Cervical Intraepithelial Neoplasia grade 2 biopsy: Do p16INK4a and Ki-67 biomarkers contribute to the decision to treat? A cross-sectional study

ABSTRACT BACKGROUND: Managing cervical intraepithelial neoplasia grade 2 (CIN2) is challenging, considering the CIN2 regression rate, perinatal risks associated with excisional procedures, and insufficient well-established risk factors to predict progression. OBJECTIVES: To determine the ability of p16INK4a and Ki-67 staining in biopsies diagnosed with CIN2 to identify patients with higher-grade lesions (CIN3 or carcinoma). DESIGN AND SETTING: Cross-sectional study conducted at a referral center for treating uterine cervical lesions. METHODS: In 79 women, we analyzed the correlation of p16INK4a and Ki-67 expression in CIN2 biopsies with the presence of a higher-grade lesions, as determined via histopathology in surgical specimens from treated women or via two colposcopies and two cytological tests during follow-up for untreated women with at least a 6-month interval. The expression of these two biomarkers was verified by at least two independent pathologists and quantified using digital algorithms. RESULTS: Thirteen (16.8%) women with CIN2 biopsy exhibited higher-grade lesions on the surgical excision specimen or during follow-up. p16INK4a expression positively and negatively predicted the presence of higher-grade lesions in 17.19% and 86.67% patients, respectively. Ki-67 expression positively and negatively predicted the presence of higher-grade lesions in 40% and 88.24% patients, respectively. CONCLUSIONS: Negative p16INK4a and Ki67 immunohistochemical staining can assure absence of a higher-grade lesion in more than 85% of patients with CIN2 biopsies and can be used to prevent overtreatment of these patients. Positive IHC staining for p16INK4a and Ki-67 did not predict CIN3 in patients with CIN2 biopsies.

Cervical Intraepithelial Neoplasia grade 2 biopsy: Do p16INK4a and Ki-67 biomarkers contribute to the decision to treat? A cross-sectional study.

BACKGROUND: Managing cervical intraepithelial neoplasia grade 2 (CIN2) is challenging, considering the CIN2 regression rate, perinatal risks associated with excisional procedures, and insufficient well-established risk factors to predict progression. OBJECTIVES: To determine the ability of p16INK4a and Ki-67 staining in biopsies diagnosed with CIN2 to identify patients with higher-grade lesions (CIN3 or carcinoma). DESIGN AND SETTING: Cross-sectional study conducted at a referral center for treating uterine cervical lesions. METHODS: In 79 women, we analyzed the correlation of p16INK4a and Ki-67 expression in CIN2 biopsies with the presence of a higher-grade lesions, as determined via histopathology in surgical specimens from treated women or via two colposcopies and two cytological tests during follow-up for untreated women with at least a 6-month interval. The expression of these two biomarkers was verified by at least two independent pathologists and quantified using digital algorithms. RESULTS: Thirteen (16.8%) women with CIN2 biopsy exhibited higher-grade lesions on the surgical excision specimen or during follow-up. p16INK4a expression positively and negatively predicted the presence of higher-grade lesions in 17.19% and 86.67% patients, respectively. Ki-67 expression positively and negatively predicted the presence of higher-grade lesions in 40% and 88.24% patients, respectively. CONCLUSIONS: Negative p16INK4a and Ki67 immunohistochemical staining can assure absence of a higher-grade lesion in more than 85% of patients with CIN2 biopsies and can be used to prevent overtreatment of these patients. Positive IHC staining for p16INK4a and Ki-67 did not predict CIN3 in patients with CIN2 biopsies.

Conventional cytologic diagnosis of human papillomavirus-induced anal intraepithelial neoplasia: The experience of a referral center in Rio de Janeiro, Brazil.

BACKGROUND: Screening of anal cancer is rarely available or performed in Brazil. This study analyzes the diagnostic performance of conventional cytology (CC) in the prevention of anal cancer in a coloproctology and gynecology outpatient clinics in a public hospital in Rio de Janeiro, Brazil. METHODS: From 2005 to 2017, 1066 conventional cytological samples were collected. We analyze the causes of unsatisfactory samples (11.3%) and compare the cytological diagnoses of 83 samples from persons living with HIV and persons not living with HIV and in specific situations, using as the gold standard high-resolution anoscopy or histopathology in cases biopsied within 6 months after cytology. RESULTS: The sensitivity of cytology with diagnosis of ASC-US for detection of anal intraepithelial neoplasia of any grade was 85%, specificity was 41%, positive and negative predictive values were 64% and 75%, respectively, and positive and negative likelihood ratios were 1.46 and 0.35, respectively. CONCLUSION: Conventional cytology available in resource-limited settings is a simple, noninvasive, low-cost method that proved feasible for outpatient screening of precursor lesions of the anal canal.

Accuracy of endocervical cytological tests in diagnosing preinvasive lesions of the cervical canal in patients with type 3 transformation zone: a retrospective observational study.

BACKGROUND: Cervical cancer screening in Brazil is done using Pap smears. Women who are most likely to have a preinvasive lesion or cervical cancer are immediately referred for colposcopy. OBJECTIVE: The aim of this study was to evaluate the diagnostic performance of endocervical cytological tests in diagnosing preinvasive cervical lesions in women with initial high-grade squamous intraepithelial lesions (HSIL), or atypical squamous cells in which high-grade lesions could not be ruled out (ASC-H), or atypical glandular cells (AGC), and whose colposcopy did not show any abnormalities, with no fully visible transformation zone (types 2 and 3). DESIGN AND SETTING: Retrospective observational study conducted in Rio de Janeiro, Brazil. METHODS: Data from women who came to the cervical pathology outpatient clinic between January 2012 and April 2017 were analyzed. The results from endocervical cytological tests were compared with the final diagnosis, which was obtained through examination of a surgical specimen or, among women who did not undergo an excisional procedure, after cytological and colposcopic follow-up for two years. RESULTS: We included 78 women. The sensitivity of endocervical cytological tests was 72.7%; specificity 98.5%; positive and negative predictive values 88.9% and 95.6%, respectively; and positive and negative likelihood ratios 48.7 and 0.28. CONCLUSION: Endocervical cytological tests are simple, inexpensive and noninvasive, and form a reliable method for determining management among patients with HSIL, ASC-H and AGC cytological findings and negative colposcopic findings without visualization of the squamocolumnar junction.

[Parameters for programming line of care procedures for cervical cancer in Brazil]. / Parâmetros para a programação de procedimentos da linha de cuidado do câncer do colo do útero no Brasil.

The study estimated parameters for planning and programming the supply of procedures for screening, diagnostic workup, and treatment of precursor lesions of uterine cervical cancer. These estimates were used as the basis for assessing the adequacy of Brazil's production of procedures performed by the Brazilian Unified National Health System (SUS) in 2017. Estimates were calculated using as the reference the recommended management in the national screening guidelines. Data on screening tests were obtained from the Information System on Uterine Cervical Cancer and the follow-up data from patient charts in a referral center for cervical pathology. Brazil's production of procedures was obtained from data in the Outpatient and Hospital Information Systems of the SUS. For every one hundred thousand women in the target age bracket for screening (25 to 64 years) there was an estimated annual need for 44,134 cytopathology tests, 1,886 colposcopies, 275 biopsies, 236 type 1 and 2 outpatient exicision procedures, 236 type 2 and 3 hospital exicision procedures, and 39 high-complexity referrals for surgery, chemotherapy, and/or radiotherapy. Applying the estimated parameters to the number of women screened in Brazil in 2017, a deficit was identified in all the procedures for adequate follow-up of the women with altered test results, varying from 7% in colposcopies to 74% in type 3 excisions. The results point to the need to expand and upgrade the supply of line of care procedures for cervical cancer. The estimated parameters can support policymakers in programming and implementing organized screening programs.

Estimaram-se parâmetros para planejamento e programação da oferta de procedimentos para rastreamento, investigação diagnóstica e tratamento de lesões precursoras do câncer do colo do útero e, com base nessas estimativas, avaliou-se a adequação da produção nacional dos procedimentos realizados pelo Sistema Único de Saúde (SUS) em 2017. As estimativas foram calculadas utilizando como referencial as condutas preconizadas nas diretrizes nacionais para o rastreamento. Os dados referentes aos exames de rastreamento foram obtidos no Sistema de Informação do Câncer do Colo do Útero, e os dados de seguimento, em prontuários médicos de uma unidade de referência em patologia cervical. A produção nacional dos procedimentos foi obtida a partir de dados dos Sistemas de Informações Ambulatoriais e Hospitalares do SUS. Para cada cem mil mulheres na faixa etária alvo do rastreamento (25-64 anos), estimou-se a necessidade anual de 44.134 exames citopatológicos, 1.886 colposcopias, 275 biópsias, 236 excisões tipo 1 e 2 ambulatoriais, 236 excisões tipo 2 e 3 hospitalares e 39 encaminhamentos para alta complexidade para realização de cirurgia, quimioterapia e/ou radioterapia. Aplicando-se os parâmetros estimados ao número de mulheres rastreadas no Brasil em 2017, identificou-se déficit de todos os procedimentos para o seguimento adequado das mulheres com alterações, variando de 7% nas colposcopias a 74% nas excisões tipo 3. Os resultados apontam necessidade de ampliar e qualificar a oferta de procedimentos da linha de cuidado do câncer do colo do útero. Os parâmetros estimados poderão subsidiar gestores na programação e implementação de programas de rastreamento organizado.

Se estimaron parámetros para la planificación y programación de la oferta de procedimientos, con el fin de detectar, realizar investigación diagnóstica y tratar lesiones precursoras del cáncer de cuello uterino. En base a las mismas, se evaluó la adecuación del protocolo nacional de procedimientos realizados por el Sistema Único de Salud (SUS) en 2017. Las estimaciones se calcularon utilizando como marco de referencia los procedimientos recomendados en las directrices nacionales para la detección de este tipo de cáncer. Los datos referentes a los exámenes de detección se obtuvieron en el Sistema de Información del Cáncer de Cuello de Útero, y los datos de seguimiento en registros médicos de una unidad de referencia en patología cervical. La producción nacional de los procedimientos se obtuvo a partir de datos de los sistemas de información ambulatoria y hospitalaria del SUS. De cada cien mil mujeres, en la franja de edad objetivo de la detección (25 a 64 años), se estimó una necesidad anual de 44.134 exámenes citopatológicos, 1.886 colposcopias, 275 biopsias, 236 escisiones tipo 1 y 2 ambulatorias, 236 escisiones tipo 2 y 3 hospitalarias y 39 derivaciones hacia centros hospitalarios de alta complejidad para la realización de cirugías, quimioterapia y/o radioterapia. Aplicando los parámetros estimados al número de mujeres a quienes se les realizó el examen en Brasil durante 2017, se identificó un déficit de todos los procedimientos para un seguimiento adecuado de las mujeres con alteraciones, variando de un 7% en las colposcopias, a un 74% en las escisiones tipo 3. Los resultados apuntan la necesidad de ampliar y dotar la oferta de procedimientos en la línea de cuidados del cáncer de cuello uterino. Los parámetros estimados podrán ayudar a los gestores en la programación e implementación de programas organizados de detección.

Parâmetros para a programação de procedimentos da linha de cuidado do câncer do colo do útero no Brasil / Parameters for programming line of care procedures for cervical cancer in Brazil / Parámetros para la programación de procedimientos en línea con el cuidado del cáncer de cuello uterino en Brasil

Estimaram-se parâmetros para planejamento e programação da oferta de procedimentos para rastreamento, investigação diagnóstica e tratamento de lesões precursoras do câncer do colo do útero e, com base nessas estimativas, avaliou-se a adequação da produção nacional dos procedimentos realizados pelo Sistema Único de Saúde (SUS) em 2017. As estimativas foram calculadas utilizando como referencial as condutas preconizadas nas diretrizes nacionais para o rastreamento. Os dados referentes aos exames de rastreamento foram obtidos no Sistema de Informação do Câncer do Colo do Útero, e os dados de seguimento, em prontuários médicos de uma unidade de referência em patologia cervical. A produção nacional dos procedimentos foi obtida a partir de dados dos Sistemas de Informações Ambulatoriais e Hospitalares do SUS. Para cada cem mil mulheres na faixa etária alvo do rastreamento (25-64 anos), estimou-se a necessidade anual de 44.134 exames citopatológicos, 1.886 colposcopias, 275 biópsias, 236 excisões tipo 1 e 2 ambulatoriais, 236 excisões tipo 2 e 3 hospitalares e 39 encaminhamentos para alta complexidade para realização de cirurgia, quimioterapia e/ou radioterapia. Aplicando-se os parâmetros estimados ao número de mulheres rastreadas no Brasil em 2017, identificou-se déficit de todos os procedimentos para o seguimento adequado das mulheres com alterações, variando de 7% nas colposcopias a 74% nas excisões tipo 3. Os resultados apontam necessidade de ampliar e qualificar a oferta de procedimentos da linha de cuidado do câncer do colo do útero. Os parâmetros estimados poderão subsidiar gestores na programação e implementação de programas de rastreamento organizado.

The study estimated parameters for planning and programming the supply of procedures for screening, diagnostic workup, and treatment of precursor lesions of uterine cervical cancer. These estimates were used as the basis for assessing the adequacy of Brazil's production of procedures performed by the Brazilian Unified National Health System (SUS) in 2017. Estimates were calculated using as the reference the recommended management in the national screening guidelines. Data on screening tests were obtained from the Information System on Uterine Cervical Cancer and the follow-up data from patient charts in a referral center for cervical pathology. Brazil's production of procedures was obtained from data in the Outpatient and Hospital Information Systems of the SUS. For every one hundred thousand women in the target age bracket for screening (25 to 64 years) there was an estimated annual need for 44,134 cytopathology tests, 1,886 colposcopies, 275 biopsies, 236 type 1 and 2 outpatient exicision procedures, 236 type 2 and 3 hospital exicision procedures, and 39 high-complexity referrals for surgery, chemotherapy, and/or radiotherapy. Applying the estimated parameters to the number of women screened in Brazil in 2017, a deficit was identified in all the procedures for adequate follow-up of the women with altered test results, varying from 7% in colposcopies to 74% in type 3 excisions. The results point to the need to expand and upgrade the supply of line of care procedures for cervical cancer. The estimated parameters can support policymakers in programming and implementing organized screening programs.

Se estimaron parámetros para la planificación y programación de la oferta de procedimientos, con el fin de detectar, realizar investigación diagnóstica y tratar lesiones precursoras del cáncer de cuello uterino. En base a las mismas, se evaluó la adecuación del protocolo nacional de procedimientos realizados por el Sistema Único de Salud (SUS) en 2017. Las estimaciones se calcularon utilizando como marco de referencia los procedimientos recomendados en las directrices nacionales para la detección de este tipo de cáncer. Los datos referentes a los exámenes de detección se obtuvieron en el Sistema de Información del Cáncer de Cuello de Útero, y los datos de seguimiento en registros médicos de una unidad de referencia en patología cervical. La producción nacional de los procedimientos se obtuvo a partir de datos de los sistemas de información ambulatoria y hospitalaria del SUS. De cada cien mil mujeres, en la franja de edad objetivo de la detección (25 a 64 años), se estimó una necesidad anual de 44.134 exámenes citopatológicos, 1.886 colposcopias, 275 biopsias, 236 escisiones tipo 1 y 2 ambulatorias, 236 escisiones tipo 2 y 3 hospitalarias y 39 derivaciones hacia centros hospitalarios de alta complejidad para la realización de cirugías, quimioterapia y/o radioterapia. Aplicando los parámetros estimados al número de mujeres a quienes se les realizó el examen en Brasil durante 2017, se identificó un déficit de todos los procedimientos para un seguimiento adecuado de las mujeres con alteraciones, variando de un 7% en las colposcopias, a un 74% en las escisiones tipo 3. Los resultados apuntan la necesidad de ampliar y dotar la oferta de procedimientos en la línea de cuidados del cáncer de cuello uterino. Los parámetros estimados podrán ayudar a los gestores en la programación e implementación de programas organizados de detección.

Roles of CDKN1A gene polymorphisms (rs1801270 and rs1059234) in the development of cervical neoplasia.

The CDKN1A gene product is a p53 downstream effector, which participates in cell differentiation, development process, repair, apoptosis, senescence, migration, and tumorigenesis. The objective of our study was investigated the importance of two polymorphisms in the CDKN1A gene, rs1801270 (31C>A) and rs1059234 (70C>T), for the development of cervical lesions in a Southeastern Brazilian population (283 cases, stratified by lesion severity, and 189 controls). CDKN1A genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and/or DNA sequencing. CDKN1A 31A allele presents a genetic pattern of protection for the development of high-grade cervical lesions (CC vs CA genotype: OR = 0.60; 95 % CI = 0.38-0.95; p = 0.029; CA+AA vs CC genotype: OR = 0.60; 95 % CI = 0.39-0.93; p = 0.021). Allele distributions of the CDKN1A 70C>T polymorphism were also different between the two study groups, with the CDKN1A 70T allele being less prevalent among cases. Moreover, the double heterozygote genotype combination 31CA-70CT decreases the chance of developing high-grade squamous intraepithelial lesion (HSIL) and cancer (OR = 0.55; 95 % CI = 0.32-0.93; p = 0.034) by 50 %, representing a protective factor against the development of more severe cervical lesions.

Preinvasive and invasive disease in women with cytological diagnosis of high-grade lesion and high-grade lesion cannot exclude microinvasion.

BACKGROUND: Cervical cancer is the third most common cancer in Brazil and has a high potential for prevention and cure. The prevalence of invasive and preinvasive disease in women with cytological diagnosis of high-grade lesion - cannot exclude microinvasion (HSIL-micro) is not known. METHODS: This cross-sectional study used a cytology lab database to identify women with HSIL-micro and HSIL referred to two colposcopic units from June 2006 to December 2012. For each woman with HSIL-micro, four women with cytologic diagnosis of HSIL who met the inclusion criteria were identified. Data were obtained from review of medical records. RESULTS: Forty-seven patients with report of HSIL-micro and 188 patients with report of HSIL were included. The final diagnoses revealed a frequency of preinvasive lesions of 31.9 % (15/47) and 59.6 % (112/188) in patients with HSIL-micro and HSIL, respectively, while the frequency of invasive disease was 63.8 % (30/47) and 11.7 % (22/188), respectively. The HSIL-micro group showed prevalence of preinvasive or invasive disease 6.5 times greater (95 % CI = 1.6-5.7) and, for invasive disease, 2.4 times greater (95 % CI = 1.7-3.6) than the HSIL group. CONCLUSION: Higher risk of preinvasive and invasive lesions in women with cytologic diagnosis of HSIL-micro reinforces recommendations for immediate investigation.

Effects of MDM2 promoter polymorphisms on the development of cervical neoplasia in a Southeastern Brazilian population.

We investigated the importance of two adjacent functional polymorphisms in the Murine Double Minute 2 (MDM2) gene, SNP285 G > C and SNP309 T > G, for the development of cervical lesions in a Southeastern Brazilian population (293 cases and 184 controls). MDM2 genotyping was performed by PCR-RFLP (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism) and/or DNA sequencing. MDM2 SNP309 has potential as a biomarker of cervical neoplasia in non-smokers, patients with family history of cancer, or those who had late sexual debut (>16 years). Besides, this polymorphism may help identify women at risk of developing severe cervical lesion at a young age (<30 years).

Association of CDKN2A polymorphisms with the severity of cervical neoplasia in a Brazilian population.

Variants of p16(INK4a) and p14(ARF), encoded by the CDKN2A locus, may respond differently to the presence of human papillomavirus (HPV). We investigated the potential association of two CDKN2A polymorphisms, 500C > G (rs11515) and 540C > T (rs3088440), with cervical neoplasia in patients with cervical lesions and healthy controls (n = 492). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), single-strand conformation polymorphism (SSCP) and/or DNA sequencing techniques were employed for genotyping. The 500G allele was found higher, whereas the 540T/T genotype was less frequent in patients with more severe lesions. The CDKN2A variants may have the potential to be markers for the management of patients with cervical neoplasia.

Risk of persistent high-grade squamous intraepithelial lesion after electrosurgical excisional treatment with positive margins: a meta-analysis.

CONTEXT AND OBJECTIVE: Even if precursor lesions of cervical cancer are properly treated, there is a risk of persistence or recurrence. The aim here was to quantify the risks of persistence of high-grade intraepithelial squamous lesions, one and two years after cervical electrosurgical excisional treatment with positive margins. DESIGN AND SETTING: Systematic review of the literature and meta-analysis at Instituto Fernandes Figueira. METHODS: This meta-analysis was on studies published between January 1989 and July 2009 that were identified in Medline, Scopus, Embase, Cochrane, SciELO, Lilacs, Adolec, Medcarib, Paho, Wholis, Popline, ISI Web of Science and Sigle. Articles were selected if they were cohort studies on electrosurgical excisional treatment of high-grade squamous intraepithelial lesions with a minimum follow-up of one year, a histopathological outcome of persistence of these lesions and a small risk of bias. RESULTS: The search identified 7,066 articles and another 21 in the reference lists of these papers. After applying the selection and exclusion criteria, only four articles were found to have extractable data. The risk of persistence of high-grade intraepithelial lesions after one year was 11.36 times greater (95% confidence interval, CI: 5.529-23.379, P < 0.0001) in patients with positive margins and after two years, was four times greater (95% CI: 0.996-16.164), although without statistical significance. CONCLUSION: This meta-analysis confirms the importance of positive margins as an indicator of incomplete treatment after the first year of follow-up and highlights the need for appropriately chosen electrosurgical techniques based on disease location and extent, with close surveillance of these patients.

Colposcopic triage methods for detecting cervical intraepithelial neoplasia grade 3 after cytopathological diagnosis of low-grade squamous intraepithelial lesion: a systematic review on diagnostic tests.

CONTEXT AND OBJECTIVE: The age-stratified performance of the oncogenic HPV-DNA (human papillomavirus deoxyribonucleic acid) test for triage of low-grade squamous intraepithelial lesions (LSIL) requires investigation. The objective of this study was to evaluate and compare the age-stratified performance (cutoff point: 35 years) of oncogenic HPV-DNA testing and repeated cytological tests, for detecting cervical intraepithelial neoplasia grade 3 (CIN3), in order to triage for LSIL. DESIGN AND SETTING: Systematic review. Studies were identified in nine electronic databases and in the reference lists of the articles retrieved. METHODS: The eligibility criteria consisted of initial cytological findings of LSIL; subsequent oncogenic HPV-DNA testing and repeated cytological tests; and CIN3 detection. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS) guidelines were used for quality assessment. Qualitative information synthesis was performed. RESULTS: Out of 7,776 studies, 284 were identified as pertinent and three fulfilled the eligibility criteria. The CIN3 prevalence ranged from 6% to 12%. The HPV-DNA positivity rate ranged from 64% to 83%; sensitivity for CIN3 detection ranged from 95.2% to 100%; and specificity was available in two studies (27% and 52%). The sensitivity of repeated cytological tests, in relation to the threshold for atypical squamous cells of undetermined significance (ASCUS), was available in two studies (33% and 90.8%); and specificity was available in one study (53%). CONCLUSIONS: Currently, there is no scientific evidence available that would prove that colposcopic triage using oncogenic HPV-DNA testing to detect CIN3 performs better than repeated cytological tests, among women with LSIL aged 35 years and over.

Colposcopic triage methods for detecting cervical intraepithelial neoplasia grade 3 after cytopathological diagnosis of low-grade squamous intraepithelial lesion: a systematic review on diagnostic tests / Métodos de triagem colposcópica para detecção de neoplasia intraepitelial cervical grau 3 após diagnóstico citopatológico de lesão intraepitelial escamosa de baixo grau: uma revisão sistemática de testes diagnósticos

CONTEXT AND OBJECTIVE: The age-stratified performance of the oncogenic HPV-DNA (human papillomavirus deoxyribonucleic acid) test for triage of low-grade squamous intraepithelial lesions (LSIL) requires investigation. The objective of this study was to evaluate and compare the age-stratified performance (cutoff point: 35 years) of oncogenic HPV-DNA testing and repeated cytological tests, for detecting cervical intraepithelial neoplasia grade 3 (CIN3), in order to triage for LSIL. DESIGN AND SETTING: Systematic review. Studies were identified in nine electronic databases and in the reference lists of the articles retrieved. METHODS: The eligibility criteria consisted of initial cytological findings of LSIL; subsequent oncogenic HPV-DNA testing and repeated cytological tests; and CIN3 detection. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS) guidelines were used for quality assessment. Qualitative information synthesis was performed. RESULTS: Out of 7,776 studies, 284 were identified as pertinent and three fulfilled the eligibility criteria. The CIN3 prevalence ranged from 6 percent to 12 percent. The HPV-DNA positivity rate ranged from 64 percent to 83 percent; sensitivity for CIN3 detection ranged from 95.2 percent to 100 percent; and specificity was available in two studies (27 percent and 52 percent). The sensitivity of repeated cytological tests, in relation to the threshold for atypical squamous cells of undetermined significance (ASCUS), was available in two studies (33 percent and 90.8 percent); and specificity was available in one study (53 percent). CONCLUSIONS: Currently, there is no scientific evidence available that would prove that colposcopic triage using oncogenic HPV-DNA testing to detect CIN3 performs better than repeated cytological tests, among women with LSIL aged 35 years and over.

CONTEXTO E OBJETIVO: O desempenho do teste de DNA-HPV (ácido desoxirribonucleico-papilomavírus humano) oncogênico estratificado por idade para triagem de lesão intraepitelial escamosa de baixo grau (LSIL) demanda investigação. O objetivo do estudo foi avaliar e comparar o desempenho, para detecção de neoplasia intraepitelial cervical (NIC3), do teste de DNA-HPV oncogênico e da citologia de repetição estratificados por idade (ponto de corte 35 anos), para triagem de LSIL. TIPO DE ESTUDO E LOCAL: Revisão sistemática da literatura. Foram identificados estudos em nove bases de dados eletrônicas e listas de referências dos artigos recuperados. MÉTODOS: Critérios de elegibilidade: citologia inicial LSIL, realização do teste de DNA-HPV oncogênico e da citologia de repetição e detecção de NIC3. A diretriz QUADAS (Quality Assessment of Diagnostic Accuracy Studies) foi utilizada para avaliação da qualidade. As informações foram sintetizadas qualitativamente. RESULTADOS: Dentre 7.776 estudos, 284 eram pertinentes ao tema e três atenderam aos critérios de elegibilidade. A prevalência de NIC3 apresentou variação entre 6 por cento e 12 por cento. A taxa de positividade do teste de DNA-HPV apresentou variação entre 64 por cento e 83 por cento; a sensibilidade para NIC3 apresentou variação entre 95,2 por cento e 100 por cento; a especificidade estava disponível em dois estudos (27 por cento e 52 por cento). A sensibilidade da citologia de repetição (ponto de corte ASCUS - células escamosas atípicas de significado indeterminado) estava disponível em dois estudos (33 por cento e 90,8 por cento); a especificidade estava disponível em um estudo (53 por cento). CONCLUSÕES: Não existem, atualmente, evidências científicas disponíveis para comprovar que, em mulheres com 35 anos ou mais e citologia LSIL, a triagem colposcópica com teste de DNA-HPV oncogênico apresenta melhor desempenho para detecção de NIC3 do que a repetição citológica.

Risk of persistent high-grade squamous intraepithelial lesion after electrosurgical excisional treatment with positive margins: a meta-analysis / Risco de persistência da lesão intraepitelial escamosa de alto grau após tratamento excisional eletrocirúrgico com margens comprometidas: uma metanálise

CONTEXT AND OBJECTIVE: Even if precursor lesions of cervical cancer are properly treated, there is a risk of persistence or recurrence. The aim here was to quantify the risks of persistence of high-grade intraepithelial squamous lesions, one and two years after cervical electrosurgical excisional treatment with positive margins. DESIGN AND SETTING: Systematic review of the literature and meta-analysis at Instituto Fernandes Figueira. METHODS: This meta-analysis was on studies published between January 1989 and July 2009 that were identified in Medline, Scopus, Embase, Cochrane, SciELO, Lilacs, Adolec, Medcarib, Paho, Wholis, Popline, ISI Web of Science and Sigle. Articles were selected if they were cohort studies on electrosurgical excisional treatment of high-grade squamous intraepithelial lesions with a minimum follow-up of one year, a histopathological outcome of persistence of these lesions and a small risk of bias. RESULTS: The search identified 7,066 articles and another 21 in the reference lists of these papers. After applying the selection and exclusion criteria, only four articles were found to have extractable data. The risk of persistence of high-grade intraepithelial lesions after one year was 11.36 times greater (95% confidence interval, CI: 5.529-23.379, P < 0.0001) in patients with positive margins and after two years, was four times greater (95% CI: 0.996-16.164), although without statistical significance. CONCLUSION: This meta-analysis confirms the importance of positive margins as an indicator of incomplete treatment after the first year of follow-up and highlights the need for appropriately chosen electrosurgical techniques based on disease location and extent, with close surveillance of these patients.

CONTEXTO E OBJETIVO: As lesões precursoras do câncer de colo uterino, mesmo se tratadas adequadamente, têm risco de persistirem ou recidivarem. O objetivo foi quantificar o risco de persistência da lesão intraepitelial escamosa de alto grau (HSIL) em um e dois anos após tratamento excisional eletrocirúrgico do colo uterino com margens comprometidas. TIPO DE ESTUDO E LOCAL: Revisão sistemática da literatura e metanálise no Instituto Fernandes Figueira. METÓDO: Metanálise de estudos publicados entre janeiro de 1989 e julho de 2009 identificados em Medline, Scopus, Embase, Cochrane, SciELO, Lilacs, Adolec, Medcarib, Paho, Wholis, Popline, Isis Web of Science e Sigle. Os artigos eram selecionados se fossem estudos tipo coorte sobre tratamento excisional eletrocirúrgico de HSIL com acompanhamento mínimo de um ano e tivessem como desfecho histopatológico a persistência de HSIL com pequeno risco de viés. RESULTADOS: Foram identificados 7.066 artigos e mais 21 nas listas de referências desses artigos. Após aplicação de critérios de seleção e de exclusão, somente quatro artigos ofereciam dados passíveis de extração. O risco de persistência da HSIL em um ano foi 11.36 vezes maior nas pacientes com margens comprometidas (intervalo de confiança, IC 95%: 5.529-23.379; P < 0,0001) e, em dois anos, chegou a quatro vezes, embora sem significância estatística (IC 95% 0.996-16.164). CONCLUSÃO: Esta metanálise confirma a importância de margem comprometida como indicador de tratamento incompleto no primeiro ano e ressalta a necessidade de uma adequada escolha da técnica eletrocirúrgica em função da localização e extensão da doença e um acompanhamento adequado dessas pacientes.

Thromboembolic event as a prognostic factor for the survival of patients with stage IIIB cervical cancer.

OBJECTIVE: The purpose of this study was to evaluate the effect of thromboembolic event (TEE) on the prognosis and survival of women diagnosed with the International Federation of Gynecology and Obstetrics (FIGO) stage IIIB cervical cancer undergoing treatment at the National Cancer Institute (Instituto Nacional de Câncer [INCA], Ministério da Saúde), Brazil. METHODS: A total of 1020 women with FIGO stage IIIB cervical cancer (International Classification of Diseases, C53.9), who had received treatment at this institute between 2000 and 2004, were identified. Data were obtained from the hospital cancer registry at INCA. Patients were followed up from the date of their diagnosis of cervical cancer at INCA until their death or last follow-up visit. The date of TEE diagnosis was defined as the date of one of the following tests diagnosing this condition: Doppler ultrasound scan, computed tomography scan, or in 1 single case echocardiography. The Kaplan-Meyer method was used to perform long-term survival analysis. CONCLUSIONS: The presence of TEE in patients with FIGO stage IIIB cervical cancer seems to be indicative of the severity of the disease and poorer prognosis. The most important finding is that in the patients who developed TEE, this complication occurred around the time of diagnosis of progression of the disease. Disease progression may have been the triggering factor for the development of TEE.

Prevalence of high-grade squamous intraepithelial lesions and cervical cancer among patients with unsatisfactory colposcopic examination, without visible lesion / Prevalência de lesão intra-epitelial escamosa de alto grau e câncer cervical em pacientes sem lesão visível à colposcopia insatisfatória

Context and objetive: Cervical cancer is a serious public health problem in Brazil. For patients with unsatisfactory colposcopic examinations without visible lesions, but with cervical cytological tests suggesting high-grade squamous intraepithelial lesion (HSIL), the national recommendation is to repeat cervical cytological tests after three months. Our aim was to assess the prevalence of HSIL and cancer among patients with initial cervical cytological tests suggestive of HSIL but with unsatisfactory colposcopic examinations without visible lesions, in order to contribute towards the discussion regarding a more effective clinical approach that might diminish the likelihood of patient abandonment of follow-up before appropriate diagnosis and treatment. Design and setting: Cross-sectional study in Colposcopy Clinic of IFF/Fiocruz. Method: Patients admitted between December 1989 and April 2007 with cytological diagnoses of HSIL but with unsatisfactory colposcopic examinations without visible lesions underwent cervical cone biopsy. Results: Sixty-five such patients were included, comprising 33.8 percent with HSIL and 4.6 percent with cancer, confirmed histologically. The other patients presented low-grade squamous intraepithelial lesion (26.1 percent), glandular dysplasia (1.5 percent) and absence of disease (33.8 percent). Cpnclusion: The observed prevalence of cancer and HSIL does not seem to be enough to justify immediate referral for cone biopsies to investigate the cervical canal in these cases. The findings suggest that the recommendation of repeated cytological tests following an initial one with HSIL, among patients with unsatisfactory colposcopic examinations without visible lesions, is appropriate in our setting. Efforts are needed to ensure adherence to follow-up protocols in order to reduce the chances of losses.

Introdução: O câncer de colo uterino é um grave problema de saúde pública no Brasil. Em pacientes com colpocitologias sugestivas de lesão intra-epitelial escamosa de alto grau (HSIL) e colposcopia insatisfatória sem lesão visível, a recomendação nacional é repetir a colpocitologia após três meses. Nosso objetivo foi medir a prevalência de HSIL e câncer em pacientes com a primeira colpocitologia sugestiva de HSIL e colposcopia insatisfatória sem lesão visível, no intuito de contribuir para a discussão sobre uma conduta clínica mais efetiva e que diminua a probabilidade de perdas de acompanhamento antes do diagnóstico e tratamento adequados. Tipo de estudo e local: Estudo transversal no Ambulatório de Colposcopia do IFF/Fiocruz. MÉTODO: Pacientes recebidas no período de dezembro de 1989 a abril de 2007 com diagnóstico citológico de HSIL sem lesão visível em colposcopias insatisfatórias foram submetidas a conização do colo uterino. Resultados: Foram incluídas 65 pacientes na situação descrita e encontrados 33,8 por cento de HSIL e 4,6 por cento de câncer confirmados histologicamente. Os demais casos apresentaram lesão intra-epitelial escamosa de baixo grau (26,1 por cento), displasia glandular (1,5 por cento) e ausência de doença (33,8 por cento). Conclusão: A prevalência de HSIL ou câncer encontrada não parece suficiente para defender a conduta de encaminhar as pacientes de imediato para conização a fim de investigar o canal cervical. Os achados sugerem que a recomendação de repetir a citologia após uma primeira com HSIL sem lesão visível e colposcopia insatisfatória é apropriada no nosso cenário. Devem ser implementados esforços para adesão às recomendações de acompanhamento e reduzir a chance de perdas.

Prevalence of cervical intraepithelial neoplasia grades II/III and cervical cancer in patients with cytological diagnosis of atypical squamous cells when high-grade intraepithelial lesions (ASC-H) cannot be ruled out / Prevalência de neoplasia intra-epitelial cervical graus II/III e câncer cervical nas pacientes com diagnóstico citológico de células escamosas atípicas, quando não se pode excluir lesão intra-epitelial de alto grau (ASC-H)

Context and objective: The latest update of the Bethesda System divided the category of atypical squamous cells of undetermined significance (ASCUS) into ASC-US (undetermined significance) and ASC-H (high-grade intraepithelial lesion cannot be ruled out). The aims here were to measure the prevalence of pre-invasive lesions (cervical intraepithelial neoplasia, CIN II/III) and cervical cancer among patients referred to Instituto Fernandes Figueira (IFF) with ASC-H cytology, and compare them with ASC-US cases. Design and setting: Cross-sectional study with retrospective data collection, at the IFF Cervical Pathology outpatient clinic. Methods: ASCUS cases referred to IFF from November 1997 to September 2007 were reviewed according to the 2001 Bethesda System to reach cytological consensus. The resulting ASC-H and ASC-US cases, along with new cases, were analyzed relative to the outcome of interest...

Contexto e objetivo: A última atualização do Sistema Bethesda dividiu a categoria de células escamosas atípicas de significado indeterminado (ASCUS) em ASC-US (de significado indeterminado) e ASC-H (quando não se pode excluir lesão intra-epitelial de alto grau). Os objetivos deste estudo foram medir a prevalência da lesão pré-invasiva (Neoplasia Intra-epitelial Cervical, NIC II/III) e câncer cervical, de pacientes que foram encaminhadas ao Instituto Fernandes Figueira (IFF), com citologia ASC-H e compará-la com os casos ASC-US. Tipo de estudo e local: Estudo transversal com coleta de dados retrospectiva, que ocorreu no ambulatório de Patologia Cervical do IFF. Métodos: Casos com diagnóstico de ASCUS recebidos no IFF entre novembro de 1997 a setembro de 2007, foram revisados de acordo com o Sistema Bethesda 2001 até um diagnóstico de consenso. Os casos ASC-H e ASC-US resultantes desta revisão, e os casos novos, foram analisados em relação ao desfecho de interesse...

Incidence of cervical intraepithelial lesions in a population of adolescents treated in public health services in Rio de Janeiro, Brazil.

This study aimed to estimate the incidence and types of cervical cytopathological findings in adolescents who were treated in public health services between 1993 and 2006. This is a cohort study, with the following inclusion criteria: < 20 years of age, sexually-active, without cervical lesions upon entry into the study or sexually active < 1 year. The data were collected from 403 adolescents' medical records. Incidence density of cytopathological alterations was estimated and the actuarial method was used to calculate the 5-year incidence during follow-up after sexual initiation. In the first year of sexual activity, the incidence of cervical lesions was 24.1%. The incidence decreased to 3-8% over the following 4 years. The incidence density was 4.7 cases per 100 persons per year. The first abnormal cytological diagnosis showed atypical squamous cells of undetermined significance (ASCUS) in 5.5% (22) of patients, low-grade squamous intra-epithelial lesions (LSIL) in 28% (113), and high-grade squamous intraepithelial lesions (HSIL) in 3% (12). Eight (67%) cases of HSIL occurred during the first year of sexual activity. The incidence of cytopathological findings at beginning of sexual life is high, suggesting the importance of including sexually-active adolescents in cervical cancer prevention programs.

Incidence of cervical intraepithelial lesions in a population of adolescents treated in public health services in Rio de Janeiro, Brazil / Incidência de lesões intra-epiteliais cervicais em população de adolescentes atendidas em serviço público de saúde no Rio de Janeiro, Brasil

This study aimed to estimate the incidence and types of cervical cytopathological findings in adolescents who were treated in public health services between 1993 and 2006. This is a cohort study, with the following inclusion criteria: <20 years of age, sexually-active, without cervical lesionsupon entry into the study or sexually active < 1 year. The data were collected from 403 adolescents’ medical records. Incidence density of cytopathological alterations was estimated and the actuarial method was used to calculate the 5- year incidence during follow-up after sexual initiation. In the first year of sexual activity, the incidence of cervical lesions was 24.1%. The incidence decreased to 3-8% over the following 4 years. The incidence density was 4.7 cases per 100 persons per year. The first abnormal cytological diagnosis showed atypical squamous cells of undetermined significance (ASCUS) in 5.5% (22) of patients, lowgrade squamous intra-epithelial lesions (LSIL) in 28% (113), and high-grade squamous intraepithelial lesions (HSIL) in 3% (12). Eight (67%) casesof HSIL occurred during the first year of sexual activity. The incidence of cytopathological findings at beginning of sexual life is high, suggesting the importance of including sexually-active adolescents in cervical cancer prevention programs.

O objetivo foi estimar a incidência e os tipos das alterações citopatológicas cervicais em adolescentes acompanhadas em serviço público entre 1993-2006. Estudo de coorte, tendo como critérios de inclusão: idade <20 anos, apresentar atividade sexual, citopatologia negativa para lesão cervical na entrada do estudo ou tempo de atividade sexual <1 ano. Os dados foram coletados de prontuários de 403 adolescentes. Foi estimada densidade de incidência, e para o cálculo da incidência das alterações citopatológicas referentes a cinco anos de acompanhamento após atividade sexualfoi utilizado o método atuarial. No primeiro ano de atividade sexual, a incidência de lesões cervicais foi de24,1%. Houve redução da incidência nos quatro anos subseqüentes com variação entre 3-8%. A densidade de incidência foi de 4,7 casos/100 pessoas-ano. O primeiro diagnóstico citológico anormal mostrou atipias em células escamosas de significado indeterminado(ASCUS) em 5,5% (22) das pacientes, lesão intra-epitelial escamosa de baixo grau (LSIL) em 28% (113) e lesão intra-epitelial escamosa de alto grau (HSIL) em 3% (12). Oito (67%) dos casos de HSIL ocorreram no primeiro ano de atividade sexual. A incidência de alterações citopatológicas é alta no início da vida sexual, sugerindo ser importante a inclusão das adolescentessexualmente ativas no Programa de Controle do Câncer de Colo Uterino.

Prevalence of high-grade squamous intraepithelial lesions and cervical cancer among patients with unsatisfactory colposcopic examination, without visible lesion.

CONTEXT AND OBJECTIVE: Cervical cancer is a serious public health problem in Brazil. For patients with unsatisfactory colposcopic examinations without visible lesions, but with cervical cytological tests suggesting high-grade squamous intraepithelial lesion (HSIL), the national recommendation is to repeat cervical cytological tests after three months. Our aim was to assess the prevalence of HSIL and cancer among patients with initial cervical cytological tests suggestive of HSIL but with unsatisfactory colposcopic examinations without visible lesions, in order to contribute towards the discussion regarding a more effective clinical approach that might diminish the likelihood of patient abandonment of follow-up before appropriate diagnosis and treatment. DESIGN AND SETTING: Cross-sectional study in Colposcopy Clinic of IFF/Fiocruz. METHOD: Patients admitted between December 1989 and April 2007 with cytological diagnoses of HSIL but with unsatisfactory colposcopic examinations without visible lesions underwent cervical cone biopsy. RESULTS: Sixty-five such patients were included, comprising 33.8% with HSIL and 4.6% with cancer, confirmed histologically. The other patients presented low-grade squamous intraepithelial lesion (26.1%), glandular dysplasia (1.5%) and absence of disease (33.8%). CONCLUSION: The observed prevalence of cancer and HSIL does not seem to be enough to justify immediate referral for cone biopsies to investigate the cervical canal in these cases. The findings suggest that the recommendation of repeated cytological tests following an initial one with HSIL, among patients with unsatisfactory colposcopic examinations without visible lesions, is appropriate in our setting. Efforts are needed to ensure adherence to follow-up protocols in order to reduce the chances of losses.