Maria José de Camargo

Immunohistochemical expression of cyclin D1, p16Ink4a, p21WAF1, and Ki-67 correlates with the severity of cervical neoplasia.

High-risk human papillomaviruses are closely associated with cervical cancer and its precursor lesions through interactions between the E6 and E7 oncoproteins and the cell-cycle regulatory proteins, such as p53 and pRb, respectively. As other molecules involved in the cell-cycle control seem to be important for human papillomavirus (HPV)-mediated cervical carcinogenesis, we have analyzed the expression of p53, p21, p16, cyclin D1, and Ki-67 and the presence of HPV (HPV pool and HPV-16) by immunohistochemical studies using tissue microarray in low squamous intraepithelial lesions (n=50), high squamous intraepithelial lesions (n=98), and cervical carcinoma (n=18). We have found a significant increase in the expression of p16 and p21 (P<0.001) from low- to high-grade lesions and cancer. In contrast, cyclin D1 expression showed a significant decrease in more severe lesions (P<0.001). p16, Ki-67, p21, and p53 positivity increased with the cell-layer level and the lesion severity, with stronger correlations being observed for p16 and Ki-67. High positivity for HPV pool (96.3%) and HPV-16 (77.5%) immunostaining was detected in all cases, with an association between p16 and cyclin D1 expression and HPV-16 infection. Our tissue microarray results corroborate the usefulness of the immunohistochemical assessment of cell-cycle biomarkers in distinguishing different groups of precursor lesions of the cervix and cervical carcinoma.

Recurrence of cervical intraepithelial neoplasia grades 2 or 3 in HIV-infected women treated by large loop excision of the transformation zone (LLETZ)

CONTEXT AND OBJECTIVE Women infected by HIV are more likely to have cervical cancer and its precursors. Treatment of the precursor lesions can prevent this neoplasia. The aim of this study was to assess the likelihood of recurrent cervical intraepithelial neoplasia grades 2 or 3 (CIN 2-3) in HIV-infected women, compared with HIV-negative women, all treated by large loop excision of the transformation zone (LLETZ). DESIGN AND SETTING A cohort study in Instituto Fernandes Figueira, Fundação Oswaldo Cruz (IFF-Fiocruz), Rio de Janeiro. METHOD 55 HIV-positive and 212 HIV-negative women were followed up after LLETZ for CIN 2-3 (range: 6-133 months). RESULTS The incidence of recurrent CIN 2-3 was 30.06/10,000 woman-months in the HIV-positive group and 4.88/10,000 woman-months in the HIV-negative group (relative risk, RR = 6.16; 95% confidence interval, CI: 2.07-18.34). The likelihood of recurrence reached 26% at the 62nd month of follow-up among the HIV-positive women, and remained stable at almost 0.6% at the 93rd month of follow-up among the HIV-negative women. We were unable to demonstrate other prognostic factors relating to CIN recurrence, but the use of highly active antiretroviral therapy (HAART) may decrease the risk of this occurrence among HIV patients. CONCLUSION After LLETZ there is a higher risk of recurrence of CIN 2-3 among HIV-positive women than among HIV-negative women. This higher risk was not influenced by margin status or grade of cervical disease treated. The use of HAART may decrease the risk of this occurrence in HIV patients.

Cervical stenosis following electrosurgical conization

CONTEXT AND OBJECTIVE Cervical stenosis is a postoperative complication of procedures for treating preinvasive lesions of the cervix and takes on particular importance due to the clinical repercussions associated with it. Furthermore, it causes limitations in relation to cytological and colposcopic follow-up. The aim here was to assess the incidence of cervical stenosis among a cohort of patients who underwent electrosurgical conization and to identify possible prognostic factors associated with its occurrence. DESIGN AND SETTING Retrospective study at Gynecology and Obstetrics Department, Instituto Fernandes Figueira, Rio de Janeiro. METHODS This was an observational study among a cohort of patients who underwent electrosurgical conization of the uterine cervix. The possible predictive variables were analyzed as bivariate means between the groups with and without stenosis. We also calculated the incidence density rate ratio for cervical stenosis in relation to each possible predictive variable and the respective confidence intervals (95%). Levels of 5% were considered significant. RESULTS 274 patients who underwent electrosurgical conization of the uterine cervix with a minimum follow-up period of six months were included. The crude incidence of cervical stenosis was 7.66% and the incidence density was 3.3/1,000 patients-month. CONCLUSIONS We did not find associations between the variables for stenosis. However, we observed borderline significance levels relating to hemorrhagic complications before and after the operation (p = 0.089).

Recurrence of cervical intraepithelial neoplasia in human immunodeficiency virus-infected women treated by means of electrosurgical excision of the transformation zone (LLETZ) in Rio de Janeiro, Brazil

CONTEXT AND OBJECTIVE Human immunodeficiency virus (HIV)-infected women have higher incidence, prevalence, persistence and recurrence of pre-invasive cervical lesions (CIN II or III). The aim here was to investigate the risk of recurrence of CIN II/III among HIV-infected women (HIV+) and uninfected women in a cohort treated by means of large-loop excision of the transformation zone (LLETZ). DESIGN AND SETTING Cohort study conducted at Instituto Fernandes Figueira/Fundação Oswaldo Cruz (IFF/Fiocruz). METHODS 60 HIV+ and 209 HIV-negative patients were included in a cohort for follow-up after undergoing LLETZ to treat CIN II/III. A histopathological diagnosis of CIN II/III during the follow-up was taken to constitute recurrence. The following possible confounding variables were assessed: age at treatment and at end of follow-up; histological grade of intraepithelial disease treated; surgical margin involvement; adequacy of colposcopy during the follow-up; CD4+ lymphocyte count; HIV viral load; and type of antiretroviral therapy. RESULTS Among the 60 HIV+ women, six showed recurrent disease during the follow-up. However, among the 209 HIV-negative women, seven showed a new precursor lesion. The relative risk of disease recurrence in the HIV+ women was 4.21 (95% CI = 1.42 to 12.43). The Kaplan-Meyer curve showed that the risk of recurrence was significantly higher among HIV+ women (log-rank test: P = 0.0111). CONCLUSION The HIV+ women in our cohort presented a risk of CIN II/III recurrence at least 42% higher than among the HIV-negative women. These patients should form part of a rigorous screening and follow-up protocol for identification and appropriate treatment of cervical cancer precursor lesions.

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

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. The histological diagnosis (or cytocolposcopic follow-up in cases without such diagnosis) was taken as the gold standard. RESULTS The prevalence of CIN II/III in cases with ASC-H cytology was 19.29% (95% confidence interval, CI, 9.05-29.55%) and the risk of these lesions was greater among patients with ASC-H than with ASC-US cytology (prevalence ratio, PR, 10.42; 95% CI, 2.39-45.47; P = 0.0000764). Pre-invasive lesions were more frequently found in patients under 50 years of age with ASC-H cytology (PR, 2.67; 95% CI, 0.38-18.83); P = 0.2786998). There were no uterine cervical cancer cases. CONCLUSION The prevalence of CIN II/III in patients with ASC-H cytology was significantly higher than with ASC-US, and division into ASC diagnostic subcategories had good capacity for discriminating the presence of pre-invasive lesions.

Prevalência das lesões intra-epiteliais de alto grau em pacientes com citologia com diagnóstico persistente de ASCUS

OBJETIVO: verificar a prevalencia de lesoes intra-epiteliais de alto grau (LIAG) e câncer invasor em mulheres com citologia com diagnostico de ASCUS (atipias em celulas escamosas de significado indeterminado) persistente apos 6 meses e verificar se a idade e fator indicador para a existencia destas lesoes neste grupo de mulheres. METODOS: foram incluidos 215 casos de mulheres nao-gestantes e HIV-negativas com diagnostico de ASCUS (sem especificacao) persistente em duas citologias com intervalo minimo de 6 meses. Tais resultados foram confrontados com o resultado histologico de biopsias, exereses da zona de transformacao (large loop excision of the transformation zone) ou cones. Foram considerados negativos para LIAG ou câncer quando a colposcopia foi satisfatoria e sem alteracoes ou quando, apesar de insatisfatoria, nao foi detectada lesao em pelo menos um seguimento citologico e colposcopico. Para estabelecer a prevalencia de lesoes, calculamos a frequencia de diagnosticos com seus respectivos intervalos de confianca a 95% (IC 95%). Para analise estatistica da diferenca de proporcoes de LIAG ou câncer em cada faixa de idade, foi utilizado teste do c2, e ainda estimamos o risco destas lesoes entre mulheres com mais de 35 anos pela razao de prevalencias com seu IC 95%. RESULTADOS: encontramos um total de negativos de 49,3% dos casos (IC 95%: 42,6-55,9). A prevalencia de lesoes intra-epiteliais de baixo grau foi de 38,6% (IC 95%: 32,1-45,1) e de LIAG de 10,7% (IC 95%: 6,5-14,8). Casos de câncer foram encontrados em 1,4% das pacientes (IC 95%: 0-2,9). Nao foi possivel estabelecer, de forma significativa, maior risco de LIAG/câncer considerando o corte de idade em 35 anos. CONCLUSAO: a prevalencia de LIAG/câncer encontrada em nosso estudo mostra que o risco de encontrarmos este tipo de lesao em mulheres atendidas no Sistema Unico de Saude em nosso municipio com duas citologias com diagnostico de ASCUS e de cerca de 12%. Nao foi possivel evidenciar maior probabilidade de LIAG/câncer em qualquer das faixas etarias analisadas, porem este resultado pode ter sido limitado pelo pequeno tamanho amostral.

Effectiveness of see-and-treat for approaching pre-invasive lesions of uterine cervix

OBJECTIVE To compare the effectiveness between the see-and-treat (S&T) approach and the conventional one (with prior biopsy) for squamous intraepithelial lesions of uterine cervix. METHODS A cross-sectional study was conducted with 900 nonpregnant women with cytology suggestive of high grade squamous intraepithelial lesions in the city of Rio de Janeiro, Southeastern Brazil, between 1998 and 2004. The S&T approach consists of a large loop excision of the transformation zone procedure and is recommended when cytology is suggestive of high grade squamous intraepithelial lesion, satisfactory colposcopy with abnormalities compatible with the suspected cytological results, and the lesion is limited to the ectocervix or extends up to one centimeter of the endocervical canal. A subgroup of 336 patients whose colposcopy was considered satisfactory was analyzed, and they were divided into two groups for comparison: patients treated without prior biopsy (n = 288) and patients treated after a biopsy showing high grade squamous intraepithelial lesions (n = 48). Patients who were not treated or only treated more than a year later after recruitment at the colposcopy unit were considered dropouts. RESULTS Of patients recruited during the study period, 71 were not treated or were only treated for at least a year. The overall dropout rate was 7.9% (95% CI: 6.1;9.7). Mean time elapsed between patient recruitment and treatment was 17.5 days in the S&T group and 102.5 days in the prior biopsy group. Dropout rates were 1.4% (95% CI: 0.04;2.7) and 5.% (95% CI: 0;12.3), respectively (p=0.07). The proportion of overtreated cases (negative histology) in the S&T group was 2.0% (95% CI: 0.4;3.6). CONCLUSIONS The difference in the mean time elapsed between patient recruitment and treatment indicates that S&T is a time-saving approach The proportion of negative cases from using the S&T approach can be regarded as low.

Large loop versus straight-wire excision of the transformation zone for treatment of cervical intraepithelial neoplasia: a randomised controlled trial of electrosurgical techniques

To compare two electrosurgical techniques, straight‐wire excision of transformation zone (SWETZ) with large loop excision of transformation zone, as a cone procedure (LLETZ‐cone), for the treatment of cervical intraepithelial neoplasia (CIN), when disease is present at the cervical canal.

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

Abstract 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

Abstract 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.