Distribution of HPV genotypes in cervical intraepithelial lesions and cervical cancer in Tanzanian women.

BACKGROUND: Infection with human papillomavirus (HPV) is associated with uterine cervical intraepithelial neoplasia (CIN) and invasive cancers (ICC). Approximately 80% of ICC cases are diagnosed in under-developed countries. Vaccine development relies on knowledge of HPV genotypes characteristic of LSIL, HSIL and cancer; however, these genotypes remain poorly characterized in many African countries. To contribute to the characterization of HPV genotypes in Northeastern Tanzania, we recruited 215 women from the Reproductive Health Clinic at Kilimanjaro Christian Medical Centre. Cervical scrapes and biopsies were obtained for cytology and HPV DNA detection. RESULTS: 79 out of 215 (36.7%) enrolled participants tested positive for HPV DNA, with a large proportion being multiple infections (74%). The prevalence of HPV infection increased with lesion grade (14% in controls, 67% in CIN1 cases and 88% in CIN2-3). Among ICC cases, 89% had detectable HPV. Overall, 31 HPV genotypes were detected; the three most common HPV genotypes among ICC were HPV16, 35 and 45. In addition to these genotypes, co-infection with HPV18, 31, 33, 52, 58, 68 and 82 was found in 91% of ICC. Among women with CIN2-3, HPV53, 58 and 84/83 were the most common. HPV35, 45, 53/58/59 were the most common among CIN1 cases. CONCLUSIONS: In women with no evidence of cytological abnormalities, the most prevalent genotypes were HPV58 with HPV16, 35, 52, 66 and 73 occurring equally. Although numerical constraints limit inference, findings that 91% of ICC harbor only a small number of HPV genotypes suggests that prevention efforts including vaccine development or adjuvant screening should focus on these genotypes.

Bacterial vaginosis as a risk factor for high-grade cervical lesions and cancer in HIV-seropositive women.

OBJECTIVE: To assess the effect of bacterial vaginosis (BV) on the risk of high-grade squamous intraepithelial lesions (HSIL) among HIV-seropositive women. METHODS: A hospital-based prospective cohort study of HIV-seropositive women was conducted in Johannesburg, South Africa from January 2005 to September 2009. Multivariate log-binomial and Poisson regressions were used to estimate prevalence and rate ratios, respectively. RESULTS: Among 1954 HIV-seropositive women, the baseline prevalence of HSIL was 17%. BV prevalence was high (54%) and showed no association with prevalence of HSIL (adjusted prevalence ratio, 1.12; 95% confidence intervals (CI), 0.92-1.35) nor with cervical lesion progression at follow-up visit (n=503) (adjusted rate ratio: 1.00; 95% CI, 0.65-1.53). CONCLUSION: Among HIV-seropositive women, BV was not associated with an increased risk of HSIL or cervical lesion progression.

A randomized trial comparing the diagnostic accuracy of visual inspection with acetic acid to Visual Inspection with Lugol's Iodine for cervical cancer screening in HIV-infected women.

Visual inspection with Acetic Acid (VIA) and Visual Inspection with Lugol’s Iodine (VILI) are increasingly recommended in various cervical cancer screening protocols in low-resource settings. Although VIA is more widely used, VILI has been advocated as an easier and more specific screening test. VILI has not been well-validated as a stand-alone screening test, compared to VIA or validated for use in HIV-infected women. We carried out a randomized clinical trial to compare the diagnostic accuracy of VIA and VILI among HIV-infected women. Women attending the Family AIDS Care and Education Services (FACES) clinic in western Kenya were enrolled and randomized to undergo either VIA or VILI with colposcopy. Lesions suspicious for cervical intraepithelial neoplasia 2 or greater (CIN2+) were biopsied. Between October 2011 and June 2012, 654 were randomized to undergo VIA or VILI. The test positivity rates were 26.2% for VIA and 30.6% for VILI (p = 0.22). The rate of detection of CIN2+ was 7.7% in the VIA arm and 11.5% in the VILI arm (p = 0.10). There was no significant difference in the diagnostic performance of VIA and VILI for the detection of CIN2+. Sensitivity and specificity were 84.0% and 78.6%, respectively, for VIA and 84.2% and 76.4% for VILI. The positive and negative predictive values were 24.7% and 98.3% for VIA, and 31.7% and 97.4% for VILI. Among women with CD4+ count < 350, VILI had a significantly decreased specificity (66.2%) compared to VIA in the same group (83.9%, p = 0.02) and compared to VILI performed among women with CD4+ count ≥ 350 (79.7%, p = 0.02). VIA and VILI had similar diagnostic accuracy and rates of CIN2+ detection among HIV-infected women.

Cervical cancer precursors and hormonal contraceptive use in HIV-positive women: application of a causal model and semi-parametric estimation methods.

OBJECTIVE: To demonstrate the application of causal inference methods to observational data in the obstetrics and gynecology field, particularly causal modeling and semi-parametric estimation. BACKGROUND: Human immunodeficiency virus (HIV)-positive women are at increased risk for cervical cancer and its treatable precursors. Determining whether potential risk factors such as hormonal contraception are true causes is critical for informing public health strategies as longevity increases among HIV-positive women in developing countries. METHODS: We developed a causal model of the factors related to combined oral contraceptive (COC) use and cervical intraepithelial neoplasia 2 or greater (CIN2+) and modified the model to fit the observed data, drawn from women in a cervical cancer screening program at HIV clinics in Kenya. Assumptions required for substantiation of a causal relationship were assessed. We estimated the population-level association using semi-parametric methods: g-computation, inverse probability of treatment weighting, and targeted maximum likelihood estimation. RESULTS: We identified 2 plausible causal paths from COC use to CIN2+: via HPV infection and via increased disease progression. Study data enabled estimation of the latter only with strong assumptions of no unmeasured confounding. Of 2,519 women under 50 screened per protocol, 219 (8.7%) were diagnosed with CIN2+. Marginal modeling suggested a 2.9% (95% confidence interval 0.1%, 6.9%) increase in prevalence of CIN2+ if all women under 50 were exposed to COC; the significance of this association was sensitive to method of estimation and exposure misclassification. CONCLUSION: Use of causal modeling enabled clear representation of the causal relationship of interest and the assumptions required to estimate that relationship from the observed data. Semi-parametric estimation methods provided flexibility and reduced reliance on correct model form. Although selected results suggest an increased prevalence of CIN2+ associated with COC, evidence is insufficient to conclude causality. Priority areas for future studies to better satisfy causal criteria are identified.

Role of mast cells in inflammatory bowel disease and inflammation-associated colorectal neoplasia in IL-10-deficient mice.

BACKGROUND: Inflammatory bowel disease (IBD) is hypothesized to result from stimulation of immune responses against resident intestinal bacteria within a genetically susceptible host. Mast cells may play a critical role in IBD pathogenesis, since they are typically located just beneath the intestinal mucosal barrier and can be activated by bacterial antigens. METHODOLOGY/PRINCIPAL FINDINGS: This study investigated effects of mast cells on inflammation and associated neoplasia in IBD-susceptible interleukin (IL)-10-deficient mice with and without mast cells. IL-10-deficient mast cells produced more pro-inflammatory cytokines in vitro both constitutively and when triggered, compared with wild type mast cells. However despite this enhanced in vitro response, mast cell-sufficient Il10(-/-) mice actually had decreased cecal expression of tumor necrosis factor (TNF) and interferon (IFN)-gamma mRNA, suggesting that mast cells regulate inflammation in vivo. Mast cell deficiency predisposed Il10(-/-) mice to the development of spontaneous colitis and resulted in increased intestinal permeability in vivo that preceded the development of colon inflammation. However, mast cell deficiency did not affect the severity of IBD triggered by non-steroidal anti-inflammatory agents (NSAID) exposure or helicobacter infection that also affect intestinal permeability. CONCLUSIONS/SIGNIFICANCE: Mast cells thus appear to have a primarily protective role within the colonic microenvironment by enhancing the efficacy of the mucosal barrier. In addition, although mast cells were previously implicated in progression of sporadic colon cancers, mast cells did not affect the incidence or severity of colonic neoplasia in this inflammation-associated model.

Prognostic value of the diagnostic criteria distinguishing endometrial stromal sarcoma, low grade from undifferentiated endometrial sarcoma, 2 entities within the invasive endometrial stromal neoplasia family

The World Health Organization (WHO 2003) recognizes 3 endometrial stromal neoplasms: noninvasive endometrial stromal nodule and the 2 invasive neoplasms, endometrial stromal sarcoma (ESS), low grade and undifferentiated endometrial sarcoma (UES). It is important to note that the WHO 2003 does not define moderate atypia (an important differentiating diagnostic criterion for ESS, low grade and UES), nor does it discuss its significance. Moreover, studies on reproducibility and additional prognostic value of other diagnostic features in large are lacking. Using strict definitions, we analyzed the agreement between routine and expert-review necrosis and nuclear atypia in 91 invasive endometrial stromal neoplasias (IESN). The overall 5-year and 10-year recurrence-free survival rate estimates of the 91 IESN patients were 82% and 75%, respectively. Necrosis was well reproducible, and nuclear atypia was reasonably well reproducible. The 10-year recurrence-free survival rates for necrosis absent/inconspicuous versus prominent were 89% and 45% (P<0.001) and those for review-confirmed none/mild, moderate, severe atypia were 90%, 30%, and <20% (P<0.00001). Therefore, cases with moderate/severe atypia should be grouped together. Nuclear atypia and necrosis had independent prognostic values (Cox regression). Once these features were taken into account, no other feature had an independent additional prognostic value, including mitotic count. Using "none/mild atypia, necrosis absent/inconspicuous" as ESS, low grade versus "moderate/severe atypia present or necrosis present" as UES resulted in 68 ESS, low grade and 23 UES cases with disease-specific overall mortality-free survival of 99% versus 48% (P<0.00001, hazard ratio=45.4). When strictly defined microscopic criteria are used, the WHO 2003 diagnoses of ESS, low grade and UES are well reproducible and prognostically strong. © 2012 International Society of Gynecological Pathologists.