RESUMEN
BACKGROUND: Matrix metalloproteinases (MMP) are important enzymes in the tumor microenvironment associated with progression of cervical intraepithelial neoplasia (CIN) toward squamous cell carcinoma (SCC) of the cervix. However, the role of MMPs in the inflammatory process associated with Chlamydia trachomatis infection concomitant with the carcinogenic process driven by HPV has not yet been addressed. In the present study, we analyzed the state of the MMP-9-RECK axis in cervical carcinogenesis. METHODS: The levels of MMP-9 and RECK expression were analyzed by immunocytochemistry in liquid-based cytology samples from 136 women with high-grade cervical lesions (CIN2/CIN3) and cervical SCC diagnosed by LLETZ, and in 196 women without cervical neoplasia or CIN1. Real-time qPCR was performed to analyze expression of MMP-9 and RECK in 15 cervical samples. The presence of HPV-DNA and other genital pathogens was evaluated by PCR. RESULTS: We found a higher expression of MMP-9 [OR, 4.2; 95% confidence interval (CI), 2.2-7.8] and lower expression of RECK (OR, 0.4; 95% CI, 0.2-0.7) in women with CIN2/CIN3/SCC when compared with women from the control group (no neoplasia/CIN1). A statistically significant association was also found between MMP-9/RECK imbalance and infection by alpha-9 HPV and C. trachomatis. The prevalence of C. trachomatis infection was significantly higher in women with high-grade cervical disease (OR, 3.7; 95% CI, 1.3-11.3). CONCLUSIONS: MMP-9/RECK imbalance in cervical smears is significantly associated with high-grade cervical diseases and infection by alpha-9 HPV and C. trachomatis. IMPACT: MMP-9/RECK imbalance during cervical inflammation induced by C. trachomatis might play a role in HPV-mediated cervical carcinogenesis.
Asunto(s)
Infecciones por Chlamydia/genética , Proteínas Ligadas a GPI/genética , Regulación Neoplásica de la Expresión Génica , Metaloproteinasa 9 de la Matriz/genética , Infecciones por Papillomavirus/genética , Neoplasias del Cuello Uterino/genética , Cervicitis Uterina/genética , Adulto , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virología , Cuello del Útero/metabolismo , Cuello del Útero/patología , Infecciones por Chlamydia/metabolismo , Infecciones por Chlamydia/patología , Chlamydia trachomatis/genética , Estudios Transversales , ADN Bacteriano/genética , ADN de Neoplasias/genética , ADN Viral/genética , Femenino , Proteínas Ligadas a GPI/biosíntesis , Regulación Bacteriana de la Expresión Génica , Genotipo , Papillomavirus Humano 16/genética , Humanos , Inmunohistoquímica , Metaloproteinasa 9 de la Matriz/biosíntesis , Prueba de Papanicolaou , Infecciones por Papillomavirus/metabolismo , Infecciones por Papillomavirus/virología , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/virología , Cervicitis Uterina/metabolismo , Cervicitis Uterina/microbiología , Frotis VaginalRESUMEN
OBJECTIVE: This cross-sectional study was intended to assess the association between immunohistochemical analysis of p16 and fragile histidine triad (FHIT) and the presence of precancerous cervical lesions. MATERIALS AND METHODS: Women seen at Pérola Byington Hospital, São Paulo, Brazil, with histologically confirmed cervicitis (n = 31), cervical intraepithelial neoplasia (CIN) 1 (n = 30), CIN 2,3 (n = 30), and cervical cancer (n = 7) had also cervical material collected for liquid-based cytology, human papillomavirus Hybrid Capture 2 (HC2) test, and p16 and FHIT immunohistochemical reactions. RESULTS: p16 and FHIT reactions were scored as the following: <1%, 1% to 5%, >5% to 25%, and >25%. Receiver operating curve analysis was used to select p16 and FHIT score cutoffs for further categorical analyses. All but one of the 37 CIN 2,3/cancer cases had a p16 score of greater than 1% to 5%. Among the 61 cervicitis/CIN 1 cases, 46 (75%) had a p16 score lower than 1% to 5%. In contrast, no association of FHIT expression and severity of cervical lesions could be demonstrated in this data set. Receiver operating curve analyses suggested the score of 1% to 5% for p16 as the cutoff that best discriminates CIN 2,3/cancer from cervicitis/CIN 1. No cutoff for FHIT scores could be suggested with data set. CONCLUSIONS: p16, but not FHIT expression, has the potential to be used as complementary diagnostic tool to investigate human papillomavirus-induced cervical lesions, if these results are confirmed in larger studies.
Asunto(s)
Ácido Anhídrido Hidrolasas/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Proteínas de Neoplasias/metabolismo , Displasia del Cuello del Útero/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Cervicitis Uterina/metabolismo , Alphapapillomavirus , Área Bajo la Curva , Estudios Transversales , Femenino , Humanos , Inmunohistoquímica , Infecciones por Papillomavirus/metabolismo , Curva ROC , Sensibilidad y Especificidad , Displasia del Cuello del Útero/genética , Displasia del Cuello del Útero/virología , Neoplasias del Cuello Uterino/genética , Cervicitis Uterina/genéticaRESUMEN
OBJECTIVE: To assess the different patterns of DNA nuclear content in cervical intraepithelial neoplasia. STUDY DESIGN: DNA nuclear content patterns (DNA ploidy) were assessed in 82 paraffin embedded samples diagnosed as chronic cervicitis CIN 1, CIN 2 and CIN 3 by image analysis using the CAS200 BD System. These results were compared to the consensus diagnosis of two pathologists. The chi-square test was used to evaluate the results of classificatory variables (CIN 1, CIN 2 and CIN 3). RESULTS: Aneuploidy was found in 86% of CIN 3; 59% CIN 2; 26%% CIN 1. All samples classified as chronic cervicitis were diploid. CONCLUSIONS: The DNA nuclear content was found to parallel the three grades of the histological WHO classification. Aneuploidy was strongly associated with the high-grade lesions; the detection of a subset aneuploidy of low grade lesions would suggest a indicate closer follow-up of these cases.
Asunto(s)
ADN/análisis , Procesamiento de Imagen Asistido por Computador , Ploidias , Displasia del Cuello del Útero/genética , Neoplasias del Cuello Uterino/genética , Cervicitis Uterina/genética , Aneuploidia , Enfermedad Crónica , ADN de Neoplasias/análisis , Femenino , Humanos , Adhesión en Parafina , Displasia del Cuello del Útero/patología , Neoplasias del Cuello Uterino/patología , Cervicitis Uterina/patologíaRESUMEN
The objective of this study was to determine whether some morphometric parameters and two different methods of counting AgNOR dots were correlated with the grade of cervical intraepithelial neoplasia. Thirty uterine cervix biopsies (8 cases of cervicitis, 9 CIN I, CIN II and 6 CIN III) were studied. Two methods were used to count AgNOR dots. The first one consisted of counting the number of epithelial cells with 1, 2, 3, 4, or more dots. The second method, based on a computer analysis system, consisted of counting the total number of dots in 100 cells, without considering the number of dots per cell. Using the same computer analysis system, the following parameters were measured: area, diameter, perimeter, roundness and length of each dot. The following parameters were found to be correlated with the grade of intraepithelial neoplasia: 1) number of cells with 1 dot, which decreased with increasing grade of cervical intraepithelial neoplasia; 2) number of cells with 4 dots or more, which increased with increasing grade of cervical intraepithelial neoplasia; 3) total number of dots per 100 cells, which progressively increased with increasing grade of intraepithelial neoplasia. We conclude that counting cells with 4 or more dots is the more trustworthy parameter for distinguishing the grade of cervical intraepithelial neoplasia.