Luis Otávio Sarian

Evaluation of visual inspection with acetic acid (VIA), Lugol's iodine (VILI), cervical cytology and HPV testing as cervical screening tools in Latin America: This report refers to partial results from the LAMS (Latin AMerican Screening) study

Objectives: To assess the performance indicators of visual inspection with acetic acid (VIA) and visual inspection with Lugols iodine (VILI) in four Latin American centres participating in the ongoing Latin AMerican Screening (LAMS) study, in settings with moderate incidence of cervical disease and with poorly to moderately well-organized cervical cancer screening. Setting: Three Brazilian centres (São Paulo, Campinas and Porto Alegre) and one Argentine centre (Buenos Aires) recruited a total of 11,834 healthy women to undergo VIA, VILI, conventional Pap smear and Hybrid Capture II (HCII). Methods: Women who had a positive result from any of these tests were subjected to colposcopy and biopsies (if necessary), and women with high-grade cervical intraepithelial neoplasia (CIN) were properly treated. To control for verification bias, 5% of women with normal tests were referred for colposcopy, as were 20% of HCII-negative women. Results: Data on VIA (n=11,834), VILI (n=2994), conventional Pap smear (n=10,138) and HCII (n=4195) were available for test comparisons, calculating sensitivity, specificity, and positive and negative predictive values. Overall test positivity was 11.6% for VIA, 23.0% for VILI, 2.2% for Pap smear (LSIL threshold), 1.1% for Pap smear (HSIL threshold) and 17.1% for HCII. VIA was positive in 61.8% of the women with CIN 1, 57.0% of those with CIN 2, 35.0% of women with CIN 3 and in 21 of 28 (75%) of women with cancer. Approximately 10% of women with no detectable disease had an abnormal VIA. Regarding VILI, 83.3% of women diagnosed with CIN 1 and 62.5% of those with CIN 3 had an abnormal test. VILI failed to detect one of three cases of cancer. Both the sensitivity, specificity and positive predictive value of VIA and VILI in detecting CIN 2 or CIN 3 could be significantly improved depending on the combination with Pap smear or HCII (sensitivity up to 100.0% and specificity up to 99.8%). Conclusions: The LAMS study failed to reproduce the performance figures obtained with VIA and VILI (as stand-alone tests) in some other settings, where the prevalence of cervical disease was higher. However, a combined use of VIA or VILI with the Pap test or HCII allowed specific detection of cervical abnormalities.

Prevalência do HPV em mulheres rastreadas para o câncer cervical

OBJECTIVE To assess the prevalence of high-risk genital human papillomavirus (HPV) infection by age group and risk factors associated. METHODS Cross-sectional study in a sample of 2,300 women (15-65 years old) who self-referred to cervical cancer screening in Sao Paulo and Campinas, Southeastern Brazil, between February 2002 and March 2003. An epidemiological questionnaire was applied and cervical specimens were obtained for cytology and hybrid capture II test (HCII) for HPV detection. Statistical analysis included Pearson Chi-square and unconditional multiple logistic regression model (forward likelihood ratio). RESULTS High-risk genital HPV infection prevalence in this sample was 17.8% and age distribution was as follows: 27.1% (<25 years), 21.3% (25-34 years), 12.1% (35-44 years), 12.0% (45-54 years) and 13.9% (55-65 years). Subjects with the highest number of lifetime sexual partners had the highest rates of genital HPV infection. To be living with a partner, aged 35 to 44 years, and former smokers were protective factors. High-risk genital HPV infection was 14.3% in normal cytology, 77.8% in high grade squamous intraepithelial lesions and in the two cases (100%) of cervical cancer. CONCLUSIONS High-risk HPV prevalence was high in the sample studied. The highest prevalence of HPV infection was seen in women under 25 years old and then a new increase was seen over the age of 55 and the highest rates were found among those with many sexual partners during their lifetime.

Prognostic significance of PD-L1 and PD-L2 in breast cancer

PD-L1 and PD-L2 constitute an important antitumor immune response. In breast cancer, their prognostic value is still to be defined. In this study, we investigate the correlation between PD-L1 and PD-L2 protein expressions with clinical and pathologic features and disease-free survival and overall survival. To assess PD-L1 and PD-L2 expressions, we conducted immunohistochemistry studies using a breast cancer tissue microarray encompassing a total of 192 breast cancer cases, stages I, II, and III, with detailed clinical and outcome data. PD-L1 expression was present in 56.6% (107/189), and PD-L2 expression was identified in 50.8% (97/191) of breast cancer cases. Younger age at diagnosis, lymph node positivity, negative estrogen receptor, and recurrence at distant sites were all associated with both PD-L1 and PD-L2 expressions. The presence of larger tumors was associated only with PD-L1 expression. In our study, PD-L1 expression was significantly associated with better overall survival (P = .04) in breast cancer patients. Despite its association with poor clinical and pathologic features, PD-L1 expression emerges as a positive prognostic biomarker in breast cancer. This survival result might be due to the presence of a strong antitumor immune response leading to PD-L1 expression.

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 Lugols Iodine, cervicography and Hybrid Capture II [HCII] (Digene Brazil, São 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, São 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.

Human papillomavirus viral load in predicting high-grade CIN in women with cervical smears showing only atypical squamous cells or low-grade squamous intraepithelial lesion

CONTEXT Human papillomavirus (HPV) viral load may have an important role in predicting high-grade cervical intraepithelial neoplasia (CIN) in women with cervical smears showing atypical squamous cells or LSIL. OBJECTIVE To determine whether the assessment of the viral load of high-risk HPV DNA is useful in predicting the detection of high-grade cervical intraepithelial neoplasia (CIN2 and 3) in women referred because of cervical smears showing only atypical squamous cells or LSIL. TYPE OF STUDY Cross-sectional. SETTING Colposcopy Clinic in a University hospital. METHODS A series of 119 women referred because of atypical squamous cells or LSIL between August 2000 and April 2001 were included. All women were subjected to a new cervical smear, HPV testing for the high-risk types using hybrid capture II (HCII), viral load measurement in relative light units (RLU) and colposcopy, with cervical biopsies (n = 97). Cervical lesions were graded using the CIN classification. RESULTS Cervical biopsies revealed CIN2 or CIN3 in 11% of the cases, equally among women referred because of atypical squamous cells or LSIL. The HCII test was positive in 16% of women with atypical squamous cells and 52% of those with LSIL (OR = 5.8; 95% CI 1.4 to 26.7). There was strong correlation between CIN2 or CIN3 and positivity for HPV DNA when this group was compared with women with only CIN1 or normal cervix (OR = 7.8; 95% CI 1.5 to 53.4). In ROC analysis for HCII in diagnosing CIN2 and CIN3, the area under the ROC curve was 0.784, and the viral load cutoff point of 10.0 RLU/cutcuff presented 77% sensitivity and 73% specificity. Second cytology showing at least atypical squamous cells did not accurately detect CIN2 or CIN3 (OR = 6.4; 95% CI 1.0 to 50.9). The sensitivities of the second cervical smear and HCII were similar, although the specificity of HCII was significantly higher than the second cervical smear. CONCLUSIONS The viral load of high-risk HPV types was significantly associated with the diagnosis of CIN2 or CIN3 in women referred because of atypical squamous cells and LSIL abnormalities in their cervical smear.

Ultrasound criteria and CA 125 as predictive variables of ovarian cancer in women with adnexal tumors

To evaluate the capacity to predict malignancy in women with adnexal tumors using CA 125 measurement and ultrasound criteria.

Rastreamento anterior para câncer de colo uterino em mulheres com alterações citológicas ou histológicas

OBJETIVO: Analisar a historia de rastreamento citologico anterior em mulheres que apresentaram alteracoes citologicas e confirmacao histologica para câncer cervical. METODOS: Estudo transversal com 5.485 mulheres (15-65 anos) que se submeteram a rastreamento para o câncer cervical entre fevereiro de 2002 a marco de 2003, em Sao Paulo e Campinas, SP. Aplicou-se questionario comportamental e foi feita a coleta da citologia oncologica convencional ou em base liquida. Para as participantes com alteracoes citologicas indicou-se colposcopia e, nos casos anormais, procedeu-se a biopsia cervical. Para investigar a associacao entre as variaveis qualitativas e o resultado da citologia, utilizou-se o teste de qui-quadrado de Pearson com nivel de significância de 5%. RESULTADOS: Dentre os resultados citologicos, 354 (6,4%) foram anormais, detectando-se 41 lesoes intra-epitelial escamosa de alto grau e tres carcinomas; em 92,6% revelaram-se normais. De 289 colposcopias realizadas, 145 (50,2%) apresentaram alteracoes. Dentre as biopsias cervicais foram encontrados 14 casos de neoplasia intra-epitelial cervical grau 3 e quatro carcinomas. Referiram ter realizado exame citologico previo: 100% das mulheres com citologia compativel com carcinoma, 97,6% das que apresentaram lesoes intra-epiteliais de alto grau, 100% daquelas com confirmacao histologica de carcinoma cervical, e 92,9% das mulheres com neoplasia intra-epitelial cervical grau 3. A realizacao de citologia anterior em periodo inferior a tres anos foi referida, respectivamente, por 86,5% e 92,8% dessas participantes com alteracoes citologicas e histologicas. CONCLUSOES: Entre as mulheres que apresentaram confirmacao histologica de neoplasia intra-epitelial cervical grau 3 ou carcinoma e aquelas que nao apresentaram alteracoes histologicas nao houve diferenca estatisticamente significante do numero de exames citologicos realizados, bem como o tempo do ultimo exame citologico anterior.

Increased risk of oncogenic human papillomavirus infections and incident high-grade cervical intraepithelial neoplasia among smokers: experience from the Latin American screening study.

Background: The purpose of this study was to assess the effect of smoking on the prevalence and incidence of high-risk human papillomavirus (hr-HPV) infection and cervical intraepithelial neoplasia (CIN) in a large sample of Latin American women. Methods: The study examines baseline data on over 12,000 women included in the Latin American Screening Study (Brazil and Argentina), and over 1000 women followed-up for a period of 36 months. Three groups were formed: never smokers, current, and past smokers. The prevalence of hr-HPV infection and CIN were compared between the study groups. In the prospective analysis, women were controlled at 6-month intervals to assess the cumulative risk of incident hr-HPV infection, smear abnormalities, and CIN. Results: A higher prevalence (21.7%) of hr-HPV infection was found among current smokers as compared to never smokers (16.5%) or past smokers (13.5%). Being current smoker was significantly (P <0.01) associated with hr-HPV detection (OR = 1.6; 95% CI = 1.2–2.1). Being a current smoker was a significant predictor of incident hr-HPV during the follow-up [Hazards ratio (HR) = 1.4; 95% CI 1.0–1.9]. For incident CIN2+, being a past smoker (HR = 3.6; 95% CI 1.6–9.8) or current smoker (HR = 3.6; 95% CI 1.5–8.6) were the significant independent predictors. Current and past smokers had a significantly increased risk of incident CIN2+ (P <0.01). Conclusions: Smoking increases the risk of contracting hr-HPV infection and modifies the effect of a persistent hr-HPV infection by further increasing the risk of developing CIN2+. It seems that this effect modification persists over several years after smoking cessation.

Immunosuppressive cytokine Interleukin-10 (IL-10) is up-regulated in high-grade CIN but not associated with high-risk human papillomavirus (HPV) at baseline, outcomes of HR-HPV infections or incident CIN in the LAMS cohort.

Bypassing the local immunological defense reactions in the cervix is one of the prerequisites for human papillomaviruses (HPV) infections to progress to intraepithelial neoplasia (CIN). The role of potent immunosuppressive cytokines, e.g., interleukin-10 (IL-10), depressing these local virus-specific immunological responses is incompletely studied. To assess, whether IL-10 expression in cervical HPV lesions has any implications in the outcome of HPV infections or disease progression to CIN. Baseline cervical biopsies from 225 women of the LAMS study sub-cohort were analyzed for IL-10 expression using immunohistochemistry, to assess its associations with CIN grade, and high-risk HPV (HR-HPV) at baseline, as well as in predicting outcomes of HR-HPV infections, and development of incident CIN1+ and CIN2+ in this longitudinal setting. Expression of IL-10 in cervical lesions was up-regulated most often in high-grade CIN, and IL-10 over-expression retained its value as independent predictor of CIN2+ (odds ratio (OR) = 4.92) and CIN3+ (OR = 7.51) also in multivariate model, including HR-HPV and several known covariates of IL-10 expression. Up-regulation was not related to HR-HPV detection, and showed no relationship to HR-HPV viral loads. Using longitudinal predictive indicators (SE, SP, PPV, NPV), IL-10 expression was of no value in predicting (1) the outcomes of HR-HPV infections, or (2) the surrogate endpoints (incident CIN1+, CIN2+) of progressive disease. IL-10 over-expression (along with HR-HPV) was one of the independent covariates of CIN2/3. This immunosuppressive cytokine might play an important role in creating a microenvironment that favors progressive cervical disease and immune evasion by HR-HPV.

Associação entre idade ao início da atividade sexual e subseqüente infecção por papilomavírus humano : resultados de um programa de rastreamento brasileiro

PuRPOse : to investigate women’s age at their first sexual intercourse and its correlation with their present age, human papillomavirus (HPV) infection and cytological abnormalities at Pap smear. MethOds : women from the general population were invited to be screened for cervical cancer and pre-malignant lesions. After answering a behavior questionnaire, they were submitted to screening with cervical cytology and high-risk HPV testing with Hybrid Capture 2 (HC2). This report is part of the Latin American Screening (LAMS) study, that comprises centers from Brazil and Argentina, and the data presented herein refer to the Brazilian women evaluated at the cities of Porto Alegre, Sao Paulo and Campinas. Results : from 8,649 women that answered the questionnaire, 8,641 reported previous sexual activity and were included in this analysis. The mean age at the interview was 38.1±11.0 years and the mean age at the first sexual intercourse was