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In 2018, WHO called for global action to eliminate cervical cancer. The complexity of the processes involved in terms of prevention is often underestimated. Low- and middle-income countries do not have a robust healthcare framework to ensure high-quality programs. The present article discusses how fragile healthcare systems are barriers to eliminating cervical cancer, and also reports the experience of a Brazilian prevention program. The article considers how cervical cancer can be interpreted as an indicator of inequality: how women's attitudes and access to care determine an early or late diagnosis, and how strategies combining vaccine and DNA-HPV tests are crucial. New vaccine schemes, the critical analysis of local data, strengthening communication, managing sentinel events, and integrating vaccination and screening data for the health information system are some of the key activities to sustainable improvement in both access and quality of care.

Summary Background Cervical cancer is a preventable disease, and the Brazilian screening is opportunistic and has low impact. The current study evaluated an initiative to organize screening using DNA–HPV testing as a replacement for cytology. Methods This demonstration study examined information from 16 384 DNA–HPV tests for screening in women aged 25–64 years from Indaiatuba city between October 2017–March 2020. The comparison was 20 284 women screened using cytology between October 2014–March 2017. The flowchart indicates the repetition of a negative test in five years. HPV16- and/or HPV18-positive tests and the 12 pooled high–risk HPV-positive tests with abnormal liquid–based cytology were referred for colposcopy. If cytology was negative, the HPV test was repeated in 12 months. The analyses evaluated coverage, age–group compliance, and cancer detected. Findings After 30 months, the coverage projection was greater than 80%. The age compliance for the HPV test was 99.25%, compared to 78.0% in the cytology program. The HPV test program showed 86.8% negative tests and 6.3% colposcopy referrals, with 78% colposcopies performed. The HPV testing program detected 21 women with cervical cancer with a mean age of 39.6 years, and 67% of cancers were early–stage compared to 12 cervical cancer cases detected by cytological screening (p=0.0284) with a mean age of 49.3 years (p=0.0158), and one case of early–stage (p=0.0014). Interpretation Organizing cervical cancer screening using DNA–HPV testing demonstrated high coverage and age compliance in a real–life scenario, and it had an immediate impact on cervical cancer detection at an early–stage. Funding University of Campinas, Indaiatuba City, and Roche Diagnostics.

Objective This paper searches an ideal cone height for stage definition and safe treatment of cervical microinvasive squamous carcinoma stage IA1 (MIC IA1), avoiding excessive cervix resection, favoring a future pregnancy. Methods A retrospective study was performed involving 562 women with MIC IA1, from 1985 to 2013, evaluating cone margin involvement, depth of stromal invasion, lymph vascular invasion, conization height, and residual uterine disease (RD). High-grade squamous lesions or worse detection was considered recurrence. Univariate and multivariate regression analyses were performed, including age, conization technique (CKC, cold-knife, or ETZ, excision of transformation zone), and pathological results. Conization height to provide negative margins and the risk of residual disease were analyzed. Results Conization was indicated by biopsy CIN2/3 in 293 cases. Definitive treatments were hysterectomy (69.8%), CKC (20.5%), and ETZ (9.7%). Recurrence rate was 5.5%, more frequent in older women (p = 0.030), and less frequent in the hysterectomy group (p = 0.023). Age ≥40 years, ETZ and conization height are independent risk factors for margin involvement. For ages Conclusion Conization 10 mm height for women

BackgroundA Brazilian guideline on cervical cancer screening was released in 2011. The objective was to verify changes in screening indicators around this period.MethodsAn audit study which sample was all screening tests performed by the public health system of Campinas city from 2010 to 2016. Variables were absolute tests numbers, excess tests, intervals and results, by age. For trend analysis was used Cochran-Armitage × 2 and linear regression.ResultsWere carried out 62,925 tests in 2010 and 43,523 tests in 2016, a tendency at a reduction (P = 0.001). Excess tests were higher than 50% over the years, with a tendency at a reduction (P P P P = 0.04 andP = 0.001, respectively), and a tendency at an increase in HSIL-CIN3 result (P = 0.02).ConclusionThe proportion of cervical cancer screening tests performed out of the recommendation showed a significant reduction in the period. This indicates a tendency to align cervical cancer screening in Campinas with the standards recommended.

Background: Cervical cancer is a preventable disease and the Brazilian screening is opportunistic without impact. This study aims to evaluate an initiative to organize the screening with DNA–HPV testing replacing the cytology. Methods: This demonstration study considered information from 16 384 DNA–HPV tests for screening in women aged 25–64 years, from Indaiatuba city, between OCT2017–MAR2020. The comparison was 20 384 women screened by cytology between OCT2014–MAR2017. The flowchart indicates the repetition in five years of a negative test. If HPV16 and/or HPV18 positive test refers to colposcopy, and if other 12 pooled high–risk HPV positive with abnormal liquid–based cytology refers to colposcopy too. If cytology negative, repeat HPV test in 12 months. The analyses evaluated coverage, age–group compliance, and cancer detected. Findings: After 30 months working, the coverage projection was more than 80%. The age compliance for the HPV test was 99·25% compared to 77·3% in the cytology program. The HPV test program showed 86·8% of negative tests and 6·3% of colposcopy referrals, with 78% of colposcopies done. The HPV testing program detected 21 women with cervical cancer, mean age of 39·6 years, and 76% of cancer at early–stage, compared to 12 cervical cancer cases detected by cytological screening (p=0·0284), mean age of 49·3 years (p=0·0158), and one case at early–stage (p=0·0014). Interpretation: Organizing the cervical cancer screening with DNA–HPV testing demonstrated high coverage and age compliance in a real–life scenario, with immediate impact on cervical cancer detection at an early stage. Funding: University of Campinas, Indaiatuba City, and Roche Diagnostics. Declaration of Interest: None to declare. Ethical Approval: This study was approved by the research ethics committee of the University of Campinas (number 1045580, May 1, 2015).

OBJECTIVE To evaluate the pattern of cervical cancer (CC) diagnosis and outcomes in women under 25. METHODS Thirty-two women younger than 25 years of age treated between 2001 and 2016 were studied and the year, symptom or cytology before diagnosis, time since sexual debut, age group, histology, and stage were considered. Data were compared with older age groups, and survival analysis was performed using a subset of them. RESULTS Thirty-two CC diagnoses (1.5% of all cases) exhibited a positive linear trend (P = 0.075). Driven by cytology, 18 were asymptomatic and 14 were symptomatic (with vaginal bleeding in 11). The mean time since sexual debut was 6.9 years. Advanced stage (44% vs 29%) and adenosquamous histology (12.5% vs 1.7%-5.0%) were higher in younger women. Five-year overall survival rate was 76%, better for squamous cell carcinoma (SCC) (86% vs 43% for other histologies; P = 0.018). There were seven deaths, all within 15 months of diagnosis. Age groups of less than 25 years (53%) and 25-29 years (48.5%) had similar proportions of Stage IA1. CONCLUSION The rate of CC-diagnosed women under 25 years was 1.5% of all cases, exhibiting more advanced stage and non-SCC histology. For asymptomatic women, cytology allowed the diagnosis at an early stage. Being symptomatic and non-SCC was associated with a higher proportion of advanced stages and poor survival.

Background The causal relationship between high-risk (hr) HPV infection and precancerous lesions or cervical cancer has led to the development of strategies to increase screening performance and prevent this cancer. The increased sensitivity of DNA-HPV testing compared to cervical cytology favors DNA-HPV testing as a primary screening test. Cervical cancer screening in Brazil is opportunistic, and this cancer remains a considerable health problem with a high proportion of diagnoses in advanced stages. This paper aims to describe the design and implementation of the Cervical Cancer Screening Program with primary DNA-HPV testing (CCSP-HPV) planned for Indaiatuba City (SP), Brazil; the strategies to achieve higher population coverage; and a study protocol for cost-effectiveness analyses. Methods The CCSP-HPV was designed based on successful guidelines that replaced cervical cytology-based screening by the DNA-HPV test performed at 5-year intervals. The screening will be performed for the female population aged 25-64 years cared for by the public health system and aim to reach 80% coverage after completing the first round. The chosen DNA-HPV test detects 14 hr-HPV types and genotypes HPV-16 and 18. All women with a negative test will be reassessed after five years. Women showing a positive test for HPV-16 and/or 18 will be referred for colposcopy. Those showing the other 12 hr-HPV types will be tested by cytology, and if any abnormality is detected, they will also be referred for colposcopy. The histopathologic evaluation will be reviewed by a pathologist panel and aided by p16 immunohistochemistry. A cost-effectiveness analysis will be performed by a Markov model comparing the cost of the new program and the screening performed by conventional cytology five years prior (2011–2016). Discussion The new screening program is considered a breakthrough for public health regarding cervical cancer, which is the third leading cause of cancer death among Brazilian women. Achieving at least 80% coverage will have the possibility to change this scenario. The proposed program will provide a modern cervical cancer screening method for women, and information about cost-effectiveness will help other similar places support the decision of implementing cervical cancer screening using the DNA-HPV test.

Evidence-based clinical guidelines ensure best practice protocols are available in health care. There is a widespread use of human papillomavirus deoxyribonucleic acid (HPV-DNA) tests in Brazil, regardless of the lack of official guidelines. On behalf of the Brazilian Association for the Lower Genital Tract Pathology and Colposcopy (ABPTGIC, in the Portuguese acronym), a team of reviewers searched for published evidence and developed a set of recommendations for the use of HPV-DNA tests in cervical cancer screening in Brazil. The product of this process was debated and consensus was sought by the participants. One concern of the authors was the inclusion of these tests in the assessment of women with cytologic atypia and women treated for cervical intraepithelial neoplasia (CIN). Testing for HPV is recommended in an organized screening scenario to identify women with precursor lesions or asymptomatic cervical cancer older than 30 years of age, and it can be performed every 5 years. It also has value after the cytology showing atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSILs) as a triage test for colposcopy, in the investigation of other cytological alterations when no abnormal findings are observed at colposcopy, seeking to exclude disease, or, further, after treatment of high-grade cervical intraepithelial neoplasia, to rule out residual disease.O uso de diretrizes clínicas baseadas em evidências visa assegurar as melhores práticas na área de cuidado à saúde. O uso de testes de ácido desoxirribonucleico de papilomavírus humano (DNA-HPV) vem crescendo e se disseminando sem que existam recomendações de uso no cenário brasileiro. Em nome da Associação Brasileira de Patologia do Trato Genital Inferior e Colposcopia (ABPTGIC), grupos de revisores pesquisaram evidências e formularam recomendações para o uso dos testes de DNA-HPV no rastreamento do câncer do colo do útero, no seguimento de mulheres com atipias citológicas, e após tratamento de neoplasia intraepitelial cervical (NIC). O produto desse processo foi debatido e foi buscado consenso entre participantes. Os testes de DNA-HPV são recomendados num cenário de rastreamento organizado para identificação de mulheres portadoras de lesões precursoras ou câncer assintomático com mais de 30 anos e podem ser realizados a cada 5 anos. Também têm valor após a citologia mostrando células escamosas atípicas de significado indeterminado (ASC-US) ou lesão intraepitelial escamosa de baixo grau (LSIL) como teste de triagem para colposcopia, na investigação de outras alterações citológicas quando não são observados achados anormais à colposcopia, buscando excluir doença, ou, ainda, no seguimento após tratamento das neoplasias intraepiteliais de alto grau, para exclusão de doença residual.

Cervical cancer is the third leading cancer in Brazil and national screening program targets women from 25 to 64 years, with the Papanicolaou (Pap) test as the standard method. A few countries or medical associations recommend the start of the screening at age 21, a policy that remains controversial, for the higher risk of unnecessary treatment and morbidities related. Previous studies reported that 1% of the cases diagnosed before the age of 25. The aim of this study is to assess evolution of cases diagnosed among females younger than 25 years old in a regional hospital and their evolution. Cases selected were diagnosed from 2001 to 2015 and medical records were analysed until 2018 in a cohort study, gathering 32 cases (1,6% of 2041 cervical cancer registries, only 2 of them under 20 years old). Data gathered was registered and survival was measured by Kaplan-Meier estimates. There was an increasing trend of cervical cancers (p=0,04), with a higher rate of adenocarcinomas (19%) and stage I cancers (56%). Five-year overall survival rate was 76%, with worse rates among females under 22 years old (66% vs. 82%) and adenocarcinomas (43% vs. 86%). Survival rates between stage I cancer were 100%, in contrast with 46% observed in advanced stages. Therefore, although less frequent, cervical cancer in younger females tend to rise; these findings also suggest a higher rate of adenocarcinoma, with worse survival rates in this histological type and in advanced clinical stages.

Objectives To evaluate the prognosis of hysterectomy post-radiotherapy in women with endocervical adenocarcinoma from a university hospital (Unicamp/Brazil), compared to those undergoing exclusive radiotherapy. Methods Were selected 80 cases of women with endocervical adenocarcinomas FIGO IB to IIIB from 1988–2015, 39 treated with radiotherapy followed by hysterectomy and isolated radiotherapy for 41. Disease-free interval (DFI) and overall survival (OS) were analysed using Kaplan-Meier curves and log-rank test. Results There was no difference in OS between the groups (P=0.579) or in the DFI (p=0.963). It was observed that the DFI in patients with residual disease was lower, however without statistical significance (P=0.072). Recurrences were observed in 9/39 patients of the hysterectomy group and 10/41 patients of the isolated radiotherapy group. Residual disease in the hysterectomy group was associated with a higher rate of local and distance recurrence (P=0.028). Conclusions There were no differences in recurrence rates, disease-free interval, and overall survival among the groups, although the detection of residual disease in the hysterectomy was associated with a higher occurrence of recurrences. The findings do not support the routine hysterectomy in women previously irradiated in endocervical adenocarcinoma.

Objectives To evaluate outcomes related to nephrostomy in women before and after cervical cancer treatment for acute obstructive renal failure. Methods Were included 52 cases of women with cervical cancer IIIB+ and acute obstructive renal failure that have undergone nephrostomy at the University Women’s Hospital of Unicamp (Campinas, Brazil), from 2003 to 2017. Two groups were evaluated: before and after radiotherapy treatment (BR and AR). Variables were analyzed by frequencies and survival by Kaplan-Meier curves and log-rank. Results The mean age was 47.8 years old (ST 13.4), and the mean urea and creatinine before the procedure were respectively 134.8 and 13.2 (ST 76.9 and 29.7). Average days of hospitalization were 25 days. After three years of the procedure, 56% of the women in BR and 100% of the women in AR were dead (p=0.047). The six-months overall survival after nephrostomy was 46.4 in BR and 14.8 in AR, while the one-year overall survival was 19.3 in BR and 3.7 in AR (log-rank three-year overall survival P=0.007). Conclusions Nephrostomy for acute renal failure due to cervical cancer is associated with prolonged hospitalization regardless of the stage of the treatment. Overall survival was low in both groups, but higher in women in the BT procedure. Although nephrostomy might be considered useful in treatment-naive patients with obstructive renal failure, the validity of this type of treatment in the group of women that had already undergone treatment is not yet defined.

Objective: To evaluate the indication and performance of systematic lymphadenectomy (SL) in Stage I endometrioid endometrial carcinoma (EEC), at intermediate risk (FIGO IAG2/G3, IBG1/G2) on recurrence, disease-free survival (DFS) and survival. Study design: 194 women underwent hysterectomies by laparotomy, with SL (n = 95) or without SL (n = 99) between 1990 and 2014 was evaluated. Diagnosis period, age, BMI, comorbidities, stage, and adjuvant radiotherapy were analyzed. DFS and cancer-specific survival were analyzed by Kaplan-Meier and log-rank test, and recurrences by Cox regression. Results: SL was performed in 93% (41/44) of women managed before 1998 and decreasing after that (p

Population-based screening programs have reduced significantly cervical cancer burden in high-income countries over the past few decades. Low- and middle-income countries have failed to show a major impact on cervical cancer control, even in settings where cytology- or visual inspection-based screening activities are ongoing. Widespread use of HPV vaccine is the most promising strategy to avoid disease development. Nevertheless, a vaccine population-based approach is still limited to some settings, and the impact of mass vaccination is not expected for some time. In 2016 the American Society of Clinical Oncology issued a stratified guideline addressing global resources disparities. The goal of this chapter is to debate challenges from low- and middle-income countries to implement successful cervical cancer screening programs in order to reduce cancer burden. The feasibility for introduction of new technologies, like the HPV-DNA-based tests, will be analyzed according to the different scenarios. This intends to be a critical review addressing aspects of organization of screening programs in the view of global disparities.

Cervical adenocarcinoma is associated with a poor prognosis, which may be caused by the infiltrative growth pattern and metastasis of tumor cells. There is a lack of consensus on hysterectomy after radiotherapy for the improvement of selected cases. The present study aimed to assess the oncological outcome of post-radiotherapy hysterectomy in females with cervical adenocarcinoma. A total of 39 females with cervical adenocarcinoma at stages IB1 to IIIB, managed primarily with radiotherapy with complete response, and underwent extrafascial hysterectomy as consolidation therapy between 1988 to 2015 were studied. Surgery complications and residual disease were evaluated. A comparison group was constructed, comprising 41 females with cervical adenocarcinoma managed with exclusive radiotherapy or chemoradiotherapy demonstrating complete response, without surgery. Descriptive and survival analysis was performed. The groups were comparable in terms of age, cancer stage, radiotherapy (dose and duration) and follow-up, although 67% of hysterectomies were performed prior to 2002 and 46% of the radiotherapy group received chemoradiation. Late complications were similar. There were nine recurrences (23%) in the case series and 10 recurrences (24%) in the radiotherapy group. Residual disease was detected in 56% (22/39) of uterine specimens, of which 12 were up to 10 mm. Residual disease was associated with recurrence (31% vs. 6%, P=0.028). The overall survival rate was 75% for the case series vs. 88% for the radiotherapy group (P=0.579), and the disease-free survival rate was 79-80% for both. Removal of residual disease by hysterectomy did not improve the overall survival rate (P=0.283) and disease-free survival rate (P=0.072). Post-radiotherapy hysterectomy in cervical adenocarcinoma is a feasible procedure with acceptable complications, however, it did not bring relevant benefits in recurrences, disease-free survival, and overall survival rates.

ObjectivesTo evaluate pathologic features with implications on surgical radicality in women treated with radical hysterectomy and pelvic lymphadenectomy for cervical cancer stage IA1 with lymph vascular space invasion (LVSI) and stage IA2 by correlating findings in conization and hysterectomy specimens.MethodsWomen with cervical cancer stage IA1 with LVSI and stage IA2 diagnosed by loop electrosurgical excisional procedure or cold knife conization were treated with radical hysterectomy and pelvic lymphadenectomy from January 1999 to December 2011 in 2 institutions.ResultsFifty patients were enrolled: 40 with stage IA2 and 10 with stage IA1 with LVSI. Median age was 43 (30–67) years. All patients underwent cervical conization for diagnosis (45 loop electrosurgical excisional procedure, 5 cold knife). Lymph vascular space invasion was detected in 15 patients (30%). Two patients had positive pelvic nodes. No parametrial involvement was detected in the entire cohort. Positive margins were present in 35 patients, and residual disease was detected in 22 patients (44%). Positive margins predicted residual disease at radical hysterectomy (P = 0.02). Medium follow-up time was 51 months. One patient developed a pelvic recurrence, and there were no disease-related deaths.ConclusionsPatients with positive margins in cone biopsy specimens have an increased risk of residual disease at radical hysterectomy and require careful evaluation before conservative surgery. Pelvic lymph node evaluation is essential because lymph node metastasis may occur even in early stages. The lack of parametrial invasion in this study reinforces the knowledge that the select group of patients with microinvasive cervical carcinoma stages IA1 LVSI and stage IA2 have a very low risk of parametrial infiltration. Less radical surgery can be carefully considered for these patients.

To assess the value of vaginal screening cytology after hysterectomy for benign disease.This cross-sectional study used cytology audit data from 2,512,039 screening tests in the metropolitan region of Campinas from 2000 to 2012; the object was to compare the prevalence of abnormal tests in women who had undergone a hysterectomy for benign diseases (n=53,891) to that of women who had had no hysterectomy. Prevalence ratios (95% confidence intervals, 95% CI) were determined, and chi-square analysis, modified by the Cochrane-Armitage test for trend, was used to investigate the effects of age.The prevalence of atypical squamous cells (ASC), low-grade squamous intraepithelial lesion (LSIL), and high-grade squamous intraepithelial lesion or squamous-cell carcinoma (HSIL/SCC) was 0.13%, 0.04% and 0.03%, respectively, in women who had undergone hysterectomy, and 0.93%, 0.51% and 0.26% in women who had not undergone hysterectomy. The prevalence ratios for ASC, LSIL and HSIL/SCC were 0.14 (0.11-0.17), 0.08 (0.06-0.13) and 0.13 (0.08-0.20), respectively, in women with a hysterectomy versus those without. For HSIL/SCC, the prevalence ratios were 0.09 and 0.29, respectively, for women50 or ≥50 years. The prevalence rates in women with a previous hysterectomy showed no significant variation with age.The prevalence rates of ASC, LSIL and HSIL/SCC were significantly lower in women with a previous hysterectomy for benign disease compared with those observed in women with an intact uterine cervix. This study reinforces the view that there is no evidence that cytological screening is beneficial for women who have had a hysterectomy for benign disease.

Drug abuse (addiction) has been listed among the risk factors for human papillomavirus (HPV) infections, but no case-control studies exist to rule out sexual behaviour and other potential confounders. The aim of this study is to evaluate the role of drug addiction as an independent predictor of HR-HPV infections and (cervical intraepithelial neoplasia) CIN2+ in an age-matched case-control (1:4) study nested within the prospective Latin American Screening (LAMS) study cohort. All 109 women in the LAMS cohort (n=12,114) reporting drug abuse/addiction were matched with four controls (n = 436) of non-abusers strictly by age. Conditional logistic regression analysis was used to estimate the co-variates of drug abuse, and the whole series (n=545) was analysed for predictors of HR-HPV and CIN2+ using univariate and multivariate regression models. Oncogenic HPV infections were significantly (P=0.019) more prevalent among abusers (37.7%) than in controls (21.9%), but there was no difference in high-grade squamous intraepithelial lesions (P=0.180) or CIN2+ lesions (P=0.201). In multivariate conditional logistic regression, number of lifetime sexual partners (P=0.0001), ever smokers (P=0.0001), non-use of OCs (P=0.013), ever having sexually transmitted diseases (STD) (P=0.041) and no previous Pap smear (P=0.027) were independent co-variates of drug addiction. Drug abuse was not an independent risk factor of high-risk (HR)-HPV infection, which was significantly predicted by (1) age below 30 years (P=0.045), (2) more than five lifetime sexual partners (P=0.046) and (3) being current smoker (P=0.0001). In multivariate model, only HR-HPV infection was an independent risk factor of CIN2+ (P=0.031), with adjusted OR=11.33 (95% CI 1.25-102.50). These data indicate that drug addiction is not an independent risk factor of either HR-HPV infections or CIN2+, but the increased prevalence of HR-HPV infections is explained by the high-risk sexual behaviour and smoking habits of these women., European Commission (LAMS denotes Latin American Screening study funded by European Commission), INCO-DEV Programme (Contract No. ICA4-CT-2001-10013). The generous contribution of DIGENE Inc. (USA) donating the HCII tests at our disposal is gratefully acknowledged

The objective of the study was to investigate the expression of p53 and p16INK4ain cervical intraepithelial neoplasia (CIN) and their relation with disease severity and high-risk human papillomavirus (HR-HPV) status. A series of 125 women with previous positive Pap smear were selected for this cross-sectional study. All patients underwent gynecological examination, including colposcopy. Specimens for Pap smears, Hybrid Capture 2 (HC2) test, and pathologic analysis were obtained. After evaluation of CIN grade, immunohistochemical detection of proteins p53 and p16INK4awas performed on paraffin-embedded sections. The extent of immunoexpression of both proteins was analyzed in relation to CIN grade and HR-HPV status. CIN was graded as 1 in 21, 2 in 17, and 3 in 87 specimens. p16INK4apositivity (at least 5% of epithelial cells stained) was found in 99 of 125 cases (79.2%) and was significantly higher in high-grade lesions as compared to low-grade CIN (P< 0.001). The expression of p53 did not differ across histologic strata. Protein expression neither of p16INK4anor of p53 correlated with HR-HPV status. Expression of p16INK4awas not related with that of p53. Our study gives further support to previous findings of strong association of p16INK4aimmunostaining with severity of epithelial atypia, but this protein may not be considered a predictor of HR-HPV status determined with HC2. By contrast, immunoexpression of p53 was related neither to CIN grade nor to HR-HPV status.

ObjectiveThe objective of this study was to evaluate the impact of cervical cytology screening on the prevalence of cervical cytological results in women, as a function of age and test interval.MethodsThis is a cross-sectional study of cytology screening data of 2,002,472 tests obtained from previously screened women and 217,826 tests from unscreened women. The central cytopathology laboratory database was analyzed. The tests were collected for screening purposes from Campinas metropolitan region, Brazil. A prevalence ratio (PR) with a 95% confidence interval was calculated for the screened women, in relation to the unscreened women, and for different tests intervals. Protection afforded by screening (1-PR) was calculated.ResultsFor high-grade squamous intraepithelial lesion, the PR was 0.97 (0.83–1.13) for women aged 20 years or younger and 0.99 (0.86–1.14) for women aged 20 to 24 years, decreasing significantly in women aged 25 to 29 years (PR, 0.63 [0.52–0.76]). The PR for squamous cell carcinoma, adenocarcinoma in situ (AIS), and invasive adenocarcinoma showed a significant reduction in all age groups older than 30 years. For the age group ranging from 30 to 59 years, protection for squamous cell carcinoma, AIS, and invasive adenocarcinoma was 83% or higher for screening intervals from 1 to 5 years. Protective effect was not demonstrated for screening intervals longer than 5 years for AIS and invasive adenocarcinoma.ConclusionsCytology screening is effective at preventing cytological high-grade squamous intraepithelial lesion, squamous cell carcinoma, AIS, and invasive adenocarcinoma. On the basis of cytological results, protection against AIS and invasive adenocarcinoma was observed with screening intervals shorter than 5 years. Cytological screening in women 25 years or younger should be critically evaluated.

This study was conducted to evaluate 3 different methods, used alone or in combination, of screening for cervical intraepithelial neoplasia (CIN), and to compare the outcomes with colposcopic findings. Eight hundred nine patients were recruited to undergo cervical screening with visual inspection of the cervix using acetic acid (VIA), human papillomavirus (HPV) testing using hybrid capture II (HCII), and conventional Pap smear. Social and demographic information and clinical history were obtained at the enrollment visit by interview and questionnaire before pelvic examination. After collection of Pap and HCII samples, VIA was conducted 1 minute after application of 5% acetic acid to the cervix. Cervical abnormalities were recorded according to the Atlas of Visual Inspection. The presence of areas suggestive of condyloma, CIN 1, CIN 2, CIN 3, or cancer was recorded as positive VIA results. All patients underwent colposcopy after pelvic examination, and suspicious areas were biopsied. There were 99 (12%) patients with positive VIA results, of which 28% were suspected condyloma, 57% were thought to be CIN 1, 13% were suspicious for CIN 2/3, and one was a potential case of invasive cancer. In all, there were 57 (7%) positive Pap smear results, including 22 atypical squamous cells of undetermined significance (ASCUS) (38% of abnormalities), 20 low-grade squamous intraepithelial lesions (LSIL) (35%), 14 high-grade intraepithelial lesions (HSIL) (25%), and one diagnosis of atypical glandular cells (AGC) (2%). One smear was inadequate for evaluation. HPV testing identified 151 (19%) patients positive for high-risk HPV. In the final histologic diagnoses, 40 (5%) women had cervical neoplasia, including 29 CIN 1, 7 CIN 2, 3 CIN 3, and one invasive cancer. The sensitivity and specificity for each test alone or in combination are shown in Tables 1 and 2. For identifying CIN 2 or worse, HCII had the highest sensitivity (73%) and Pap smear was the most specific (93%). Together, Pap and HCII had the highest sensitivity (82%) for detection of CIN 2 or worse. The highest specificity was seen in the combination of VIA and Pap smear (83%).

To assess the prediction potential of a 5-biomarker panel for detecting high-risk human papillomavirus (HR-HPV) infections and/or cervical intraepithelial neoplasia (CIN) progression. Five biomarkers, lipocalin, plasminogen activator inhibitor-2, p300, interleukin-10, and stratifin, were assessed in cervical biopsies from 225 women of the Latin American Screening Study. Competing-risks regression models were constructed to assess their predictive power for (i) HR-HPV outcomes (negative, transient, or persistent infection) and (ii) CIN outcomes (no progression, incident CIN1, CIN2, or CIN3). p300, LCN2, stratifin were significantly associated with prevalent HR-HPV but lost their significance in multivariate analysis. In the multivariate model, only p300 was an independent predictor of CIN3 (odds ratio=2.63; 95% confidence interval, 1.05-6.61; P=0.039). In univariate competing-risks regression, lipocalin predicted permanent HR-HPV-negative status, but in the multivariate model, IL-10 emerged as a independent predictor of HPV-negative status (subhazard ratio=4.04; 95% confidence interval, 1.81-9.01; P=0.001). The clinical value of the panel in predicting longitudinal outcomes of HR-HPV infection and/or incident CIN is limited., Supported by the European Commission, INCO-DEV Programme (Contract# ICA4-CT-2001-10013).

Objective To evaluate the performance of mesothelin, CA125, HE4 and ROMA index in the detection of malignant ovarian tumors. Study Design This is a cross-sectional study including 199 women with adnexal masses (67 with malignant tumors and 132 with benign tumors) and 150 healthy women (controls). We used a recursive multivariate partitioning algorithm to assess the contribution of each of the serum markers and the ROMA index to the discrimination of women with malignant tumors. Also, the areas under the ROC curves (AUC) for each of the serum markers and for the ROMA index were compared using the Venkatraman's projection-permutation test. Results In the recursive model, CA125 had the best performance in discriminating women with malignant tumors. In women with normal-range CA125 levels, none of the other markers contributed to the discrimination of women with malignant tumors. In women with elevated CA125 levels, elevated HE4 levels were associated with an increased risk of harboring a malignant tumor. The AUC for mesothelin was smaller than that for all the other curves, and both the ROMA index and CA125 had better AUC than HE4. Conclusion In women with normal CA125 levels, neither mesothelin nor HE4 contributed to discriminate women with malignant ovarian tumors; however, for women with elevated CA125 levels HE4 may help discriminating those who have a malignant ovarian tumor.

To examine the effect of smoking on the incidence of low- and high-grade cervical intraepithelial neoplasia (CIN) in women with a baseline Pap smear of atypical squamous cells (ASC) or a low-grade squamous intraepithelial lesion (LSIL). Objective. To examine the effect of smoking on the incidence of low‐ and high‐grade cervical intraepithelial neoplasia (CIN) in women with a baseline Pap smear of atypical squamous cells (ASC) or a low‐grade squamous intraepithelial lesion (LSIL). Design. Prospective study in which a cohort of women with normal colposcopy and ASC/LSIL at baseline were followed at 6‐month intervals of up to 36 months. Women were grouped in post‐hoc analysis according to their smoking behavior: never (or past) smokers and current smokers. Setting. This report was based on data from the Latin American Screening Study, conducted in São Paulo, Campinas, Porto Alegre (Brazil) and Buenos Aires (Argentina). Population. A subset of 150 women derived from a cohort of 1,011 women. Methods. Multivariate Cox analysis and Kaplan–Meier curves were used. Main outcome measures. Low‐ and high‐grade CIN during follow‐up. Results. The only factor related to an increased risk of developing CIN was the positive high‐risk (hr) HPV status (hazard ratio (HR) = 3.42; 95% CI: 1.11–9.43). A total of 21 cases of incident CIN were detected during follow‐up. Of these, 11 appeared in the group of 67 smokers and 10 among the 83 non‐smoker women (log‐rank, p = 0.33). Smoking status was not associated with the risk of developing CIN (HR = 0.73; 95% CI: 0.40–1.33). However, when restricting the analysis to high‐grade CIN only (11 cases), the probability of developing the disease was significantly higher among smokers (p = 0.04). Conclusions. Smoking contributes additional risk for developing high‐grade CIN in women with ASC or LSIL cytology but normal colposcopy., LAMS (Latin American Screening) study, entitled: Improving health systems towards equality‐based control of cervical cancer in Latin America, and supported by the Inco‐Dev Program of the European Commission (Project No. ICA4‐CT‐2001‐10013). The contribution of Digene Inc. (USA)

To assess whether human papillomavirus (HPV) testing is a safe enough approach to warrant extension of the screening intervals of baseline Papanicolaou (Pap)-/HPV- women in low-income settings., European Commission, INCO-DEV Programme (Contract # ICA4-CT-2001-10013). The generous contribution from DIGENE Inc. (USA) donating the HC 2 tests

Hybrid capture II (HC II) test for oncogenic human papillomaviruses (HPV) was carried out in a cohort of 4284 women at their first clinical visit. Overall prevalence of HPV was 17.1%, decreasing with age from 33.9% among women below 20 years to only 11.0% among those older than 41 years. HPV prevalence was significantly higher among current smokers (odds ratio [OR] = 1.31; 95% CI 1.1–1.6), in women with two or more lifetime sexual partners (OR = 1.9; 95% CI 1.6–2.4), and those women with two or more sexual partners during the past 12 months prior to examination (OR = 1.6; 95% CI 1.2–2.2). HPV detection increased in parallel with increasing cytologic abnormality, being highest in women with high-grade squamous intraepithelial lesion (P = 0.001). Specificity of the HPV test in detecting histologically confirmed cervical disease was 85% (95% CI 83.9–86.1). Sensitivity of the HPV test in detecting histologic abnormalities increased in parallel with disease severity, ranging from 51.5% for cervical intraepithelial neoplasia (CIN) 1 to 96.5% for CIN 3 and 100.0% for cancer, with respective decline of positive predictive value. These data suggest that HPV testing with HC II assay might be a viable screening tool among this population with relatively high prevalence of cervical disease.

Objective To assess the role of HPV as determinant of the incident cytological abnormalities (SIL) and cervical lesions (CIN) during a 24-month follow-up of baseline PAP smear-negative subgroup of women included in the Latin American Screening study (LAMS). Study design A group of 365 women with normal Pap smear and negative or positive high-risk Hybrid Capture II test were prospectively followed-up for 24 months at Campinas and São Paulo (Brazil). The incidence rate (IR) and risk ratio (RR and 95% CI) of developing cytological or histological abnormality during the follow-up was calculated for HPV-negative and HPV-positive women. Results During the 12-month follow-up, women HPV-positive at baseline had developed a significantly higher rate of incident LSIL (IR = 3.5%, RR = 1.4; 95% CI 1.1–1.7) and HSIL (IR = 0.7%, RR = 1.5; 95% CI 1.4–1.7) abnormality. For HSIL, the IR increased to 2.1% and the RR increased to 1.7 (95% CI 1.5–1.9) among those followed for 24 months. Similarly, women with positive HPV tests were at a higher risk of developing CIN 2–3 (IR = 2.6%, RR = 1.5; 95% CI 1.4–1.6) during the first 12 months of follow-up, and for those followed for 24 months, this RR increased further to 1.7 (95% CI 1.5–1.9) although the IR was 0.7%. Conclusions Oncogenic HPV infections comprise a significant risk factor for incident cervical abnormalities, and HPV test is a useful adjunct to cytology in detecting the high-risk patients among baseline PAP smear-negative women., This study was funded by European Commission, INCO DEV Contract #ICA4-CT-2001-10013.

Objectives: To assess the performance indicators of visual inspection with acetic acid (VIA) and visual inspection with Lugol's 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.

Objectives: We compared the indication of laparoscopy for treatment of adnexal masses based on the risk scores and tumor diameters with the indication based on gynecology-oncologists' experience. Methods: This was a prospective study of 174 women who underwent surgery for adnexal tumors (116 laparotomies, 58 laparoscopies). The surgeries begun and completed by laparoscopy, with benign pathologic diagnosis, were considered successful. Laparoscopic surgeries that required conversion to laparotomy, led to a malignant diagnosis, or facilitated cyst rupture were considered failures. Two groups were defined for laparoscopy indication: (1) absence of American College of Obstetrics and Gynecology (ACOG) guideline for referral of high-risk adnexal masses criteria (ACOG negative) associated with 3 different tumor sizes (10, 12, and 14 cm); and (2) Index of Risk of Malignancy (IRM) with cutoffs at 100, 200, and 300, associated with the same 3 tumor sizes. Both groups were compared with the indication based on the surgeon's experience to verify whether the selection based on strict rules would improve the rate of successful laparoscopy. Results: ACOG-negative and tumors ≤10 cm and IRM with a cutoff at 300 points and tumors ≤10cm resulted in the same best performance (78% success = 38/49 laparoscopies). However, compared with the results of the gynecology-oncologists' experience, those were not statistically significant. Discussion: The selection of patients with adnexal mass to laparoscopy by the use of the ACOG guideline or IRM associated with tumor diameter had similar performance as the experience of gynecology-oncologists. Both methods are reproducible and easy to apply to all women with adnexal masses and could be used by general gynecologists to select women for laparoscopic surgery; however, referral to a gynecology-oncologist is advisable when there is any doubt.

OBJETIVO: avaliar a contribuicao da inspecao visual com acido acetico e da captura hibrida II como metodos adjuntos a colpocitologia oncologica na deteccao das lesoes precursoras ou câncer cervical. SUJEITOS E METODOS: realizou-se inicialmente um estudo descritivo de corte transversal e posteriormente validacao de teste diagnostico. Foram incluidas 809 mulheres (18 a 64 anos) atendidas no Centro de Atencao Integral a Saude da Mulher da Universidade Estadual de Campinas, de janeiro de 2002 a julho de 2003. Na primeira consulta, as mulheres responderam a um questionario pre-estruturado e todas foram submetidas a exame ginecologico que consistiu em coleta de material para olpocitologia oncologica com espatula de Ayres e escova endocervical; coleta de material para deteccao de papilomavirus humano de alto risco oncogenico por captura hibrida II; inspecao visual, com aplicacao de acido acetico a 5% e colposcopia com biopsia dirigida das areas anormais. Para avaliar a associacao entre o resultado de cada exame de rastreamento e o resultado da colposcopia foi calculada a razao de prevalencia com intervalo de confianca a 95%. Para avaliar o desempenho dos exames de rastreamento na deteccao de lesao histologica foram calculadas a sensibilidade e a especificidade, assim como os valores preditivos positivo e negativo de cada metodo, considerando o padrao-ouro sem doenca, a colposcopia normal ou biopsia sem lesao induzida pelo papilomavirus humano e, com doenca, biopsia NIC 1 ou mais. Em uma primeira analise avaliou-se o desempenho dos testes para a deteccao de qualquer lesao histologica induzida pelo papilomavirus humano e posteriormente este calculo foi realizado para NIC 2 ou mais. RESULTADOS: das 809 mulheres avaliadas, 12% apresentavam inspecao visual com acido acetico anormal, 19% tinham captura hibrida II positiva e 7% apresentaram alteracoes na colpocitologia oncologica. Cento e quatorze mulheres (14,7%) foram submetidas a biopsia e, destas, 39 (4,8%) apresentaram lesoes associadas com papilomavirus humano, sendo que 12 apresentavam neoplasia intra-epitelial cervical 2 ou mais. Houve uma associacao estatisticamente significativa entre os exames de rastreamento e a colposcopia, sendo a melhor associacao encontrada com a inspecao visual com acido acetico. Em relacao ao desempenho dos exames pode se observar que com sensibilidade maior que 70% para lesao histologica e especificidade de 91%, a inspecao visual com acido acetico apresentou melhor desempenho como metodo isolado na deteccao de neoplasia intra-epitelial 1 ou mais. A sensibilidade da captura hibrida foi maior para a deteccao de neoplaisia intra-epitelial 2 ou mais. A especificidade da colpocitologia oncologica foi superior a dos outros dois metodos para lesoes de baixo e alto graus, embora sua sensibilidade tenha sido significativamente inferior. Ao avaliar a associacao dos diferentes metodos de rastreamento considerando-se sempre pelo menos um positivo, observou-se que a associacao da inspecao visual a colpocitologia oncologica aumentou significativamente a deteccao de doenca histologica sem perda significativa da especificidade. A sensibilidade da associacao dos tres metodos para o diagnostico de neoplasia intra-epitelial 1 ou mais foi significativamente melhor do que a da colpocitologia oncologica isoladamente ou associada a inspecao visual com acido acetico. Ja para a deteccao de lesoes de alto grau, a associacao da captura hibrida a colpocitologia oncologica foi o metodo que apresentou melhor sensibilidade sem perda na especificidade. CONCLUSAO: A inspecao visual com acido acetico contribuiu significativamente na deteccao de doenca histologica, embora a associacao da colpocitologia oncologica e captura hibrida tenha sido o melhor metodo para deteccao de lesoes de alto grau. Abstract

OBJETIVO: avaliar o desempenho da citologia oncológica (CO), de captura híbrida II (CH II) e da inspeção visual com ácido acético na detecção de lesões pré-neoplásicas e neoplásicas cervicais. MÉTODOS: 2281 mulheres foram submetidas a exame clínico além da coleta de material para citologia, para CH II para detecção de DNA-HPV. Foi feita a inspeção visual do colo após aplicação do ácido acético a 5% (IVA). As mulheres com pelo menos um exame positivo eram convocadas para colposcopia, que também foi realizada em 420 mulheres com todos os exames normais. O desempenho dos testes foi calculado utilizando como padrão ouro a colposcopia com ou sem biopsia. RESULTADOS: a CO foi anormal em 209 mulheres (9,2%); a CH II foi positiva em 399 (17,5%) e em 249 (10,9%) foram encontradas alterações na IVA. Entre as 2281 mulheres avaliadas, 671 (29,4%) apresentaram pelo menos um resultado de exame positivo, embora apenas 82 (3,6%) apresentassem doença confirmada histologicamente (50 NIC1, 20 NIC2, sete NIC3 e cinco carcinomas invasores). As sensibilidades da IVA e da CH II foram semelhantes e significativamente maiores que a da CO. A especificidade da CO foi maior que a da IVA e da CH II. Nos casos com resultado de CO negativo, a IVA apresentou melhor desempenho comparada à CH II. CONCLUSÃO: o desempenho da CO associada à IVA foi melhor que o da CO associada à CH II e do que o da CO isolada. OBJECTIVE: to evaluate the performance of Pap smear, hybrid capture II (HC II), and visual inspection with acetic acid in the detection of pre-invasive and invasive cervical lesions. METHODS: a total of 2281 women were submitted to a clinical exam, including Pap smear, HC II for HPV DNA detection and visual inspection with 5% acetic acid (VIA). When at least one of the tests was positive, colposcopy was performed and targeted biopsies were taken from suspicious lesions. Colposcopy was also performed in 420 women with negative results. Test performance was evaluated, using colposcopy as the gold standard, with or without biopsy. RESULTS: Pap smear, VIA and HC II were positive in 9.2, 10.9 and 17.5% of all women screened, respectively. Although at least one positive test was found in 671 women (29.4%), only 82 (3.6%) presented histologically confirmed disease (50 NIC1, 20 NIC2, 7 NIC3, and 5 invasive carcinoma). VIA and HC II sensitivities were similar and significantly higher than Pap smear. Pap smear showed better specificity than VIA and than HC II. In women with a negative Pap smear result, VIA showed better performance than HC II. CONCLUSION: Pap smear combined with VIA performed better than Pap smear combined with HC II or than Pap smear alone.