The 46359CT polymorphism of DNMT3B is associated with the risk of cervical cancer

Abnormal methylation is related to cancer development. Since DNMT3B is an enzyme that modulates genomic methylation, we hypothesized that genetic variants of the promoter DNMT3B may be associated with an increased risk of developing cervical cancer. Our aim was to investigate the association between ?579GT and 46359CT polymorphisms of DNMT3B and cervical cancer, high-grade squamous intraepithelial lesions (HSIL), and low-grade squamous intraepithelial lesions (LSIL). Samples from 200 healthy women and 130 women with squamous intraepithelial lesions (70 with cervical cancer, 30 with HSIL, and 30 with LSIL) were analyzed. Polymorphism genotyping was performed using PCR and restriction fragment length polymorphism. The ?579GT polymorphism was not associated with cervical cancer, HSIL, or LSIL. The CT genotype of 46359CT polymorphism was significantly associated with cervical cancer risk (OR 8.75, CI 1.27–374.1), whereas the TT genotype was associated with a significantly decreased risk of HSIL (OR 0.66, CI 0.01–0.32) and LSIL (OR 0.11, CI 0.026–0.45). Our results suggest that genotyping the 46359CT polymorphism in DNMT3B may help identify women who are genetically susceptible to cervical cancer development. Additional studies with larger sample sizes are necessary to confirm our findings.     

IL-1RN VNTR polymorphism and genetic susceptibility to cervical cancer in Portugal

Human Papillomavirus infection is considered as the main etiological factor of cervical cancer (ICC), although, the role of host genetic factors in ICC susceptibility has been increasing. Immunological response is crucial for the prevention of viral associated diseases. Interleukin 1 receptor antagonist (IL-1RN) is considered to be an important regulator of host immunity and several studies have shown a potential role of a 86?bp VNTR polymorphism within intron 2 of the IL-1RN gene in host immune response variability. We investigated the role of this polymorphism in cervical cancer development in Portugal with a case–control study developed with peripheral blood samples from 196 healthy women and 340 women with cervical lesions from the Northern Region of Portugal. We observed that IL-1RN Allele 2 homozygosis was significantly higher in cases than in controls. In fact, IL-1RN A2*A2 homozygous revealed to be associated with an increased risk of HSIL?+?ICC (OR?=?1.90; 95?% IC 1.13–3.21; p?=?0.015). Furthermore, we also observed that median age of onset of HSIL?+?ICC was significantly different (46.0 vs 52.0) in IL-1RN A2*A2 homozygous comparing to non-A2*A2 (p?=?0.028). Our results indicated that IL-1RN A2 allele is associated with an increased susceptibility to cervical cancer development, probably by increasing predisposition to shorter immune responses.     

CCR2 and CCR5 genes polymorphisms in women with cervical lesions from Pernambuco,Northeast Region of Brazil: a case-control study

Polymorphisms in chemokine receptors play an important role in the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer (CC). Our study examined the association of CCR2-64I (rs1799864) andCCR5-Δ32 (rs333) polymorphisms with susceptibility to develop cervical lesion (CIN and CC) in a Brazilian population. The genotyping of 139 women with cervical lesions and 151 women without cervical lesions for the CCR2-64I and CCR5-Δ32 polymorphisms were performed using polymerase chain reaction-restriction fragment length polymorphism. The individuals carrying heterozygous or homozygous genotypes (GA+AA) for CCR2-64I polymorphisms seem to be at lower risk for cervical lesion [odds ratio (OR) = 0.37, p = 0.0008)]. The same was observed for the A allele (OR = 0.39, p = 0.0002), while no association was detected (p > 0.05) with CCR5-Δ32 polymorphism. Regarding the human papillomavirus (HPV) type, patients carrying the CCR2-64Ipolymorphism were protected against infection by HPV type 16 (OR = 0.35, p = 0.0184). In summary, our study showed a protective effect ofCCR2-64I rs1799864 polymorphism against the development of cervical lesions (CIN and CC) and in the susceptibility of HPV 16 infection.     

Association between the p73 exon 2 G4C14-to-A4T14 polymorphism and cancer risk: a meta-analysis

The TP53 homolog p73 is structurally and functionally similar to TP53 and plays an important role in modulating cell-cycle control, apoptosis, and cell growth. G4C14-to-A4T14 is the most commonly studied polymorphism of this gene for its association with risk of cancers, but the results are confusing rather than conclusive. We performed a meta-analysis using 21 eligible studies with a total of 7581 patients and 10,413 controls to summarize the data for an association between the p73 G4C14-to-A4T14 polymorphism and cancer risk. Compared with the common GC/GC genotype, the AT carriers (AT/GC, AT/AT) had a 1.18-fold elevated risk of cancer (95% confidence interval [CI]=1.11-1.25, p<0.00001) in a dominant genetic model as estimated in a fixed effect model. The effect of the G4C14-to-A4T14 polymorphism was further evaluated through stratification analysis. In four lung cancer studies, the variant genotypes had a significantly increased risk of lung cancer (odds ratio [OR]=1.16, 95% CI=1.04-1.28, p=0.005). Similar phenomena were also found in two squamous cell carcinoma of the head and neck studies (OR=1.32, 95% CI=1.12-1.56, p=0.0010), two oral cancer studies (OR=1.57, 95% CI=1.26-1.95, p<0.0001), and three colorectal cancer studies (OR=1.23, 95% CI=1.01-1.50, p=0.04). Increased risk of cancer associated with G4C14-to-A4T14 variant genotypes was pronounced in Caucasians (OR=1.21, 95% CI=1.11-1.31, p<0.00001), the Japanese population (OR=1.24, 95% CI=1.01-1.52, p=0.04), and the Korean population (OR=1.27, 95% CI=1.07-1.52, p=0.007). Our meta-analysis suggests that the p73 G4C14-to-A4T14 polymorphism genotypes (GC/AT+AT/AT) may be associated with an increased risk of cancer in most cancer types and ethnicities.     

No Association Between p73 G4C14-to-A4T14 Polymorphism and the Risk of Lung Cancer in a Korean Population

A member of the p53 family, p73 may play an important role in the development of lung cancer. Variations in the DNA sequence in the p73 gene can lead to alterations in the production of p73 and/or activity, which can affect an individual's susceptibility to lung cancer. To test this hypothesis, this study examined the association between the G4C14-to-A4T14 polymorphism in the p73 gene and the risk of lung cancer in a Korean population. The p73 G4C14-to-A4T14 genotypes were determined in 582 lung cancer patients and 582 healthy age- and gender-matched control subjects. Compared with the GC/GC genotype, the GC/AT and the AT/AT genotypes were not significantly associated with the risk of lung cancer [adjusted odds ratio (OR) = 1.08, 95% confidence interval (CI) = 0.84-1.38; and adjusted OR = 1.37, 95% CI = 0.83-2.24, respectively]. In addition, the risk estimate for the combined variant genotype (GC/AT + AT/AT) was similar to that of the GC/GC genotype (a dominant model for the AT allele, adjusted OR = 1.12, 95% CI = 0.88-1.41). These results suggest that the p73 G4C14-to-A4T14 polymorphism does not significantly affect susceptibility to lung cancer in the Korean population.     

Haemochromatosis gene (HFE) mutations in viral-associated neoplasia: Linkage to cervical cancer

The present study examines the frequency of the two main HFE mutations (C282Y and H63D) in a randomly selected population of 346 individuals including 201 DNA samples from women with cervical neoplasia (including high-grade squamous intraepithelial lesions and invasive squamous cell carcinoma) and a control population of 146 women from the same geographical area. We found a significantly lower risk of development of cervical neoplasia in H63D carriers (OR = 0.56; 95% CI 0.35-0.92; p = 0.01). Multivariate logistic regression analysis confirms this observation (OR = 0.55; 95% CI 0.35-0.88, p = 0.01). Regarding the C282Y mutation no association was found (OR = 1.32; 95% CI 0.53-3.33; p = 0.52). In addition, a significant difference between H63D carrier and non-carrier women on the time-to-onset of cervical lesions was observed (log-rank test: p = 0.0012). These results indicate that HFE could be considered a candidate modifier gene of viral-related neoplasia such as cervical carcinoma possibly by a dual role on iron metabolism and immunological system.     

Cervical scrapes levels of insulin-like growth factor-II and insulin-like growth factor binding protein 3 in women with squamous intraepithelial lesions and cervical cancer

A growing number of studies have demonstrated an association between serum levels of insulin-like growth factors (IGFs) and IGF binding protein-3 (IGFBP-3) and increased risk for various cancers. The aim of this study was to evaluate the relationship between levels of IGF-II or IGFBP-3 in cervical scrapes with cervical cancer and precancerous lesions: low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL). 4 groups of cases were examined: LSIL (n=20), HSIL (n=28), cervical cancer (n=45), and controls (n=51). Control subjects were women with normal, HPV DNA-negative Papanicolau (Pap) test. IGF-II and IGFBP-3 levels in cervical scrapes were measured by ELISA. Results show that median protein levels of IGF-II were significantly lower in cervical cancer cases vs. controls (446.5 ng/mg vs. 1,168.6 ng/mg, p<0.001). Significantly higher values of IGFBP-3 were found in HSIL vs. controls (median: 549.5 ng/mg vs. 216 ng/mg; p=0.018), and were not affected by HR HPV infection, meanwhile no significant differences were observed in IGFBP-3 levels between LSIL or cervical cancer as compared to controls. These data suggests that the progression to cervical cancer is associated with alterations in the IGF system and not affected by HR HPV infection. More studies are needed to understand the possible role of IGFBP-3 in cervical carcinogenesis.     

Variables associated with squamous intraepithelial lesions among women with a cytologic diagnosis of atypical squamous cells of undetermined significance.

OBJECTIVE: To identify factors among women with atypical squamous cells of undetermined significance (ASCUS) cytologic diagnosis that are associated with either low grade squamous intraepithelial lesions (LSILs) or high grade squamous intraepithelial lesions (HSILs). STUDY DESIGN: From January 1992 to June 1995, 1,660 women with a diagnosis of ASCUS were followed until the next follow-up appointment after the ASCUS diagnosis. Logistic regression analysis with either LSIL or HSIL at follow-up examination as a dependent variable was done with the following independent variables: patient age, method of follow-up, follow-up time, type of health care coverage and household income. RESULTS: In multivariate analyses, there was a 2.7-fold increase in the odds of LSIL (OR = 2.7, 95% CI = 1.3-5.8) for young women (< or = 25 years), a 2-fold decrease in the odds of LSIL (OR = .5, 95% CI .3-.9) for long time to follow-up (> 18 weeks after ASCUS diagnosis) and an 7.8-fold increase in the odds of LSIL (OR = 7.8, 95% CI = 5.1-11.9) for follow-up by colposcopic biopsy. For the odds of HSIL, there was a 6.8-fold increase (95% CI = 3.2-14.5) for follow-up by colposcopic biopsy as compared to Pap smears and a 3-fold decrease in the odds of HSIL (OR = 3, 95% CI = .1-.7) for high-income women (> $34,857). CONCLUSION: Our findings suggest that among ASCUS patients, younger women and those with shorter follow-up time are more likely to be diagnosed with LSIL. Women with a high income showed a protective association for HSIL. Colposcopic biopsy identified more LSIL and HSIL as compared to repeat Pap smear.     

Evaluation of p16INK4a in cervical lesion of premenopausal and postmenopausal women

Pap smears of postmenopausal women are often misdiagnosed because of the difficulty in distinguishing atrophic epithelial cells groups only by morphological criteria. In this study we investigated the diagnostic application of immunocytochemical staining of p16INK4a on conventional Pap smear. A total of 137 cervical specimens were enrolled in this study, of which 77 and 60 cervical smears were taken from premenopausal and postmenopausal women, respectively. Two cervical smears were taken simultaneously in 68 women, one for conventional cytology and the other for immunostaining. Additional 69 cervical smears were taken from the archive, decolorized and then used for immunostaining. In premenopausal women 1 out of 14 (7.1%) with negative cytology, 7 out of 24 (29.2%) with low grade squamous intra-epithelial lesion (LSIL), all 35 (100%) with high grade squamous intraepithelial lesion (HSIL) and all 4 (100%) with squamous cell carcinoma (confirmed by histopathology) had positive staining to p16INK4a. In postmenopausal women p16INK4a positivity was observed in 4 out of 7 (57.1%) cases of LSIL, 12 out of 14 (85.7%) cases of HSIL and all 4 out of 5 (80%) different cases of carcinoma (1 cervical adenosquamous carcinoma and 3 cervical squamous cell carcinoma in situ confirmed by histopathology), but none of 34 smears with normal cytology. Twenty smears with normal cytology chosen for the negative control in this study were from the group of postmenopausal women and were as expected negative for p16INK4a immunostaining. In the group of postmenopausal women, 16 out of 60 (26.7%) cases the cytological diagnosis was established on the basis of pl6lNK4a immunostaining as being HSIL. From our preliminary study on a limited number of samples, we can however conclude that pl6INK4a immunostaining is a very useful tool for cytological diagnosis enabling to distinguish HSIL from normal, reactive or inflammatory changes.     

Utility of p16(ink4a) immunocytochemistry in liquid-based cytology specimens from women treated for high-grade squamous intraepithelial lesions

OBJECTIVE: To examine whether p16(ink4a) immunocytochemical (ICC) expression detected intraepithelial disease in liquid-based cytology (LBC) specimens from women with high-grade squamous intraepithelial lesions (HSIL), whose specimen was labeled negative for intraepithelial lesion or malignany (NILM). STUDY DESIGN: Residual LBC specimens from women treated for HSIL (n = 21), whose LBC test was interpreted as NILM including marked benign inflammatory changes (BCC) were used. The control (n = 25) consisted of residual LBC specimens from women with documented HSIL. ICC for p16p(16k4a) was performed on a second ThinPrep (ThinPrep 2000, Cylyl Corporation, Boxborough, Massachusetts, U.S.A.) preparation; the percentage ofpositive cells and intensity of immunostaining were recorded. Standard LBC preparations for p16(ink4a) ICC-positive and ICC-negative control cases were reviewed. RESULTS: Twenty-four of 25 (96%) of the HSIL control group were ICC p16(ink4a) positive. In the NILM/BCC group, 2 of 21 with adequate LBC residua were ICC p16(ink4a) positive; on review both were reclassified as epithelial abnormality--1 HSIL and 1 atypical squamous cells cannot exclude HSIL. In both, subsequent colposcopic biopsy yielded HSIL. CONCLUSION: p16(ink4a) ICC positivity on NILM/BCC LBC residua from patients with HSIL may identify cases that merit cytologic review and possible reclassification. The utility of p16(ink4a) ICC in this situation requires further study.     

Prevalence of human papillomavirus among Croatian women attending regular gynecological visit

Human papillomavirus (HPV) infection has been identified as major risk factor for cervical intraepithelial neoplasia (CIN) and invasive cervical cancer. About 40 HPV viral types are commonly found in the genital tract. Most HPV infections resolve spontaneously, while persistent infection with oncogenic types, namely HPV 16 and 18 is necessary for CIN to occur and progress to cancer. Cervical screening is presently based on the Pap smear that is designed to diagnose precancerous lesions and cervical cancer The aim of this study was to investigate the prevalence of HPV DNA and to determine HPV types distribution among 361 women attending regular gynecological visit. There were 205 women (29+/-8 years old) without determined abnormal cervical lesions and 156 women (34+/-15 years old) with abnormal Pap smear; low grade squamous intraepitehelial lesions (LSIL, n=69), high grade squamous intraepithelial lesions (HSIL, n=72) and atypical squamous cells of undetermined significance (ASCUS, n=15). HPV DNA detection and genotyping was performed by Hybrid Capture 2 assay and additionally by consensus and type-specific primers directed PCR. The overall prevalence of high-risk HPV (hrHPV) in women with abnormal Pap smears was 67.9% (106/156), of which in ASCUS 33.4% (5/15), LSIL 62.3% (43/69) and HSIL 80.6% (58/72). In HPV positive specimens, HPV 16 was found as predominant type in 60.4% cases, followed by HPV 31 (8.5%), HPV 33 (6.6%) and HPV 18 (3.7%). In the group of women without obvious cervical changes the overall hrHPV prevalence was 35.6% with HPV 16 found in 43.8% cases, followed by HPV 31 (17.8%), HPV33 (9.5%) and HPV18 (6.8%). In both study groups, women with and without cervical lesions, the prevalence of HPVof indeterminate type was 14.2% and 13.7%, respectively. Our results indicate that cervical intraepithelial lesions are largely associated with HPV type 16, followed by HPV types 31, 33, 18 and HPV of indeterminate type. Although there is a significant difference in hrHPV DNA prevalence among two groups, no significant differences between particular hrHPV types distribution were observed.     

Germline polymorphisms of glutathione-S-transferase GSTM1, GSTT1 and p53 codon 72 in cervical carcinogenesis

The clinical significance of glutathione-S-transferase GSTM1, GSTT1 and p53 codon 72 polymorphisms in cervical carcinogenesis was investigated. Germline polymorphisms of GSTM1, GSTT1 and p53 codon 72 together with human papillomavirus (HPV) types were examined in a total of 457 blood and cervical smear samples from normal healthy women and the patients with premalignant and malignant cervical lesions. The 167 patients with low-grade squamous intraepithelial lesion (LSIL), 49 with high-grade SIL (HSIL) and 83 with squamous cell carcinoma (SCC) had significantly higher frequency of high-risk HPV than 158 controls. The 49 patients with HSIL and 83 with SCC had statistically higher frequency of null GSTT1 genotype than 158 controls. There was an increased odds ratio for null GSTT1 genotype in HSIL and SCC cases compared with controls among 191 patients with high-risk HPV. The 67 cases with HPV types 16 and/or 18 had higher frequency of the GSTT1 null genotype than 186 with other types of HPV. There was no statistical difference in the polymorphic frequency of GSTM1 and p53 codon 72 genotypes between SILs and controls with or without high-risk HPV. These results suggest that GSTT1 null genotype may increase the risk of cervical cancer particularly in the cases with high-risk HPV types in a Japanese population.     

IFN-gamma and IL-12B polymorphisms in women with cervical intraepithellial neoplasia caused by human papillomavirus

The Human Papillomavirus (HPV) is a sexually transmitted organism associated with Cervical Intraepithelial Neoplasia (CIN) and cervical cancer, the second main cause of malignancy in women worldwide. The virus itself, however, is not enough to cause lesions on the cervix. Several studies suggest that some polymorphic sites changes the cytokines levels and influence the cancer development in HPV infected patients. In this study, we evaluated the presence of functional polymorphisms at +874 (T/A) IFNG and +1188 (A/C) IL-12B genes in cervical smears samples from 76 healthy women and 162 women, HPV positive, with CIN lesion--CIN I (45), CIN II (55), CIN III (53) and cervical cancer (9)--in Brazilian population. There was no significant differences in genotype (p = 0.4192) and allele (p = 0.370; OR = 1.20) distributions between CIN patients and control groups on IFNG allelic polymorphism. Moreover, for IL-12B gene, there was a significant difference in genotype (p = 0.015) and allele distribution (p = 0.014; OR = 0.5754) between the groups. When samples were stratified according to grade of cervical lesion, the AA genotype and A allele were less frequent in the group with low-grade cervical lesions than in group with high-grade cervical lesions (p = 0.0036 and p = 0.0010; OR = 0.3819, respectively), suggesting that the C allele (mutant) may protect against the emergence of CIN lesions and its progression.     

Conventional Pap smear and liquid-based cytology as screening tools in low-resource settings in Latin America: experience of the Latin American screening study

OBJECTIVE: To evaluate the performance of the conventional Pap test and liquid-based cytology (LBC) in an ongoing multicenter trial testing optional screening tools (cytology, screening colposcopy, visual inspection with acetic acid, visual inspection with Lugol's Iodine, cervicography and Hybrid Capture II [HCII] (Digene Brazil, S?o Paulo, Brazil) conventional and self-sampling), for cervical cancer in Brazil and Argentina. STUDY DESIGN: A cohort of 12,107 women attending four clinics (Campinas, S?o Paulo, Porto Alegre, Buenos Aires) were randomized into the 8 diagnostic arms. Women testing positive with any of the tests were referred for colposcopy, and cervical biopsies were used as the gold standard to assess performance characteristics of the diagnostic tests. Conventional Pap smears were sampled by all clinics (n = 10,240), and LBC (Autocyte PREP, [TriPath Imaging, Burlington, North Carolina, U.S.A.], n=320, and DNA-Citoliq [Digene Brazil], n =1,346) was performed by 1 of the clinics. RESULTS: Conventional Pap smears showed no squamous intraepithelial lesions (normal) in 8,946 (87.4%) and LBC in 1,373 (82.4%). Using high grade squamous intraepithelial lesions (HSIL) as the cutoff, Pap smears predicted high grade (cervical intraepithelial neoplasia [CIN] 3) with OR 63.0 (95% CI, 36.90-107.70), standard error (SE) 59%, SP 97.8%, positive predictive value (PPV) 68.1% and negative predictive value (NPV) 96.7%. The same figures for Autocyte PREP were: OR 9.0 (95% CI, 2.43-33.24), sensitivity (SE) 33.3%, specificity (SP) 100%, PPV 100% and negative PV (NPV) 88.8%. DNA-Citoliq detected CIN 3 as follows: OR 11.8 (95% CI 2.60-53.26), SE 40.0%, SP 94.6%, PPV 40.0% and NPV 94.6%. Lowering the cutoff to low grade squamous intraepithelial lesions increased SE and NPV but compromised SP and PPV. The detection rates for high grade lesions after an atypical squamous cells of undetermined significance diagnosis were similar with the 3 techniques. In our settings, the 3 methods of cervical cytology were slightly different in performance. The conventional Pap smear had the highest SE, while Autocyte PREP had 100% SP and PPV in detecting CIN3 with the HSIL cutoff. All 3 tests had lower SE but higher SP as compared to HCII.     

Cervical squamous intraepithelial lesions and associated cervical infections in an HIV‐positive population in Rural Mpumalanga,South Africa

P. J. Swanepoel, P. Michelow, R. Du Plessis, I. G. Proudfoot, G. A. Tarr, S. L. Bockel, C. J. Swanepoel
Cervical squamous intraepithelial lesions and associated cervical infections in an HIV‐positive population in Rural Mpumalanga, South Africa Background: The incidences of genital human papillomavirus (HPV) infection, associated squamous intraepithelial lesions and cervical squamous cell carcinoma are significantly increased in HIV‐positive women. The role of other cervicovaginal infections in the acquisition of the HPV infection, cervical carcinogenesis and genital HIV infection remains largely speculative. Methods: A retrospective study was conducted including 1087 HIV‐positive women in rural Mpumalanga province, South Africa, for the period 1 May 2009 to 31 August 2010. For each patient, the age at first presentation, cervical cytological diagnosis, subsequent follow‐up cytology and histology, and microscopically visible infections (including endemic Bilharzia) were tabulated and statistically analysed. Results: The prevalence of low‐grade squamous intraepithelial lesion (LSIL), high‐grade squamous intraepithelial lesion (HSIL), squamous cell carcinoma, atypical squamous cells of undetermined significance (ASC‐US) and atypical squamous cells, cannot exclude HSIL (ASC‐H) in the study population were 22.1%, 30.9%, 0.6%, 13.5% and 4.0%, respectively. LSIL, HSIL and squamous cell carcinoma were diagnosed, respectively, at the average ages of 35.7, 37.9 and 37.2 years. Four patients with cervical intraepithelial neoplasia grade 1 (CIN1), 32 with CIN2/CIN3 and two with cervical squamous cell carcinoma were also diagnosed with Bilharzia. Of the other infections only bacterial vaginosis had a positive statistical correlation with HPV‐induced cervical abnormalities (LSIL, HSIL or squamous cell carcinoma). Conclusion: This study confirms the high prevalence of progressive HPV‐associated cervical disease in a rural Southern African HIV‐positive population, which is at least equal to or worse than in other African HIV‐positive studies. The high incidence of Bilharzia infection in those cases that underwent cervical cone excision suggests a possible relationship with progressive HPV disease and cervical carcinogenesis. Bacterial vaginosis (perhaps in combination with Bilharzia) may compromise the normal barriers against HPV and HIV infection.     

Human Papillomavirus Infection in HIV-1 Infected Women in Catalonia (Spain): Implications for Prevention of Cervical Cancer

Background

High-risk human Papillomavirus infection is a necessary factor for cervical squamous intraepithelial lesions and invasive cervical cancer. In HIV-1-infected women, HPV infection is more prevalent and a higher risk of cervical cancer has been identified. We aimed to calculate the prevalence of infection by HR-HPV, determine the factors associated with this infection and abnormal cytology findings and to describe the history of cervical cancer screening in HIV-1-infected women.

Methods

We enrolled 479 HIV-1–infected women from the PISCIS cohort. Each patient underwent a gynecological check-up, PAP smear, HPV AND Hybrid capture, HPV genotyping, and colposcopy and biopsy, if necessary. We applied questionnaires to obtain information on sociodemographic, behavioral, clinical, and cervical screening variables. We present a cross-sectional analysis.

Results

Median age was 42 years. The prevalence of HR-HPV infection was 33.2% and that of high-grade squamous intraepithelial lesions (HSIL) was 3.8%. The most common genotypes were 16(23%), 53(20.3%), and 52(16.2%). The factor associated with HR-HPV infection was age <30 years (odds ratio[OR],2.5; 95%confidence interval[CI],1.1–5.6). The factors associated with the presence of HSIL or low-grade squamous intraepithelial lesions (LSIL) were CD4T-lymphocyte count <200cells/mm³ versus >500cells/mm³ (OR,8.4; 95%CI,3.7–19.2), HIV-1 viral load >10,000copies/mL versus <400copies/mL (OR,2.1; 95%CI,1.0–4.4), and use of oral contraceptives (OR,2.0; 95%CI,1.0–3.9). Sixty percent of HIV-1–infected women had had one Pap smear within the last 2 years.

Conclusions

The high prevalence of HPV infection and cervical lesions in the HIV-1–infected population in Catalonia, as well as the low coverage and frequency of screening in this group, means that better preventive efforts are necessary and should include vaccination against HPV, better accessibility to screening programs, training of health care professionals, and specific health education for HIV-1–infected women.     

Progression of abnormal MIB-1 staining patterns of reserve cells in cervical smears from women ultimately developing high grade squamous intraepithelial lesions

OBJECTIVE: To assess, in a longitudinal study in women diagnosed with high grade squamous epithelial lesion (HSIL), the progression over time of proliferative activity in reserve cells using population screening cervical cytology specimens. STUDY DESIGN: Twenty consecutive, unselected patients with HSIL lesions were part of the national cervical screening program. From the archives, for each patient, the last prior normal population screening smear was included in the study. Concurrent sets of cervical smears from 80 age-matched women without pathology formed the controls. The original slides were stained using MIB-1 monoclonal antibody. The fraction of MIB-1-positive reserve cells was assessed using systematic random sampling and running progressive means assessment to ensure a sufficient sample size. RESULTS: The proliferation fraction in reserve cells of HSIL patients was significantly raised (mean, 65.0%; range, 53.5-94.1%; p < 0.01) as compared with that in concurrent controls (mean, 12.8%; range, 1.9-45.4%). Prior smears from HSIL patients, although without morphologic abnormalities, had abnormally high proliferation fractions (mean, 59.1%; range, 1.0-94.7%), significantly raised over those from concurrent controls (mean, 9.4%; range CONCLUSION: In population-based cervical smear screening, HSIL patients already have abnormally raised proliferation fractions of reserve cells, even without morphologic changes in squamous cells, 1-5 (mean, 3.6) years prior to diagnosis.     

Cervicovaginal smear abnormalities in sexually active adolescents. Implications for management

OBJECTIVE: To assess the prevalence and spectrum of Pap smear (PS) abnormalities in sexually active adolescents in comparison to adult women in order to determine whether management of adolescents should differ from that of adults. STUDY DESIGN: Five hundred twenty-four adolescents who had an initial PS at our institution from January to September 1997 were followed for 36 months with repeat PS and/or cervical biopsy. Initial PS results were compared with those of adult women. The chi 2 test was used to calculate the statistical significance of differences between the two groups. The qualified atypical squamous cells of undetermined significance (ASCUS) cytologic diagnosis in adolescents was correlated with follow-up data. RESULTS: The overall prevalence of squamous intraepithelial lesions (SILs) in adolescents was 29% as compared to 23% in adults. Almost all initial squamous lesions were ASCUS and low grade squamous intraepithelial lesion (LSIL); only one case of high grade squamous intraepithelial lesion (HSIL) was detected. On follow-up 18% and 2.4% of adolescents developed LSIL and HSIL, with a LSIL/HSIL ratio of 8/1 as compared to 5/1 in adults. The average time from initial PS to detection of HSIL was 20 months. All patients with HSIL except one had had one or more previous abnormal PSs. The positive predictive values (PPVs) for subsequent dysplasia for ASCUS favor reactive (ASCUS.R), ASCUS not otherwise specified (ASCUS.NOS) and ASCUS favor dysplasia (ASCUS.D) in adolescents were .13, .17 and .31, respectively. ASCUS.NOS (P = .01) and ASCUS.D (P = .007) were strong indicators of dysplasia as compared to ASCUS.R. CONCLUSION: PS abnormalities are more common in sexually active adolescents, with a significantly higher prevalence of LSIL over HSIL as compared to adult women. Given the natural history of HPV infection, we recommend follow-up with cytology rather than colposcopy/biopsy for adolescents with ASCUS and LSIL PSs. Qualification of ASCUS is useful in determining which adolescents are at the highest risk of cervical dysplasia.     

Polymorphism of Ag(+)-NORs in cervical smears from women with cervical cancer

OBJECTIVE: To evaluate Ag(+)-stained (Ag(+)-NOR) polymorphism in four groups of patients with various grades of cervical lesions and in a control group. STUDY DESIGN: Forty-five women were selected, diagnosed and classified on the bases of the Pap smear and colposcopy/biopsy at Hospital de Ginecologia y Obstetricia del Instituto Mexicano del Seguro Social in Monterrey, Mexico. Five categories were considered: (1) inflammatory, (2) low grade squamous intraepithelial lesions (LSILs), (3) high grade squamous intraepithelial lesions (HSILs), (4) invasive cervical cancer, and (5) normal. The cervical smears were stained by the Ag(+)-NOR method. One hundred cells per slide were counted and classified according to the polymorphism of Ag(+)-NOR dots: typical (spherical) and atypical (large, kidney shaped and clustered). The four shapes of Ag(+)-NORs were quantified by percentage and transformed using the arcsine root procedure. RESULTS: Statistical analysis showed a significant decrease in spherical shape according to neoplastic development. The three atypical shapes showed a significant increase in patients with HSIL and invasive carcinoma in respect to LSIL. Principal components analysis grouped the data at five locations in the plane formed by the first two principal components according to the diagnosis. CONCLUSION: These findings suggest the potential diagnostic and prognostic value of the determination of Ag(+)-NOR polymorphism in cervical cytology studies.     

Natural history of cervical intraepithelial neoplasia: a meta-analysis

OBJECTIVE: To determine the probabilities of transition of stages in the cervical cancer by conducting a meta-studies on the topic. STUDY DESIGN: We identified health states of interest in the natural history of cervical precancer, identified all possible papers that could meet selection criteria, developed relevance and acceptability criteria for inclusion, then thoroughly reviewed the selected studies. To determine the transition probability data we used a random effects model. We determined probabilities for 4 health state transitions. The 6-month mean predictive transition probability (95% confidence intervals with "prediction interval" in parentheses) for high grade squamous intraepithelial lesions (HSIL) to cancer was 0.0037 (0.00004, 0.03386), for low grade squamous intraepithelial lesions (LSIL) to HSIL was 0.0362 (0.00055, 0.23220), for HSIL to LSIL was 0.0282 (0.00027, 0.35782), and for LSIL to normal was 0.0740 (0.00119, 0.42672). CONCLUSION: The transition probabilities between cervical cancer health states for 6-month intervals are small; however, the cumulative risk of cervical cancer is significant. Markers to identify the cervical precursors that will lead to the transition to cervical cancer are needed.