RESUMEN
BACKGROUND: Expression of matrix metalloproteases 2, 9 and 14 (MMP-2, MMP-9, MMP-14), tissue inhibitors of metalloprotease 1 and 2 (TIMP-1, TIMP-2) and vascular endothelial growth factor A (VEGF-A) is involved in tumor invasion and metastasis via extracellular matrix degradation and angiogenesis. This study aimed to assess whether the expression of MMP-2, MMP-9, MMP-14, TIMP-1, and TIMP-2 in tumors and in the adjacent stroma is associated with cervical cancer prognosis. METHODS: This study analyzed a retrospective cohort of 64 patients. Protein expression was previously obtained by immunohistochemistry from biopsies containing both tumor and stroma. The expression and percentage of stained cells were categorized as high or low according to the cutoff points by using ROC curves. The follow-up data was collected from diagnosis to the last clinical visit. Clinical status categorized as alive without disease, alive with disease, death due to other causes, and death from the disease. The relative risk of death from the disease was evaluated according to the proteins expression using a cause-specific Cox regression model with a 95% confidence interval (95%CI). For the significant associations (p < 0.05), survival curves of patients with low and high expression were plotted for the competing risk survival curve analyses. RESULTS: High expression levels of stromal MMP-2 (RR; 95%CI: 3.91; 1.17-13.02) and stromal TIMP-2 (RR, 95%CI: 8.67; 1.15-65.27) were associated with a greater relative risk of death from the disease and with lower survival (p = 0.03; p = 0.04) than lower expression levels. Low expression levels of stromal MMP-9 (RR, 95%CI: 0.19; 0.05-0.65) and tumoral MMP-9 (HR, 95%CI: 0.19; 0.04-0.90) were protective factors against death from the disease and were associated with poorer survival. CONCLUSIONS: High expression levels of MMP-2 and TIMP-2 in the stroma were significantly associated with poor survival in cervical cancer patients. High expression of MMP-9 was associated with a favorable cervical cancer prognosis.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/mortalidad , Cuello del Útero/patología , Displasia del Cuello del Útero/mortalidad , Neoplasias del Cuello Uterino/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Cuello del Útero/cirugía , Femenino , Estudios de Seguimiento , Humanos , Histerectomía , Metaloproteinasa 14 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Medición de Riesgo/métodos , Análisis de Supervivencia , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Resultado del Tratamiento , Microambiente Tumoral , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/cirugía , Factor A de Crecimiento Endotelial Vascular/metabolismo , Adulto Joven , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/cirugíaRESUMEN
OBJECTIVE: This study analyzed whether HPV (human papillomavirus) testing contributes towards defining histological abnormalities in women with atypical glandular cells (AGC) diagnosed at cervical cytology. STUDY DESIGN: One hundred and eight women with conventional cervical cancer screening smears suggestive of AGC not otherwise specified (AGC-NOS) and favor neoplastic (AGC-FN) were consecutively enrolled. All women underwent colposcopic examinations and biopsy was performed according to the cytopathologic and/or colposcopic abnormalities present. All specimens were tested for high risk HPV genotypes by Roche's polymerase chain reaction reverse line blot assay. The chi-square test was used to evaluate the association between HPV findings and a diagnosis of high-grade pre-invasive or invasive disease (CIN 2 or worse) taking negative tests or CIN 1 as a reference. Odds ratios (OR) with their respective 95% confidence intervals (95%CI) were used to evaluate the magnitude of the association between HPV testing and CIN 2 or worse. Sensitivity, specificity and their respective 95% confidence intervals (95%CI), positive predictive values (PPV) and negative predictive values (NPV) were also calculated. RESULTS: Final diagnosis revealed a negative outcome in 80 cases (74%), cervical epithelial neoplasia 1 (CIN 1) in 13 cases (12%), CIN 2 or worse in 12 cases (11%) and glandular neoplasia in 3 (3%) cases. The overall detection rate of HPV was 21% (23/108). Neoplasia was significantly associated with positive HPV-DNA in women with AGC-NOS (OR=15.21; 95%CI: 2.64-87.50); however, there was no significant association between a histological diagnosis of neoplasia and HPV positivity in women with AGC-FN (OR=3.00; 95%CI: 0.36-24.92). The sensitivity, specificity, positive predictive value and negative predictive value of HPV-DNA testing for the detection of CIN 2 or worse in women with AGC-NOS were 71%, 86%, 29% and 97%, respectively. In women with AGC-FN, these values were 50%, 75%, 66% and 60%, respectively. CONCLUSIONS: HPV testing at the time of colposcopy for patients with AGC in whom no colposcopic abnormality is found may be a powerful ancillary tool for identifying women at a high risk of underlying significant cervical lesions.
Asunto(s)
Cuello del Útero/patología , Cuello del Útero/virología , ADN Viral/metabolismo , Neoplasias Glandulares y Epiteliales/diagnóstico , Papillomaviridae/aislamiento & purificación , Neoplasias del Cuello Uterino/diagnóstico , Frotis Vaginal , Adulto , Brasil/epidemiología , Colposcopía , Femenino , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias Glandulares y Epiteliales/epidemiología , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Glandulares y Epiteliales/virología , Riesgo , Sensibilidad y Especificidad , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , Displasia del Cuello del Útero/diagnóstico , Displasia del Cuello del Útero/epidemiología , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/virologíaRESUMEN
This study was designed to analyze whether specific human papillomavirus (HPV) genotypes may predict histologic outcomes in women with glandular abnormalities in their cervical smears. Of the 160 women included, 111 were diagnosed with atypical glandular cells, 35 had both atypical glandular cells and high-grade squamous intraepithelial lesions, whereas 14 women had AIS, in 1 case associated with high-grade squamous intraepithelial lesions. All women underwent colposcopic examinations and biopsy was performed in 129/160 (80.6%). Thirty-one women (19.3%) were considered negative for neoplasia and scheduled for follow-up. All specimens were tested for 27 HPV genotypes by Roche's polymerase chain reaction-reverse line blot assay. Histologic diagnoses were either cervical intraepithelial neoplasia or invasive carcinoma in 75 (58%) women, and negative for neoplasia in 54 (42%). The overall prevalence of HPV was 43%. HPV 16 was the most prevalent type followed by HPV 18. HPV 16 was significantly associated with squamous and glandular neoplasia and HPV 18 with glandular neoplasia. In women with cervical intraepithelial neoplasia 2 or 3, 11 different HPV genotypes were found, whereas in those who had invasive glandular or invasive carcinoma HPV 16 and HPV 18 were found predominantly. The detection of HPV 16 in women with glandular abnormalities in cervical smears did not help differentiating squamous from glandular lesions. However, the detection of HPV 53 in abnormal smears can predict squamous neoplasia, whereas HPV 18 can predict glandular neoplasia as histologic diagnoses.
Asunto(s)
Adenocarcinoma/virología , Papillomaviridae/genética , Infecciones por Papillomavirus/genética , Displasia del Cuello del Útero/virología , Neoplasias del Cuello Uterino/virología , Adenocarcinoma/genética , Adenocarcinoma/patología , Femenino , Genotipo , Humanos , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/epidemiología , Reacción en Cadena de la Polimerasa , Prevalencia , Factores de Riesgo , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Frotis Vaginal , Displasia del Cuello del Útero/genética , Displasia del Cuello del Útero/patologíaRESUMEN
Human papillomavirus (HPV) genotypes cannot fully explain the histological diagnosis of women with glandular abnormalities detected by cervical smear. Thus, this study was designed to analyze the distribution of HPV-16 and HPV-18 variants in women referred because of atypical glandular cells and adenocarcinoma in situ in their cervical smears and its association with histological results. Twenty-four women with HPV-16 and 6 with HPV-18, selected from 160 women with cervical smears suggestive of glandular abnormalities, were included. Histological results showed cervicitis (1 case), squamous neoplasia (18 cases), glandular neoplasia (7 cases), and glandular neoplasia associated with a squamous component (4 cases). Among the 24 cases presenting HPV-16, the European variant was detected in 15 (62%) and the Asian American in 9 (38%). Among the 15 cases associated with the European variant, 14 (93%) presented squamous neoplasia and 1 (7%) invasive adenocarcinoma. Asian-American HPV-16 variants were significantly associated with histological diagnosis of glandular neoplasia alone (odds ratio, 9.3 [1.4-60.2]) or associated with squamous neoplasia (odds ratio, 18.7 [1.5-232.3]). Adenocarcinomas were detected in 4 of 6 HPV-18-positive cases, being 2 cases had the European variant, 1 had the Asian Amerindian variant, and 1 had the African variant. The association of HPV-16 with squamous or glandular neoplasia is explained by its variants. In this study, squamous neoplasia was related to the European variant of HPV-16, whereas glandular neoplasia was related to the Asian-American variant. Glandular neoplasia is associated with HPV-18, but the results of our analysis of its variants were inconclusive.
Asunto(s)
Adenocarcinoma/virología , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Displasia del Cuello del Útero/virología , Neoplasias del Cuello Uterino/virología , Cervicitis Uterina/virología , Adenocarcinoma/patología , Adulto , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , ADN Viral/análisis , Femenino , Variación Genética , Genotipo , Humanos , Persona de Mediana Edad , Neoplasias del Cuello Uterino/patología , Cervicitis Uterina/patología , Frotis Vaginal , Displasia del Cuello del Útero/patologíaRESUMEN
OBJECTIVE: To evaluate the association between high-risk human papillomavirus (HPV) DNA detection and histological diagnosis in women referred for atypical glandular cells (AGC) or adenocarcinoma in situ (AIS) at Pap smear. METHODS: In this cross-sectional study, 146 women referred for AGC (124), AGC with high-grade squamous intraepithelial lesion (HSIL) (15), or AIS (7) were tested for HPV DNA using Hybrid Capture II (HC II). All women underwent colposcopic examination, and cervical biopsy was performed for 95 patients. Fifty-one women referred due to AGC with normal colposcopy and normal second Pap smear were scheduled for control visits every 4 months. RESULTS: The overall prevalence of HPV DNA was 38%. HPV DNA was detected in 93% of the women with HSIL associated with AGC and in 71% of women with AIS Pap smear, being significantly higher when compared with the prevalence (29%) in women with AGC alone. Forty-five women (30.8%) had clinically significant histological lesions (CIN 2 or worse). High-risk HPV DNA was detected in only 16% of the women without significant abnormalities in biopsy, in contrast to 96% of those who had CIN 2 or CIN 3 and 75% of women with AIS. Eighty-five percent of women with invasive cervical carcinoma (squamous or adenocarcinoma) tested positive for HPV DNA. HPV DNA detection was significantly associated with histological diagnosis of CIN 2 or worse, with an odds ratio (OR) = 51.8 (95% CI 14.3-199.9). CONCLUSION: HPV DNA detection was strongly associated with the severity of cervical lesion (CIN 2 or worse) in women referred for AGC or AIS in their Pap smear. These data implicate the use of HPV testing in triage of women with AGC Pap smears.