2ª PONENCIA
FACTORES DE RIESGO EN GINECOLOGÍA ONCOLÓGICA
Risks factors for endometrial cancer
(Factores de riesgo del cáncer de endometrio)
E. Hernández, MD
Professor of Obstetrics, Gynecology, and Reproductive Sciences
Professor of Pathology and Laboratory Medicine
Temple University School of Medicine
Director, Division of Gynecologic Oncology
Temple University Hospital
3400 N Broad St.
Philadelphia, PA 19140
Hay dos tipos de cáncer endometrial. El tipo I esta representado por tumores grado 1 y 2 de invasión miometrial poco profunda. Estos tumores responden a tratamiento con progestagenos. Su prognosis es favorable. Los carcinomas endometriales tipo II son tumores grado 3 o de tipo histológico agresivo (e.g., célula clara, seroso papilar) los cuales tienden a invadir profundamente el miometrio y están asociados con una prognosis pobre. Factores que aumentan el riesgo de que una mujer desarrolle cáncer endometrial tipo I incluyen: obesidad, nuliparidad, diabetes mellitus, hipertensión, uso de estrogeno o tamoxifeno. Mujeres que tienen el gene del cáncer colorectal no-poliposo hereditario tienen una probabilidad de hasta un 30 por ciento de desarrollar cáncer endometrial. Los embarazos a término y el uso de anticonceptivos orales reducen el riesgo de desarrollar cáncer endometrial. Los factores de riesgo asociados con el cáncer endometrial tipo II no están aún bien definidos. No obstante, estudios de pacientes con carcinoma uterino seroso papilar no demuestran asociación alguna de este tipo histológico de cáncer endometrial con el uso de estrogeno, obesidad, diabetes, o hipertensión.
It has been suggested that there are two types of endometrial carcinoma(1). The first type is characteristically a well-differentiated tumor with superficial myometrial invasion. It is sensitive to progestogens and exhibits a more favorable prognosis. The second type is a poorly differentiated tumor or an aggressive histologic cell type (e.g., clear cell, and papillary serous) which invades deeply into the myometrium and exhibits a decreased 5-year survival. Women with type I endometrial carcinoma tend to be younger than those with type II.
Of 82 patients recently treated by us for endometrial carcinoma, 70 (85%) had endometrioid tumors, 7 (8%) were papillary serous, 4 (5%) clear cell and one had both papillary serous and clear cell features. Of the 70 patients with endometrioid tumors, 12 (17%) were grade 3. Therefore, one-third of patients with endometrial carcinoma has poorly differentiated tumors or aggressive histologic types.
The type I endometrial carcinomas are associated with unopposed estrogen of either endogenous or exogenous origin, while the type II carcinomas might not be. Obesity of 13 to 22 kg over ideal body weight is associated with a 3-fold increase in the risk of developing endometrial carcinoma(2). The risk is 10-fold higher in women who are 23 kg overweight. Peripheral conversion of androstenedione to estrone by the fibroblasts in the fat accounts for the higher rate of endometrial carcinoma in obese women.
Nulliparity is associated with a 2-fold increase in endometrial cancer risk. This is probably related to the production of unopposed estrogen in women who are experiencing anovulation.
Other characteristics associated with patients who develop endometrial cancer include diabetes mellitus (1.8-fold increased risk), hypertension (1.5-fold increased risk), and the presence of complex atypical endometrial hyperplasia (29-fold increased risk). The use of unopposed estrogen replacement therapy has been reported to be associated with a 4-fold increased risk of developing endometrial carcinoma(3).
The use of tamoxifen (20 mg/day) in the North American breast cancer trials resulted in an increased risk of developing endometrial cancer of 7.5(2). In women taking placebo the annual incidence of endometrial cancer was 0.2/1000 while it was 1.6/1000 in women on tamoxifen. Since the expected mortality in this group is approximately 15%, annual screening of the thousands of women who take tamoxifen could potentially decrease mortality in 0.024% of all women on tamoxifen. Therefore, endometrial sampling for women on tamoxifen should be reserved for patients with abnormal bleeding. A baseline endometrial biopsy should be considered to exclude an already present hyperplasia or cancer.
A number of studies have shown a protective effect from endometrial cancer of a full-term pregnancy and the use of oral contraceptives. There is a linear inverse relationship between the number of full-term pregnancies and the risk of developing endometrial cancer(4,5). The use of oral contraceptives has been consistently associated with an almost 50% reduction in the risk of developing endometrial carcinoma(6).
The incidence of endometrial cancer is significantly increased among members of families with hereditary nonpolyposis colorectal cancer (HNPCC)(7). This disorder is subdivided into Lynch I and II syndromes. Lynch I syndrome is characterized by early onset (mean age, 40-45 years) colorectal cancer that shows a predilection (60-70%) for the proximal colon (i.e., to the right of the splenic flexure) and has a high rate of multiple primary colorectal carcinomas. The Lynch II syndrome has all of the above features but in addition includes a number of extracolonic cancers the most common of which is endometrial cancer.
Mutations of DNA mismatch repair genes in the region of chromosome 2p (hMSH2) and chromosome 3p (hMLH1) account for 90% of all known HNPCC families. This disturbance in DNA mismatch repair leads to genetic instability in somatic cells.
The lifetime risk for developing endometrial carcinoma for HNPCC gene carriers may be as high as 30%. It is recommended that endometrial sampling be obtained annually beginning at the age of 30 years in women from HNPCC families(8). These women should also have a full colonoscopy every two years from age 20 to 35 years, and annually after the age of 35 years. It is also recommended that they undergo annual transvaginal ultrasound and CA-125 determination. Prophylactic oophorectomy should be considered after completion of the family.
The risk factors for type II endometrial cancer have not been thoroughly studied. Studies of patients with uterine papillary serous carcinoma suggest a lack of association between estrogen use, obesity, diabetes, and hypertension and this histologic type of endometrial carcinoma(9). Interestingly, type I endometrial carcinomas and malignant mixed mesodermal tumors of the uterus share the same risk factors. A recent study showed that obesity, exogenous estrogen and nulliparity were associated with an increased risk of developing either of these cancers(10). Oral contraceptive use was associated with a protective effect against the development of both endometrial carcinoma and uterine malignant mixed mesodermal tumor.
Additional studies are needed to better define the risk factors associated with type II endometrial carcinoma.
BIBLIOGRAFIA
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