HLA-DQB1 and cervical cancer in Venezuelan women

BACKGROUND: Cervical cancer represents a major health problem in Venezuela as well as in other Latin American countries. High-risk human papillomavirus (HR-HPV) infection is known as the major risk factor of cervical cancer. However, whether or not a HR-HPV-infected woman progresses to cervical cancer may depend on the immune system effectors induced by viral antigens presented by her specific human leukocyte antigens (HLA) alleles. The role of the HLA system in presenting peptides to antigen-specific T-cells may be critical for genetic susceptibility and genetic resistance to cervical carcinoma. OBJECTIVE: We aimed to investigate the relationship between HLA-DQB1, HPV infection, and cervical cancer in Venezuelan women. METHODS: Blood samples and cervical swabs were obtained from 36 patients and 79 healthy controls; additional cervical biopsies were obtained from all the patients. HPV DNA was detected by PCR and HLA-DQB1 genotyping was performed using a PCR-SSP protocol. RESULTS.: A positive association with cervical cancer was observed for HLA-DQB1*0201-0202 and *0402 alleles, however after Bonferroni correction only HLA-DQB1*0402 remained statistically significant (P value = 0.004, RR = 5.067). CONCLUSION: This is the first report of HLA-DQB1 alleles associated with cervical carcinoma in Venezuelan women. Larger studies are needed to assess whether these HLA-DQB1*0201-0202 and *0402 alleles have a direct effect on disease susceptibility.     

Association of human leukocyte antigen and T cell message with human papillomavirus 16–positive cervical neoplasia in Japanese women

To investigate whether an association exists between human leukocyte antigen (HLA) haplotype and cervical neoplasia within the Japanese population, we analyzed the human papillomavirus (HPV) genotypes, the HLA class I specificities and class II alleles, and the T-cell responses in the lesions of patients with cervical neoplasia. Eighty-one patients, consisting of 62 cervical intraepithelial neoplasia (CIN) lesions and 19 invasive cervical cancers (ICC), were examined. The frequencies of HPV infection in the CIN I/II and CIN III/ICC groups were 68.0% (17/25) and 80.4% (45/56), respectively. All patients and 138 local Japanese controls were analyzed for HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1. For major histocompatibility complex (MHC) class II HLA-DRB1 alleles, the frequency of DRB1*0901 was significantly elevated in HPV 16-positive CIN III/ICC patients compared with controls (59.3% versus 29.7%, P = 0.0031, OR = 3.44). Similarly for the HLA-DQB1 alleles, a significant increase in the DQB1*03032 frequency was observed in HPV 16-positive CIN III/ICC patients compared with controls (59.3% versus 28.3%, P = 0.0018, OR = 3.69). In the analysis of the T-cell responses in the lesions, Fas ligand was detected at a decreased frequency in HPV 16-positive CIN III/ICC patients with the HLA-DRB1*0901-DQB1*03032 haplotype. The presence of helper T cell-specific messenger RNAs in the cervical lesions supports an association among MHC class II, helper T cells, the immune response to HPV, and the development of cervical carcinoma. Accordingly, a specific MHC class II haplotype, DRB1*0901-DQB1*03032, may be a risk factor for cervical carcinoma in the Japanese population.     

Association between DQB1 and cervical cancer in patients with human papillomavirus and family controls

OBJECTIVE: The role of human leukocyte antigen (HLA) DQB1 alleles and human papillomavirus (HPV) as contributing factors to invasive cervical cancer was investigated. To overcome problems of misleading causal inferences common in traditional case-control studies, a family-based test, the transmission/disequilibrium test, was used. METHODS: Ninety-six patients with pathologically confirmed invasive cervical cancer were ascertained. Human papillomavirus types were determined in 80 patients, of whom 81.25% were HPV-positive, and 18.75% were HPV-negative. Deoxyribonucleic acid was extracted from samples, taken from patients and their parents, and sequenced to determine DQB1 genotypes. Nuclear family data were used to test whether the DQB1 locus is associated with invasive cervical cancer while controlling for high-risk HPV-positive patients. The transmission/disequilibrium test evaluates whether the frequency of transmission of parental marker alleles to their affected offspring deviates from the expected Mendelian frequency of 50%. RESULTS: The HLA DQB1 locus showed evidence for allelic association with invasive cervical cancer in high-risk HPV-positive patients (P = .006). The transmission/disequilibrium test showed that the DQB1*0303 allele was transmitted to high-risk HPV patients more often than expected by chance, chi2(1) = 8.0, P = .005 (P = .035 when correcting for multiple tests). Tests of association were negative when applied to all 96 patients, irrespective of HPV status. No significant differences were found in the distribution of the DQB1 alleles among HPV-positive patients compared with those who were HPV-negative, indicating that HLA alleles are not associated with susceptibility to HPV infection. CONCLUSION: These results suggest that the DQB1*0303 allele increases the risk for invasive cervical cancer in women who are HPV-positive.     

Lack of association between HLA DQB1 alleles with HPV infection and histology findings in cervical cancer in Australian women

Chen S, Tabrizi SN, O'Sullivan H, Fairley CK, Quinn MA, Garland SM. Lack of association between HLA DQB1 alleles with HPV infection and histology findings in cervical cancer in Australian women. Int J Gynecol Cancer 1999; 9: 220–224.
The association of human leukocyte antigen (HLA) types with cervical cancer and human papillomavirus (HPV) infection is controversial. In this study we examined 186 Australian women who had biopsy-confirmed cervical cancer and detected HLA DQB1 alleles and HPV DNA, using the polymerase chain reaction (PCR) amplification and sequence specific oligonucleotides probe (SSOP) hybridization methods. We analyzed the frequencies of 11 DQB1 alleles according to HPV DNA status (HPV positivity and HPV genotyping) and histology (tumor type, staging, grades, lymphocyte infiltration and nodal status). No significant differences among these 11 HLA DQB1 alleles were found with respect to HPV status and histology.     

Epidemiological characteristics of women with high grade CIN who do and do not have human papillomavirus.

OBJECTIVE: Human papillomavirus infection is an important aetiological agent associated with the development of cervical neoplasia. However, even with the most sensitive methods of detection, human papillomavirus DNA has been detected in only 90% of cases of cervical cancer and between 80%-90% of cases of dysplasia. This study aimed to determine if there are epidemiological differences between women who are positive or negative for human papillomavirus, with high grade cervical intraepithelial neoplasia (CIN). DESIGN: Four hundred and sixty women with CIN II and III lesions were studied. To ensure optimal detection of human papillomavirus DNA, two specimens (i.e. tampon and cervical biopsy) were collected from each woman and tested by three techniques: L1-polymerase chain reaction, E6-PCR and low stringency Southern blotting. A detailed questionnaire was completed and blood sample collected for determination of serum levels of beta-carotene, vitamin A and E from each patient. Human leucocyte antigen (HLA)-DQB 1 alleles were also compared between the groups of women who were positive or negative for human papillomavirus. RESULTS: Overall, human papillomavirus DNA analysis was positive in 411 women (89%). Age, number of sexual partners in the last 12 months, past pregnancy and marital status were associated with human papillomavirus detection in the crude analysis. However, in the adjusted analysis no epidemiological features remained significantly different between the human papillomavirus positive and negative patients. Moreover, examination of vitamin A, E and beta-carotene levels did not show a significant difference between the two groups of patients. However, in the HLA-DQB1 allele profile a significantly higher proportion of women who were negative for human papillomavirus had DQB1 *0201, *0603 and *0604 (P = 0.05, 0.001, 0.03, respectively). CONCLUSION: We did not find a significant difference in epidemiological factors between women with human papillomavirus positive and negative high grade CIN. However differences between the frequency of three HLA DQB1 alleles suggest that women with these allele profiles have a higher chance of clearing human papillomavirus, without affecting their chance of developing dysplasia.     

HLA-DQB1 polymorphisms and risk for cervical cancer: a case-control study in a southern Chinese population

OBJECTIVES AND METHODS: HLA II DQB1 polymorphisms have been shown to associate with cervical cancer risk, but results varied among different populations. In this study, the HLA DQB1 alleles among 221 southern Chinese women with cervical intraepithelial neoplasia grade III (CIN III)/invasive cervical carcinoma (ICC) were compared to 191 controls. RESULTS: The frequency of DQB1*03 was significantly lower among ICC overall as compared to controls (65.4% vs. 79.1%, odds ratio [95% confidence interval]: 0.50 [0.28-0.88], corrected p-value: 0.04). The protective association of DQB1*03 remained significant for human papillomavirus (HPV) 16-positive ICC, but not for HPV16-negative cases. This is in contrast to studies on European populations where DQB1*03 was associated with an increased risk for ICC. In the current study, 70.1% of the HPV16 isolates were Asian variants, and 28.0% were European variants. However, no significant association between HPV16 variant and DQB1*03 distribution was observed. HPV52 and HPV58 were found respectively in 16.3% and 10.0% of CIN III/ICC, which were higher compared to that of Europe and North America. Further analyses revealed a positive risk association between DQB1*06 and HPV58-positive CIN III/ICC (3.68 [1.37-9.92], corrected p-value: 0.012). CONCLUSION: The host genetics and the distribution of HPV types/variants may account for the observed differences among southern Chinese and other populations.     

TAP1, TAP2, and HLA-DR2 alleles are predictors of cervical cancer risk

OBJECTIVE: The likelihood of developing cervical cancer has been shown to be increased in persons with certain HLA alleles. We evaluated immune response genes in the HLA region of chromosome 6 to see if individual or interactive associations with cervical cancer risk could be identified. METHODS: Tissue was obtained from 127 women undergoing surgical treatment for cervical cancer. Blood samples were obtained from 175 control subjects. A combination of polymerase chain reaction (PCR), sequence-specific PCR, and DNA sequencing was used to evaluate polymorphic alleles, including HLA class I B7, TNF alpha, HLA class II DR2, TAP1, and TAP2 genes. Fisher's exact test and logistic regression modeling were used for statistical analysis. RESULTS: A significantly greater proportion of the patients with cervical cancer were found to have the HLA class II DR2 1501 allele (P = 0.023) and the TAP2 A/B heterozygous pattern of alleles (P = 0.0006) than were women without cervical cancer. A proportion of patients with cervical cancer significantly smaller than that of the control women had a polymorphism at the -238 position of the TNF promoter and the TAP1 C/C homozygous pattern of alleles. With logistic modeling, the markers that showed consistent association with the occurrence of cervical cancer were TAP2 A/B, HLA-DR2 1501, and TAP1 C/C. CONCLUSIONS: We demonstrated a significant association between immune response genes and the risk of cervical cancer. Our data create a compelling argument for a gene or a cluster of genes in the HLA region of chromosome 6 that regulates host immune responses to human papillomavirus infection in a manner that results in inherited susceptibility or resistance to the transforming properties of oncogenic papillomaviruses.     

Prevalence and genotyping of HPV in cervical cancer among Australian women.

OBJECTIVE: To investigate the association between HPV DNA detection and histological examination of tumor biopsies from women with cervical cancer. METHOD: A total of 186 women with cervical cancer were screened for HPV infection using MY09/MY11 primer based PCR. The status of HPV infection was correlated with histological and demographic characteristics by Fisher's exact test or Chi square test. RESULT: The prevalence of HPV infection in this Australian population was 91.9% (171). Among these 53.8% (100) were HPV type 16, 17.2% (32) HPV type 18, and 21.0% (39) other HPV types. Three significant associations were identified: (1) HPV genotype 18 and adenocarcinomas/adenosquamous carcinomas (P < 0.001); (2) HPV DNA negativity and postmenopausal status (P = 0.02); and (3) HPV DNA positivity and lymphocyte infiltration of tumor tissues (P = 0.03). CONCLUSION: HPV infection is present in the vast majority of cervical cancer patients. However, its presence or genotyping does not seem to have a major influence on the pathogenesis of cervical cancer, such as tumor grade, FIGO staging and metastasis (P > 0.1).     

HPV testing in cervical screening

High-risk human papillomavirus (hrHPV) bearing cervical intraepithelial neoplasia (CIN) is considered, as the real precursor lesion of cervical cancer and persistence of an hrHPV infection is necessary for the progression to cervical cancer. This knowledge warrants the use of hrHPV testing as an adjunct to cervical cytology in population-based screening programmes and for monitoring therapy efficacy of high-grade CIN lesions. Replacement of cytology by hrHPV testing altogether is considered, but for this to be (cost-) effective, accurate information about the specificity of the hrHPV test is required. Additional test systems that can be used to stratify women with a positive hrHPV test are HPV genotyping, viral load analysis and hrHPV mRNA analysis. The need for HPV genotyping of cervical smears is illustrated by the increased risk for high-grade cervical lesions associated with HPV types 16 and 18. In particular, for women who have normal but persistently (>1 year) HPV18-positive smears, endocervical curettage is suggested (evidently considering the age and possible future pregnancies of the respective woman) because HPV18 is associated with glandular lesions in the cervix, which are difficult to detect by cytology.     

HLA-DQB1 and HLA-DPB1 genotypes in severe preeclampsia

OBJECTIVE: To clarify whether there are susceptible HLA-DQB1 or HLA-DPB1 alleles in women with preeclampsia. METHODS: The frequency of HLA-DQB1 and HLA-DPB1 alleles was analyzed in 47 women with previous severe preeclampsia and compared with that in 85 normal fertile women. The types of HLA-DQB1 and HLA-DPB1 alleles were assessed using a polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The frequency of HLA-DQB1*04 allele in previously preeclamptic women was 21.3% (20 of 94 loci) and in the controls was 11.2% (19 of 170 loci). Thus, the HLA-DQB1*04 allele frequency was significantly higher in preeclamptic women compared with controls (P <.05 by chi(2) test, OR 2.15, 95% confidence interval 1.08, 4.27). The frequency of other HLA-DQB1 alleles and all HLA-DPB1 alleles was not significantly different between groups. The incidence of homozygosity of HLA-DQB1 or HLA-DPB1 alleles in preeclamptic women was not significantly different compared with that of normal fertile women. CONCLUSION: These data suggest that women who have the HLA-DQB1*04 allele might be susceptible to preeclampsia.     

Prevalence of human papillomavirus types 11, 16 and 18 in cervical swabs. A study of 1362 pregnant women

Cervical smears from 1362 pregnant women were examined by filter in situ hybridisation for human papillomavirus (HPV) types 11, 16 and 18. 119 women (8.7%) had HPV-positive smears, HPV 16 being the most common type (61% of all infections). There was a correlation with age (r = 0.63, p = 0.004), the highest incidence found in women less than 22 years old with a decline after the age of 30. The incidence of cervical HPV infection was significantly higher (20.3%, p less than 0.01) in the subgroup of women with past or present vulvar condyloma, but not in women with previous pelvic inflammatory disease or genital herpes. In 18 women with current dysplasia the smears harboured HPV 16, 18, or both in eight cases (40%). The incidence of HPV infection in 71 women with earlier dysplasia did not differ from that of the women who never had dysplasia.     

Association between the HLA DQB1*0301 gene and human papillomavirus infection in high-grade cervical intraepithelial neoplasia.

This study describes the distribution of DQB1genes in Norwegian women treated for high-grade cervical intraepithelial neoplasia (CIN). Formalin-fixed, paraffin-embedded tissue sections from 170 biopsy specimens with diagnoses of CIN II (n = 54) or CIN III (n = 116) were DQB1-typed using allele-specific polymerase chain reaction. The follow-up period for cases was 13 to 15 years. The control material comprised blood samples and endocervical brushes from 213 women without CIN. Both cases and controls had previously been human papillomavirus (HPV)-typed. The DQB1*0301 allele was overrepresented among cases compared with controls (odds ratio [OR] = 1.8). Presence of CIN was related to HPV infection, and HPV 16 positivity was significantly associated with the presence of DQB1*0301 (OR 1.8). The DQBI*0301 allele was significantly more prevalent in CIN III than in CIN II cases. The lesions in two women recurred in the follow-up period, one of whom was carrying the DQB1*0301 allele. Women carrying the HLA-DQB1*0301 allele have an increased risk of developing CIN when infected by HPV 16, although there was not an increased frequency of recurrent disease among women carrying this allele.     

Koilocytosis and squamous (pre)neoplasia as detected in population-based cervical screening: practice and theory

INTRODUCTION: Koilocytosis (cavitation of the cytoplasm due to active HPV infection) can be detected in the screening process for cervical carcinoma. OBJECTIVE: To report the practice of detection of koilocytosis and (pre)neoplasia in population screening and to exploit the collected data to propose an explanation for the relationship between HPV infection and nuclear precancerous changes. STUDY DESIGN: Centrally collected and stored (SBBW, Leiden, the Netherlands) data from all smears of six regional pathology laboratories (1995-2002), coded according to KOPAC (the national cervical smear coding system; S1: normal thru S9: invasive carcinoma) were accessed. Prevalences per 100,000 smears were calculated for koilocytosis and for squamous abnormalities after stratification for country of origin of screenees. The relative risk (RR) for the ethnic (age) groups was computed by dividing the prevalence of the relevant ethnic (age) group by the prevalence of all women. RESULTS: Surinamese women featured the highest prevalence of koilocytosis and of all squamous abnormalities. Moroccan women the lowest. The RR for koilocytosis was highest at 30 years (1.84) and lowest at 60 (0.26). RR dependence on age of S5-S9 lesions was similar. Compared to nonkoilocytotic smears, koilocytosis was 104 times more frequent in the 1,500 S4 smears, 36x more frequent in the 6,700 S2-S3 smears, and 24x more frequent in the 1,740 S5-S9 smears. In all three categories this difference is statistically significant. CONCLUSION: High prevalences for both koilocytosis and for preneoplasia were detected in Surinamese immigrants, however, it still does not exclude HPV infection as a confounder linked to sexual lifestyle. The presence of koilocytosis in cervical smears may serve to identify patients with an increased risk for cervical cancer and perhaps warrant more intensive surveillance than what is provided through five-yearly screening.     

Regression of low-grade cervical intraepithelial neoplasia in patients with HLA-DRB1*13 genotype

OBJECTIVE: The human leukocyte antigen (HLA)-DRB1*13 allele frequency is lower in women with cervical carcinoma than in the general population, suggesting that this allele could exert a protective effect against progression of cervical intraepithelial neoplasia (CIN) associated with human papillomaviruses (HPV). To test this hypothesis, we designed a prospective study of low-grade CIN (CIN1) and analyzed the probability of regression of these lesions according to HLA-DR and HPV status. METHODS: The study sample was composed of 86 women with CIN1 who agreed to regular colposcopic follow-up and no immediate treatment. Biopsy specimens were taken under colposcopy for histology and for the determination of HPV and HLA status. Cases were classified into 3 groups: CIN1 regression, persistence for at least 12 months, or progression to CIN2 or 3. RESULTS: The rate of spontaneous regression (95% confidence interval) at 24 months was 51.6% (39-61.6%) overall compared with 34.7% (13.4-50.8%) in HPV16/18 positive cases and 59.9% (43.7-71.4%) in HPV16/18-negative cases (P =.051). The rate of regression was 71.8% (40.8-86.5%) in patients with HLA-DRB1*13 and 45.9% (31.5-57.2%) in patients with other genotypes (P =.03). Regression reached 90.5% (38.9-98.5%) at 18 months in DRB1*13 patients with HPV16/18-negative-associated CIN (15.1% of the cases). In multivariable analysis, HLA-DRB1*13 allele and HPV16/18-negative status were independently associated with an increased probability for regression (adjusted hazard ratio 2.1 [1.0-4.1] and 2.5 [1.2-5.4], respectively). CONCLUSION: A subset of approximately 15% of CIN1 highly likely to show spontaneous regression can be defined using 2 biologic parameters that characterize the viral causative agent and the host. LEVEL OF EVIDENCE: II-2     

Increased frequency of genital human papillomavirus infection in human immunodeficiency virus-seropositive Taiwanese women.

BACKGROUND AND PURPOSE: Human papillomavirus (HPV) infection is associated with increased incidence and severity of HPV-related cervical dysplasia and cervical cancer in women with human immunodeficiency virus (HIV) infection. This study examined the incidence of genital HPV infection in HIV-infected Taiwanese women and its relationship with cervical neoplasia. METHODS: This hospital-based, case-control study enrolled 31 consecutive HIV-seropositive women and 124 age-matched women who were free from HIV infection. Polymerase chain reaction (PCR) was used to distinguish high-risk (types 16, 18, 31, 33, 52 and 58) and low-risk HPV (types 6 and 11). The occurrence of genital HPV infection was compared between women with and without HIV infection. In addition, CD4 lymphocyte counts were determined by flow cytometry and Papanicolaou test was done in women with HIV infection. RESULTS: HPV and Papanicolaou test were done soon after the diagnosis of HIV infection. HIV seropositive women had a significantly greater high-risk HPV infection rate (48.4%; 15/31) than women without HIV infection (20.2%; 25/124; odds ratio, 3.71; p = 0.001). However, the prevalence of cervical intraepithelial neoplasia was similar between women with and without HIV infection. The CD4 lymphocyte counts in HIV-seropositive women were similar between those with and without genital HPV infection. CONCLUSIONS: The risk of genital HPV infection was significantly increased in HIV-infected women. Due to the association between high-risk HPV infection and the development of cervical dysplasia and cervical cancer, regular follow-up of Papanicolaou test is necessary in these women.     

Genetic polymorphisms of GSTM1, p21, p53 and HPV infection with cervical cancer in Korean women

OBJECTIVES: The aim of this study was to determine whether GSTM1 or GSTT1 might be associated with risk of cervical cancer development in Korean women. The multiplicative interaction of GSTM1 and GSTT1 genotype with p21, p53 polymorphism, and HPV genotype was also investigated. METHODS: From 1997 to 1999, uterine cervical carcinoma was diagnosed in 215 Korean women at the Department of Obstetrics and Gynecology of Seoul National University Hospital. None of the women in the control groups (n = 98) had any evidence of cervical lesions, which were confirmed by Pap smear. Finally, 81 cases and 86 controls were genotyped for p21, p53, and GSTM1 and T1 and HPV infection. A multiplex PCR method was used for the genotyping of GSTM1 and GSTT1; direct sequencing for p53 codon 72, high-risk HPV, and PCR-RFLP (BsmAI) for p21 codon. The unconditional logistic regression analysis was used to calculate ORs and 95% CI. RESULTS: Although the GSTM1 and GSTT1 genotype was not significantly associated with cervical cancer development for all women, the GSTM1 null genotype was significantly associated with an increased risk of cervical cancer development in women with high-risk HPV infection (OR = 2.9, 95% CI: 1.0-8.2). Although the frequency of overall GSTT1 null genotype was significantly lower in cervical carcinoma patients with high-risk HPV infection (OR = 0.3, 95% CI: 0.1-1.0), almost 2-fold increased risk was observed among women with GSTT1 null and Arg/Arg genotype (OR = 1.9, 95% CI: 0.7-5.4). Although the cervical cancer risk was 3.3-fold increased in women with null and Arg/Arg genotype compared to women with GSTM1 present and p21 Ser-containing genotype, there was no significant multiplicative interaction between GSTM1 and p21 (P for interaction = 0.785) or p53 (P for interaction = 0.815). CONCLUSIONS: These findings suggest that the risk of cervical cancer may be related to GSTM1 genotype in women with high-risk HPV infection and that there is a possible gene-gene interaction in the incidence of cervical cancer.     

Evaluation of the Possible Protective Role of Adeno-Associated Virus Type 2 Infection in HPV-Associated Premalignant Disease of the Cervix

Objective. Our objective was to examine the prevalence of adeno-associated virus (AAV) infection in women with normal cervical smears and those with HPV-associated cervical intraepithelial neoplasia (CIN).Methods. HPV typing was performed on DNA from cervical smears of 211 women with CIN (CIN 1 = 83, CIN 3 = 128) and 433 healthy women who had a normal cervical smear. HPV typing was performed on all cases and controls using type-specific oligonucleotide primers (HPV 16, 18, 31, 33). AAV DNA was amplified by nested PCR from the same samples. The amplified DNA were separated on 2% agarose gels, blotted, and hybridized to AAV-2 DNA labeled by random priming with [α-³²P]dCTP to confirm specificity of amplification.Results. A total of 131 cases of CIN were positive for one of the HPV types either alone or in combination. HPV 16 was present in 120 (57%) cases, HPV 18 in 15 (7%), HPV 31 in 27 (13%), and HPV 33 in 15 (7%) and there were multiple HPV types detected in 34 (16%) cases. All of the controls were selected to be negative for HPV. A total of 6/433 (1.4%) control cervical smears and 4/211 (1.9%) of CIN (CIN1 = 2; CIN3 = 2) contained AAV DNA. No correlation between AAV and any clinical feature was observed.Conclusions. These results are different from some that have been previously published and suggest that AAV DNA is not frequently present in either normal control cervical samples or cervical intraepithelial neoplasia. This does not support the hypothesis that AAV may be protective against cervical cancer. Further research is necessary to understand the natural history of AAV infection and its role in human disease.     

Significance of atypical squamous cells of undetermined significance on ThinPrep papanicolaou smears

OBJECTIVE: The aim of this study was to assess the prevalence and risk factors predictive of dysplasia among women seen in a gynecologic oncology service with the cytologic diagnosis of atypical squamous cells of undetermined significance (ASCUS) on Papanicolaou smears obtained by the ThinPrep method. METHODS: Patients with ASCUS ThinPrep Papanicolaou smears seen at the Division of Gynecologic Oncology, University of Vermont, between 1997 and 1999 were identified. The cytologic smears were reviewed and subtyped into reactive or suggestive of squamous intraepithelial lesion (SIL). The charts of these patients were reviewed and the following information was abstracted: age, gravidity, parity, menopausal status, use of hormonal replacement therapy, smoking, history of pelvic cancer, history of radiation therapy, history of abnormal Papanicolaou smear and its treatment, history of human papillomavirus (HPV) infection, and follow-up information including results of repeat Papanicolaou smears, colposcopy, and biopsies. The prevalence of dysplasia was calculated. The demographic features of women with ASCUS, reactive, were compared with those with ASCUS, SIL, using a two-sample t test, chi(2), and Fisher's exact test. Risk factors predictive of dysplasia were calculated using the odds ratio and the 95% confidence interval. P < 0.05 was considered significant. RESULTS: One hundred twenty-six patients with ASCUS on ThinPrep Papanicolaou smear were identified; 63 patients had ASCUS, reactive, and 63 patients had ASCUS, SIL. The demographic features of both groups were similar. The overall prevalence of dysplasia was 15.9% and was significantly higher among women with ASCUS, SIL, than among women with ASCUS, reactive (25.4% versus 6.4%, P = 0.003). The type of ASCUS cytology (reactive versus SIL), smoking, and history of HPV were significant risk factors for dysplasia (P = 0.003, 0.037, and 0. 042, respectively). CONCLUSIONS: The prevalence of dysplasia among women seen in a gynecologic oncology service with ASCUS cytology on ThinPrep Papanicolaou smears is 15.9%. Women with ASCUS favor SIL, those who smoke, and those with a history of HPV are at higher risk for dysplasia and should be offered colposcopy.     

The IL-10 -1082G polymorphism is associated with clearance of HPV infection

The role of cytokines in protecting against human papillomavirus (HPV) and HPV-associated disease is not fully understood. We compared the frequency of the interleukin (IL)-10 polymorphism (G allele) at position --1082 and the distribution of GG/GA/AA genotypes among 116 HPV-positive women, grouped according to their cervical cytological profiles, with 119 HPV-negative controls with normal smears. No difference was observed in genotype frequency between the groups. Among women in the HPV-positive, smear-normal group, who were re-tested for HPV after 12 months, there was a significant inverse association between presence of at least one variant G allele (high activity) and HPV persistence (OR per G allele = 0.082 [95% CI 0.009-0.73], P= 0.001; after controlling for ethnicity). This association remained significant after controlling for age, smoking and hormonal contraception (OR = 0.028 [95% CI 0.001-0.66], P= 0.001). This preliminary study suggests that higher levels of IL-10 may prevent cervical neoplasia through their role in eliminating HPV.     

Human papillomavirus (HPV) DNA in primary cervical cancer and in cancer free pelvic lymph nodes--correlation with clinico-pathological parameters and prognostic significance

OBJECTIVE: To assess whether the presence of human papilloma virus (HPV) DNA and/or several genotypes of HPV DNA in primary cervical cancer and cancer free pelvic lymph nodes are correlated with several clinicopathological parameters of well-defined prognostic significance and whether virological parameters are predictors of long-term survival in cancer patients. PATIENTS AND METHODS: 223 cases of cervical cancer patients included in this retrospective study underwent follow-up evaluation. Survival and cause of death were examined for 204 (91.4%) patients, with a mean follow-up time of 4.4 years. HPV DNA was detected using the high sensitive polymerase chain reaction (PCR) method followed by HPV DNA sequencing for HPV genotyping. These results were correlated with well-defined clinicopathological parameters and survival data. RESULTS: HPV DNA was detected by PCR in 150 of 203 (73.4%) tissue specimens of cervical cancer patients. DNA sequence analysis revealed the presence of HPV 16 (n = 68, 45.3%), HPV 18 (n = 49, 32.6%) and rare HPV types (n = 33, 22.1%). HPV genotypes correlated significantly with histological tumor types, node status, blood vessel invasion and lymph space involvement. The presence of HPV DNA in cervical cancer as well as the genotype of HPV 16 could also be confirmed as significant prognostic factors in the univariate Cox Regression Analysis (RR 2.856, p < 0.003 resp. RR 3.444, p < 0.0001). The presence of HPV DNA in cancer free pelvic lymph nodes was significantly correlated to the concomitant manifestation of pelvic lymph node metastases (RR 3.1, p < 0.0001). In the multivariate analysis, however, HPV DNA in primary tumor and in negative pelvic lymph nodes failed to be of prognostic relevance. Exclusively, HPV 16 appears to impact independently on the overall survival in cervical cancer patients (RR 3.653, p < 0.002). CONCLUSION: The detection of HPV 16 genotype may play an important adjunct role in assessing prognosis of cervical cancer patients. The clinical impact of the presence of HPV DNA in primary tumors and cancer free pelvic lymph nodes remains to be investigated in further studies. The exact mechanisms by which HPV influence the prognosis of cervical cancer patients have to be defined.