In the absence of (early) invasive carcinoma, vulvar intraepithelial neoplasia associated with lichen sclerosus is mainly of undifferentiated type: new insights in histology and aetiology

BACKGROUND: Differentiated vulvar intraepithelial neoplasia (VIN) is presumed to be the precursor of invasive squamous cell carcinoma (SCC) of the vulva. It is commonly assumed that differentiated VIN is related to lichen sclerosus (LS). However, evidence for this is limited to a small number of studies describing epithelial alterations adjacent to vulvar SCC. AIM: To study the histology and human papillomavirus (HPV) status in patients with a history of both LS and VIN without coexistent SCC. METHODS: Original biopsy specimens and surgical specimens of patients retrieved from the pathology files were revised for the presence of LS, VIN and (early) invasive SCC, specifically focused on the two different types of VIN: differentiated and undifferentiated. Thereafter, VIN lesions were tested for the presence of HPV DNA. RESULTS: Twenty-seven patients fulfilled the criteria for LS and VIN without SCC. In all 27 patients, LS was found to be related to undifferentiated VIN. Grading yielded the following results: VIN 1 (n=10), VIN 2 (n=11) and VIN 3 (n=6). Additionally, VIN lesions from 26 patients could be tested for the presence of HPV DNA. HPV DNA, predominantly type 16, was present in 8 (31%) of them. Seven of these eight patients had VIN 2 or 3. During follow-up, three patients progressed to (early) invasive carcinoma. In two of these patients, differentiated VIN was observed overlying early invasive SCC. CONCLUSIONS: VIN related to LS without coexisting SCC is likely to be undifferentiated, in contrast to what was previously thought. HPV DNA was demonstrated in 31% of the lesions, and was strongly related to high-grade VIN.     

Prevalence of HPV 16 and 18 DNA sequences in CIN III lesions of adults and adolescents

Adolescents may be more susceptible to cervical human papillomavirus (HPV) infections and may have more rapid progression of cervical intraepithelial neoplastic (CIN) lesions than adults. We evaluated Papanicolaou (Pap) smears and cervical tissue specimens from a consecutive series of 25 adolescent (age 15-20 yr) and 17 adult (age 35-40 yr) patients with a histologic diagnosis of CIN III. The study patients were all Detroit residents enrolled in a health maintenance organization (HMO) affliated with Henry Ford Hospital. The cervical tissue specimens were evaluated for HPV 6b/11, HPV 16, and HPV 18 using agarose gel electrophoresis and Southern hybridization following polymerase chain reaction (PCR) DNA amplification. While the small sample size precluded testing for statistical significance, HPV 16 and/or HPV 18 DNA was detected in specimens from 21/25 (84%) adolescents compared to 12/17 (71%) adults (odds ratio [OR] = 2.2; 95% confidence interval [CI] = 0.49-9.74). The relationship between adolescence and HPV infections appears to be stronger for HPV 18 and mixed HPV 16/18 infections (OR = 5.6; 95% CI = 0.7-42.4) than for HPV 16 infections (OR = 1.93; 95% CI = 0.4-8.8). None of the cervical specimens contained HPV 6b/11 DNA. Oral contraceptive (OC) use was associated with HPV infection in patients with CIN III, but there was no association between cigarette smoking and HPV infection. The effect of OC use on the relationship of age and HPV could not be evaluated due to small sample size. The effects of previous sexually transmitted disease (STD) on the relationship of age and HPV were assessed. Among women with a history of STD, there was a strong association between HPV and adolescent age (OR = 18.0; 95% CI = 1.2-260.0). Our data suggest that among women with CIN III, adolescents have a higher prevalence of certain high-risk types of HPV infections than adults. The excess is due predominantly to the higher rates of HPV 18 and mixed HPV 16/18 infections in adolescents. The positive relationship between high-risk HPV infections and young age was most evident in adolescents with a history of STD. The results from this study suggest that differences in HPV type infections may be related to the more aggressive clinical course of CIN in adolescents. © 1994 Wiley-Liss, Inc.     

Predictors of seropositivity to human papillomavirus type 53: one of the most prevalent high risk-related cervical human papillomaviruses

Persistent cervicovaginal infection with high-risk types of HPV is the major risk factor for subsequent cervical neoplasia. HPV53, part of the alpha 6 species group along with HPV types 30, 56, and 66, is one of the most prevalent high risk-related HPV types, yet little is known about the molecular basis of its benign behavior. We generated and utilized HPV53 virus-like particles (VLPs) to investigate risk factors for its seroprevalence in a population of young college women. Seropositivity to HPV53 VLPs was determined using a polymer-based ELISA to measure IgG reactive antibodies. Cervicovaginal cells were collected for HPV DNA detection and typing by MY09/11 PCR. A questionnaire queried for HPV risk factors to estimate odds ratios (ORs). Prevalence of cervicovaginal HPV DNA was 26% (n = 148); 3% of women (n = 17) had HPV53 DNA and 7% (n = 40) were seropositive to HPV53. Seroprevalence of IgG to HPV53 VLPs in women with cervicovaginal HPV53, HPV53-related types (HPV30, 55, and 66), other HPV types, and no HPV was 41%, 11%, 7%, and 6%, respectively (p(trend) < 0.001). Risk factors independently associated with HPV53 VLP seropositivity included use of oral contraceptive pills (OCPs) (OR: 4; 95% CI: 1.8, 9), having >or=2 regular partners in the last 6 months (OR: 2.5; 95 % CI: 1.1, 5.8), having a regular male partner with >or=4 lifetime sex partners (OR: 2.6; 95% CI: 1.1 6), seropositivity to HPV16 (OR: 6.7; 95% CI: 3.1, 14.5), and isolation of HPV53 DNA from cervicovaginal lavage (OR: 17.3; 95% CI: 5.3, 55.9). In conclusion, host serological responses to HPV53 VLPs are strongly type-specific, and subjects' risk for HPV53 seropositivity is independently associated with sexual behavior and OCP use.     

Epidemiologic correlates of cervical human papillomavirus prevalence in women with abnormal Pap smear tests: a Taiwan Cooperative Oncology Group (TCOG) study

To explore factors affecting human papillomavirus (HPV) prevalence in all grades of cervical neoplasia among Chinese women, 1,264 women with abnormal cervical cytology attending the gynaecologic clinics of 11 major medical centres in Taiwan. Patients were interviewed and underwent complete gynaecologic examination including colposcopy. Cervical scrapings were collected for HPV DNA detection by both Hybrid Capture-2 (high-risk probe) and L1 consensus PCR-reverse line blot. The prevalences of HPV in the four different diagnosis groups: (i) suspicious (n = 316), (ii) low-grade intraepithelial lesion (n = 474), (iii) high-grade intraepithelial lesion (n = 450), and (iv) cancer (n = 16), were 36.1%, 74.7%, 83.6%, and 100%, respectively. In the latter two groups, Patients less than 30 or 40 years old, respectively, tended to be infected more frequently with HPV than the older patients were. The main correlates of HPV prevalence were lifetime number of sex partners (odds ratio (OR) for two or more partners: 2.44; 95% CI, 1.44-4.15), vaginal douching after intercourse (OR for douching frequently: 1.44; 95% CI, 1.01-2.04), vitamin supplementation (OR for regular vitamin supplement: 0.71, 95% CI, 0.55-0.92), and performance of Pap smear tests (OR for never having a Pap smear performed: 2.22; 95% CI, 1.19-4.17). The risk for vaginal douching was augmented by the promiscuity of sex partners (OR of 3.19 (1.91-5.34)) and smoking (OR of 1.90 (1.15-3.13)), whereas vitamin supplementation reduced the odds ratio to 1.35 (0.85-2.15). The results of this study provide further evidence of the role of HPV in cervical carcinogenesis. The data also indicate the main areas of risk for the prevalence of HPV in cervical neoplasia in Chinese women living in Taiwan.     

Prevalence of human papilloma virus infections and cervical cytological abnormalities among Korean women with systemic lupus erythematosus

We performed a multicenter cross-sectional study of 134 sexually active systemic lupus erythematosus (SLE) patients to investigate the prevalence of and risk factors for high risk human papilloma virus (HPV) infection and cervical cytological abnormalities among Korean women with SLE. In this multicenter cross-sectional study, HPV testing and routine cervical cytologic examination was performed. HPV was typed using a hybrid method or the polymerase chain reaction. Data on 4,595 healthy women were used for comparison. SLE patients had greater prevalence of high-risk HPV infection (24.6% vs. 7.9%, P<0.001, odds ratio 3.8, 95% confidence interval 2.5-5.7) and of abnormal cervical cytology (16.4 vs. 2.8%, P<0.001, OR 4.4, 95% CI 2.5-7.8) compared with controls. SLE itself was identified as independent risk factors for high risk HPV infection among Korean women (OR 3.8, 95% CI 2.5-5.7) along with ≥2 sexual partners (OR 8.5, 95% CI 1.2-61.6), and Pap smear abnormalities (OR 97.3, 95% CI 6.5-1,456.7). High-risk HPV infection and cervical cytological abnormalities were more common among Korean women with SLE than controls. SLE itself may be a risk factor for HPV infection among Korean women, suggesting the importance of close monitoring of HPV infections and abnormal Pap smears in SLE patients.     

Comparison of Human Papillomavirus Detections in Urine,Vulvar, and Cervical Samples from Women Attending a Colposcopy Clinic

While urine-based sampling for human papillomavirus (HPV) is being explored as a simple and noninvasive approach for cervical cancer screening, data comparing HPV genotyping in urine and those in cellular sampling of the cervix and vulva, and their correlation with rigorously confirmed cervical disease status, are sparse. We performed HPV genotyping on voided-urine and clinician-collected vulvar and cervical samples from 72 women undergoing colposcopy. Although urine-based HPV carcinogenic HPV detection was lower (58.3%) than cervical (73.6%) and vulvar (72.1%) detection (P = 0.05 and 0.07, respectively), the agreement of urine HPV with cervical and vulvar HPV was moderate (kappa = 0.55) and substantial (kappa = 0.62), respectively. Urine-based carcinogenic HPV detection had a clinical sensitivity of 80.8% (95% confidence interval [CI] = 60.7 to 93.5) and a specificity of 53.3% (95% CI = 37.9 to 68.3) for diagnosing cervical intraepithelial neoplasia grades 2/3 (CIN2/3) on histology; 90.0% of CIN3 was positive for urine HPV. The corresponding sensitivity and specificity values for vulvar sampling were 92% (95% CI = 74 to 99) and 40.5% (95% CI = 25.6 to 56.7), and those for cervical sampling were 96.2% (95% CI = 80.4 to 99.9) and 40% (95% CI = 25.7 to 55.7), respectively. HPV16 was the most common carcinogenic genotype detectable in 25% of urine, 33.8% of vulvar, and 31.9% of cervical samples overall, with prevalence increasing with cervical disease grade, regardless of the sampling method. Stronger cervical HPV PCR signal strengths were associated with increased frequency of urine HPV detection. In summary, the relatively lower detection rates but comparable clinical performance of urine-based HPV sampling underscore the need for larger studies to evaluate urine-based sampling for cervical cancer screening, epidemiologic studies, and postvaccination HPV disease surveillance.     

Polymorphisms for chemical metabolizing genes and risk for cervical neoplasia

Infection with high-risk human papillomavirus (HPV) plays a major role in the etiology of cervical cancer (CC). However, most infected women do not develop cancer. Therefore, exposure to other carcinogenic agents may be a contributing risk factor for CC. We investigated the hypothesis that environmental exposure to cigarette smoke and inheritance of polymorphic chemical metabolizing genes (CYP2E1, GSTM1, and mEH) significantly increase the risk for neoplasia. We selected 76 cases with high-grade cervical neoplasia or with invasive CC and 75 matched healthy controls. The collected data support the well-established observation that infection with high-risk HPV is the major risk factor for CC (OR = 75; 95% CI = 26-220). In addition, our data show that women who smoked more than 15 "pack-year" had a significant 6.9-fold increase in risk (95% CI = 1.2-40.3) after adjustment for HPV infection. The CYP2E1 variant genotype did not significantly increase the risk for neoplasia. A significant increase in risk for neoplasia was observed for the low-activity mEH 113 His allele after adjustment for smoking (OR = 3.0; 95% CI = 1.4-6.3). The GSTM1 null genotype was associated with a significant 3.3-fold increased risk for neoplasia (95% CI = 1.0-11.8) compared to women who were GSTM1-positive after adjustment for smoking and HPV infection. Our study suggests that genetic differences in the metabolism of cigarette smoke, particularly GSTM1, may confer susceptibility to CC. Further studies using larger populations will be needed to confirm our observations and to validate data for disease prevention.     

Prevalence of different HPV types and estimation of prognostic risk factors based on the linear array HPV genotyping test

The aim of the study was to evaluate the prevalence and risk factors of HPV in a gynecologic population attending outpatient clinics using two new molecular tests. The Amplicor HPV test and the Linear Array (LA) HPV Genotyping test were used for the detection of HPV DNA in 320 women. Multiple logistic regression was used to identify independent prognostic factors of HPV positivity. The agreement between the two methods in terms of their qualitative results was 89.3% (kappa: 0.63). Based on the LA results, the overall prevalence of HPV DNA was 49.1%, 95% confidence interval (95% CI: 43.5%, 54.7%). The prevalence of high‐risk HPV types was 30.3%. The predominant types were HPV‐6 (24.8%) and HPV‐16 (20.4%). Among women with normal cytology, the prevalence of HPV was much higher in those presenting other findings, such as inflammation, than those without other abnormal findings (49.5% vs. 31.5%). On the basis of multivariate analysis, the risk of HPV infection was higher among women with multiple sexual partners [>3 vs. 1: OR = 3.1, 95% CI: (1.5, 7.2)], Pap smear findings [low/high‐grade lesions vs. negative: OR = 2.8, 95% CI: (1.2, 6.5)], the presence of warts [yes vs. no: OR = 3.0, 95% CI: (1.5, 6.3)] and no history of child birth [no vs. yes: OR = 2.6, 95% CI: (1.0, 6.7)]. Younger age was an additional risk factor for HPV infection with carcinogenic genotypes [OR for 1 year increase = 0.93, 95% CI: (0.89, 0.98)]. J. Med. Virol. 81:2059–2065, 2009. © 2009 Wiley‐Liss, Inc.     

Human papillomavirus infection of the cervix uteri in women attending a Health Examination Center of the French social security

Since human papillomavirus (HPV) is the central causal factor in cervical cancer, understanding the epidemiology of this infection constitutes an important step towards development of strategies for prevention. Six hundred and fifty seven cervical samples were tested for HPV using PCR with consensus primers (MY09/MY11), by genotyping (restriction and sequencing analyses) and by cervical cytology, from women who attended a Health Examination Center of the French social security. Women with no cervical smear as well as women with cytological abnormalities within the last 3 years were recruited. HPV DNA was detected in 7.3% of the women (5.3% for high-risk, 2.4% for low-risk, and 0.5% for unknown risk types) including 6 (0.9%) mixed infections. Fifteen different genotypes were detected, of which genotypes 16 (22.2%), 58 (13.0%), 18 (11.1%), 30 (9.2%), and 33 (9.2%) were the most prevalent. In age group 17-25 years, we found the highest frequencies for both any (22.1%) and high-risk (14.7%) HPV, and prevalences gradually decreased with age. 5.2% of low-grade squamous intraepithelial lesion, 0.3% of high-grade squamous intraepithelial lesion, and 1.2% of atypical squamous cells of undetermined significance were found. The frequencies of high risk and all HPV types were significantly higher in squamous intraepithelial lesions than in those with normal and reactive/reparative changes (P < 0.0001). The prevalence of high-risk HPV in the atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion group (28.6%) was significantly higher than in the normal and reactive/reparative changes groups (3.4%) (P < 0.0001). HPV detection was associated with younger age, single marital and non-pregnant status (P < 0.0001), premenopausal status (P = 0.0004), and contraception (P = 0.0008). Marital status (OR 4.5; 95% CI = 2.3-9.0) and tobacco consumption (OR 3.0; 95% CI = 1.6-5.7) were predictive independent factors of HPV infection. The French system of Health Examination Centers might be of interest for following women regularly, especially those with a low socioeconomic status.     

The impact of the use of COL-1492, a nonoxynol-9 vaginal gel, on the presence of cervical human papillomavirus in female sex workers

This study investigated the effectiveness of a nonoxynol-9 (52.5mg, 3.5%), vaginal gel (Advantage S), in the prevention of human papillomavirus (HPV) infection in female sex workers. We showed by HPV DNA determination in cervico-vaginal rinses a significant increase in multiple (>1) HPV infection in HIV-1 seropositive women compared with HIV-1 seronegative women (OR 4.0, 95% CI 1.3-11.9). We also demonstrated a significant increase in multiple HPV infections in HIV-1 seronegative women using nonoxynol-9 compared with HIV-1 seronegative women using placebo (OR 3.5 95% CI 1.0-11.8). We conclude that the use of nonoxynol-9 did not prevent genital HPV infection and could increase the virus' ability to infect or persist.     

Genotyping of human papillomavirus DNA in anal biopsies and anal swabs collected from HIV-seropositive men with anal dysplasia

BACKGROUND: Human papillomavirus (HPV) causes anal intraepithelial neoplasia (AIN) in HIV-seropositive men. The detection of HPV genotypes in anal biopsies and swabs was compared. METHODS: HPV DNA was detected in anal swabs and biopsies obtained concurrently from 154 HIV-seropositive men [31 without AIN, 60 low-grade AIN (AIN-1), 62 high-grade AIN (AIN-2,3), and 1 indeterminate AIN] under or eligible to highly active antiretroviral therapy. RESULTS: HPV DNA was detected in 24.2% of normal biopsies compared with 93.5% with AIN-2,3 (P < 0.001) and 88.3% with AIN-1 (P < 0.001). The proportion of biopsies containing multiple genotypes was greater in AIN-1 (n = 21, 35.0%; P = 0.002) and AIN-2,3 (n = 38, 58%; P < 0.001) than in normal biopsies (n = 2, 6.5%). The most frequent genotypes in order of frequency were in AIN-2,3 biopsies HPV-16, 18, 58, and 45 and were in AIN-1 biopsies HPV-6, 11, 16, and 39. Controlling for age, CD4 count, and smoking, the presence of high-risk HPV DNA in biopsies [odds ratio (OR) = 50.8, 95% confidence interval (CI): 13.0 to 199.5] but not in swabs (OR = 2.0, 95% CI: 0.6 to 7.0) was associated with AIN-2,3. CONCLUSIONS: AIN-2,3 was associated with high-risk HPV infection detected in biopsies but not in swabs in men under or starting highly active antiretroviral therapy, possibly due to the presence of HPV foci outside of the neoplastic lesion.     

Prevalence and epidemiologic correlates of atypical squamous cells of undetermined significance in women at low risk for cervical cancer

Our aim was to determine the prevalence and epidemiologic correlates of atypical squamous cells of undetermined significance (ASCUS) in a population at low risk for cervical cancer in Porto Alegre, Brazil. Sociodemographic data and gynecological and obstetrical history from 977 women screened at an outpatient clinic were recorded. Specimens were collected for Papanicolaou cervical cytology, colposcopy, and biopsy (if indicated). Sixty-two (6.3%) patients presented ASCUS, 21 (2.1%) presented low-grade squamous intraepithelial lesions, and 6 (0.6%) presented high-grade lesions. Presence of human papillomavirus (HPV) DNA in cervical cells (odds ratio (OR) = 1.57; confidence interval (CI) 95% = 1.11-2.23), history of HPV infection (OR = 3.12; CI 95% = 1.22-7.96), and becoming sexually active at 18 yr or younger (OR = 1.70; CI 95% = 1.15-2.51) were independently associated with ASCUS. ASCUS patients reported HPV infections and presented HPV DNA in cervical cells more often than did patients with normal cytology; therefore, they should be carefully monitored to ensure early detection of cancer precursor lesions and prevention of cervical cancer.     

Detection of human herpes virus type 6 DNA in precancerous lesions of the uterine cervix

Human herpes virus type 6 (HHV-6) DNA has been suggested to be a cofactor to human papillomavirus (HPV) in cervical cancer. In a cross-sectional study, we investigated the association between HHV-6 DNA detected in cervical brushings and high-grade squamous intraepithelial lesions (HSIL), while controlling for genital infection with 27 genotypes of HPV. Of the 320 women recruited from an oncologic gynecology clinic, 50 had invasive cervical cancer, 65 had HSIL, 80 had low-grade squamous intraepithelial lesions (LSIL), and 125 were normal. Four of the seven HHV-6-positive women had HSIL. HHV-6 was associated with HSIL after adjusting for age and socioeconomic status (odds ratio [OR] of 10.9, 95% confidence interval [CI]: 1.1-107.1). This association was no longer significant after controlling for HPV (OR = 6.4, 95% CI = 0.3-128.5). HHV-6 was detected in cervical samples from women with precancerous and cancerous lesions of the cervix, but not significantly more frequently than in normal women.     

Human leukocyte antigen-DRB1*1501 and DQB1*0602 alleles are cervical cancer protective factors among Uighur and Han people in Xinjiang,China

Human papillomavirus (HPV) infection is a major risk factor for cervical cancer. However, only some high risk human papillomavirus (HR-HPV)-infected women progress to cervical cancer, host immunogenetic factors human leukocyte antigen (HLA) may account for viral antigens presenting individually or together in the progression to cervical cancer. This study examined the association between the development of invasive cervical cancer (ICC) and the determinant factors including HLA-DRB1*1501 and DQB1*0602, HR-HPV infection among Chinese Uighur and Han populations. Blood samples, cervical swabs and biopsies were obtained from 287 patients with ICC (192 Uighurs and 95 Hans) and 312 healthy controls (218 Uighurs and 94 Hans). HPV DNA was detected by PCR and HLA-DRB1*1501 and DQB1*0602 alleles were performed using PCR-SSP method. HPV16 infection rates was significantly higher among Uighur and Han with ICC as compared to healthy controls (OR = 58.317; 95% CI: 39.663-85.744; OR = 33.778; 95% CI: 12.581-90.691; P < 0.05 for all). HLA-DRB1*1501 (OR = 0.305; 95% CI: 0.115-0.813; P < 0.05) and HLA-DRB1*1501-DQB1*0602 haplotype frequencies (OR = 0.274; 95% CI: 0.086-0.874; P < 0.05) were significantly reduced in Han ICC. The HLA-DQB1*0602 frequency significantly decreased among Uighur women with ICC (OR = 0.482; 95% CI: 0.325-0.716; P < 0.05). Similar tendencies were observed for DQB1*0602 with HPV16-positive ICC (OR = 0.550; 95% CI: 0.362-0.837; P < 0.05). This study suggests that HLA-DRB1*1501 and DQB1*0602 alleles may influence the immune response to HPV16 infection and decrease the risk of ICC among Uighurs and Hans in Xinjiang, China.     

Analysis of clonality and HPV infection in benign, hyperplastic, premalignant, and malignant lesions of the vulvar mucosa

To elucidate the pathogenesis of vulvar carcinomas, we studied clonality and human papillomavirus (HPV) infection in vulvar epithelial diseases. Monoclonal composition was demonstrated in all 9 invasive tumors (squamous cell carcinoma [SCC], 6; basal cell carcinoma, 1; malignant melanoma, 2), 15 of 20 cases of vulvar intraepithelial neoplasia (VIN), 7 of 9 cases of Paget disease, 2 of 6 cases of lichen sclerosus (LS), and 2 of 3 cases of squamous cell hyperplasia (SCH); high-risk type HPV was revealed in 5 of 6 SCCs and 17 of 20 VINs. These observations might imply that a subset of cases of LS and SCH result from a neoplastic proliferation, similar to VINs but not related to infection with high-risk type HPV. In 1 case of SCC with concurrent VIN 3 in an adjacent lesion, both lesions showed the same pattern of X chromosome inactivation and the presence of HPV-16 in episomal and integrated forms, suggesting that monoclonal expansion triggered by high-risk type HPV integration is an early event for carcinogenesis of HPV-associated SCC.     

HLA-A等位基因及超型与宫颈癌易感性的关联

目的 研究湖北土家族HLA-A等位基因及超型与HPV感染、宫颈癌的关联。方法 在居住地及年龄相匹配的条件下,HPV感染阳性的癌症组分别与HPV感染阳性的对照组和HPV感染阴性的对照组进行比较。癌症组100例（其中HPV感染阳性者86例）,对照组187例（其中HPV感染阳性者95例,HPV感染阴性者92例）。采用SBT法对最具多态性的HLA-A位点的 2、3外显子进行基因型分析。结果,HPV阳性宫颈癌组与HPV阳性对照组比较,超型HLA-A3 （pcorrected=0.015,OR=2.01,95％CI＝1.26-3.21）可增加宫颈癌的易感性。HPV阳性宫颈癌组与HPV阴性对照组比较,HLA-A*0206（pcorrected=0.025 ,OR=0.20,95％CI＝0.07-0.58）超型HLA-A2(pcorrected=0.005, OR=0.57,95％CI＝0.37-0.88）可降低宫颈癌的易感性,而超型HLA-A3 （pcorrected=0.005, OR=2.36, 95％CI＝1.45-3.85) 同样增加宫颈癌的易感性。结论：超型HLA-A3为宫颈癌的风险因子。     

HPV-assoziierte Ver?nderungen an Vulva und Vagina

Non-neoplastic HPV-induced alterations of the vulva and vagina are frequent. The traditional three-tier grading system of vulvar intraepithelial neoplasia (VIN) will be replaced by the definition of usual and simplex type of VIN. The usual type is characterized by a strong association to high-risk HPV infections, the occurrence at younger age and multifocality, mostly associated with non-keratinizing squamous cell carcinoma. The differentiated (or simplex) type is rare and shows an association to older age and p53 alterations and is typically diagnosed co-incidentally with keratinizing squamous cell carcinoma. Vaginal intraepithelial neoplasia (VAIN) is still graded into VAIN 1-3 where VAIN?1 and 2 are mostly associated with low-risk HPV infections and a high spontaneous regression rate whereas VAIN 3 represents a high-risk HPV-associated lesion with capable progression into (micro-)invasive carcinoma. The differential diagnosis between a non-neoplastic condylomatous lesion and VIN common type and VAIN may be aided by p16 immunohistochemistry. The HPV-associated invasive vulvo-vaginal cancers are verrucous carcinoma (low-risk HPV) and the high-risk HPV-induced (non-keratinizing) squamous cell carcinoma (NOS), the condylomatous (warty) carcinoma and the very rare vaginal squamo-transitional carcinoma.     

IL-10 promoter nt -1082A/G polymorphism and human papillomavirus infection in cytologic abnormalities of the uterine cervix.

The role of A/G polymorphism at nucleotide -1082 in the interleukin-10 (IL-10) promoter was assessed by following the disease course of 253 patients who had had a routine diagnostic Hybrid Capture human papillomavirus (HPV) test because of cytologic or colposcopic abnormalities of the uterine cervix. At baseline, 97 (78%) of the 125 high-risk HPV-positive and 83 (65%) of the 128 HPV-negative patients had equivocal cytologic atypia classified as P3 by the Papanicolaou classification, and the rest of the patients had mild colposcopic atypia with cytologic results of no oncogenic significance. In the high-risk HPV-infected patients, the frequency distribution of the nt -1082 genotypes (A/A: 28%; A/G: 52%; G/G: 20%) did not differ significantly from that in the controls (A/A: 25%; A/G: 51%; G/G: 24%; p = 0.70). On the other hand, the nt -1082 G allele tended to decrease susceptibility to equivocal cytologic atypia unrelated to HPV infection (A/G: OR = 0.56 [95% CI: 0.31-1.02], G/G: OR = 0.27 [95% CI: 0.11-0.63], p for trend = 0.05). With respect to the development of high-grade cervical intraepithelial neoplasia (CIN), the established risk factors, such as high-risk HPV infection (RR = 104.6, 95% CI: 14.2-769.9) and cytologic atypia (RR = 9.6, 95% CI: 2.34-39.7) but not the various nt -1082 genotypes (A/A: reference; A/G: RR = 1.11 [95% CI: 0.59-2.08]; G/G: RR = 0.62 [95% CI: 0.25-1.50]) were found to increase the risk for high-grade CIN. In conclusion, the nt -1082 polymorphism had no influence on the early phase of cervical carcinogenesis but may determine different susceptibilities to cervical abnormalities unrelated to HPV infection.     

Review of precancerous vulvar lesions

Classification of squamous vulvar precancerous lesions is based on the concept of vulvar intraepithelial neoplasia (VIN) and incorporates a three grade evaluation of the intensity of dysplastic changes (VIN I, II and III). On the basis of histological features, VIN has been subdivided into the usual VIN (u-VIN) and differentiated VIN (d-VIN), which represent the two basic pathways of the pathogenesis of vulvar squamous cell carcinoma. Although u-VIN is etiologically associated with the human papillomavirus (HPV) infection and histologically corresponds to cervical intraepithelial neoplasia, d-VIN represents the HPV-negative sequence of vulvar carcinogenesis, which is linked to lichen sclerosus (LS) and lichen simplex chronicus (LSC). u-VIN preferentially occurs in relatively young women with a history of cervical, vaginal or vulvar premalignant lesions. On the other hand, d-VIN usually affects postmenopausal women without anamnestic data of other dysplastic lesions of the lower female genital tract. d-VIN is characterized by a higher tendency of stromal invasion than u-VIN and its malignant potential is analogous to carcinoma in situ (VIN III). The histological appearance of d-VIN is subtle with basal atypia and a well-preserved differentiation of the superficial parts of the squamous epithelium, therefore it is frequently misdiagnosed for u-VIN I, LS or LSC in vulvar biopsies. Primarily because of the low diagnostic reproducibility of the u-VIN I category and the doubts about its precancerous potential as well as due to the questionable differentiation between u-VIN II and III, a revised VIN classification was proposed in 2004. The grading of vulvar precancerous lesions was abandoned, the u-VIN I category was discontinued and u-VIN II and III were merged. In the revised terminology, the term u-VIN represents HPV-associated high grade precancerous vulvar lesions (formerly u-VIN II and III) and d-VIN encompasses HPV-negative high grade dysplasias. Keywords: vulvar intraepithelial neoplasia - VIN of the usual type - VIN of the differentiated type - lichen sclerosus - lichen simplex chronicus - HPV.     

Distribution of human papillomavirus genotypes in invasive squamous carcinoma of the vulva

Many studies have established a critical role for human papillomavirus (HPV) in the development of anogenital squamous neoplasia. In this report, we show the distribution of 37 high- and low-risk HPV types in 116 cases of invasive squamous vulvar carcinoma. Sections from paraffin-embedded tissue blocks were dissected as necessary to select areas of invasive carcinoma. Clinical and pathologic variables were analyzed using t-tests, univariate odds ratios and logistic regression analysis. Seventy percent of cases were HPV-positive, with an average patient age of 65 years (n=81). HPV-negative cases (n=35) had a higher average age (70 years), but these populations were not statistically different (t=1.65, P=0.10). HPV16 was most common (n=65). Other HPV types were less frequent (HPV33, n=12; HPV45, n=4; HPV52 and 6, each n=3; HPV18, 53 and 62, each n=2). Additional HPV types were identified only once. Multiple infections typically included HPV16 (12/14 cases). Tumors showing low-risk HPV (11 cases) and low-risk HPV only (three cases) were uncommon. Regional node metastasis was documented in 29 of 116 tumors, and 8/9 HPV-positive nodes contained HPV types identical to the primary tumor. Of tumor types, warty carcinoma was most strongly associated with high-risk HPV (odds ratio 4.34, 95% confidence interval 1.32-18.45), particularly high-risk HPVs other than type 16 (odds ratio 9.04, 95% confidence interval 1.60-54.00). Tumors associated with any HPV type (odds ratio 0.40, 95% confidence interval 0.14-1.17), any high-risk type (odds ratio 0.36, 95% confidence interval 0.12-1.08), or type 16 alone (odds ratio 0.34, 95% confidence interval 0.11-1.12) were less likely to metastasize than HPV-negative tumors. Correcting for possible confounding variables, such as patient age and tumor histology, linear logistic regression analysis confirmed this association (high-risk HPV odds ratio 0.28, 95% confidence interval 0.09-0.89).