Geographical Region
RegionStudies (N)Intraepithelial neoplasiaCarcinomaCountries represented
Subjects (N)HPV-positive (%)Subjects (N)HPV-positive (%)
  • 1

    Including one multicentric study (Ref. 15) whose components have been assigned to the corresponding regions.

  • 2

    Includes 805 HIV-positive individuals (mainly men who have sex with men, MSM) and 210 HIV-negative MSM.

Vulva
 Asia91978.918638.2China, Hong Kong, Japan
 Europe3452080.692934.7Austria, Czech Republic, Denmark, Finland, Germany, Italy, Israel, the Netherlands, Poland, Spain, Sweden, United Kingdom
 North America1862788.844363.2Canada, United States
 Latin America212100.016124.2Brazil, Colombia, Mexico, Peru, Puerto Rico
 Oceania31936.815428.6Australia, New Zealand
 Total6311,19784.01,87340.4 
Vagina
 Asia372100.01643.8Japan, Thailand
 Europe87497.35676.8Denmark, Germany, Finland, Italy, Sweden, the Netherlands, Portugal, United Kingdom
 North America413589.66470.3Canada, United States
 Latin America11782.4Brazil, Colombia, Mexico, Peru, Puerto Rico
 Total14129893.613669.9 
Anus
 Asia22100.02796.3Japan, Korea
 Europe1323589.869684.2Czech Republic, Denmark, France, Germany, Italy, Norway, Sweden, Switzerland, United Kingdom
 North America141,04393.323283.2United States, Canada
 Total291,280292.795584.3 

Overall HPV prevalence in VIN was 84.0%—with a breakdown by grade of 67.8% in 90 VIN1 and 85.3% in 1,061 VIN2/3 (87.7% in 856 VIN3)—and 40.4% in 1,873 vulvar carcinomas. Overall HPV prevalence in VAIN was 93.6%—with a breakdown by grade of 100.0% in 107 VAIN1 and 90.1% in 191 VAIN2/3 (88.2% in 110 VAIN3)—and 69.9% in 136 vaginal carcinomas. Finally, overall HPV prevalence in AIN was 92.7%—with a breakdown by grade of 91.5% in 671 AIN1, 93.9% in 609 AIN2/3 (94.0% in 234 AIN3)—and 84.3% in 955 anal carcinomas.

HPV type-specific prevalence

Figure 1 shows the distribution of HPV types by site and lesion severity in studies that reported on individual HPV types (see also Tables AI–AVI).

thumbnail image

Figure 1. Prevalence of human papillomavirus (HPV) types in vulvar intraepithelial neoplasia (VIN) grades 1 and 2/3, vulvar carcinoma, vaginal intraepithelial neoplasia (VAIN) 1 and 2/3, vaginal carcinoma, anal intraepithelial neoplasia (AIN) 1 and 2/3, and carcinoma of the anus. Only studies reporting individual HPV types were included. N, number tested for a given HPV type.

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The most common HPV types in VIN1 were HPV6 (22.4%), 16 (9.8%) and 11 (9.0%). In contrast, the most common HPV types in VIN2/3 and vulvar carcinoma were HPV16 (71.9% and 32.2%, respectively), 33 (8.0% and 4.5%) and 18 (5.0% and 4.4%) (Fig. 1). The prevalence of infections with multiple HPV types decreased from 13.4% in VIN1 to 2.8% in vulvar carcinoma (data not shown).

In VAIN1 HPV16 predominated (23.4%), but a broad range of other HPV types was detected, notably HPV56 (11.0%) and 51 (8.8%). In VAIN2/3, the most common HPV types were HPV16 (57.6%), 18 (6.9%) and 58 (5.9%). In vaginal carcinoma, the most common HPV types were HPV16 (53.7%), 18 (7.6%) and 31 (5.6%) (Fig. 1). The prevalence of multiple-type HPV infections decreased from 10.3% in VAIN1 to 3.4% in vaginal carcinoma (data not shown).

The most frequently detected types for AIN1 were HPV16 (37.2%), 6 (36.2%), 18 (21.3%) and 11 (18.1%). HPV16 (59.8%), 18 (17.4%), 33 (13.6%) and 58 (13.1%) were the types most frequently detected in AIN2/3. In anal carcinoma HPV16 (73.4%) predominated, followed by HPV18 (5.2%), and 33 (4.8%) (Fig. 1). The prevalence of multiple-type infections decreased from 54.4% in AIN1 to 6.8% in anal carcinoma (data not shown).

Sources of heterogeneity in HPV prevalence

Table II describes the main sources of heterogeneity in HPV prevalence in vulvar carcinoma, both overall and stratified by geographical region. The HPV prevalence was significantly higher in North American studies than studies from elsewhere (OR = 2.87, 95% CI: 2.25–3.66) and in warty-basaloid (69.4%) compared to keratinized (13.2%) carcinomas (OR = 13.47, 95% CI: 9.36–19.39). Young age at diagnosis was also associated with HPV prevalence (OR for women aged ≤60 versus women aged ≥71 years = 3.63, 95% CI: 2.40–5.47), whereas the type of PCR primers used had no influence. Consistent differences in HPV prevalence by histological type and age group were observed both in North America and elsewhere (Table II). HPV16 predominance was also consistent in all strata (data not shown). The type of specimen used (exfoliated cells or tissue samples) did not significantly affect HPV prevalence and was not included in the model (data not shown).

Table II. Sources of Heterogeneity in Human Papillomavirus (HPV) Prevalence in 1,873 Vulvar Carcinomas
 North AmericaElsewhereOverall
NHPV-positive (%)NHPV-positive (%)NHPV-positive (%)OR1 (95% CI)
  • 1

    ORs adjusted for geographical region, histological type and PCR primers, except the OR for age group, which could be adjusted for geographical region and PCR primers only.

  • OR, odds ratio; CI, confidence intervals.

Histological type
 Keratinized6825.050811.657613.21
 Warty-basaloid8085.017862.425869.413.47 (9.36–19.39)
 Unspecified29566.174441.31,03948.25.53 (4.18–7.32)
Age group (years)
 ≥7112654.016324.528937.41
 61–708072.54839.612860.22.19 (1.41–3.40)
 ≤6011379.76956.518270.93.63 (2.40–5.47)
 Unknown12451.61,15032.51,27434.41.30 (0.97–1.73)
PCR primers
 MY09/11 or GP5+/6+31266.768233.399443.81
 Other13155.074833.387936.51.09 (0.88–1.35)
Geographical region44363.21,43033.3
OR1 (95% CI)2.87 (2.25–3.66)1   

Table III shows the main sources of heterogeneity in HPV prevalence in anal carcinoma overall and stratified by geographical region. Large-cell carcinoma represented the most common histological type, but HPV prevalence was similar in large-cell and basaloid carcinoma. HPV-positive anal carcinoma was more frequent in women than men (OR = 3.46, 95% CI: 2.25–5.31), but equally frequent among the 2 genders in North American studies. PCR primers other than MY09/11 or GP5+/6+ detected fewer HPV infections (OR = 0.44, 95% CI: 0.27–0.73).

Table III. Sources of Heterogeneity in Human Papillomavirus (HPV) Prevalence in 955 Anal Carcinomas
 North AmericaElsewhereOverall
NHPV-positive (%)NHPV-positive (%)NHPV-positive (%)OR1 (95% CI)
  • 1

    ORs adjusted for geographical region, histological type, gender and PCR primers.

  • OR, odds ratio; CI, confidence intervals.

Histological type
 Large-cell11689.73571.415185.41
 Basaloid4497.72470.86888.21.11 (0.45–2.73)
 Unspecified7263.966485.873683.70.87 (0.47–1.61)
Gender
 Male5791.215068.720774.91
 Female11490.447590.958990.83.46 (2.25–5.31)
 Both6162.39878.615972.31.76 (0.92–3.37)
PCR primers
 MY09/11 or GP5+/6+17190.647887.764988.41
 Other6162.324578.830675.50.44 (0.27–0.73)
Geographical region23283.272384.6
OR1 (95% CI)0.90 (0.53–1.50)1   

Impact of HIV and lesion severity on HPV type distribution

Table IV shows HPV prevalence in AIN2/3 according to HIV status. HIV-positive individuals had a significantly higher prevalence of HPV infection (96.7%) than HIV-negative ones (90.1%) (χmath image: 7.16; p = 0.0075). A comparison of HPV type distribution by HIV status was also done, restricted to HPV-positive samples. Multiple-type infections were more frequently detected in HIV-positive individuals (OR = 12.60, 95% CI: 7.05–22.51), and the distribution of individual high-risk types also differed. HPV16 (OR = 0.38, 95% CI: 0.24–0.61) was significantly under-represented and most other types were significantly over-represented in AIN2/3 among HIV-positive, compared to HIV-negative individuals. Moreover, many HPV types were only detected in HIV-positive individuals.

Table IV. Odds Ratios (ORS) of Human Papillomavirus (HPV) Positivity for Different Types and Corresponding 95% Confidence Intervals (CIS) Among Individuals with Anal Intraepithelial Neoplasia 2/3 by HIV Status
 HIV-positiveHIV-negative/not reported 
Positive/tested (N)1%Positive/tested (N)1%OR (95% CI)
  • 1

    Only studies testing for a particular HPV type contribute to the analysis for that type, therefore sample size varies between the type-specific analyses.

Any HPV type208/21596.7145/16190.1χmath image: 7.16; p = 0.0075
Within HPV-positive samples
 Multiple infections137/20865.917/12813.312.60 (7.05–22.51)
 High-risk type
 HPV16115/20855.3111/14576.60.38 (0.24–0.61)
 HPV1853/20825.58/1276.35.09 (2.36–10.92)
 HPV3124/18213.23/1132.75.57 (1.74–17.77)
 HPV3335/18219.28/1196.73.30 (1.50–7.27)
 HPV3513/1827.10/1090.0∞ (2.16–∞)
 HPV3914/1827.70/1090.0∞ (2.34–∞)
 HPV4529/20813.91/1170.918.79 (3.19–∞)
 HPV517/1823.80/1090.0∞ (1.12–∞)
 HPV5214/1827.70/1110.0∞ (2.39–∞)
 HPV5611/1826.00/1090.0∞ (1.81–∞)
 HPV5839/18221.41/1110.930.00 (5.12–∞)
 HPV5910/1825.50/1090.0∞ (1.63–∞)
 HPV682/1821.10/1090.0∞ (0.31–∞)
 HPV739/1824.91/1090.95.62 (0.90–∞)
 HPV823/1681.80/1090.0∞ (0.51–∞)
 Low-risk type
 HPV611/11010.08/1176.81.51 (0.60–3.81)
 HPV1115/11013.64/1173.44.46 (1.50–13.21)

Figure 2 shows a comparison of HPV6, 11, 16 and 18 prevalence by lesion severity among HPV-positive lesions. Because of the strong influence of HIV infection on HPV type distribution, HIV-positive AIN were not included. The HPV16 fraction increased markedly in all 3 sites with increasing lesion severity (Fig. 2). The HPV18 fraction also increased by lesion severity in the vulva, but not in the vagina or anus. HPV6 and 11 were far more common among HPV-positive VIN1 (29.4% and 11.8%) than in VIN2/3 (3.7% and 0.7%) or vulvar carcinoma (4.4% and 0.3%), whereas no clear trend in HPV6 or 11 was detectable in the corresponding vaginal lesions. Only 7 AIN1 in HIV-negative individuals were tested for HPV6 and 11, and hence, they were not used for comparison purposes (Fig. 2).

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Figure 2. Prevalence of human papillomavirus (HPV) types 6, 11, 16 and 18 in HPV-positive intraepithelial neoplasias and carcinomas of the (a) vulva, (b) vagina and (c) anus, restricted to HIV-negative subjects. HPV types 6 and 11 not shown for AIN1, due to the low number tested (N = 7). VIN, vulvar intraepithelial neoplasia; VAIN, vaginal intraepithelial neoplasia; AIN, anal intraepithelial neoplasia.

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Discussion

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix

In our present meta-analysis of anogenital cancerous and precancerous lesions, the first to our knowledge to systematically include all published information on the topic worldwide, the highest HPV prevalence was found in anal carcinoma (84.3%), improving on the precision of the previous consensus estimation of >50% for the proportion of anal carcinoma attributed to HPV infection.14 The prevalence of HPV infection in our present meta-analysis on anal carcinoma approaches, therefore, that reported in a similar worldwide meta-analysis of cervical carcinoma (87.3%),25 for which HPV infection is considered a necessary cause.14 Also analogous with the cervix uteri, the majority of AIN and anal carcinoma are detected in a squamocolumnar junction (i.e., the dentate line, between the anal canal and the rectum).26

HPV prevalence was lower in vaginal carcinoma (69.9%) and lower still in vulvar carcinoma (40.4%). Among high-grade lesions in the vulva (85.3%) and vagina (90.1%), however, HPV prevalence was as high as that in the corresponding precursor lesions of the cervix (cervical intraepithelial neoplasia grades 2/3, 84.9%).25 Our present findings strongly support, therefore, the hypothesis raised in the early 1990s27, 28 that 2 distinct subsets of carcinoma in the vulva and vagina exist, one that is strongly associated with HPV and that may be preceded by high-grade lesions as in cervical carcinoma, and another, which arises independently of HPV infection and is of greater relative importance in the vulva than the vagina. It is conceivable that the presence of HPV in these cancer subsets may be accompanied by different gene expression profiles or genetic alterations as already shown in cancer of the oral cavity and pharynx, where HPV presence is accompanied by a lack of TP53 mutations.29

Whereas a broad range of high-risk and low-risk HPV types was detected in all grades of intraepithelial neoplasia, HPV16 was found in over three-quarters of HPV-positive anogenital carcinoma at all 3 sites. By comparison, HPV16 accounts for only approximately half of cervical carcinoma.25 A stronger predominance of HPV16 than in cervical carcinoma has also been reported in HPV-related head and neck carcinoma.30 In agreement with what has been found in cervical carcinoma, however, the relative importance of HPV16 infection in anogenital lesions increases substantially with their severity, highlighting the greater potential of HPV16 to progress to carcinoma in comparison to other types.

HPV18 seems to be rarer in noncervical anogenital carcinoma than in cervical carcinoma. In studies of cervical carcinoma, however, HPV18 has been shown to have a strong tropism for glandular epithelia, and hence adenocarcinoma.31 Adenocarcinoma is rare in the vulva and vagina32 and is excluded, by definition, from anal carcinoma in order to avoid misclassification with rectal adenocarcinoma. However, HPV18 is still under-represented in anogenital carcinoma, even if the comparison is restricted to squamous cell carcinoma of the cervix.31 HPV6 was slightly more frequent in vulvar (2.0%) and anal (2.9%) carcinoma than in cervical carcinoma (0.5%),25 but it was most often accompanied, among cases where this information was available, by multiple infections with high-risk types.

Strong sources of heterogeneity in HPV prevalence were found in our present meta-analysis, and they varied by anatomical site and type of population studied. In vulvar carcinoma, the clearest variation in HPV prevalence was found by histopathological type: HPV prevalence was 69.4% in warty-basaloid carcinoma, but only 13.2% in keratinized carcinoma. Histopathological type of vulvar carcinoma is known to be correlated with age at diagnosis, with warty-basaloid carcinoma being diagnosed more often among younger women than the keratinized type. This meta-analysis was not able to disentangle the independent effects of histological type and age, but carcinoma diagnosed at a younger age was indeed more likely to be HPV-positive. Many studies reported that the mean age at vulvar carcinoma diagnosis was significantly lower in HPV-positive than HPV-negative cases,33–35 although this was not the case in the largest North American study.36

In addition, HPV prevalence among North American vulvar carcinoma was approximately twice that among those diagnosed in other geographical regions. Higher HPV prevalence in North America did not appear to be an artefact of HPV detection methods (see also Insinga et al.37) and was observed across all age groups and histopathological types of vulvar carcinoma. Enhanced surveillance of the vulva during cervical cancer screening, combined with some misclassification of VIN3 as microinvasive vulvar carcinoma, may partly explain the higher HPV positivity found in vulvar carcinoma diagnosed in North American studies.

This meta-analysis identified 14-fold more published data on vulvar carcinoma than on vaginal carcinoma, despite an only 2- to 3-fold reported difference in their estimated incidence around the world.1 Vaginal lesions are less amenable to discovery during gynecological examination than vulvar lesions, as they can be hidden by the speculum. Thus, information on vaginal lesions and carcinoma was limited and did not allow the assessment of source of heterogeneity in HPV prevalence.

In respect to anal carcinoma, we did not find a significant difference in HPV prevalence between basaloid and other subtypes,3 and an excess of HPV positivity in women compared to men was limited to studies outside North America. As discussed for vulvar carcinoma in women, higher HPV prevalence in men in the United States than elsewhere may be related to early efforts at surveillance of MSM.38

Most studies of AIN to-date derived from populations of MSM living in North America, many of whom were HIV-positive, a characteristic that we and others14 showed to be significantly associated with increased prevalence of HPV and multiple-type infections. We showed for the first time that HPV16 was significantly under-represented, and other types over-represented, among HIV-positive AIN2/3 (i.e., the only group where data were adequate to compare HPV type distribution by HIV status). Our present findings agree, therefore, with previously reported differences in HPV type distribution between HIV-positive and HIV-negative women with high-grade precancerous lesions of the cervix.39 Indeed, HIV-related immune suppression seems to affect the course of cervical HPV16 infection less than for other HPV types,40 allowing a broader range of HPV types to develop into high-grade disease. The high prevalence of multiple-type infections in HIV-positive individuals, however, complicates the issue, and differences in HPV type distribution by HIV status have not been confirmed for cervical carcinoma41 and have never been reported for anal carcinoma.

We were able to retrieve much fewer information on low-grade than high-grade lesions, and confirmed37 that HPV6 and 11 are frequently detected in VIN1 and AIN1 (as in anogenital warts), but not in VAIN1. Distinction of low-grade lesions by presence of wart-like characteristics was, however, impossible from publications, and VIN1 has been abolished from the revised classification of VIN.42

This meta-analysis has certain limitations. The vast majority of data on anogenital carcinoma and intraepithelial lesions originated from Europe and the United States, and none from Africa. Detailed information on age, histological subtype, copresence of multiple HPV types, HIV status and, when applicable, gender were often missing. However, HPV findings were consistent across the many studies examined, thus providing reassurance on the possibility of estimating pooled prevalence. In addition, our present HPV findings broadly agree with a recent meta-analysis of female genital carcinoma in the United States37 that was smaller than our study, but applied much stricter inclusion criteria (i.e., only biopsy-based studies; specified histological types; and >7 HPV types tested) and attempted to account for multiple-type infections. Publication bias is impossible to rule out completely, but seems unlikely due to the tendency of the largest and most recent studies to show some of the highest HPV prevalence (Tables AI–AVI).

It is obviously worth bearing in mind that detection of HPV DNA does not necessarily mean that the infection is causally related to the concurrent lesion. However, a vast amount of epidemiological and mechanistic evidence shows that certain HPV types act as a potent carcinogen in the anogenital mucosae.14

In conclusion, our present meta-analysis suggests that ∼40% of vulvar carcinoma, 60% of vaginal carcinoma and 80% of anal carcinoma may be avoided by prophylactic vaccines against HPV16/18. This proportion would be similar for the corresponding high-grade intraepithelial lesions of the vagina and anus, but higher for VIN2/3 (75%) than for vulvar carcinoma. An accurate estimate of the fraction of low-grade lesions avoidable using a vaccine that also includes HPV6 and 11 or other additional types is hampered by the difficulty in distinguishing these lesions from anogenital warts and by high prevalence of multiple-type infections, particularly in high-risk populations.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix

The authors gratefully thank those who have kindly provided more detailed, or updated data than was available in the published articles: Dr. Ruth Tachezy (Institute of Hematology and Blood Transfusion, Prague, Czech Republic), Dr. Terry Dunn (University of University of Oklahoma, Oklahoma City, OK, USA), Dr. Elma Joura, (Medical University of Vienna, Vienna, Austria), Dr. Jaume Ordi (University of Barcelona, Barcelona, Spain), Dr. François Coutlée (Centre Hospitalier de l'Université de Montréal, Montreal, Canada), Dr. Cathy W. Critchlow, Dr. Stephen E. Hawes, Dr. Chunhui Wang (University of Washington, Seattle, WA, USA), Dr. Janet R. Daling (Fred Hutchinson Cancer Research Center, Seattle, WA, USA), Dr. Christophe Piketty (Hôpital Européen Georges Pompidou, Paris, France) and Dr. Alinda D. Varnai (Institut of Pathology, Bonn Duisdorf, Germany). The funders had no role in the design of the study; the collection, analysis and interpretation of the data; the decision to submit for publication; or the writing of the manuscript.

References

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix
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Appendix

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix
Table AI. Type-Specific Prevalence of Human Papillomavirus (HPV) in Vulvar Intraepithelial Neoplasia (VIN), by Study
First authorReferenceCountryPCR primersNVIN1/VIN2/VIN3/ VIN2-3/unspecHPV type1
Any6111618313345
  • 1

    Percent of all subjects tested for the specific type.

  • 2

    This study was expanded since original publication, with a change in the HPV genotyping protocol.

  • TS, type-specific.

Gao XDermatol Surg (1997)ChinaHPV6/11, 16/18 only88/0/0/0/0100.0
Xin YChinese med Science J (2002)ChinaHPV6/11,16/18 only50/0/5/0/020.0
Nagano HJ Obstet Gynecol Res (1996)JapanL1C1/C260/0/6/0/0100.00.00.066.733.30.00.00.0
Kohlberger PDCancer (1998)AustriaGP5+/6+280/0/0/0/2892.9
Skapa PAm J Surg Pathol (2007)Czech Rep.GP5+/6+464/9/33/0/0100.02.22.276.16.50.017.46.5
Hording UGynecol Oncol (1991)DenmarkTS only190/0/19/0/078.978.9
Junge JAPMIS (1995)DenmarkTS only580/3/55/0/087.90.00.077.60.00.010.3
Bryndorf TCytogenet Gen Res (2004)DenmarkSPF10111/1/9/0/081.80.00.063.60.00.018.20.0
Tervahauta AIAnticancer Res (1993)FinlandMY09/1121/0/1/0/0100.00.050.00.00.00.0
Petry KUGynecol Oncol (1996)GermanyTS only101/1/8/0/090.070.010.010.0
Hampl MJournal of Cancer Res Clin Oncol (2007)GermanyGP5+/6+; MY09/11493/11/35/0/091.82.00.067.30.08.28.20.0
Della Torre GDiagn Mol Pathol (1992)ItalyTS only70/0/7/0/0100.00.00.0100.00.0
Pilotti SDiagn Mol Pathol (1995)ItalyTS only50/0/5/0/0100.0100.00.0
Bonvicini FJ Med Virol (2005)ItalyMY09/11180/5/13/0/061.150.00.00.05.60.0
Beurden MCancer (1995)NetherlandsCpI/IIG460/0/46/0/095.70.00.089.10.00.02.22.2
Avoort IAInt J Gynecol Pathol (2005)NetherlandsSPF10295/7/17/0/065.513.80.041.40.06.93.40.0
Van Seters MJ Clin Pathol (2007)NetherlandsGP5+/6+269/11/6/0/030.80.00.026.90.00.00.00.0
Van Seters MNew Engl J Med (2008)NetherlandsGP5+/6+520/0/0/52/096.20.00.078.81.90.015.40.0
Lerma EInt J Gynecol Pathol (1999)SpainL1+VPHFast120/0/0/12/041.741.70.0
Abdel-Hady ESCancer Res (2001)UKGP5+/GP6+; TS290/0/0/29/062.144.80.00.00.0
Gasco MOncogene (2002)UKMY09/11; CpI/IIG324/6/22/0/037.537.5
Baldwin PIClin Cancer Res (2003)UKGP5+/6+110/0/11/0/0100.00.00.090.90.00.09.10.0
Todd RWGynecol Oncol (2004)UKGP5/6100/0/10/0/090.050.00.00.020.0
Woo YLJ Virol Methods (2007)UKGP5+/6+; MY09/1180/0/0/0/862.550.0
Aziz DCJ Gynecol Surg (1993)CanadaTS only100/0/0/0/1090.00.00.090.00.00.00.0
Nuovo GJGynecol Oncol (1991)USMY09/11220/0/0/22/059.10.00.040.90.04.50.0
Madeleine MJ Natl Cancer Inst (1997) part 12USMY09/113900/0/390/0/091.53.10.076.99.01.08.71.8
Madeleine MJ Natl Cancer Inst (1997) part 22USMY09/11790/0/79/0/087.377.2
Logani SMod Pathol (2003)USSPF101711/0/6/0/0100.029.45.929.45.95.90.00.0
Rufforny IJ Lower Genit Tract Dis (2005)USTS only3410/3/21/0/058.858.8
Srodon MAm J Surg Pathol (2006)USPGMY09/11; SPF106733/0/34/0/095.513.49.049.33.01.53.00.0
Park JSCancer (1991)New ZealandMY09/11; TS180/0/18/0/033.30.00.033.30.0
Joura EALancet (2007)MulticentricMY09/11330/0/0/33/087.924.26.163.63.018.23.00.0
Total   1,19790/57/856/148/4684.04.41.267.54.62.17.71.4
Table AII. Type-Specific Prevalence of Human Papillomavirus (HPV) in Carcinoma of the Vulva, by Study
First AuthorReferenceCountryPCR primersNWarty-basaloid/ keratinised/unspecHPV type1
Any6111618313345
  • 1

    Percent of all subjects tested for the specific type.

  • 2

    This study was expanded since original publication, with a change in the HPV genotyping protocol.

  • TS, type-specific.

Guo LChinese J Obstet and Gyn (1996)ChinaTS only3312/21/030.321.20.0
Gao XDermatol Surg (1997)ChinaHPV6/11, 16/18 only130/0/1323.1
Ngan HYEur J Cancer (1999)Hong KongTS only480/0/4847.937.514.6
Huang FYCancer Genet Cytogenet (2005)Hong KongTS only80/0/875.037.537.5
Toki TInt J Gynecol Pathol (1991)JapanTS only219/0/1257.10.00.047.614.3
Nagano HJ Obstet Gynecol Res (1996)JapanL1C1/C2110/0/1172.79.10.036.49.10.00.00.0
Koyamatsu YGynecol Oncol (2003)JapanL1C1/C2310/0/3112.96.56.5
Osakabe MPathol Int (2007)JapanL1C1/C2214/13/423.84.80.014.30.00.00.0
Skapa PAm J Surg Pathol (2007)Czech Rep.GP5+/6+460/0/4639.12.20.023.90.00.08.72.2
Hording UGynecol Oncol (1991)DenmarkTS only240/0/2458.358.3
Hording UInt J Cancer (1993)DenmarkTS only620/0/6230.60.00.021.04.84.8
Hording UGynecol Oncol (1994)DenmarkTS only7827/51/030.80.00.028.20.03.8
Bryndorf TCytogenet Gen Res (2004)DenmarkSPF10100/0/1060.00.00.040.00.00.020.00.0
Madsen BSInt J Cancer (2008)DenmarkGP5+/6+600/0/6051.70.00.036.70.00.011.70.0
Iwasawa AObstet Gynecol (1997)FinlandMY09/11740/0/7436.50.00.025.712.21.4
Tervahauta AIAnticancer Res (1993)FinlandMY09/1170/0/785.714.314.314.30.014.3
Milde-Langosch KInt J Cancer (1995)GermanyMY09/11406/0/3427.50.00.025.00.00.00.0
Hampl MObstet Gynecol (2006)GermanyGP5+/6+480/0/4860.439.62.14.28.3
Petry KUGynecol Oncol (1996)GermanyTS only33/0/0100.0100.00.00.0
Menczer JEur J Gynaecol Oncol (2000)IsraelTS only140/14/064.357.17.1
Bonvicini FJ Med Virol (2005)ItalyMY09/11160/16/00.00.00.00.00.00.0
Pilotti SDiagn Mol Pathol (1995)ItalyTS only231/0/2247.843.54.3
Della Torre GDiagn Mol Pathol (1992)ItalyTS only100/0/1050.00.00.040.010.0
Ansink ACGynecol Oncol (1994)NetherlandsGP5/6600/0/6031.7
Kagie MJGynecol Oncol (1997)NetherlandsCpI/IIG6624/42/019.716.70.01.51.5
Avoort IAInt J Gynecol Pathol (2005)NetherlandsSPF10160/0/160.00.00.00.00.00.00.00.0
Liss JGinekol Pol (1998)PolandMY09/11180/0/1816.716.7
Lerma EInt J Gynecol Pathol (1999)SpainL1+VPHFast577/50/012.312.30.0
Santos MAm J Surg Pathol (2006)SpainGP5+/6+; SPF109217/75/017.42.20.014.10.01.12.20.0
Ogunbiyi OAObstet Gynecol (1994)UKTS only330/0/3375.875.8
Brooks LACancer Res (2000)UKOther360/0/3636.136.1
Gasco MOncogene (2002)UKMY09/11; CpI/IIG360/0/3636.136.1
Al-Ghamdi AGynecol Oncol (2002)CanadaMY09/11; GP5/6200/0/2085.055.030.0
Tate JEGynecol Oncol (1994)USMY09/11130/0/1353.80.00.046.20.00.07.70.0
Sagerman PMGynecol Oncol (1996)USMY09/11; TS190/0/1915.80.00.00.00.0
Nuovo GGynecol Oncol (1991)USMY09/11230/16/730.40.00.017.40.00.00.0
Lee YVOncogene (1994)USTS only210/0/2157.10.047.64.8
Bloss JDHuman Pathol (1991)USTS only2010/10/050.010.040.00.0
Kim YTHuman Pathol (1996)USMY09/11184/11/338.90.00.027.85.60.00.00.0
Rufforny IJ Lower Genit Tract Dis (2005)USTS only40/0/4100.0100.0
Madeleine MJ Natl Cancer Inst (1997) part 12USMY09/11240/0/2483.366.70.0 
Madeleine MJ Natl Cancer Inst (1997) part 22USMY09/11860/0/8675.68.10.057.05.82.39.30.0
Kiyabu MTAmer J Surg Pathol (1989)USTS only80/0/875.075.012.5
Monk BIObstet Gynecol (1995)USTS only5521/31/360.01.849.15.5
Sutton BCMod Pathol (2008)USMY09/1111645/0/7169.82.60.056.01.70.010.33.4
Pinto APGynecol Oncol (2004)BrazilGP5+/6+; TS17736/122/326.618.18.50.00.60.6
Scurry JInt J Gynecol Cancer (1998)AustraliaGP5/613026/104/022.318.51.5
Allen DGBr J Cancer (2002)AustraliaMY09/11; TS180/0/1855.60.00.055.60.00.00.00.0
Park JSCancer (1991)New ZealandMY09/11; TS66/0/083.30.00.083.30.0
Total   1,873258/576/1,03940.42.00.132.24.40.64.51.0
Table AIII. Type-Specific Prevalence of Human Papillomavirus (HPV) in Vaginal Intraepithelial Neoplasia (VAIN), by Study
First authorReferenceCountryPCR primersNVAIN1/VAIN2/ VAIN3/VAIN2-3HPV type1
Any6111618313345
  • 1

    Percent of all subjects tested for the specific type.

  • 2

    This study was expanded since original publication, with a change in the HPV genotyping protocol.

  • TS, type-specific.

Sugase MInt J Cancer (1997)JapanTS only7153/15/3/0100.00.00.09.91.44.20.00.0
Hampl MJ Cancer Res Clin Oncol (2007)GermanyGP5+/6+; MY09/11182/11/5/094.411.10.061.10.05.611.10.0
Frega ACancer Lett (2007)ItalyTS only4416/23/5/0100.090.99.1
Beurden MInt J Gynecol Pathol (1998)NetherlandsCpI/IIG80/0/0/8100.00.00.075.00.00.012.50.0
Baldwin PJClin Cancer Res (2003)UKGP5+/6+10/1/0/0100.00.00.0100.00.00.00.00.0
Daling JRGynecol Oncol(2002) part 12USMY09/11630/0/63/087.36.30.065.17.90.04.80.0
Daling JRGynecol Oncol (2002) part 22USMY09/11180/0/18/077.838.9
Logani SMod Pathol (2003)USSPF101919/0/0/0100.00.00.021.115.85.30.00.0
Srodon MAmer J Surg Pathol (2006)USPGMY09/11; SPF103317/0/16/097.00.00.027.312.16.10.00.0
Aziz DCJ Gynecol Surg (1993)CanadaTS only20/0/0/250.00.00.00.050.00.00.0
Joura EALancet (2007)MulticentricMY09/11210/0/0/2181.04.80.042.99.59.59.50.0
Total   298107/50/110/3193.63.00.045.37.13.83.40.0
Table AIV. Type-Specific Prevalence of Human Papillomavirus (HPV) in Carcinoma of the Vagina, by Study
First authorReferenceCountryPCR primersNHPV type1
Any6111618313345
  • 1

    Percent of all subjects tested for the specific type.

  • 2

    This study was expanded since original publication, with a change in the HPV genotyping protocol.

  • TS, type-specific.

Koyamatsu YGynecol Oncol (2003)JapanL1C1/C21643.837.56.3
Madsen BSInt J Cancer (2008)DenmarkGP5+/6+2788.93.70.077.83.70.07.43.7
Ferreira MMod Pathol (2008)PortugalSPF102181.09.54.833.39.528.69.50.0
Habermann JKCancer Genet Cytogenet (2004)SwedenPGMY09/11825.00.00.012.50.00.00.00.0
Kiyabu MTAm J Surg Pathol (1989)USTS only1464.357.17.1
Daling JRGynecol Oncol (2002) part 12USMY09/113372.70.00.063.612.10.00.00.0
Daling JRGynecol Oncol (2002) part 22USMY09/111770.652.9
Total   13669.93.41.153.77.65.64.51.1
Table AV. Type-Specific Prevalence of Human Papillomavirus (HPV) in Anal Intraepithelial Neoplasia (AIN), by Study
First authorReferenceCountryPCR primersGender (male/female)Sexual preferenceHIV statusNAIN1/AIN2/AIN3/AIN2-3HPV type1
Any6111618313345
  • 1

    Percent of all subjects tested for the specific type.

  • TS, type-specific; MSM, men who have sex with men; n.s., not specified.

Kagawa RSurg Today (2006)Japann.s.1/1n.s.n.s.20/0/2/0100.00.00.0100.00.00.00.0
Vincent-Salomon AModern Pathology (1996)FranceTS only0/1n.s.n.s.10/0/1/00.00.00.00.00.00.0
Piketty CAnn Intern Med (2003)FranceMY09/11; GP5+/6+27/0MSMPos2719/6/2/0100.044.418.540.725.97.414.814.8
Kreuter AJ Am Acad Dermatol (2005)GermanyA5/A10; A6/A820/0MSMPos207/7/6/0100.015.015.075.045.015.050.05.0
Varnai ADInt J Colorectal Dis (2006)GermanyMY09/11; GP5+/6+11/20n.s.n.s.317/7/17/093.522.616.151.60.00.00.00.0
Hampl MJ Cancer Res Clin Oncol (2007)GermanyMY09/11; GP5+/6+0/22Heteron.s.221/4/17/0100.09.10.081.80.04.518.20.0
Fox PASex Transm Infect (2005)UKMY09/11; GP5+/6+93/0MSMBoth9319/45/29/097.864.523.715.124.717.2
Ogunbiyi OAJ Clin Pathol (1993)UKTS onlyUnknn.s.n.s.4114/7/20/053.753.7
Coutlee FJ Clin Microbiol (2006)CanadaPGMY09/11122/0MSMPos12260/0/0/6291.016.48.223.011.56.66.68.2
Palefsky JMCancer Res (1991)USPGMY09/11Unknn.s.n.s.84/0/4/075.025.012.50.00.0
Zaki SRAm J Pathol 1992USMY09/111/6n.s.n.s.70/0/7/085.70.00.028.614.314.3
Hillemanns PAIDS (1996)USMY09/110/5HeteroPos55/0/0/060.00.020.00.00.00.00.0
Critchlow CWAIDS (1998)USMY09/11223/0MSMBoth223189/0/0/3499.143.026.511.2
Palefsky JMJ Acquir Immune Defic Syndr Hum Retrovirol (1998)USMY09/11126/0MSMBoth126111/0/0/1597.6
Daling JRCancer (2004)USMY09/1135/34n.s.n.s.690/0/69/094.25.81.473.97.2   
Chin-Hong PVJ Natl Cancer Inst (2005)USMY09/11210/0MSMNeg210157/0/0/5383.8
Palefsky JMAIDS (2005)USMY09/11163/0MSMPos1630/123/40/098.2
Palefsky JMAIDS (2006)USMY09/11Bothn.s.Pos140/4/10/0100.07.128.635.728.614.37.10.0
Wang CHPV2007 Beijing Conf (2007)USMY09/1196/0MSMPos9678/8/10/091.735.422.950.022.912.514.613.5
Total      1,280671/211/234/16492.720.012.348.119.59.514.510.6
Table AVI. Type-Specific Prevalence of Human Papillomavirus (HPV) in Carcinoma of the Anus, by Study
AuthorReferenceCountryPCR primersGender (male/female)NHPV type1
Any6111618313345
  • 1

    Percent of all subjects tested for the specific type.

  • 2

    In this study, ∼60 carcinoma in situ and 328 anal carcinoma could not be separated, hence they were all included as anal carcinoma.

  • HR, high-risk; LR, low-risk; TS, type-specific; n.s., not specified.

Kagawa RSurg Today (2006)Japann.s.2/4683.30.00.083.30.00.00.0
Youk EGDis Colon Rectum (2001)KoreaMY09/11; L1C1/L1C214/721100.0100.00.0
Tachezy RAPMIS (2007)Czech Rep.GP5+/6+14/182281.80.00.081.80.00.00.00.0
Frisch MN Eng J Med (1997)2Denmark/SwedenGP5+/6+84/30438887.61.30.072.95.70.85.9
Vincent-Salomon AModern Pathology (1996)FranceTS only8/192770.40.00.063.07.40.0
Varnai ADInt J Colorectal Dis (2006)GermanyMY09/11; GP5+/6+13/344785.10.00.078.70.02.16.42.1
Indinnimeo MJ Exp Clin Cancer Res (1999)ItalyTS onlyBoth1464.342.90.0
Holm RModern Pathology (1994)NorwayTS only25/749980.80.00.075.82.05.14.0
Poletti PAInt J Colorectal Dis (1998)SwitzerlandPU-IM (HR)/PU-31B (LR)0/151580.0
Crook TOncogene (1991)UKTS onlyBoth5084.076.08.0
Ogunbiyi OAJ Clin Pathol (1993)UKTS onlyBoth3476.576.5
Palefsky JMCancer Res (1991)USTS onlyBoth1384.676.90.023.17.7
Zaki SRAm J Pathol (1992)USMY09/114/71172.79.19.127.39.19.1
Noffsinger AEModern Pathology (1995)USTS onlyBoth4452.36.840.94.5
Shroyer KRAnatomic Pathology (1995)USMY09/112/81080.070.020.00.010.0
Kiyabu MTAm J Surg Pathol (1989)USTS onlyBoth4100.0100.025.0
Daling JRCancer (2004)USMY09/1151/9915092.79.30.781.37.31.32.70.0
Total    95584.32.90.373.45.21.94.80.5