RESUMEN
OBJECTIVES: We aimed to evaluate the risk of cervical and vaginal clear cell adenocarcinoma (CCA) in women, aged 50 years or more, exposed in utero to diethylstilbestrol (DES) and contribute to a reevaluation of the recommendations for cervical and vaginal cancer and pre-cancer screening for these women. METHODS: We carried out a retrospective review for patients received in a cancer institute. Two cohorts were consecutively studied, the first from 1970 to 2003 and the second from 2004 to 2021, and then linked. RESULTS: During the first period, we observed 61 CCA cases, with a mean age at diagnosis of 23 years (7-42), 36 (59%) following DES exposure in utero. During the second period, we found 27 cases, with one case of DES exposure (4%) for a women diagnosed at the age of 40 years. The mean age of the second cohort was 38 years (14-79). For the seven women aged 50 years or more at the time of CCA diagnosis, DES exposure was excluded for five and considered unlikely for the other two. CONCLUSION: In total, 88 cases of cervical or vaginal CCA were observed over a period of 51 years in a cancer center. The 37 cases associated with DES exposure represented approximatively one third of the CCA related to DES expected in France. DES exposure was improbable for the seven cases of CCA for women aged 50 years or more. These results do not support the hypothesis of late cervical or vaginal CCA in women exposed to DES in utero and indicate the need for larger multicentric studies. For the present, we propose specific screening for women exposed to DES in utero in terms of : 1) methods: association of cytology and hrHPV testing, with cervical and vaginal sampling, 2) timing : annual, or without exceeding a three-year interval, continuing after 65 years of age and after hysterectomy.
Asunto(s)
Adenocarcinoma de Células Claras , Carcinoma in Situ , Neoplasias del Cuello Uterino , Neoplasias Vaginales , Humanos , Femenino , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Niño , Neoplasias Vaginales/inducido químicamente , Neoplasias Vaginales/diagnóstico , Neoplasias Vaginales/epidemiología , Dietilestilbestrol/efectos adversos , Adenocarcinoma de Células Claras/inducido químicamente , Adenocarcinoma de Células Claras/diagnóstico , Adenocarcinoma de Células Claras/epidemiología , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/epidemiología , Cuello del Útero/patologíaRESUMEN
PURPOSE: Women exposed to diethylstilbestrol (DES) in utero were at elevated risk of clear-cell adenocarcinoma of the vagina and cervix (CCA) as young women. Previous research suggested that this elevated risk of CCA may persist into adulthood. We extended a published analysis to measure CCA risk as these women aged. METHODS: Standardized incidence ratios (SIR) compared CCA risk among women born from 1947 through 1971 (the DES-era) to CCA risk among the comparison group of women born prior to 1947, using registry data that covered the US population. RESULTS: Incidence rates of CCA among both cohorts increased with age. Among the DES-era birth cohort, higher rates of CCA were observed across all age groups except 55-59 years. SIR estimates had wide confidence intervals that often included the null value. CONCLUSIONS: Results are consistent with prior research and suggest an elevated risk of CCA in midlife and at older ages among women exposed in utero to DES. These results highlight unresolved issues regarding cancer risk among aging DES daughters and appropriate screening guidance. The examination of population-based cancer surveillance data may be a useful tool for monitoring trends in the incidence of other rare cancers over time among specific birth cohorts.
Asunto(s)
Adenocarcinoma de Células Claras , Efectos Tardíos de la Exposición Prenatal , Neoplasias del Cuello Uterino , Neoplasias Vaginales , Adenocarcinoma de Células Claras/inducido químicamente , Adenocarcinoma de Células Claras/epidemiología , Adulto , Cuello del Útero , Dietilestilbestrol/efectos adversos , Femenino , Humanos , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/epidemiología , Neoplasias del Cuello Uterino/inducido químicamente , Neoplasias del Cuello Uterino/epidemiología , Vagina , Neoplasias Vaginales/inducido químicamente , Neoplasias Vaginales/diagnóstico , Neoplasias Vaginales/epidemiologíaRESUMEN
To date, vaginal/cervical clear cell adenocarcinoma (CCAC) has not been reported in the granddaughters of women treated with diethylstilbestrol (DES) during pregnancy. We present an 8-year-old girl with a history of severe vaginal bleeding who was diagnosed with cervical CCAC. She underwent fertility-sparing surgery and radiotherapy. No sign of recurrence was detected throughout a 10-year follow-up. Her grandmother had received DES therapy during pregnancy with the patient's mother. Although no direct causal link is demonstrated, this case raises for the first time, the hypothesis of multigenerational effects of DES in girls and strongly suggests the need to follow the granddaughters of DES-treated women.
Asunto(s)
Adenocarcinoma de Células Claras , Disruptores Endocrinos , Efectos Tardíos de la Exposición Prenatal , Adenocarcinoma de Células Claras/inducido químicamente , Cuello del Útero , Niño , Dietilestilbestrol/efectos adversos , Femenino , Humanos , Recurrencia Local de Neoplasia , EmbarazoRESUMEN
In the Diethylstilbestrol [DES] Combined Cohort Follow-up, the age- and calendar-year specific standardized incidence ratio [SIR] for clear cell adenocarcinoma [CCA] was 27.6 (95% confidence interval [CI] 7.51-70.6) for the exposed women. The SIR for breast cancer was 1.17 (95% CI 1.01-1.36) and the hazard ratio [HR] adjusted for birth year and cohort for comparison with the unexposed was 1.05 (95% CI 0.79-1.41). The SIR for pancreatic cancer was 2.43 (95% CI 1.21-4.34) and the adjusted HR for comparison with unexposed women was 7.16 (95% CI 0.84-61.5). There was little evidence of excess risk for other sites. There appeared to be a deficit in risk for endometrial cancer among the exposed (SIR 0.61; 95% CI 0.35-0.98), and an excess in the unexposed (SIR 1.55; 95% CI 0.95-2.40); the adjusted HR was 0.45 (95% CI 0.22-0.93) for the internal comparison. There was no overall excess cancer risk in exposed women compared with general population rates (1.06; 95% CI 0.95-1.17) or with unexposed participants (adjusted HR 1.03; 95% CI 0.84-1.25). These data do not support the suggestion that there is a diathesis of cancers in DES exposed female offspring The excess risk of breast and pancreatic cancers that we observed is concerning and warrants continued follow-up and mechanistic investigation. Environ. Mol. Mutagen. 60:395-403, 2019. Published 2017. This article is a US Government work and is in the public domain in the USA.
Asunto(s)
Carcinógenos/toxicidad , Dietilestilbestrol/toxicidad , Exposición Materna , Intercambio Materno-Fetal/fisiología , Efectos Tardíos de la Exposición Prenatal/patología , Adenocarcinoma de Células Claras/inducido químicamente , Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/epidemiología , Neoplasias Endometriales/inducido químicamente , Neoplasias Endometriales/epidemiología , Femenino , Humanos , Neoplasias Pancreáticas/inducido químicamente , Neoplasias Pancreáticas/epidemiología , Embarazo , Encuestas y CuestionariosAsunto(s)
Adenocarcinoma de Células Claras/mortalidad , Dietilestilbestrol/efectos adversos , Efectos Tardíos de la Exposición Prenatal , Neoplasias del Cuello Uterino/mortalidad , Neoplasias Vaginales/mortalidad , Adenocarcinoma de Células Claras/inducido químicamente , Adolescente , Adulto , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Embarazo , Análisis de Supervivencia , Neoplasias del Cuello Uterino/inducido químicamente , Neoplasias Vaginales/inducido químicamente , Adulto JovenRESUMEN
OBJECTIVES: The aim of this study was to summarize the clinical and pathological characteristics and to conduct prognosis analysis of patients who were diagnosed with clear cell carcinoma of the uterine cervix (CCCUC) and without a history of exposure to diethylstilbestrol. METHODS: We performed a retrospective review of all the patients with CCCUC who were diagnosed and treated at Zhejiang Cancer Hospital between 1998 and 2014. Charts were reviewed for clinical and pathological characteristics, and prognosis analysis was conducted. RESULTS: A total of 47 patients were included. Median age was 52 years. No patient had a history of exposure to diethylstilbestrol. The International Federation of Gynecology and Obstetrics stage distribution was 55.3% (n = 26) stage I, 40.4% (n = 19) stage II, 2.1% (n = 1) stage III, and 2.1% (n = 1) stage IV. Forty-two patients (89.4%) underwent radical hysterectomy and pelvic lymphadenectomy. Pathological examination revealed deep cervical stromal invasion (greater than two thirds) in 20 patients (48.4%), pelvic lymph node (PLN) metastasis in 10 patients (23.8%), lymphovascular space involvement in 9 patients (21.4%), and ovarian metastasis in 1 patient (2.4%). Advanced tumor stage (IIB-IV), larger tumor size (>4 cm), and PLN metastasis had negative effects on progression-free survival (PFS) and overall survival (OS) (P < 0.05). Adjuvant radiation therapy alone or concurrent chemoradiation therapy after radical surgery did not affect PFS or OS in patients with risk factors (P > 0.05). CONCLUSIONS: International Federation of Gynecology and Obstetrics stage, tumor size, and PLN status were prognostic factors for both PFS and OS in patients with CCCUC. The long-term effects of adjuvant radiation therapy or concurrent chemoradiation therapy may be limited for CCCUC patients with risk factors. Future larger case series or clinical trials are required to confirm these findings.
Asunto(s)
Adenocarcinoma de Células Claras/epidemiología , Adenocarcinoma de Células Claras/patología , Dietilestilbestrol/administración & dosificación , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/patología , Adenocarcinoma de Células Claras/inducido químicamente , Adenocarcinoma de Células Claras/terapia , Adulto , Anciano , China/epidemiología , Dietilestilbestrol/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Neoplasias del Cuello Uterino/inducido químicamente , Neoplasias del Cuello Uterino/terapia , Útero/efectos de los fármacos , Adulto JovenAsunto(s)
Anomalías Inducidas por Medicamentos/etiología , Aborto Espontáneo/prevención & control , Amenaza de Aborto/tratamiento farmacológico , Adenocarcinoma de Células Claras/inducido químicamente , Dietilestilbestrol/efectos adversos , Dietilestilbestrol/uso terapéutico , Efectos Tardíos de la Exposición Prenatal , Neoplasias Testiculares/inducido químicamente , Neoplasias del Cuello Uterino/inducido químicamente , Neoplasias Vaginales/inducido químicamente , Adolescente , Adulto , Niño , Femenino , Humanos , Recién Nacido , Masculino , Embarazo , Medición de Riesgo , Adulto JovenRESUMEN
This story, that has been going on for 75 years begins with an infatuation for a "miraculous" drug supposed to, according to a theory and without scientific proof of effectiveness, reduce the pregnancy complications, especially the number of miscarriages. The next steps are painful with the discovery during the seventies, for the in utero exposed daughters, of particular cancers (clear cells adenocarcinoma) of the uterus cervix or the vagina, then during the eighties infertility and pregnancy accidents. This story is exemplary because it involves the different society actors whose roles will be analysed: health professionals, health authorities, patients associations, media and pharmaceutical companies. We will propose lessons for the future.
Asunto(s)
Aborto Espontáneo/prevención & control , Dietilestilbestrol/efectos adversos , Efectos Tardíos de la Exposición Prenatal/epidemiología , Adenocarcinoma de Células Claras/inducido químicamente , Dietilestilbestrol/administración & dosificación , Femenino , Humanos , Infertilidad Femenina/inducido químicamente , Embarazo , Neoplasias del Cuello Uterino/inducido químicamente , Neoplasias Vaginales/inducido químicamenteRESUMEN
BACKGROUND: Compensation of diethylstilbestrol exposure depends on the judicial system. In France, girls having been exposed to diethylstilbestrol are currently being compensated, and each exposure victim is being evaluated. Fifty-nine expert evaluations were studied to determine the causal relation between exposure to diethylstilbestrol and the pathologies attributable to diethylstilbestrol. METHODS: The following were taken into consideration: age at the first signs of the pathology; age of the sufferer at the time of evaluation; the pathologies grouped into five categories: fertility disorders - cancers - mishaps during pregnancy - psychosomatic complaints - pathologies of "3rd generation DES victims"; submission of proof of DES exposure; the degree of causality determined (direct, indirect, ruled out). RESULTS: 61% of the cases related to fertility disorders, 28.8% to cancer pathologies (clear-cell adenocarcinoma), 18.6% to mishaps during pregnancy, 8.5% to disorders resulting from preterm delivery, and 3.4% to psychosomatic disorders. Some cases involved a combination of two types of complaints. Indirect causality was determined in 47.1% of the cases involving primary sterility, in 66.7% involving secondary sterility, and in 5 out of 6 cases of total sterility. There is direct causality between in utero diethylstilbestrol exposure and vaginal or cervical clear cell adenocarcinoma. Causality is indirect in the case of disorders linked to prematurity in third generation victims. CONCLUSION: Causality was determined by the experts on the basis of scientific criteria which attribute the presenting pathologies to diethylstilbestrol exposure. When other risk factors come into play, or when exposure is indirect (third generation), this causality is diminished.
Asunto(s)
Adenocarcinoma de Células Claras/inducido químicamente , Dietilestilbestrol/efectos adversos , Estrógenos no Esteroides/efectos adversos , Efectos Tardíos de la Exposición Prenatal , Neoplasias del Cuello Uterino/inducido químicamente , Neoplasias Vaginales/inducido químicamente , Adenocarcinoma de Células Claras/epidemiología , Adolescente , Adulto , Compensación y Reparación/legislación & jurisprudencia , Femenino , Francia/epidemiología , Humanos , Lactante , Infertilidad Femenina/epidemiología , Embarazo , Complicaciones del Embarazo/epidemiología , Neoplasias del Cuello Uterino/epidemiología , Neoplasias Vaginales/epidemiología , Adulto JovenRESUMEN
OBJECTIVE: To compare clinico-pathologic variables and protein expression of potential regulatory components in patients who develop type II endometrial cancer with and without antecedent tamoxifen. METHODS: Clinico-pathologic variables were compared for all surgically staged patients (2000-2008) with grade 3 endometrioid, papillary serous, clear cell, and carcinosarcoma of the uterus based on tamoxifen exposure [Tam (+) vs. Tam (-)]. Overall survival was analyzed using a multivariable Cox regression model and Kaplan-Meier estimates. Protein expression of ERα, PR, mTOR, p-mTOR, IGF-1R, EGFR, VEGF and HER-2/neu was compared by immunohistochemistry using a semiquantitative scoring system. RESULTS: Of 115 patients with high grade endometrial cancers, 15 received tamoxifen. These patients were older at diagnosis than Tam (-) patients. A higher percentage of Tam (+) patients had carcinosarcoma compared to Tam (-) patients (60% vs. 30%, P=0.038). Overall survival for Tam (+) patients was shorter than Tam (-) patients (16.6 vs. 32.2 months, P=0.004). The hazard ratio for death for Tam (+) patients was 2.53 (P=0.014), controlling for age and stage. Intensity and extent of staining were similar for ERα, PR, VEGF, EGFR, p-mTOR and HER-2/neu. The average expression score for IGF-1R and mTOR in the Tam (+) group was significantly higher than the Tam (-) group: 10.3 vs 7.0, P=0.001 and 6.0 vs 3.1, P=0.029, respectively. CONCLUSION: There are differences in the biology of type II endometrial cancers that develop in women with prior tamoxifen exposure. Tamoxifen associated cancers show higher expression of IGF-1R and mTOR, which should be further investigated.
Asunto(s)
Antineoplásicos Hormonales/efectos adversos , Biomarcadores de Tumor/metabolismo , Carcinosarcoma/inducido químicamente , Neoplasias Endometriales/inducido químicamente , Neoplasias Glandulares y Epiteliales/inducido químicamente , Tamoxifeno/efectos adversos , Adenocarcinoma de Células Claras/inducido químicamente , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/mortalidad , Adenocarcinoma de Células Claras/patología , Anciano , Carcinoma Endometrioide/inducido químicamente , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/mortalidad , Carcinoma Endometrioide/patología , Carcinosarcoma/metabolismo , Carcinosarcoma/mortalidad , Carcinosarcoma/patología , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/patología , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Clasificación del Tumor , Neoplasias Glandulares y Epiteliales/metabolismo , Neoplasias Glandulares y Epiteliales/mortalidad , Neoplasias Glandulares y Epiteliales/patología , Pronóstico , Receptor IGF Tipo 1/metabolismo , Análisis de Supervivencia , Serina-Treonina Quinasas TOR/metabolismo , Análisis de Matrices TisularesRESUMEN
Exposure to exogenous hormones during development can result in permanent health problems. In utero exposure to diethylstilbestrol (DES) is probably the most well documented case in human history. DES, an orally active synthetic estrogen, was believed to prevent adverse pregnancy outcome and thus was routinely given to selected pregnant women from the 1940s to the 1960s. It has been estimated that 5 million pregnant women worldwide were prescribed DES during this period. In the early 1970s, vaginal clear cell adenocarcinomas (CCACs) were diagnosed in daughters whose mother took DES during pregnancy (known as DES daughters). Follow-up studies demonstrated that exposure to DES in utero causes a spectrum of congenital anomalies in female reproductive tracts and CCACs. Among those, cervical and vaginal adenoses are most commonly found, which are believed to be the precursors of CCACs. Transformation related protein 63 (TRP63/p63) marks the cell fate decision of Müllerian duct epithelium (MDE) to become squamous epithelium in the cervix and vagina. DES disrupts the TRP63 expression in mice and induces adenosis lesions in the cervix and vagina. This review describes mouse models that can be used to study the development of DES-induced anomalies, focusing on cervical and vaginal adenoses, and discusses their molecular pathogenesis.
Asunto(s)
Adenocarcinoma de Células Claras/inducido químicamente , Dietilestilbestrol/efectos adversos , Estrógenos no Esteroides/efectos adversos , Efectos Tardíos de la Exposición Prenatal , Neoplasias del Cuello Uterino/inducido químicamente , Neoplasias Vaginales/inducido químicamente , Adenocarcinoma de Células Claras/genética , Animales , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Fosfoproteínas/genética , Embarazo , Transactivadores/genética , Neoplasias del Cuello Uterino/genética , Neoplasias Vaginales/genéticaRESUMEN
Diethylstilboestrol (DES) is an endocrine disrupter which causes cancer in rodents. It was prescribed in large amounts to treat women with gynaecological problems; some of the daughters of these women subsequently developed a rare cancer (vaginal clear cell adenocarcinoma) while genital abnormalities were found in some of the sons. It was used for decades in livestock feed and this may have contaminated the food chain leading to the exposure of the more general population. DES appears to cause epigenetic effects in animals and there is some evidence that this also occurs in man. The mechanisms of carcinogenesis are complex and the effects are difficult to prove due to the background of dietary and environmental phyto- and xenooestrogens. It has been suggested that, like other endocrine disrupters, DES may have acted as an obesogen in the human population.
Asunto(s)
Aborto Espontáneo/prevención & control , Dietilestilbestrol/efectos adversos , Dietilestilbestrol/uso terapéutico , Adenocarcinoma de Células Claras/inducido químicamente , Alimentación Animal/efectos adversos , Animales , Modelos Animales de Enfermedad , Epigénesis Genética , Femenino , Contaminación de Alimentos , Neoplasias de los Genitales Masculinos/inducido químicamente , Humanos , Masculino , Neoplasias Vaginales/inducido químicamenteRESUMEN
Ovarian cancer is a leading cause of cancer death among women in the United States and it has the highest mortality rate of all gynecologic cancers. Internationally, there is a five-fold variation in incidence and mortality of ovarian cancer, which suggests a role for environmental factors, including diet. Nitrate and nitrite are found in various food items and they are precursors of N-nitroso compounds, which are known carcinogens in animal models. We evaluated dietary nitrate and nitrite intake and epithelial ovarian cancer in the National Institutes of Health (NIH)-AARP Diet and Health Study, including 151 316 women aged 50-71 years at the time of the baseline questionnaire in 1995-1996. The nitrate and nitrite intake was assessed using a 124-item validated food frequency questionnaire. Through 31 December 2006, 709 incident epithelial ovarian cancer cases with complete dietary information were identified. Using Cox proportional hazards regression to estimate hazard ratios and 95% confidence intervals (CIs), women in the highest intake quintile of dietary nitrate had a 31% increased risk (95% CI: 1.01-1.68) of epithelial ovarian cancer, compared with those in the lowest intake quintile. Although there was no association for total dietary nitrite, those in the highest intake category of animal sources of nitrite had a 34% increased risk (95% CI: 1.05-1.69) of ovarian cancer. There were no clear differences in risk by histologic subtype of ovarian cancer. Our findings suggest that a role of dietary nitrate and nitrite in ovarian cancer risk should be followed in other large cohort studies.
Asunto(s)
Adenocarcinoma de Células Claras/epidemiología , Adenocarcinoma Mucinoso/epidemiología , Dieta , Neoplasias Endometriales/epidemiología , Nitratos/efectos adversos , Nitritos/efectos adversos , Neoplasias Ováricas/epidemiología , Adenocarcinoma de Células Claras/inducido químicamente , Adenocarcinoma Mucinoso/inducido químicamente , Adulto , Anciano , Encuestas sobre Dietas , Neoplasias Endometriales/inducido químicamente , Femenino , Humanos , Incidencia , Persona de Mediana Edad , National Institutes of Health (U.S.) , Neoplasias Ováricas/inducido químicamente , Estudios Prospectivos , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Before 1971, several million women were exposed in utero to diethylstilbestrol (DES) given to their mothers to prevent pregnancy complications. Several adverse outcomes have been linked to such exposure, but their cumulative effects are not well understood. METHODS: We combined data from three studies initiated in the 1970s with continued long-term follow-up of 4653 women exposed in utero to DES and 1927 unexposed controls. We assessed the risks of 12 adverse outcomes linked to DES exposure, including cumulative risks to 45 years of age for reproductive outcomes and to 55 years of age for other outcomes, and their relationships to the baseline presence or absence of vaginal epithelial changes, which are correlated with a higher dose of, and earlier exposure to, DES in utero. RESULTS: Cumulative risks in women exposed to DES, as compared with those not exposed, were as follows: for infertility, 33.3% vs. 15.5% (hazard ratio, 2.37; 95% confidence interval [CI], 2.05 to 2.75); spontaneous abortion, 50.3% vs. 38.6% (hazard ratio, 1.64; 95% CI, 1.42 to 1.88); preterm delivery, 53.3% vs. 17.8% (hazard ratio, 4.68; 95% CI, 3.74 to 5.86); loss of second-trimester pregnancy, 16.4% vs. 1.7% (hazard ratio, 3.77; 95% CI, 2.56 to 5.54); ectopic pregnancy, 14.6% vs. 2.9% (hazard ratio, 3.72; 95% CI, 2.58 to 5.38); preeclampsia, 26.4% vs. 13.7% (hazard ratio 1.42; 95% CI, 1.07 to 1.89); stillbirth, 8.9% vs. 2.6% (hazard ratio, 2.45; 95% CI, 1.33 to 4.54); early menopause, 5.1% vs. 1.7% (hazard ratio, 2.35; 95% CI, 1.67 to 3.31); grade 2 or higher cervical intraepithelial neoplasia, 6.9% vs. 3.4% (hazard ratio, 2.28; 95% CI, 1.59 to 3.27); and breast cancer at 40 years of age or older, 3.9% vs. 2.2% (hazard ratio, 1.82; 95% CI, 1.04 to 3.18). For most outcomes, the risks among exposed women were higher for those with vaginal epithelial changes than for those without such changes. CONCLUSIONS: In utero exposure of women to DES is associated with a high lifetime risk of a broad spectrum of adverse health outcomes. (Funded by the National Cancer Institute.).
Asunto(s)
Neoplasias de la Mama/inducido químicamente , Dietilestilbestrol/efectos adversos , Estrógenos no Esteroides/efectos adversos , Neoplasias de los Genitales Femeninos/inducido químicamente , Complicaciones del Embarazo/inducido químicamente , Efectos Tardíos de la Exposición Prenatal , Adenocarcinoma de Células Claras/inducido químicamente , Femenino , Estudios de Seguimiento , Humanos , Menopausia Prematura , Embarazo , Mortinato , Displasia del Cuello del Útero/inducido químicamenteRESUMEN
OBJECTIVE: Over 90% of all cervical adenocarcinoma are caused by a transforming infection with a high-risk type human papillomavirus (hrHPV). Previous studies demonstrated that the association between hrHPV positivity and cervical clear-cell adenocarcinoma (CCAC) varies between 0% and 100%. As approximately 60% of all CCAC are associated with intra-uterine diethylstilbestrol (DES) exposure, we determined in a cohort of both DES-exposed and DES-unexposed women the prevalence of hrHPV infections, and the potential etiological role of hrHPV by additional analysis of p16INK4a and p53 expression. METHODS: Representative slides of 28 women diagnosed with CCAC were tested for hrHPV by two PCR methods (the clinically validated GP5+/6+ PCR and the very sensitive SPF(10)PCR/LiPA(25)). Fifteen women were DES-exposed, 10 unexposed and of 3 women DES-exposure was unknown. Twenty-one cases with sufficient material were immuno-histochemically stained for p16INK4a and p53. RESULTS: Seven tumors, of which four DES-exposed and two unexposed tested positive for hrHPV with GP5+/6+ PCR. Thirteen tumors, of which five DES-exposed and seven unexposed, tested positive with SPF(10)PCR/LiPA(25). In one women with unknown exposure, a CCAC tested positive in both assays. Only three cases, none in DES-exposed women, and all positive with both hrHPV assays, revealed diffuse p16INK4a immuno-staining and weak p53 staining as well, supporting indisputable hrHPV involvement. CONCLUSIONS: Although the prevalence of hrHPV was high, only two DES-unrelated CCAC (25%) and one tumor in a woman with unknown exposure could be attributed to hrHPV.
Asunto(s)
Adenocarcinoma de Células Claras/etiología , Dietilestilbestrol/efectos adversos , Papillomaviridae/aislamiento & purificación , Efectos Tardíos de la Exposición Prenatal , Neoplasias del Cuello Uterino/etiología , Adenocarcinoma de Células Claras/inducido químicamente , Adenocarcinoma de Células Claras/virología , Adolescente , Adulto , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Proteínas de Neoplasias/análisis , Reacción en Cadena de la Polimerasa , Embarazo , Riesgo , Proteína p53 Supresora de Tumor/análisis , Neoplasias del Cuello Uterino/inducido químicamente , Neoplasias del Cuello Uterino/virologíaAsunto(s)
Adenocarcinoma de Células Claras/inducido químicamente , Dietilestilbestrol/efectos adversos , Disruptores Endocrinos/efectos adversos , Efectos Tardíos de la Exposición Prenatal , Neoplasias Vaginales/inducido químicamente , Aborto Espontáneo/prevención & control , Adenocarcinoma de Células Claras/historia , Dietilestilbestrol/historia , Dietilestilbestrol/uso terapéutico , Disruptores Endocrinos/historia , Disruptores Endocrinos/uso terapéutico , Femenino , Desarrollo Fetal/efectos de los fármacos , Historia del Siglo XX , Humanos , Conductos Paramesonéfricos/efectos de los fármacos , Conductos Paramesonéfricos/embriología , Embarazo , Tiempo , Vagina/efectos de los fármacos , Vagina/embriología , Neoplasias Vaginales/historiaRESUMEN
OBJECTIVE: We examined long-term risk of cancer in women exposed to diethylstilbestrol (DES) in utero. METHODS: A total of 12,091 DES-exposed women in the Netherlands were followed prospectively from December 1992 till June 2008. Cancer incidence was assessed through linkage with the Dutch pathology database (PALGA) and the Netherlands Cancer Registry and compared with the Dutch female population. RESULTS: A total of 348 medically verified cancers occurred; median age at end of follow-up was 44.0 years. No overall increased risk of cancer was found (standardized incidence ratio [SIR] = 1.01; 95% confidence interval [CI] = 0.91, 1.13). The risk of clear cell adenocarcinoma of the vagina and cervix (CCA) was statistically significantly increased (SIR = 24.23; 95% CI = 8.89, 52.74); the elevated risk persisted above 40 years of age. The risk of melanoma diagnosed before age 40 was increased (SIR = 1.59; 95% CI = 1.08, 2.26). No excess risks were found for other sites, including breast cancer. CONCLUSIONS: Except for an elevated risk of CCA, persisting at older ages, and an increased risk of melanoma at young ages, we found no increased risk of cancer. Longer follow-up is warranted to examine cancer risk at ages when cancer occurs more frequently.
Asunto(s)
Adenocarcinoma de Células Claras/epidemiología , Dietilestilbestrol/efectos adversos , Núcleo Familiar , Neoplasias Vaginales/epidemiología , Adenocarcinoma de Células Claras/inducido químicamente , Adulto , Estudios de Cohortes , Estrógenos no Esteroides/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Persona de Mediana Edad , Países Bajos/epidemiología , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/epidemiología , Estudios Prospectivos , Sistema de Registros/estadística & datos numéricos , Factores de Riesgo , Encuestas y Cuestionarios , Neoplasias Vaginales/inducido químicamenteRESUMEN
OBJECTIVE: To determine the current situation regarding the epidemic of clear cell adenocarcinoma of the vagina and the uterine cervix (CCAC) in relation to the exposure in utero to diethylstilbestrol (DES). DESIGN: Descriptive. METHODS: Patients with CCAC of the uterine cervix or vagina born after 1946 and diagnosed in the period 1969-2005, were identified through the Nationwide network and registry of histo- and cytopathology in the Netherlands and from 2003 onwards through the Netherlands Cancer Registry. Exposure data and clinical data were obtained by means of questionnaires and medical records. The histology slides of tumours were reviewed. For the patients who did not provide consent, only the date of diagnosis and age at diagnosis were known (n = 10). RESULTS: Up to 2005, 144 CCAC patients were registered. Age at diagnosis varied from 8-54 years (mean: 28 years). In the years 1981-2000, the number of new diagnoses in 4 successive 5-year periods was fairly stable (n=26-30) but it was considerably lower in 2001-2005 (n=13). Of the patients whose history of intrauterine exposure to DES was known, 62% had been exposed (76/122). The mean age at diagnosis was 24 years for exposed patients compared to 32 years for non-exposed patients. The 10-year survival rate was 78% (95% CI: 68-87) for exposed and 69% (95% CI: 56-82) for non-exposed patients. CONCLUSION: Since 2000, the incidence of CCAC of the vagina and cervix has decreased markedly compared to the situation in the 1980s and 1990 s. In particular, the number of patients with CCAC exposed in utero to DES has decreased. Whether this decrease shall continue over the coming years remains to be seen.
Asunto(s)
Adenocarcinoma de Células Claras/epidemiología , Dietilestilbestrol/efectos adversos , Neoplasias del Cuello Uterino/epidemiología , Neoplasias Vaginales/epidemiología , Adenocarcinoma de Células Claras/inducido químicamente , Adenocarcinoma de Células Claras/patología , Adolescente , Adulto , Distribución por Edad , Carcinógenos , Niño , Femenino , Humanos , Persona de Mediana Edad , Países Bajos/epidemiología , Embarazo , Efectos Tardíos de la Exposición Prenatal , Sistema de Registros , Neoplasias del Cuello Uterino/inducido químicamente , Neoplasias del Cuello Uterino/patología , Neoplasias Vaginales/inducido químicamente , Neoplasias Vaginales/patología , Adulto JovenRESUMEN
BACKGROUND: Clear cell adenocarcinoma of the vagina and cervix were previously shown to be tumors occurring in female offspring exposed prenatally to diethylstilbestrol. This report describes the first clinical case of clear cell adenocarcinoma of the ovary linked to early diethylstilbestrol exposure in utero. CASE: A 45-year-old woman presented with a self-discovered lump in the lower abdominal quadrant. She underwent surgery and staging that revealed clear cell adenocarcinoma confined to the left ovary. Foci of high-grade squamous neoplastic proliferation, inflammation, and a paratubal cyst were also present on the pathology specimen. Medical records established unequivocally that the patient's mother received diethylstilbestrol therapy throughout the pregnancy. CONCLUSION: Our case is consistent with clear cell adenocarcinoma, probably related to diethylstilbestrol exposure in utero. It reinforces the need for continued vigilance in individuals prenatally exposed to this drug.
Asunto(s)
Adenocarcinoma de Células Claras/inducido químicamente , Dietilestilbestrol/efectos adversos , Neoplasias Ováricas/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Adenocarcinoma de Células Claras/diagnóstico por imagen , Adenocarcinoma de Células Claras/patología , Dietilestilbestrol/administración & dosificación , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/diagnóstico por imagen , Neoplasias Ováricas/patología , Embarazo , Efectos Tardíos de la Exposición Prenatal/diagnóstico por imagen , Efectos Tardíos de la Exposición Prenatal/patología , UltrasonografíaRESUMEN
OBJECTIVE: To conduct an outcome analysis of patients with cervical clear cell carcinoma (CCCC) in the post-DES era. METHODS: A retrospective review was conducted at 3 major gynecologic cancer centers of all primary CCCC between 1982 and 2004. RESULTS: CCCC was confirmed in 34 patients. Median age was 53 years. DES exposure was confirmed in 2 (6%) patients. A history of smoking was elicited in 22%, and of abnormal Pap smear 18% patients. Primary surgical resection was performed in all stage I or IIA patients (n=26); they displayed superior 3-year overall survival (OS) compared to advanced stage (n=8) patients (91% vs. 22%, p<0.001). Pelvic lymph node involvement was noted in 25%; all patients with positive para-aortic nodes (20% of patients sampled) had positive pelvic nodes. All node positive patients were treated with adjuvant radiation, but nevertheless displayed reduced progression free (31% vs 92%, p<0.001) and overall survival (80% vs. 100%, p=0.02). Adjuvant radiotherapy did not appear to impact OS in patients with negative lymph nodes. DISCUSSION: This series provides insight into the management of early stage CCCC in the post-DES era. Although these patients may be at slightly higher risk of nodal spread, clear cell histology by itself does not appear to portend a worse prognosis than squamous cell carcinoma of the cervix in the absence of traditional risk factors. Our data suggest that patients with low risk early stage CCCC may be managed with radical surgery alone, without the need for adjuvant chemotherapy or radiation.