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Contents: Cancer: Original Research

Human Papillomavirus Genotypes From Vaginal and Vulvar Intraepithelial Neoplasia in Females 15–26 Years of Age

Garland, Suzanne M. MD; Joura, Elmar A. MD; Ault, Kevin A. MD; Bosch, F. Xavier MD, PhD; Brown, Darron R. MD; Castellsagué, Xavier MD; Ferenczy, Alex MD; Ferris, Daron G. MD; Giuliano, Anna R. PhD; Hernandez-Avila, Mauricio MD; Huh, Warner K. MD; Iversen, Ole-Erik MD, PhD; Kjaer, Susanne K. MD; Kurman, Robert J. MD; Luna, Joaquin MD; Monsonego, Joseph MD; Muñoz, Nubia MD; Paavonen, Jorma MD; Pitisuttihum, Punnee MD; Ronnett, Brigitte M. MD; Steben, Marc MD; Stoler, Mark H. MD; Wheeler, Cosette M. PhD; Wiley, Dorothy J. PhD, MPH; Perez, Gonzalo MD; Saah, Alfred J. MD; Luxembourg, Alain MD, PhD; Li, Se PhD; DiNubile, Mark J. MD; Wagner, Monika PhD; Velicer, Christine PhD

Author Information
doi: 10.1097/AOG.0000000000002736

Many common human papillomavirus (HPV) types have been detected in vulvar and vaginal lesions typically diagnosed in women in the third to sixth decade of life.1–8 Human papillomavirus-related vulvar intraepithelial neoplasia (VIN) is divided into low-grade squamous intraepithelial lesions (LSIL, VIN 1) and potentially precancerous high-grade squamous intraepithelial lesions (HSIL, VIN 2/3).9,10 A substantial number of untreated vulvar HSILs (87.5%) progress to cancer.11 Low-grade and high-grade vaginal intraepithelial neoplasia (VAIN) are also classified as LSIL (VAIN 1) and HSIL (VAIN 2/3), respectively; HSILs variably progress to invasive vaginal cancer.12 Delayed diagnosis of vulvar and vaginal cancers is common and can adversely affect prognosis.

Cervical cancer is predominately caused by 12 high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59), and most anogenital warts are caused by two low-risk HPV types (6 and 11).13 Three highly efficacious HPV vaccines are in widespread worldwide use against genital HPV infection and associated anogenital lesions: bivalent (HPV16/18 [Cervarix]),14 quadrivalent (HPV6/11/16/18 [GARDASIL]),15,16 and nonavalent vaccines (HPV6/11/16/18/31/33/45/52/58 [GARDASIL9]).17

Estimates for the frequencies of HPV types associated with vulvovaginal lesions remain imprecise.7,18–21 To delineate the association of HPV genotypes with incident vulvovaginal abnormalities, we estimated the proportion of vulvar or vaginal lesions attributable to the 14 HPV genotypes most frequently linked to cervical cancer and anogenital warts among females 15–26 year old prospectively followed in the placebo arms of two pivotal trials assessing the prophylactic efficacy of the quadrivalent vaccine.15,16


For this post hoc descriptive analysis, we used data to delineate the association of HPV genotypes from females 15–26 years of age in the placebo arms of two already published, randomized, double-blind clinical trials of the quadrivalent HPV vaccine (FUTURE I, NCT00092521,15 and FUTURE II, NCT0009253416) who developed vulvar or vaginal LSILs and HSILs during approximately 4 years of follow-up. Secondary objectives were to compare baseline characteristics of females with and without incident vulvar or vaginal lesions and to explore patterns of lesion development at multiple (vulvar, vaginal, and cervical) sites in the same female. An exploratory, but clinically informative, objective was to estimate the proportion of vulvar or vaginal LSILs or HSILs attributable to genotypes covered by current vaccines.

The study designs, protocols, and results for each study have been previously published.15,16 Both studies were sponsored by Merck & Co, Inc., conducted in accordance with principles of Good Clinical Practice, and approved by the appropriate institutional review boards and regulatory agencies governing each site. Females reporting a history of abnormal cervical Pap test results or multiple sexual partners (defined as four or greater lifetime partners by most but not all sites) were excluded. These trials enrolled a total of 17,622 healthy, nonpregnant females aged 15–26 years, 8,812 of whom were randomized to the placebo arms. Participants underwent pelvic examinations for cytologic testing with visual inspection of the vulvovaginal and perianal areas and collection of cervical and anogenital swabs for HPV testing by polymerase chain reaction assay at randomization on day 1, at months 7 and 12, and then every 6–12 months for up to 48 months.

The 8,798 placebo recipients who received one or greater study injections and had follow-up data were included in the current descriptive analysis. Individual participants could have more than one lesion of the same or different histologic type. Biopsies were obtained from all external anogenital lesions deemed possibly HPV-related on inspection. If multiple lesions were apparent, each suspicious lesion was sampled. All biopsy specimens were first read for clinical management by pathologists at a central laboratory (Diagnostic Cytology Laboratories, Indianapolis, Indiana) and then adjudicated by a panel of four gynecologic pathologists blinded to central laboratory and clinical diagnoses, treatment group, and HPV status. Specimens were tested for 14 prespecified HPV genotypes (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) using a type-specific multiplex polymerase chain reaction assay developed by Merck Research Laboratories (Merck & Co, Inc.) to simultaneously amplify and detect the L1, E6, and E7 open reading frames of HPV6, 11, 16, 18, 31, 45, 52, and 58 or the E6 and E7 open reading frames of HPV33, 35, 39, 51, 56, and 59.22,23 The adjudicated diagnoses of vaginal and vulvar LSILs (not including condylomata) and HSILs were captured for these analyses.

Baseline characteristics of females who did and did not develop vulvar or vaginal lesions were analyzed by lesion location and grade. If a female developed greater than one lesion at a site, the highest grade lesion was used in the analysis. To calculate age-adjusted associations between baseline characteristics and lesion development, odds ratios (ORs) and 95% CIs were computed using a nested case–control approach. Five controls per case were randomly selected from females who did not develop cervical or anogenital lesions throughout the follow-up period. The comparison group was not matched by person-time at risk.

We explored patterns of lesion development at cervical, vulvar, and vaginal sites in individual females. The proportion of females with incident lesions at a specified site who also had lesions at other sites was calculated from females with histologically confirmed cervical, vulvar, or vaginal lesions during follow-up.

Human papillomavirus types were grouped into bivalent vaccine types (16/18), quadrivalent vaccine types (6/11/16/18), nonavalent vaccine types (6/11/16/18/31/33/45/52/58), the five additional types included in the nine-genotype vaccine, but not in the quadrivalent vaccine (31/33/45/52/58), and the most common nonvaccine high-risk types identified in the quadrivalent HPV vaccine trials (35/39/51/56/59).

Proportional attribution was the primary attribution approach.18–21,24 The relative proportion of co-infected lesions attributed to each HPV type detected in the lesion corresponded to the relative proportion of lesions from the same population in which that HPV type had been detected as a single infection. Four other approaches18–21,24 were used as sensitivity analyses (Appendix 1, available online at For additional interpretative context, we also present the type-specific analyses for only the subset of lesions in which any of the 14 HPV types being tested was identified.


There were 8,812 females aged 15–26 years at baseline randomized to the two placebo arms, but 14 females were excluded from this analysis because of missing data or cross-treatment with vaccine. During approximately 4 years of follow-up in the remaining 8,798 females, a total of 86 vulvar lesions (40 LSILs and 46 HSILs) were diagnosed in 68 females, and 151 vaginal lesions (118 LSILs and 33 HSILs) were diagnosed in 107 females (Appendix 2, available online at

Females who developed vulvar or vaginal lesions during follow-up tended to have higher numbers of lifetime and recent (last 6 months) sex partners and also tended to test positive for at least one measured HPV genotype at baseline than females who remained lesion-free. Females who developed vaginal lesions during follow-up were more likely to have a Pap test result abnormality at baseline compared with those with no lesions during follow-up (LSIL crude OR 3.1, 95% CI 1.7–5.7; HSIL crude OR 2.3, 95% CI 0.9–6.0); however, development of vulvar lesions during follow-up was not associated with abnormal Pap test results at baseline (Appendix 2,

By the end of the approximately 4 years of follow-up, 41.2% of females with vulvar lesions and 49.5% of females with vaginal lesions also had cervical lesions, whereas only 6.5% of females with cervical lesions had vaginal or vulvar lesions (Table 1). Overall, 10.3% of females with vulvar lesions had vaginal lesions, whereas 6.5% of females with vaginal lesions also had vulvar lesions. In 47.1% of females who developed vulvar lesions and 53.3% of females who developed vaginal lesions, abnormalities involving cervical and other sites were also present. Females who developed vulvar HSILs had the highest likelihood of having lesions at all three genital sites (8.33%). For females with lesions at multiple sites, no consistent pattern in the relative timing of diagnosis was observed.

Table 1.:
Proportion of Young Females Who Developed Lesions at Multiple Sites (Cervical, Vulvar, or Vaginal) During Follow-up

In total, 72.5% of vulvar LSILs and 91.3% of vulvar HSILs tested positive for one or greater of the 14 HPV types assayed (Table 2 and Fig. 1A), and co-infections multiple HPV types were present in 24.1% and 45.2% of the HPV-positive LSILs and HSILs, respectively. Using proportional attribution, 87.7% and 89.4% of all HPV-positive vulvar LSILs were attributable to HPV types in the quadrivalent and nonavalent vaccines, respectively (Fig. 1B). Specifically, 52.0% of all vulvar LSILs and 71.7% of HPV-positive vulvar LSILs were associated with HPV6, predominantly as single-type infections. Overall, 60.0–67.5% of vulvar LSILs were linked to nonavalent vaccine types, most (60.0–65.0%) of which were quadrivalent vaccine types (Appendix 3, available online at

Table 2.:
Type-specific Prevalence and Proportional Attribution of Human Papillomavirus Genotypes in Vulvar Lesions Among Females 15–26 Years of Age
Table 2-A.:
Type-specific Prevalence and Proportional Attribution of Human Papillomavirus Genotypes in Vulvar Lesions Among Females 15–26 Years of Age
Fig. 1.:
Vulvar or vaginal lesion attribution in females aged 15–26 years to nonavalent vaccine types (6/11, 16/18, and 31/33/45/52/58) and high-risk nonvaccine types (35/39/51/56/59). A. Based on the proportional attribution method, percentage of all human papillomavirus (HPV)–positive vulvar low-grade squamous intraepithelial lesions (LSILs) or high-grade squamous intraepithelial lesions (HSILs) attributable to quadrivalent and nonavalent vaccine types were measured, respectively; denominator includes all lesions (n=40 for vulvar LSILs and n=46 for vulvar HSILs). B. Using multitype-adjusted attribution methods; percentage of all vulvar LSIL and HSILs attributable to all HPV vaccine types; denominator includes HPV-positive lesions (n=29 for vulvar LSILs and n=42 for vulvar HSILs). C. Based on the proportional attribution method; denominator includes all lesions (n=118 for vaginal LSILs and n=33 for vaginal HSILs). D. Using multitype-adjusted attribution methods, percentage of all vaginal LSILs and HSILs attributable to HPV genotypes; denominator includes HPV-positive lesions only (n=72 for vaginal LSILs and n=23 for vaginal HSILs).Garland. Human Papillomavirus-Related Vulvar and Vaginal Lesions. Obstet Gynecol 2018.

In vulvar HSILs, HPV16 was the predominant type detected with proportional attribution rates of 67.9% among all lesions and 74.3% among HPV-positive lesions (Table 2). Using multitype adjusted attribution methods, 76.1–91.3% of all vulvar HSILs were attributable to nonavalent vaccine types and a smaller proportion (65.2–78.3%) to quadrivalent vaccine types, indicating a nontrivial contribution of types 31, 33, 45, 52, and 58 (10.9–14.7%) (Appendix 3, All HPV-positive vulvar HSILs were attributable to nonavalent vaccine types (Table 2 and Fig. 1B).

In vaginal LSILs (Table 3), HPV31, 56, and 16 were the most prevalent types and only HPV33 went undetected. Overall, 61.9% of vaginal LSILs and 72.7% of vaginal HSILs tested positive for one or greater of the 14 HPV types assayed with co-infections present in 41.1% and 33.3% of the HPV-positive LSILs and HSILs, respectively. By the proportional method, 3.9% of all vaginal LSILs (6.3% of HPV-positive vaginal LSILs) were attributable to the low-risk types (HPV6 [2.2%] and HPV11 [1.7%]) (Fig. 1C, D). Of all HPV-positive vaginal LSILs, 56.0% were attributable to nonavalent vaccine types by the proportional method (Fig. 1D). Adjusting for co-infections, 27.1–43.2% of all vaginal LSILs were attributable to the nonavalent vaccine types and 15.3–21.2% to quadrivalent vaccine types, revealing a substantial contribution of types 31, 33, 45, 52, and 58 (11.9–22.0%; Appendix 4, available online at An estimated 18.6–26.8% of vaginal LSILs were attributable to the nonvaccine types 35, 39, 51, 56, and 59.

Table 3.:
Type-specific Prevalence and Proportional Attribution of Human Papillomavirus Genotypes in Vaginal Lesions Among Females 15–26 Years of Age
Table 3-A.:
Type-specific Prevalence and Proportional Attribution of Human Papillomavirus Genotypes in Vaginal Lesions Among Females 15–26 Years of Age

The most common HPV type in vaginal HSILs was HPV16, accounting for 32.5% of all lesions and 46.6% of HPV-positive lesions using the proportional method (Table 3). Most other HPV types tested were also detected (except 11, 45, and 39), but usually as co-infections with HPV16. For all vaginal HSILs, multitype-adjusted attribution estimates ranged from 30.3–48.5% for quadrivalent vaccine types; from 12.1–21.2% for types 31, 33, 45, 52, and 58 (Appendix 4,; and from 42.4–60.6% for all nonavalent vaccine types. Although nonvaccine HPV types were detected in 30.3% of vaginal HSILs, 60% of these lesions were co-infected with quadrivalent HPV types; therefore, only 12.1–15.1% of vaginal HSILs were exclusively attributable to this group (Table 3; Appendix 4 []). Of all HPV-positive vaginal HSILs, 78.3% were attributable to nonavalent vaccine types (Table 3 and Fig. 1D).

The majority of HPV-positive lesions were attributable to types targeted by the nonavalent vaccine using the proportional method, including 89.4% and 100% of vulvar LSILs and HSILs and 56.0% and 78.3% of vaginal LSILs and HSILs, respectively (Appendix 5, available online at These estimates compare with 87.7% and 83.9% of vulvar LSILs and HSILs and 25.2% and 57.4% of vaginal LSILs and HSILs, respectively, attributable to the four genotypes (6, 11, 16, and 18) in the quadrivalent vaccine. The nonvaccine high-risk types (35, 39, 51, 56, and 59) measured in the quadrivalent vaccine trials were detected in 10.6% of vulvar LSILs, no vulvar HSILs, 44.0% of vaginal LSILs, and 21.7% of vaginal HSILs.


These analyses show 14 high-risk HPV types are detectable more often than not in both vaginal and vulvar LSIL and HSIL. Most HPV-positive lesions were attributable to HPV types targeted by the nonavalent vaccine using the proportional attribution method, including 89.4% and 100% of vulvar LSILs and HSILs and 56.0% and 78.3% of vaginal LSILs and HSILs, respectively. The five additional HPV types in the nonavalent vaccine, but not in the quadrivalent vaccine, were detected in 1.7% of vulvar LSILs, 16.1% of vulvar HSILs, 30.8% of vaginal LSILs, and 20.9% of vaginal HSILs. Nonvaccine HPV types contributed more frequently to vaginal LSIL but less to vaginal HSIL, which is also seen in cervical intraepithelial neoplasia.24

Of the 40 vulvar LSILs, 72.5% were positive for one or greater of the 14 HPV types tested. These findings are consistent with several meta-analyses.3,4 Applying the proportional method to HPV-positive vulvar LSILs, 89.4% were attributed to nonavalent vaccine types with only 1.7% attributed to the five additional HPV types not in the quadrivalent vaccine. The most common type in these lesions was HPV6, identified in 71.7% of HPV-positive vulvar LSILs and targeted by the quadrivalent and nonavalent vaccine.

All HPV-positive vulvar HSILs were attributable to genotypes covered by the nonavalent vaccine, including HPV16 found in 74.3% of lesions by the proportional method. Nonvaccine types were unusual and only identified in co-infections with vaccine types. In close agreement with our findings, a multinational, retrospective analysis reported that 88.7% (509/587) of vulvar HSILs were HPV-positive, 77.3% of the positive lesions were attributable to HPV16, and 94.2% to nonavalent vaccine types.1 Both HPV positivity exceeding 80% and the predominance of HPV16 in vulvar HSILs have been observed previously.3,4 Human papillomavirus-31, closely related to type 16,25 appeared to play a relatively modest role in vulvar HSILs (14.7% in our study using proportional attribution), whereas HPV33 was infrequently detected. In contrast, prior analyses identified HPV33 (10.6%) in vulvar HSILs, whereas type 31 (1.2%) was rare.1

Nonavalent HPV types were found in 56.0% of vaginal LSILs in this study, as also observed in cervical intraepithelial neoplasia.24,26 Other investigators have observed mainly HPV16 associated with vaginal LSILs.3,4,12 Non-HPV causes of vaginal LSILs may reflect past in utero exposure to diethylstilbestrol in women 40 years of age and older.27,28

Of the 33 vaginal HSILs in our study, 72.7% tested HPV-positive, of which 78.3% were attributable to nonavalent vaccine types by the proportional attribution method. A nearly identical attribution of 79.0% was found in 181 HPV-positive vaginal HSILs from a recent multinational, retrospective survey.5 In contrast to our findings, most previous reports have identified greater than 90% of vaginal lesions as HPV-positive.29 Differences in assays to detect HPV, variations in the prevalent genotypes, sample storage and handling, age distribution of study participants, sample size, and intraobserver variability in the cytologic or histologic diagnosis may explain some differences across studies.

Approximately 41% and 50% of females with vulvar and vaginal lesions, respectively, also developed cervical lesions in our study, confirming the multifocal nature of anogenital infection and subsequent disease, particularly the association of cervical disease with HPV-related vaginal and vulvar lesions.30,31 Although the coexistence of HPV-related cervical, vulvar, and vaginal cancers and precancerous lesions has not been well studied, a history of cervical cancer or cervical intraepithelial neoplasia 2/3 has been associated with an increased risk of both vulvar and vaginal cancers. Approximately 30% of patients with vaginal cancer had previous premalignant or cancerous cervical lesions.

Our study has several important limitations. This study was a post hoc, descriptive analysis of clinical trial data; the relatively small number of events can affect the precision of the estimated attribution fractions. Applying five attribution approaches may be a better measure of biological variability as opposed to statistical variability. The ideal approach for measuring attribution is laser-capture microdissection. Because our study was limited to females 15–26 years of age, it is possible that older women could differ in HPV type attribution or positivity. Nonetheless, our results were consistent with those reported from recent large multinational studies of vulvar and vaginal HSILs conducted in women over a wider age range with mean (±SD) ages of 50 (±15) years for vulvar HSILs and 50 (±14) years for vaginal HSILs.1,2

Vulvar and vaginal lesions are rare but increasing findings in young women.7 Human papillomavirus infections, including vaccine genotypes, cause the majority of genital abnormalities. Widespread adoption of an efficacious prophylactic vaccine has the potential to prevent a substantial fraction of HPV-related vulvar and vaginal lesions in addition to preventing the majority of cervical lesions.15–17,24,32


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