Human papillomavirus deoxyribonucleic acid in lesions of the female genital tract: evidence for type 6/11 in squamous carcinoma of the vulva

Tissue specimens from 51 patients with genital condyloma acuminata or invasive cervical or vulvar carcinomas were analyzed for the presence of human papillomavirus deoxyribonucleic acid (DNA) using the dot blot technique. Of ten condylomas, 80% contained DNA related to human papillomavirus 6 or 11. Sixty percent had evidence of DNA related to human papillomavirus 16, and 30% contained DNA related to human papillomavirus 18. Of 24 squamous cervical carcinomas, 58% had human papillomavirus type 16-related DNA, 33% had type 6- or 11-related DNA, and 4% had type 18-related DNA. Nine primary or recurrent vulvar carcinomas were analyzed. Seventy-eight percent contained human papillomavirus type 6- or 11-related DNA, 33% type 16-related DNA, and 22% type 18-related DNA. Whereas invasive cervical carcinomas predominantly contained DNA related to human papillomavirus 16 or 18, invasive vulvar carcinomas predominantly contained DNA related to types 6 or 11. Thus, human papillomavirus type alone cannot distinguish benign from malignant epithelial disease in the female genital tract.     

Vulvar squamous cell carcinoma and papillomaviruses: two separate entities?

Vulvar squamous precancers (vulvar intraepithelial neoplasia) are associated with sexual factors, cigarette smoking, and human papillomaviruses. However, epidemiologic studies of invasive carcinoma of the vulva have produced conflicting evidence for these associations, in part because of a strong association with vulvar inflammatory disease (dystrophies) in older women. We analyzed a series of 42 vulvar invasive carcinomas for papillomavirus nucleic acids by deoxyribonucleic acid-deoxyribonucleic acid in situ hybridization and correlated their presence with age, smoking history, and morphologic type. The carcinomas were divided into well-differentiated, moderately and poorly differentiated, and intraepithelial-like growth patterns, the latter composed of nests of invasive neoplastic epithelium with preserved cell polarity, similar to intraepithelial disease. Of the lesions studied, 28% were human papillomavirus deoxyribonucleic acid-positive. Intraepithelial-like neoplasms segregated in women with a younger mean age (64 versus 73 years) than that of women with conventional squamous cell carcinoma and they more frequently had a history of cigarette smoking (88% versus 28%). Moreover, intraepithelial-like lesions contained human papillomavirus nucleic acids more frequently (67% versus 13%) when analyzed by in situ hybridization. These observations confirm the diverse nature of vulvar squamous cell carcinoma and may explain in part why conflicting results are obtained from studies investigating the role of sexual and viral factors in the genesis of vulvar cancer. They suggest that many invasive vulvar cancers may not be linked to papillomaviruses.     

Interleukin 1 receptor antagonist gene polymorphism in women with vulvar vestibulitis

OBJECTIVE: Vulvar vestibulitis is a chronic inflammatory syndrome of unknown cause and pathogenesis. We examined the relation between vulvar vestibulitis and polymorphisms in the gene coding for the interleukin 1 receptor antagonist, a naturally occurring down-regulator of proinflammatory immune responses. STUDY DESIGN: Cells from the lower genital tract of 68 women with vulvar vestibulitis, 343 women with no history of vulvodynia, and 40 women with human papillomavirus cervical infection were tested by polymerase chain reaction for the different alleles of the gene encoding for interleukin 1 receptor antagonist. The presence of human papillomavirus in the specimens was determined by polymerase chain reaction with the use of degenerate consensus primers to the conserved L1 gene. RESULTS: Allele 2 of the gene encoding the interleukin 1 receptor antagonist was present in homozygous form in 52.9% of women with vulvar vestibulitis. In marked contrast only 8. 5% of the control women and 2.5% of women with human papillomavirus were homozygous for this allele (P 相似文献   

Human immunodeficiency virus infection and female lower genital tract malignancy

The risk of lower genital tract neoplasia is increased in women infected with HIV. This has been best demonstrated in cervical squamous intraepithelial lesions, but has also been observed in vulvar and perianal intraepithelial lesions in some studies. Alterations in the prevalence and natural history of human papillomavirus infections of the lower genital tract appear to account for much of the increase. HIV-infected women are approximately four times more likely to be infected with human papillomavirus (including infection with high oncogenic risk human papillomavirus types) than are HIV-uninfected women, and these infections are more likely to be persistent. Human papilomavirus-associated lesions may be more difficult to treat in HIV-infected women. These data highlight the need to develop effective cervical cancer prevention programs for HIV-infected women.     

Analysis of invasive squamous cell carcinoma of the vulva and vulvar intraepithelial neoplasia for the presence of human papillomavirus DNA

We have analyzed a number of invasive squamous cell carcinomas for the presence of human papillomavirus (HPV) DNA using dot blot and Southern blot analysis. Seven of 31 samples (23%) were positive by dot blot and/or Southern blot analysis. In contrast, six of 11 (55%) of vulvar intraepithelial neoplasias contained HPV DNA by dot blot and/or Southern blot hybridization. Less than 50% of the invasive vulvar carcinomas contained detectable HPV DNA. The average age at onset of vulvar carcinoma is higher than that for cervical carcinoma (in which HPV DNA is detected in over 80% of cases). Therefore, the role of HPV in the genesis of vulvar carcinoma may be different from the role of HPV in the genesis of cervical carcinoma.     

Epidemiology of vulvar intra-epithelial neoplasias

The vulvar intraepithelial neoplasia has been identified as one of the 12 neoplasias whose incidence increases in the developed countries. The vulvar intraepithelial neoplasia (VIN) and invasive vulvar cancer incidence increases by 2.4% per annum; and this principally in young women. The VIN account for 57% of the vulvar neoplasias and are actually more frequent than invasive carcinomas. In the United States, between 1973 and 2000, the incidence of the VIN increased by 411% against 20% for invasive cancers. Similar figures were reported from Norwegian registers. The VIN have a different age distribution than invasive cancers: the incidence of the VIN increases until the age of 40-49 years then decreases while the incidence of invasive cancers increases after 50 years without real peak of incidence. The increase in the incidence of VIN could be followed by an increase in the incidence of invasive cancers but the unknowns on the natural history of the VIN and the impact of the treatments make any extrapolation hazardous. The association between the VIN and the human papillomavirus (HPV) has been well established. It should be noted that, contrary to the cervical neoplasia that are related for nearly 100% to the HPV, only 30-40% of invasive cancers of the vulva are related to HPV, while the other carcinomas are related to the evolution of a vulvar lichen sclerous. The HPV induce various types of anogenital lesion according to their genotype. These lesions can be benign for the HPV6 and 11 and preneoplastic or neoplastic for the HPV16 and 18. The presence of HPV16 and 18 is found in 70 to 80% of the VIN suggesting that HPV vaccines could decrease the incidence VIN and HPV related invasive vulvar cancer.     

Carcinoma of the vulva: epidemiology and pathogenesis.

Vulvar squamous carcinoma is an uncommon neoplasm that afflicts a spectrum of women and has been associated with granulomatous vulvar diseases, human papillomaviruses (HPVs), and chronic inflammatory disorders of the vulva. This review summarizes the epidemiologic, histopathologic, and viral data supporting the division of invasive vulvar carcinomas into distinct subsets. Although HPVs have received attention as etiologic agents, histopathologic and viral data indicate that a substantial proportion of vulvar carcinomas in this country may not be related to a veneareally transmitted agent. One of the principal challenges is to produce studies integrating the various disciplines in order to place HPV in proper perspective and develop strategies to identify women at risk for vulvar carcinomas that are not associated with this virus.     

Vulvo-vaginal cancers: risks, evaluation, prevention and early detection

Vulvar and vaginal cancers are rare and account for approximately 7% of cancers of the female reproductive tract. Vulvar and vaginal neoplasia share similar risk factors: human papillomavirus infection, previous cervical intraepithelial neoplasia or cervical cancer, current smoking, sexual factors, and immunosuppression. Several treatment options are available for patients with documented histologic high-grade intraepithelial vulvar or vaginal neoplasia, including excision, laser vaporization, and 5-fluorouracil. After treatment, lifetime follow-up with cytology and colposcopy is recommended. With the widespread use of the human papillomavirus vaccine, one half to two thirds of vulvar and vaginal cancers may be prevented. Patient education regarding reduction of risk factors for progression and close surveillance of at-risk individuals may prevent the progression to invasive disease.     

Sebaceous Carcinoma of the Vulva: A Case Report and Review of the Literature

Although sebaceous glands are prominent on the vulva, sebaceous carcinomas of the vulva rarely occur. In fact, there have been only two cases of sebaceous carcinomas of the vulva reported in the literature. Eighty percent of vulvar cancers are squamous in origin with human papillomavirus (HPV) DNA detected in approximately 60% of these cancers. We present a third patient with sebaceous carcinoma of the vulva and the first to our knowledge that has been analyzed for HPV DNA. The case report and a review of the literature are presented.     

Effect of human papillomavirus vaccines on vulvar, vaginal, and anal intraepithelial lesions and vulvar cancer

OBJECTIVE: Human papillomavirus (HPV) is a necessary cause for cervical cancer, and it has been associated with vulvar and vaginal cancer and vulvar (VIN) and vaginal (VaIN) and anal (AIN) intraepithelial neoplasia. We assessed the prevalence of HPV (and the types) to estimate the possible effect of a HPV vaccine on lower genital tract disease prevention. 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.     

Human papillomavirus type 16 in vulvar carcinoma, vulvar intraepithelial neoplasia, and associated cervical neoplasia.

Vulvar intraepithelial neoplasia (VIN) is becoming more widespread and the patients are becoming still younger. Although progression to invasive vulvar carcinoma is uncommon, local recurrences are frequent and about one-quarter of the patients have multicentric genital disease. The aim of the present study was to search for a possible significant association of human papillomavirus (HPV) infection with vulvar carcinoma, recurrences, and multicentric disease. We used the polymerase chain reaction to examine vulvar and cervical biopsies from 43 patients with vulvar neoplasia for HPV type 16, which is the subtype most often detected in genital malignant or premalignant lesions. HPV 16 DNA sequences were found in 14 of 24 (58%) vulvar squamous carcinomas and in 15 of 19 (79%) VIN lesions. Nine patients (21%) had associated cervical neoplasia and six of these harbored HPV 16 in both lesions. Patients with recurrent intraepithelial neoplasia had a significantly higher incidence of HPV 16-positive lesions. No association was found with regard to the occurrence of multicentric disease or risk of malignant progression.     

Specific serologic response to genital human papillomavirus types in patients with vulvar precancerous and cancerous lesions

OBJECTIVE: Antibodies to human papillomavirus are indicative for previous human papillomavirus exposure. Human papillomavirus antibody reactivities to vulvar precancerous lesions were reported poorly, and the role of human papillomavirus in some of these lesions is still unclear. STUDY DESIGN: In a direct enzyme-linked immunosorbent assay, serum samples from 126 healthy control subjects, 97 women with lichen sclerosus with or without squamous hyperplasia, 78 women with vulvar intraepithelial neoplasia, and 16 women with verrucous carcinoma were examined for immunoglobulin G and A antibodies to L1 virus-like particles of genital human papillomavirus types 6, 11, 16, 18, and 31, cutaneous human papillomavirus type 8, bovine papilloma virus, and cottontail rabbit papilloma virus. RESULTS: In lichen sclerosus/squamous hyperplasia with atypia immunoglobulin G and A, antibody positivity rates to high-risk human papillomavirus virus-like particle types 16, 18, and 31 were significantly higher than in the control group and the lichen sclerosus/squamous hyperplasia group without atypia. In patients with vulvar intraepithelial neoplasia I, increased immunoglobulin G antibody prevalences with both high-risk and low-risk human papillomavirus-virus-like particles were detected; whereas in patients with vulvar intraepithelial neoplasia II/III, this was observed only with the human papillomavirus types 16, 18, and 31. When only reactivities with 2 genital human papillomavirus types were compared, percentages of positives to only 1 of these 2 types ranged between 43% and 82%, with regard to all respective positives. CONCLUSION: Our data support the role of high-risk human papillomavirus types, mainly human papillomavirus-16, in the pathogenesis of different vulvar lesions with atypia. Serologically, there are no indications that lichen sclerosus/squamous hyperplasia without atypia is associated with human papillomavirus, but high-risk human papillomavirus in lichen sclerosus/squamous hyperplasia with atypia could play a role in carcinogenesis. High antibody specificity was clearly demonstrated among 5 genital, 1 cutaneous human, and 2 animal papillomavirus types.     

Immunoperoxidase localization of papillomavirus antigens in cervical dysplasia and vulvar condylomas

Biopsies of 50 cases of cervical dysplasia (46 mild and 4 moderate) and 40 cases of vulvar condyloma acuminata (genital warts) were screened for the presence of papillomavirus antigens by means of a peroxidase-antiperoxidase method having immunospecificity against the genus-specific (common) antigen(s) of the papillomaviruses. With the use of this technique, on formalin-fixed, paraffin-embedded tissue, papillomavirus antigens were detected in cells with cytologic and histologic features of wart virus infection (so-called koilocytotic atypia). Cells showing a positive reaction for papillomavirus antigens were identified in 24 of 50 (48%) cases of cervical dysplasia and in 20 of 40 (50%) cases of vulvar condyloma. The results of this study provide specific confirmation of the presence of papillomavirus antigens in cervical dysplasia and suggest that the papillomavirus may be an important factor in the etiology of this disease.     

Testing for high-risk human papillomavirus types will become a standard of clinical care

Testing for high-risk human papillomavirus types should become a standard of care for women in the United States because cervical cancer is an infectious disease. Current care is based on cytologic screening and a pathologic staging of cellular tissue changes. Before these cellular modifications, there is a demonstrable pattern of human papillomavirus infection. Human papillomavirus is the most frequently acquired sexually transmitted disease in women and is usually eliminated without treatment. Persistence of high-risk human papillomavirus types can lead to abnormal cervical cellular changes. When these cervical cellular changes occur, physician interventions hasten human papillomavirus elimination. Currently, adding human papillomavirus screening to the Papanicolaou smear identifies a population for closer follow-up studies. In the future a vaccine should be introduced to prevent infections, and medical treatments to hasten the elimination of high-risk human papillomavirus types should become part of standard medical practice.     

Detection of human papillomavirus deoxyribonucleic acid in exfoliated cervicovaginal cells as a predictor of cervical neoplasia in a high-risk population

Specific types of human papillomavirus are currently implicated as etiologic agents of precancerous and cancerous lesions of the cervix. We have previously described the use of cervicovaginal lavage and molecular hybridization to detect human papillomavirus infections of the cervix. We report here the predictive value of this method of human papillomavirus detection to identify women with biopsy proved dysplastic and cancerous lesions of the cervix. One hundred ninety-one women from a city hospital colposcopy clinic underwent concurrent Papanicolaou smear, cervicovaginal lavage, and coloposcopically directed cervical biopsy. Human papillomavirus deoxyribonucleic acid was detected in 114 (59.7%) of these women. Of the positive results, human papillomavirus type 16 accounted for 23.7%, human papillomavirus type 18 for 10.5%, human papillomavirus type six or 11 for 6.2%, related human papillomavirus types for 52.6%, and 7.0% contained more than one type. The distribution of human papillomavirus types was similar in both women younger than 40 years of age and in older women. Eighty-nine of 128 (69.5%) women less than 40 years old with cervical lesions had positive findings of human papillomavirus, and 18 of 29 (62.1%) older women with cervical lesions had positive findings of human papillomavirus. Detection of human papillomavirus types 16 and 18 identified only 35 of 157 (22.3%) women with cervical lesions. The sensitivity of detecting all types of human papillomavirus as a predictor of a biopsy proved lesion (68.0%) was comparable with the sensitivity of cytologic examination alone (74.0%). However, human papillomavirus detection combined with the Papanicolaou smear provided an increased overall sensitivity of 89.3% (p less than 0.01). In fact, women either positive for human papillomavirus or having abnormal cytologic findings were 11.8 times more likely to have a biopsy proved cervical lesion than human papillomavirus-negative women with negative cytologic results (95% confidence interval for odds ratio: 5.3 to 26.6). We conclude that the sensitivity of cytologic examination plus human papillomavirus detection is superior to the use of either cytologic studies or human papillomavirus detection alone in identifying patients with cervical lesions.     

Human papillomavirus as a form of risk assessment

There is a huge amount of interest in the use of human papillomavirus testing to improve both the sensitivity and specificity of cervical screening. Although oncogenic human papillomavirus subtypes are recognized to be the most important factor in the development of cervical disease, only a minority of such infections results in invasive cancer. Given our current, albeit limited, knowledge of the natural history of human papillomavirus infection and the development of cervical intra-epithelial neoplasia, it may be possible to identify well-defined high-risk groups of women. Such groups may benefit from intensive surveillance, or indeed new developments in immunoprophylaxis, while allowing low-risk women less screening intervention. Known high-risk groups include those with chronic immunosuppression and previous treatment for high-grade cervical intra-epithelial neoplasia. Lowering the upper age limit for cervical screening is already under consideration because of the low incidence of both human papillomavirus infection and cervical intra-epithelial neoplasia in older women, and human papillomavirus testing could rationalize the screening programme.     

Herpes simplex virus and human papillomavirus infection in cervical disease in Argentine women.

The aim of the present study was to determine that prevalence of herpes simplex virus (HSV) type 1 and 2 in cervical samples from Argentine women and to assess the role of HSV-2 in cervical cancer. A sample of 79 normal and 200 neoplastic cervical tissues (35 invasive cervical carcinomas, 75 high-grade squamous intraepithelial lesions, 79 low-grade squamous intraepithelial lesions and 11 abnormal squamous cells of undermined significance) was analyzed for herpes simplex and human papillomavirus DNA using the polymerase chain reaction method. Viral genotyping was performed by single strand conformation polymorphisms and restriction fragment length polymorphisms. The overall prevalence of HSV was 21.5% in controls and 29% in cases. Among women with normal cytology, herpes simplex prevalence in HPV positive (20.8%) women was approximately the same as in negative (21.8%) women. HPV- and age- adjusted ORs of high-grade squamous intraepithelial lesions and invasive cervical carcinomas for HSV-2 were 1.4 (p = 0.6) and 1.6 (p = 0.5), respectively. The obtained results indicated that herpes simplex virus may not be involved in cervical cancer development. Future investigations are needed to provided conclusive evidence on the role of this pathogen in cervical cancer.     

Cervical and vaginal pathology in women with vulvar condylomata

All women referred to the Department of Obstetrics and Gynecology, School of Medicine, State University of New York at Stony Brook, for evaluation of vulvar condylomata were reviewed to identify concurrent cervical and vaginal pathology. Over the five-year period 1981-1985, referrals to our colposcopy clinic for vulvar condylomata increased from 7.8% to 29.2%. All patients underwent a thorough history, physical examination and colposcopic evaluation of the cervix, vulva and vagina. Of the patients with vulvar condylomata, 68% had biopsy-proven cervical and vaginal pathology. While 50% of patients with cervical disease had human papillomavirus infection alone, the other 50% had concurrent cervical intraepithelial neoplasia (CIN) or CIN only. Proper evaluation of patients with vulvar condylomata must include colposcopy of the cervix and vagina.     

The development of cervical cancer and its precursors: what is the role of human papillomavirus infection?

Human papillomavirus (HPV) is a significant health care burden in the United States. The majority of sexually active men and women will be infected with HPV at some point in their lives and are subject to developing human papillomavirus-associated disease. Current estimates suggest that 20 million Americans are currently infected, and more than 5 million new infections occur each year. The prevalence of human papillomavirus is highest in populations in their late teens and early twenties, with nearly half of all new human papillomavirus infections occurring within 3 years of first intercourse. HPV is the necessary cause of genital warts, cervical intraepithelial neoplasia, and invasive cervical cancer. As such, human papillomavirus is responsible for significant medical morbidity and health care costs. Screening with cervical cytology has significantly reduced mortality rates; however, approximately 3900 women will die in 2005 from cervical cancer in the United States. Human papillomavirus DNA testing has shown promise in identifying high-grade abnormalities as an adjunct to traditional cytology, and should be used according to guidelines established by the American Cancer Society and the American College of Obstetricians and Gynecologists. The epidemiology of HPV infection and a brief introduction to the natural history of HPV infection will be presented here.     

Characterization of genital human papillomavirus infection in women who have or who are at risk of having HIV infection.

OBJECTIVE: The purpose of this study was to describe the prevalence of human papillomavirus infection and the likelihood of human papillomavirus expression and Papanicolaou test abnormalities among women who have and who are at risk of having human immunodeficiency virus infection. STUDY DESIGN: Cross-sectional analysis of 767 women who had human immunodeficiency virus infection and 390 women who were at risk of having human immunodeficiency virus infection in 4 cities in the United States. RESULTS: Women who were infected with human immunodeficiency virus were more likely than women who were not infected to have human papillomavirus infection (prevalence ratio, 2.3; 95% CI, 2.0-2.8) but had similar human papillomavirus types. Among women who tested positive for human papillomavirus by polymerase chain reaction, human immunodeficiency virus infection was associated with a high level of human papillomavirus expression (prevalence ratio, 1.3-1.6) and multiple human papillomavirus infections (prevalence ratio, 1.9). However, among women with a high level of human papillomavirus expression or infection with multiple types, there was no association between human immunodeficiency virus serostatus and risk of cervical dysplasia. CONCLUSION: Through its association with a high level of expression and multiple human papillomavirus infections, human immunodeficiency virus infection may increase the risk of cervical dysplasia in women who are infected with human papillomavirus.