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ORIGINAL RESEARCH |
From the 1Department of Gynecology and Obstetrics, Institute of Pathology, University Hospital, Heinrich Heine University, Duesseldorf, Germany; 2Department of Molecular Pathology/Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; and 3Dysplasia Clinic, Koenigsallee, Duesseldorf, Germany.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: Two hundred fifty-eight samples of VIN, VaIN, AIN, and vulvar cancer from 241 women were included in the study. The diagnosis of surgical samples was made using published histomorphologic criteria. The DNA was extracted for HPV detection and typed using polymerase chain reaction and sequencing.
RESULTS: The analyses were performed on 210 intraepithelial neoplasia samples (VIN2/3, VaIN2/3, AIN2/3) and 48 vulvar carcinoma samples. Human papillomavirus DNA was detected in 92%, 91%, 89%, and 60% of the VIN, VaIN, AIN, and vulvar carcinoma samples, respectively. High-risk HPV types 16 or 18 were detected in 76%, 64%, 81%, and 42% of the VIN2/3, VaIN2/3, AIN, and vulvar carcinoma samples. Women with HPV-positive samples were younger than those with HPV-negative samples (46 years compared with 55 years and 51 years compared with 61 years, for the VIN2/3 and vulvar carcinoma samples, respectively). Human papillomavirus–positive vulvar carcinoma was more frequent in women aged younger than 56 years (77%), than in those aged 56 years or older (41%).
CONCLUSION: Based on the data obtained in this study, widely-implemented prophylactic HPV vaccination could make an important contribution to the reduction of the risk for cervical cancer and could also prevent about half the vulvar carcinomas in younger women and about two thirds of the intraepithelial lesions in the lower genital tract.
LEVEL OF EVIDENCE: II-3
There has been a striking increase in the incidence of VIN and vulvar carcinoma over the past 30 years, especially in younger women. The observed increase in younger women could be due to a higher incidence of infection of the lower genital tract with human papillomavirus or it may be explained by better diagnostic procedures or both.
Vulvar carcinoma can be HPV-positive or HPV-negative.8,9 Human papillomavirus–positive tumors tend to be nonkeratinizing basaloid or warty tumors, often surrounded by bowenoid-type vulvar intraepithelial neoplasia. Human papillomavirus 16 is the most frequently observed virus in these tumors.2,10,11,13–16 Human papillomavirus–positive tumors, which are associated with younger patients, have been diagnosed more frequently in recent decades and are thought to have a better prognosis than the HPV-negative tumors.2,5,7,11,17–20
Human papillomavirus–negative tumors are more frequently found in older women, often with a history of nonneoplastic epithelial disorders of the vulvar skin, such as lichen sclerosis.10,11,21 These are differentiated keratinizing squamous cell carcinoma and the corresponding precursor lesions are called "simplex" or well-differentiated VIN.9,11,21 These latter tumors are usually unifocal, more aggressive, and they tend to recur and metastasize earlier.18,20
At least 70% of women are infected with HPV during their lifetime, and this virus is responsible for the most common sexually transmitted infections worldwide. However, most HPV infections are asymptomatic and clear spontaneously within 12–18 months. Less then 10% of women have persistent infection but this is a risk factor for the development of lower genital tract intraepithelial dysplasia, predominantly located at the cervix (cervical intraepithelial neoplasia: CIN). When untreated, these precursor lesions can progress to invasive cervical cancer in a gradual process that might take between 10 and 12 years from primary infection to the development of invasive cancer.22
The results from epidemiologic studies of cervical cancer specimens show that 99.7% of these tumors are HPV-positive, with HPV 16 and 18 being responsible for approximately 70% of the tumors.23 Two prophylactic vaccines have been developed to prevent infections with these high-risk HPV types, aiming to reduce the worldwide incidence of these tumors. Initial trials have shown highly efficient protection against infections with HPV 16 and 18. In addition, one of the two vaccines is directed against two low-risk HPV types, 6 and 11, that are responsible for 90% of genital warts. At the time that this article was written, the quadrivalent vaccine (HPV 6/11/16/18) has been granted product licenses for the United States and Australia. Furthermore, in Europe it has received a favorable opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use.
Recent studies have provided more data on the prevalence of HPV infection in women with CIN and cervical cancers. Similar data for VIN, vaginal intraepithelial neoplasia (VaIN), anal lesions (AIN) and vulvar cancers are sparse, partly because these conditions are rarer. However, because HPV is known to be present in VIN, AIN, and VaIN lesions and in vulvar cancers, it was decided to analyze the HPV types present in surgical samples from a cohort of 241 women from two centers in Duesseldorf, Germany. The aim was to determine the frequency of high-risk HPV types in these lesions, and to use these data to estimate the possible effect of the prophylactic HPV vaccines on the incidence of VIN, VaIN, AIN, and vulvar cancer.
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MATERIALS AND METHODS |
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The study protocol was approved by the institutional review boards at both sites. All patients underwent surgical treatment consisting of either CO2 laser vaporization after biopsy, CO2 laser excision or knife excision for vulvar, vaginal, or anal intraepithelial neoplasia. Vulvar squamous cell carcinomas were treated by wide local excision or vulvectomy, including complete inguinofemoral lymphadenectomy. Before surgery, all women gave their signed informed consent to inclusion in this study. In the majority of women, a colposcopy-guided biopsy was performed before surgical treatment to confirm the diagnosis. Only surgical specimens of histologically confirmed intraepithelial neoplasia of the vagina, vulva, or anal region or vulvar carcinoma were included in the study. The specimens were examined by an experienced gynecologic pathologist and the diagnosis was based on published histomorphologic criteria.27 For each patient the location and number of lesions, their age at diagnosis, smoking habits, prior history of HPV induced diseases (ie, cervical HPV-induced disease, condyloma, multicentric HPV-induced lesions) and their human immunodeficiency virus (HIV) status were recorded.
All histologic and molecular tests were performed under blind conditions. Single-use scalpels were used to prevent carry-over contamination in the subsequent DNA extraction and polymerase chain reaction (PCR) amplification. The histologic diagnosis was made on serial sections of formalin-fixed paraffin-embedded tissue samples. Serial sections (5 mcm) of intraepithelial neoplastic lesions or invasive vulvar cancer from the paraffin blocks containing the most disease-specific changes were selected for HPV DNA analysis by PCR and sequencing. After deparaffinization, genomic DNA was extracted using the QIAamp DNA Mini Kit (QIAGEN, Hilden, Germany) according to the manufacturer’s instructions. The quality of the extracted DNA was evaluated by spectrophotometry (Beckman Coulter, Krefeld, Germany).
Human papillomavirus DNA was detected using a two-tier PCR-direct sequencing method, modified as indicated below.28,29 We used the general primers GP5+/GP6+30 and the consensus primer pair MY09 and MY11 for amplification of the corresponding part of the HPV L1 gene, with different fluorescent labeling of each of the forward primers. A 20-mcL standard PCR (3 mcL DNA, 2 mcL 10xPCR buffer, 0.2 mM dNTPs, 20 pmol primer each, MgCl2 1.5 mM, 1 Unit Taq polymerase) was run with 40 cycles of denaturation at 94°C for 20 seconds, and annealing for 20 seconds at 39°C for the general primers and at 55°C for the MY09, MY11, and ß-globin primers, followed by an extension at 72°C for 40 seconds. The initial denaturation was performed at 94°C for 5 minutes, and the final extension was performed at 72°C for 5 minutes. The integrity of human genomic DNA was verified by PCR amplification of a 268 base-pair fragment of the ß-globin gene. The DNA extracted from HPV 16-positive Caski cells was used as a positive control, and for the negative control, water was used as template instead of DNA. The lower limit of the number of viral copies to result in a positive test was estimated to be 300–400 copies of HPV depending on the type.
An aliquot (0.8 mcL) of each of the three PCR products was mixed with 10 mcL formamide and 0.5 µL internal standard (GENESCAN 500-ROX; Applied Biosystems, Foster City, CA). After denaturation at 90°C for 2 minutes and cooling, the PCR products were analyzed on an automated ABI 310 genetic analyzer (Applied Biosystems). The PCR product sizes were determined using GENESCAN 2.1.1 software (Applied Biosystems). We controlled for inter- and intra-assay variation by monitoring the fluorescence in the positive controls in each run and by duplicate testing of randomly selected samples in one run.
Positive PCR products were purified using the High Pure PCR product purification kit (Roche Diagnostics, Mannheim, Germany) according to the manufacturer’s instructions. The sequence of one strand of the purified PCR fragments was determined with the Big-Dye Terminator sequencing kit (Applied Biosystems) using 3–5 pMol of GP6+ or MY09 as sequencing primers, and analyzed on an ABI Prism 310 automated sequencer (Applied Biosystems). These sequences were compared with the documented virus sequences available in the GenBank databank using the BLAST Program (Blast, Pittsboro, NC). When multiple fluorescent peak patterns were observed in the GENESCAN analyzes, type-specific PCR for the seven most common HPV types 6, 11, 16, 18, 31, 33 and 51 was performed.31 Stratified analyses were performed by age, histology, and center, and a two-sample Wilcoxon rank sum test, Pearson 
2 test, or t test, were applied, where applicable, to test for significant differences. Furthermore, univariable and multivariable data analyses were conducted using logistic regression, to examine factors independently associated with HPV status (ie, positive or negative for HPV). All data analyses were conducted using STATA 8.2 (StataCorp, College Station, TX). P values presented are two-tailed and the results were considered statistically significant at P
.05).
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RESULTS |
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Multifocal disease was observed in 27% (70 of 258) of the samples. Of the 48 samples of invasive vulva carcinoma, 11 were diagnosed as microinvasive carcinoma (depth of infiltration less than 1 mm) arising from VIN 3. Only two patients were seropositive for HIV, and none of the other women had any immunodeficiency conditions. The two HIV-infected patients were aged 21 and 41 years. The 21 year old had multicentric disease with a HPV 16–positive VIN 3 and CIN 3, and the 41 year old presented with a HPV 16–positive VIN3 with microinvasive cancer, depth of invasion less then 1 mm. No evidence of PCR amplification was observed for the negative control samples run in each PCR test, and HPV 16 DNA was detected in the positive control samples (HPV 16-positive Caski cells).
The mean age of the patients is listed in Table 1, as well as the number of HPV positive samples (92%, 91%, 88%, and 60% of the VIN2/3, VaIN2/3, AIN2/3, and vulvar carcinoma samples, respectively). Women with VIN2/3 and vulvar carcinoma HPV-positive samples were significantly younger than those with HPV-negative samples (P<.05; Table 1). This was observed in both treatment centers. As expected, HPV-positive vulvar carcinoma was more frequent in women aged younger than 56 years (77%), than in those aged 56 years or older (41%); adjusting for center, this difference was statistically significant (odds ratio [OR] 4.3, 95% confidence interval [CI] 1.2–15.4) (Table 2). However, we identified a HPV-positive vulva carcinoma (HPV 6, 31, and 68) in an 83-year-old woman and a HPV-negative microcarcinoma with 1.2-mm infiltration and without surrounding lichen sclerosus in a 32-year-old woman.
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Females in center 2 with a VIN2/3 were, independent of age, more likely to have HPV-positive samples compared with center 1 (P=.03). This difference in HPV positivity between centers was not seen in women with vulvar carcinoma, VaIN2/3, or AIN2/3. Testing for effect modification between HPV positivity, age, and center did not show any significant differences.
The majority of the HPV-positive samples (91%, 90%, 71%, and 83%, for the VIN2/3, VaIN2/3, AIN, and vulvar carcinoma samples, respectively) contained only high-risk HPV types (single or multiple infections: Table 3). Low-risk HPV types only were observed in less than 5% of the samples. Infections with two or more different HPV types were present in 13%, 10%, 21%, and 13% of the VIN2/3, VaIN2/3, AIN, and vulvar carcinoma samples, respectively.
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The distribution of HPV types is summarized in Table 3. High-risk HPV types 16 or 18 were found in 139 of 183 VIN 2/3 (76%), 7 of 11 VAIN2/3 (64%), and 13 of 16 AIN 2/3 specimens (81%). In addition, 20 of 48 (42%) vulvar cancer specimens tested positive for HPV 16 or 18, and therefore a total of 179 of 258 lesions included in this study (69%) were HPV 16 or 18 induced. The low-risk HPV types 6 and 11 were only found in 14 samples (5%). High-risk HPV types 16/18 were detected in 76%, 70%, 93%, and 42% of the VIN2/3, VaIN2/3, AIN2/3, and vulvar carcinoma samples. Human papillomavirus 16 (n=134) and 33 (n=18) were the most common HPV types identified in the VIN2/3 samples. Human papillomavirus 16 was the only high-risk type found in the VaIN2/3 and AIN samples. The most frequent HPV type in the vulvar carcinoma samples was HPV 16 (n=19; 66%), followed by HPV 33 DNA (n=4; 14%). Independent of treatment center, younger women (younger than 56 years) with vulvar carcinoma were 4.4 times more likely to be infected with HPV type16 compared with older women (OR 4.4, 95% CI 1.19–16.36). This difference was not observed in women with VIN2/3, VAIN 2/3, or AIN 2/3.
Human papillomavirus 18 was identified in only 6 samples (5 VIN2/3 and 1 vulvar carcinoma). Only rare HPV types or HPV with unknown risk (eg, HPV 40, 53, 55, 66, 67, 91, and HPV IA 18) were identified in one sample each of the VIN2/3, AIN2/3, and vulvar carcinoma samples. In total, 26 different HPV types (6,11,16,18,31,33,35,40,42,44,45,51,52,53,55,56,58,61,66,67,68,73,74,91,IS887/MM4, and HPVIA18) were identified in the samples examined.
Human papillomavirus 16 and 18 were detected in 76% of the VIN2/3 lesions (139 of the 183 lesions analyzed); therefore, if the prophylactic HPV vaccine were to be implemented, we could expect that three in four VIN2/3 lesions would be prevented, because the vaccine has been shown to prevent 100% of infections by HPV 16 and 18. In addition, HPV 16 and 18 were detected in 58% (15/26) of the vulvar carcinoma samples in the subgroup of younger women (younger than 56 years); and therefore, widespread vaccination could prevent more than one half of the vulvar carcinomas in these women.
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DISCUSSION |
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A literature search performed in PubMed (http://www.ncbi.nlm.nih.gov) using the search terms vulvar carcinoma, HPV, and pathogenesis from 1970 to May 2006 with no language restrictions showed that presence of HPV DNA in VIN and vulvar cancerous lesions has been reported to vary from 0% to 89%.2,8–17,20,34–47 The published studies have generally involved relatively few samples and the methods used for HPV DNA detection have had different sensitivities. This wide variation is probably due to the small sample sizes, differences in patients recruited and HPV detection methods used, and the year of publication.
In our study, HPV DNA was detected in 86% of all samples (Table 1), which seems to be high compared with the percentages reported in other studies. However, many of these previous studies were conducted more than 10 years ago. In addition, our results, which show that 60% of the vulvar carcinomas and 92% of the VIN2/3, VaIN2/3, and AIN samples were HPV-positive (Table 1), are similar to results from the most recent studies, which reported 60–85% HPV-positive vulvar carcinomas2,20 and 71–80% HPV-positive high-grade VIN.39,48
Many epidemiologic studies assessing the presence of HPV in lower genital tract carcinomas have focused on cervical carcinoma. Their results show that HPV DNA can be detected in more than 99% of the lesions, thus establishing the role of HPV infection as a necessary cause of these carcinomas.23,49 In contrast, until recently, few studies have examined the role of HPV infection in vulvar carcinoma.2,8–17,20,33,34,36–44
The number of HPV-positive invasive vulvar carcinoma in younger woman has increased in the last decade from about 2–5% to more than 20% of all cases of invasive vulvar carcinoma.2,5,7,19 We observed a similar trend toward younger age in our cohort of patients with invasive vulvar carcinoma. The increase in the incidence of VIN with microinvasion, and of invasive carcinoma in younger woman seems to be associated with the increased incidence of HPV infection of the lower genital tract.
In the majority of women with basaloid and warty type of vulvar cancer (more frequent among younger women),11,50 HPV 16, 18, 31, and 33 are the most frequent HPV types detected, whereas HPV 45, 6, and 11 are rarely detected.2,7,13–16,20,35,39,44,51 Our data are consistent with these findings, with HPV 16 being, by far, the most common type (76% of the HPV-positive samples) followed by HPV 33 (10%).
This analysis has been performed on one of the largest series of samples, using PCR techniques that are very sensitive for detecting HPV. However, in our study, the samples were paraffin-embedded, and therefore the PCR technique is not as sensitive as with non–paraffin-embedded samples. We estimate that the sensitivity is between 100 and 300 viruses, depending on the HPV type, compared with sensitivity reported in the original publication of the method, which was 10 viruses. Therefore, our analysis may underestimate the presence of HPV in our samples. Despite this limitation, our results confirm those obtained in the previously reported studies.2,8–17,20,33–46
Prophylactic HPV vaccines have been reported to be highly immunogenic and well-tolerated with no severe adverse events.24,26,52 Results from phase III studies with the quadrivalent prophylactic vaccine in more than 25,000 young persons, including 1,000 adolescent boys and girls, show a high seroconversion rate of up to 98%, with a persistent antibody titer for at least 5 years. The efficacy for preventing HPV 6-, 11-, 16- and 18-related genital warts, VIN, and vaginal or vulvar carcinoma after 2 years follow-up in 2,261 vaccine and 2,279 placebo recipients was 100% (95% CI 88–100%): 40 histologically confirmed events in the placebo group and none in the vaccine group (Villa et al. Oral presentation at EUROGIN 2006, Paris, France, April 24–26, 2006). Thus, a prophylactic vaccine for HPV 16 and 18 might be effective in reducing the incidence of high-grade VIN, VaIN, and AIN, because HPV 16 and 18 were detected in 76% of the VIN2/3, VaIN2/3, and AIN2/3 lesions (159 of a total of 210 lesions analyzed). In addition, although HPV 16 and 18 were detected in 42% of the vulvar carcinoma samples, independent of the patient’s age (20 of 48 samples analyzed), in the subgroup of younger women (younger than 56 years; n=26), HPV 16 and 18 were detected in 58% (15/26) of the samples.
Although the incidence of vulvar cancer has increased over the past 30 years4,6 and is still increasing (in the United States it is estimated to be increasing at a rate of 1.2% per year1) vulvar lesions remain less frequent than cervical lesions. Although the results from a recent systematic review suggest that although some VIN lesions do progress to invasive vulvar carcinoma, the progression rate is low.53 However, the treatment of vulvar lesions is often mutilating and traumatic for women, and the high-grade lesions have an elevated risk of recurrence. Therefore, prevention of these lesions would reduce the number of multiple treatment sessions, mutilating operations, and trauma in women with these lesions. Prophylactic HPV vaccination might have a large effect on the control of HPV-associated human cancers, and could make a significant contribution to the reduction of the risk for cervical as well as that for vulvar cancers in women. We conclude that if prophylactic HPV vaccination is widely implemented, approximately one half of the vulvar carcinomas in younger women (younger than 56 years) (current incidence: approximately 1 per 100,000 women per year), and approximately two thirds of the intraepithelial precursor lesions in the lower genital tract (current incidence: 2.1 per 100,000 women per year) might be prevented.
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Footnotes |
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Corresponding author: Monika Hampl, MD, Department of Gynecology and Obstetrics, University Hospital of Duesseldorf, Moorenstr. 5, 40 225 Duesseldorf, Germany; e-mail: hampl{at}med.uni-duesseldorf.de.
doi:10.1097/01.AOG.0000245786.86267.80
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REFERENCES |
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2. Al-Ghamdi A, Freedman D, Miller D, Poh C, Rosin M, Zhang L, et al. Vulvar squamous cell carcinoma in young women: a clinicopathologic study of 21 cases. Gynecol Oncol 2002;84:94–101.[Medline]
3. Carter J, Carlson J, Fowler J, Hartenbach E, Adcock L, Carson L, et al. Invasive vulvar tumors in young women—a disease of the immunosuppressed? Gynecol Oncol 1993;51:307–10.[Medline]
4. Iversen T, Tretli S. Intraepithelial and invasive squamous cell neoplasia of the vulva: trends in incidence, recurrence, and survival rate in Norway. Obstet Gynecol 1998;91:969–72.[Abstract]
5. Jones RW, Baranyai J, Stables S. Trends in squamous cell carcinoma of the vulva: the influence of vulvar intraepithelial neoplasia. Obstet Gynecol 1997;90:448–52.[Abstract]
6. Judson PL, Habermann EB, Baxter NN, Durham SB, Virnig BA. Trends in the incidence of invasive and in situ vulvar carcinoma. Obstet Gynecol 2006;107:1018–22.
7. Messing MJ, Gallup DG. Carcinoma of the vulva in young women. Obstet Gynecol 1995;86:51–4.[Abstract]
8. Andersen WA, Franquemont DW, Williams J, Taylor PT, Crum CP. Vulvar squamous cell carcinoma and papillomaviruses: two separate entities? Am J Obstet Gynecol 1991;165:329–35.[Medline]
9. Bloss JD, Liao SY, Wilczynski SP, Macri C, Walker J, Peake M, et al. Clinical and histologic features of vulvar carcinomas analyzed for human papillomavirus status: evidence that squamous cell carcinoma of the vulva has more than one etiology. Hum Pathol 1991;22:711–8.[Medline]
10. Hording U, Junge J, Daugaard S, Lundvall F, Poulsen H, Bock JE. Vulvar squamous cell carcinoma and papillomaviruses: indications for two different etiologies. Gynecol Oncol 1994;52:241–6.[Medline]
11. Toki T, Kurman RJ, Park JS, Kessis T, Daniel RW, Shah KV. Probable nonpapillomavirus etiology of squamous cell carcinoma of the vulva in older women: a clinicopathologic study using in situ hybridization and polymerase chain reaction. Int J Gynecol Pathol 1991;10:107–25.[Medline]
12. Trimble CL, Hildesheim A, Brinton LA, Shah KV, Kurman RJ. Heterogeneous etiology of squamous carcinoma of the vulva. Obstet Gynecol 1996;87:59–64.[Abstract]
13. Hording U, Daugaard S, Iversen AK, Knudsen J, Bock JE, Norrild B. Human papillomavirus type 16 in vulvar carcinoma, vulvar intraepithelial neoplasia, and associated cervical neoplasia. Gynecol Oncol 1991;42:22–6.[Medline]
14. Iwasawa A, Nieminen P, Lehtinen M, Paavonen J. Human papillomavirus in squamous cell carcinoma of the vulva by polymerase chain reaction. Obstet Gynecol 1997;89:81–4.[Abstract]
15. Kagie MJ, Kenter GG, Zomerdijk-Nooijen Y, Hermans J, Schuuring E, Timmers PJ, et al. Human papillomavirus infection in squamous cell carcinoma of the vulva, in various synchronous epithelial changes and in normal vulvar skin. Gynecol Oncol 1997;67:178–83.[Medline]
16. Park JS, Rader JS, Wu TC, Laimins LA, Currie JL, Kurman RJ, et al. HPV-16 viral transcripts in vulvar neoplasia: preliminary studies. Gynecol Oncol 1991;42:250–5.[Medline]
17. Ansink A, Mooi WJ, van Doornewaard G, van Tinteren H, Heintz AP, Ivanyi D. Cytokeratin subtypes and involucrin in squamous cell carcinoma of the vulva. An immunohistochemical study of 41 cases. Cancer 1995;76:638–43.[Medline]
18. Husseinzadeh N, DeEulis T, Newman N, Wesseler T. HPV changes and their significance in patients with invasive squamous cell carcinoma of the vulva: a clinicopathologic study. Gynecol Oncol 1991;43:237–41.[Medline]
19. Losch A, Joura EA. Vulvar neoplasia in young women. Gynecol Oncol 1999;75:519.[Medline]
20. Monk BJ, Burger RA, Lin F, Parham G, Vasilev SA, Wilczynski SP. Prognostic significance of human papillomavirus DNA in vulvar carcinoma. Obstet Gynecol 1995;85:709–15.[Abstract]
21. Leibowitch M, Neill S, Pelisse M, Moyal-Baracco M. The epithelial changes associated with squamous cell carcinoma of the vulva: a review of the clinical, histologic and viral findings in 78 women. Br J Obstet Gynaecol 1990;97:1135–9.[Medline]
22. Schiffman M, Kjaer SK. Chapter 2: Natural history of anogenital human papillomavirus infection and neoplasia. J Natl Cancer Inst Monogr 2003;14–9.
23. Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518–27.
24. Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, Schuind A, et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet 2004;364:1757–65.[Medline]
25. Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002;347:1645–51.
26. Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Giuilano AR, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol 2005;6:271–8.[Medline]
27. Ridley CM, Frankman O, Jones IS, Pincus SH Wilkinson EJ, Fox H, et al. New nomenclature for vulvar disease: International Society for the Study of Vulvar Disease. Hum Pathol 1989;20:495–6.[Medline]
28. Bollmann R, Mehes G, Torka R, Speich N, Schmitt C, Bollmann M. Human papillomavirus typing and DNA ploidy determination of squamous intraepithelial lesions in liquid-based cytologic samples. Cancer 2003;99:57–62.[Medline]
29. Feoli-Fonseca JC, Oligny LL, Filion M, Brochu P, Simard P, Russo PA, et al. A two-tier polymerase chain reaction direct sequencing method for detecting and typing human papillomaviruses in pathologic specimens. Diagn Mol Pathol 1998;7:317–23.[Medline]
30. Jacobs MV, Snijders PJ, van den Brule AJ, Helmerhorst TJ, Meijer CJ, Walboomers JM. A general primer GP5+/GP6(+)-mediated PCR-enzyme immunoassay method for rapid detection of 14 high-risk and 6 low-risk human papillomavirus genotypes in cervical scrapings. J Clin Microbiol 1997;35:791–5.[Abstract]
31. van den Brule AJ, Meijer CJ, Bakels V, Kenemans P, Walboomers JM. Rapid detection of human papillomavirus in cervical scrapes by combined general primer-mediated and type-specific polymerase chain reaction. J Clin Microbiol 1990;28:2739–43.
32. Sideri M, Jones RW, Wilkinson EJ, Preti M, Heller DS, Scurry J, et al. Squamous vulvar intraepithelial neoplasia: 2004 modified terminology, ISSVD Vulvar Oncology Subcommittee. J Reprod Med 2005;50:807–10.[Medline]
33. Jones RW, Rowan DM, Stewart AW. Vulvar intraepithelial neoplasia: aspects of the natural history and outcome in 405 women. Obstet Gynecol 2005;106:1319–26.
34. Brandenberger AW, Rudlinger R, Hanggi W, Bersinger NA, Dreher E. Detection of human papillomavirus in vulvar carcinoma. A study by in situ hybridisation. Arch Gynecol Obstet 1992;252:31–5.[Medline]
35. Buscema J, Naghashfar Z, Sawada E, Daniel R, Woodruff JD, Shah K. The predominance of human papillomavirus type 16 in vulvar neoplasia. Obstet Gynecol 1988;71:601–6.
36. Hillemanns P, Wang X. Integration of HPV-16 and HPV-18 DNA in vulvar intraepithelial neoplasia. Gynecol Oncol 2006;100:276–82.[Medline]
37. Nuovo GJ, Darfler MM, Impraim CC, Bromley SE. Occurrence of multiple types of human papillomavirus in genital tract lesions. Analysis by in situ hybridization and the polymerase chain reaction. Am J Pathol 1991;138:53–8.[Abstract]
38. Rusk D, Sutton GP, Look KY, Roman A. Analysis of invasive squamous cell carcinoma of the vulva and vulvar intraepithelial neoplasia for the presence of human papillomavirus DNA. Obstet Gynecol 1991;77:918–22.
39. van der Avoort IA, Shirango H, Hoevenaars BM, Grefte JM, de Hullu JA, de Wilde PC, et al. Vulvar squamous cell carcinoma is a multifactorial disease following two separate and independent pathways. Int J Gynecol Pathol 2006;25:22–9.[Medline]
40. Kiyabu MT, Shibata D, Arnheim N, Martin WJ, Fitzgibbons PL. Detection of human papillomavirus in formalin-fixed, invasive squamous carcinomas using the polymerase chain reaction. Am J Surg Pathol 1989;13:221–4.[Medline]
41. Neill SM, Lessana-Leibowitch M, Pelisse M, Moyal-Barracco M. Lichen sclerosus, invasive squamous cell carcinoma, and human papillomavirus. Am J Obstet Gynecol 1990;162:1633–4.[Medline]
42. Sutton GP, Stehman FB, Ehrlich CE, Roman A. Human papillomavirus deoxyribonucleic acid in lesions of the female genital tract: evidence for type 6/11 in squamous carcinoma of the vulva. Obstet Gynecol 1987;70:564–8.
43. Venuti A, Marcante ML. Presence of human papillomavirus type 18 DNA in vulvar carcinomas and its integration into the cell genome. J Gen Virol 1989;70:1587–92.
44. Carson LF, Twiggs LB, Okagaki T, Clark BA, Ostrow RS, Faras AJ. Human papillomavirus DNA in adenosquamous carcinoma and squamous cell carcinoma of the vulva. Obstet Gynecol 1988;72:63–7.
45. Jones RW, Park JS, McLean MR, Shah KV. Human papillomavirus in women with vulvar intraepithelial neoplasia III. J Reprod Med 1990;35:1124–6.[Medline]
46. Almeida G, do Val I, Gondim C, Lima R, Takiya C, Carvalho G. Human papillomavirus, Epstein-Barr virus and p53 mutation in vulvar intraepithelial neoplasia. J Reprod Med 2004;49:796–9.[Medline]
47. Hording U, Kringsholm B, Andreasson B, Visfeldt J, Daugaard S, Bock JE. Human papillomavirus in vulvar squamous-cell carcinoma and in normal vulvar tissues: a search for a possible impact of HPV on vulvar cancer prognosis. Int J Cancer 1993;53:394–6.
48. Hillemanns P, Wang X, Staehle S, Michels W, Dannecker C. Evaluation of different treatment modalities for vulvar intraepithelial neoplasia (VIN): CO(2) laser vaporization, photodynamic therapy, excision and vulvectomy. Gynecol Oncol 2006;100:271–5.[Medline]
49. Schiffman MH, Castle P. Epidemiologic studies of a necessary causal risk factor: human papillomavirus infection and cervical neoplasia. J Natl Cancer Inst 2003;95:E2.
50. Kurman RJ, Toki T, Schiffman MH. Basaloid and warty carcinomas of the vulva. Distinctive types of squamous cell carcinoma frequently associated with human papillomaviruses [published erratum appears in Am J Surg Pathol 1993;17:536]. Am J Surg Pathol 1993;17:133–45.[Medline]
51. Hording U, Daugaard S, Junge J, Lundvall F. Human papillomaviruses and multifocal genital neoplasia. Int J Gynecol Pathol 1996;15:230–4.[Medline]
52. Harper DM, Franco EL, Wheeler CM, Moscicki AB, Romanowski B, Roteli-Martins CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 2006;367:1247–55.[Medline]
53. van Seters M, van Beurden M, de Craen AJ. Is the assumed natural history of vulvar intraepithelial neoplasia III based on enough evidence? A systematic review of 3322 published patients. Gynecol Oncol 2005;97:645–51.[Medline]
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