Endometrial "sarcomas" complicating ovarian thecoma, polycystic ovarian disease and estrogen therapy

Unopposed endogenous and exogenous estrogenic stimulation has been considered by most investigators to have a role in the pathogenesis of carcinoma of the endometrium. Although a few cases of "sarcomas" of the endometrium that had developed in an estrogenic setting have been reported, a clear-cut association between estrogenic stimulation and these forms of endometrial cancer has not been established. We report six cases of endometrial sarcomas complicating ovarian thecomas, polycystic ovarian disease, or prolonged estrogen therapy. Three ovarian thecomas, which are considered to be estrogenic tumors, were associated with endometrial malignant mullerian mixed tumor, mullerian adenosarcoma, and low-grade stromal sarcoma in postmenopausal women. Polycystic ovarian disease, a condition characterized by unopposed estrinism due to the peripheral conversion of excessive androstenedione to estrone, was found in a 27-year-old infertile woman with an endometrial malignant mullerian mixed tumor. A pure osteogenic sarcoma of endometrial stromal origin developed in a 28-year-old woman with gonadal dysgenesis (Turner's syndrome) who had received estrogens for 18 years. The sixth woman, with an empty sella turcica after radiation therapy of a pituitary adenoma, had an endometrial mullerian adenosarcoma at the age of 40 years after 16 years of estrogen therapy. None of these patients had had pelvic radiation therapy. The evidence from this series of cases and from six additional cases identified in the literature suggests that the risk of endometrial sarcomas may be increased by estrogen therapy or endogenous disorders that lead to unopposed estrogenic stimulation of the uterus.     

Polycystic ovary syndrome and gynecological cancers: is there a link?

Polycystic ovary syndrome [PCOS] is the most common endocrinopathy of women in reproductive age. An association between PCOS and type-1 endometrial cancer has often been reported in the literature. The prolonged anovulation with consequent continued secretion of estrogen unopposed by progesterone may enhance the development and growth of this malignancy, particularly in young women. Hypersecretion of luteinizing hormone [LH], chronic hyperinsulinemia and increased serum insulin-like growth factor [IGF]-I levels may represent risk factors for endometrial cancer. However, data available in the literature do not allow a meta-analysis to be carried out to calculate an estimate of the relative risk of endometrial cancer in women with PCOS. Anecdotal cases of low-grade endometrial stromal sarcoma and carcinosarcoma have been reported in association with prolonged unopposed estrogen stimulation, and in particular with PCOS. A few studies have addressed the possibility of an association between PCOS and epithelial ovarian cancer risk, and the results are conflicting but generally reassuring, and similarly the few available data appear to exclude a strong association between PCOS and breast cancer.     

Polycystic ovary syndrome and gynecological cancers: Is there a link?

Polycystic ovary syndrome [PCOS] is the most common endocrinopathy of women in reproductive age. An association between PCOS and type-1 endometrial cancer has often been reported in the literature. The prolonged anovulation with consequent continued secretion of estrogen unopposed by progesterone may enhance the development and growth of this malignancy, particularly in young women. Hypersecretion of luteinizing hormone [LH], chronic hyperinsulinemia and increased serum insulin-like growth factor [IGF]-I levels may represent risk factors for endometrial cancer. However, data available in the literature do not allow a meta-analysis to be carried out to calculate an estimate of the relative risk of endometrial cancer in women with PCOS. Anecdotal cases of low-grade endometrial stromal sarcoma and carcinosarcoma have been reported in association with prolonged unopposed estrogen stimulation, and in particular with PCOS. A few studies have addressed the possibility of an association between PCOS and epithelial ovarian cancer risk, and the results are conflicting but generally reassuring, and similarly the few available data appear to exclude a strong association between PCOS and breast cancer.     

Endometrial carcinoma in gonadal dysgenesis with and without estrogen therapy

Two phenotypically female patients with gonadal dysgenesis who developed endometrial carcinoma are described. One patient has not received exogenous estrogen therapy. No such patient has been reported previously. This patient developed the unusual mixed adenosquamous carcinoma. Both carcinomas were detected at an early age. It is postulated that the carcinomas developed essentially because of unopposed endogenous estrogen secretion due to anovulation.     

Role of estrogens and progesterone in the etiology and prevention of endometrial cancer: review

Our present knowledge of the role of sex steroids in the development as well as the prevention of endometrial cancer is reviewed. Factors which increase the exposure of the uterus to unopposed estrogens, either exogenous or endogenous, are associated with increased risk of endometrial adenocarcinoma. However, there is increasing evidence that progestogens can reverse endometrial hyperplasia and protect against the development of endometrial cancer. The mechanisms to explain the antiestrogenic effects of progestogens include changes in enzyme activity and steroid receptors in endometrial tissue. Postmenopausal women treated with combined estrogen and progestogen have the lowest incidence of endometrial carcinoma. Oral contraceptives containing both estrogen and progestogen in each tablet are protective against adenocarcinoma of the endometrium, while the sequential oral contraceptive pills afforded less protection. The risks and benefits of these hormone therapies are discussed in relation to the etiology and prevention of endometrial cancer.     

Current molecular aspects of the carcinogenesis of the uterine endometrium

Abstract. Inoue M. Current molecular aspects of the carcinogenesis of the uterine endometrium.
Carcinogenesis in many tissues is a multistep process accompanied by a variety of morphologic, biochemical, and genetic changes in each step. It is well known that endometrial cancers arise through a series of precursor lesions, simple, complex, and atypical hyperplasia, by unopposed and prolonged estrogen stimulation. It is also accepted that there is an estrogen-independent type in which the precursor lesions are not identified. Recent molecular-based evidence has revealed three possible pathways for endometrial carcinogenesis, namely hyperplasia, metaplasia, and de novo pathways. The pathways each have their own features in both histopathology and molecular biology. Such understanding of the molecular profile of endometrial carcinoma prompted us to revise the classic criteria in histopathology regarding endometrial carcinogenesis. The recent molecular-based studies have provided a concept of endometrial intraepithelial lesions: endometrial intraepithelial neoplasia (EIN) as the precursor lesions of endometrial carcinomas. The new terminology might improve cancer screening protocols and treatment modalities.     

The cancer question: An overview of recent epidemiologic and retrospective data

Unopposed estrogen stimulates mitotic activity in endometrial and breast tissue. Numerous case-control studies have evaluated the relationship between estrogen use and the risk of endometrial and breast cancers. In general, exogenous, unopposed estrogen use increases the risk of endometrial cancer by tenfold and of breast cancer by twofold after long-term use of high doses. Estrogen's positive effects on osteoporosis and coronary heart disease must be considered when evaluating the potential risks associated with its use in postmenopausal women.     

Hormone replacement therapy (HRT) and endometrial morphology under consideration of the different molecular pathways in endometrial carcinogenesis

The majority of modern hormone replacement therapy (HRT) regimens contain estrogen and progestogens, given either in a cyclical or continuous manner. About 15% of the endometrial biopsies taken from women on sequential HRT show proliferative activity including atypical endometrial hyperplasia in up to 1% of the cases. The majority of biopsies from women under continuous combined HRT show an endometrial atrophy. About 2-3% of these women will present proliferative activity, usually without atypical hyperplasia. Contrary to breast cancer, an increased risk of endometrial cancer has not been reported in the WHI- and HERS-studies. However, endogenous factors, such as obesity, diabetes mellitus, the distribution of estrogen receptors alpha and beta and genetic polymorphisms for receptors and enzymes might alter the endometrial stimulation under different types of HRT. There should be a liberal indication for endometrial biopsies in Hereditary Non-Polyposis Colorectal Cancer (HNPCC). HNPCC-patients under HRT as well as for ultrasonographic evaluation of the endometrium. The risk of atypical hyperplasias or carcinoma under unopposed estrogen-therapy varies from 2 to 10%. So, this kind of HRT should not be used in non-hysterectomised women. As far as the risk of endometrial cancer under any kind of HRT is concerned, the different molecular pathways of endometrial carcinogenesis (type 1 and 2 cancers) should be taken into account. The use of tibolone leaves the endometrium unaffected.     

Ultrastructural effects of estrogen replacement on postmenopausal endometrium

Endometrial adenocarcinoma occurs almost exclusively in postmenopausal women, and excessive or unopposed estrogen stimulation is suspect as a causative factor in its pathogenesis. Furthermore, the incidence of endometrial adenocarcinoma has increased in women undergoing estrogen replacement therapy. In the present study, the cellular response of premenopausal and postmenopausal endometrium to estrogenic stimulation was compared with endometrial adenocarcinoma by the electron microscope. Tissues were obtained at hysterectomy, endometrial biopsy, or endometrial curettage and were processed routinely for light and electron microscopy. Ultrastructurally the endometrium from postmenopausal patients undergoing estrogen replacement therapy was similar to normal cyclic endometrium in the late proliferative phase. At least three features of the estrogen-treated postmenopausal tissue resembled those observed in adenocarcinoma of the endometrium: accumulation of lipid droplets, irregular nuclei, and perinuclear whorls of microfibrils.     

Persistence of endometrial activity after radiation therapy for cervical carcinoma

Radiation therapy is a proved treatment for cervical carcinoma; however, it destroys ovarian function and has been thought to ablate the endometrium. Estrogen replacement therapy is often prescribed for patients with cervical carcinoma after radiation therapy. A review of records of six teaching hospitals revealed 16 patients who had endometrial sampling for uterine bleeding after standard radiation therapy for cervical carcinoma. Fifteen patients underwent dilatation and curettage, and one patient underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy when a dilatation and curettage was unsuccessful. Six patients had fibrosis and inflammation of the endometrial cavity, seven had proliferative endometrium, one had cystic hyperplasia, one had atypical adenomatous hyperplasia, and one had adenocarcinoma. Although the number of patients who have an active endometrium after radiation therapy for cervical carcinoma is not known, this report demonstrates that proliferative endometrium may persist, and these patients may develop endometrial hyperplasia or adenocarcinoma. Studies have indicated that patients with normal endometrial glands have an increased risk of developing endometrial adenocarcinoma if they are treated with unopposed estrogen. Patients who have had radiation therapy for cervical carcinoma should be treated with estrogen and a progestational agent to avoid endometrial stimulation from unopposed estrogen therapy.     

Cancer and the use of estrogens

Although unopposed estrogen therapy, as well as persistent or increased endogenous estrogens, increases the risk for endometrial hyperplasia and cancer, added progestogen decreases the risk for adenocarcinoma of the endometrium to less than that observed in untreated women. The progestogen challenge test should be administered to all postmenopausal women with an intact uterus--including estrogen-treated postmenopausal women and those with sufficient endogenous estrogens to remain asymptomatic--and the progestogen continued for 13 days each month for as long as withdrawal bleeding results. Estrogen replacement therapy should not be withheld from postmenopausal women who are estrogen deficient, since there is no evidence that estrogens increase the risk for breast cancer. Progestogen added to estrogen replacement significantly reduces the risk for mammary malignancy; therefore, progestogens should be given, even to women who have had a hysterectomy, for 10 to 13 days each month whenever they are prescribed estrogen therapy.     

Endometrial carcinoma following chronic anovulation in a premenopausal woman with systemic lupus erythematosus

Endometrial carcinoma was diagnosed in a premenopausal woman suffering with systemic lupus erythematosus. She had received both prednisolone and an immunosuppressive agent for more than 10 years. Anovulatory cycles persisted during drug administration, along with dysfunctional uterine bleeding. The serum estrogen: progesterone ratio was high. Repeated endometrial biopsies revealed a progression of change from benign proliferation to cystic hyperplasia, adenomatous hyperplasia, atypical hyperplasia and invasive adenocarcinoma. These clinical data suggest that a result of long-term unopposed endogenous estrogen can have been the cause of the endometrial carcinoma.     

Clinical studies concerning the relationship of estrogens to the development of cancer of the corpus uteri

A total of 105 cases of endometrial carcinoma are studied with regard to (1) age at the onset of the menopause; (2) preceding periods of metrorrhagia; (3) presence or absence of menopausal complaints; (4) marital status and fertility; (5) histological picture of the possibly apparently normal part of the endometrium; (6) intensity and duration of estrogen therapy possibly given.The present studies show that in these cancer patients the menopause commences later and is more often preceded by periodic metrorrhagia, and less frequently accompanied by hot flushes, indicating that these patients have often been under the influence of endogenous estrogens through longer periods than the average woman. The women in this series suffering from cancer of the corpus uteri have often given a history of treatment with estrogens in a larger amount and for a longer duration than was recorded for the controls. Thus 16 of the cancer patients had had continuous treatment with estrogens for from 2 to 15 years (average 6.5 years, Table III).The difficulty in making the histological diagnosis in such cases is pointed out; and it is emphasized that in dubious cases it is essential to keep the patient under observation for a few months without administration of any estrogen before a conclusive biopsy can be performed. During this interval, in some instances a cancerlike hyperplasia of the endometrium will disappear.The conclusion is drawn that a continuous estrogenic stimulation (endogenous or exogenous) constitutes an important factor in the etiology of endometrial cancer.Precautions concerning estrogen therapy in the menopause are emphasized.     

Hyperestrogenism: a relevant risk factor for the development of cancer from endometriosis

OBJECTIVE: Endometriosis is extremely common in developed countries. Obesity is a major health concern and may cause hyperestrogenism. Hormonal replacement, particularly unopposed estrogens after hysterectomy, is becoming popular. Because endometriosis is ectopic endometrium, hyperestrogenism (either endogenous or exogenous) may cause hyperplasia or transformation into cancer. This study was conducted to describe the main clinical and pathologic features of malignancies in endometriosis and define the treatment and outcome and to compare patients who had cancer arising in endometriosis with patients who had endometriosis but no cancer. METHODS: Patients who had tumors from endometriosis diagnosed from 1986 to 1997 were analyzed retrospectively. Each patient was matched with two control patients (endometriosis without cancer) treated during the same study interval. Clinical and epidemiologic variables were compared to identify risk factors for the development of cancer. RESULT: We identified 31 patients with cancer developing from endometriosis. Fifteen women were obese, 9 had a history of endometriosis, and 9 were taking unopposed estrogen. Endometrioid adenocarcinoma was the most common histologic type (16 patients). When the patients with cancer were compared with controls, no significantly higher risk for the development of cancer was found with prolonged use of unopposed estrogens or with higher body mass index, but a trend was observed. When obesity and use of unopposed estrogens were considered together, the difference was statistically significant (P = 0.05). CONCLUSION: Hyperestrogenism, either endogenous or exogenous, is a significant risk factor for the development of cancer from endometriosis. The prevalences of endometriosis, obesity, and use of hormonal replacement therapy in women in developed countries are increasing, and this trend justifies the assumption that cancer developing in endometriosis might become more common in the future.     

Endometrial carcinoma in Turner's syndrome

A case of endometrial carcinoma in a patient with Turner's syndrome is presented and the literature is reviewed. Ten similar cases were already published and the clinical and laboratory findings in all 11 cases are tabulated and analyzed. One or more of three possible etiological factors contributing to the development of this very unusual situation are discussed :(i) the prolonged unopposed use of estrogen, (ii) the use of the contraceptive pill (particularly the sequential type), and (iii) a genetic predisposition to cancer in patients with Turner's syndrome.     

Clinical, endocrine and ultrastructural study of XY gonadal dysgenesis. A case report

About 120 cases of XY gonadal dysgenesis have been reported on. We treated such a patient with bilateral gonadectomy. The gonadal tissue's capacity to respond to hormonal trophic stimulation was assessed. When the gonads were examined ultrastructurally, structures with the morphologic characteristics of stromal ovarian cells, Sertoli's cells and Leydig's cells were found. Because of the potential malignancy of the XY gonads, bilateral gonadectomy and hormonal substitution therapy are recommended for these patients. We prefer to use combined hormone replacement with sequential estrogen and progesterone rather than sequential unopposed estrogen because of the small but increased risk of endometrial hyperplasia and carcinoma after long-standing sequential therapy.     

Girls with Turner's syndrome with spontaneous menarche have an increased risk of endometrial carcinoma: a case report and review from the literature

BACKGROUND: Patients with Turner's syndrome receiving unopposed estrogens for the induction of feminization have an increased risk of endometrial carcinoma. Only seven patients who were not treated with estrogen replacement therapy have been reported to have developed endometrial carcinoma at different age levels. CASE: A young girl with Turner's syndrome phenotype, spontaneous puberty, and karyotype 45,X0/47,XXX from peripheral blood, after irregular menstrual cycles of 9 years, at the age of 21, was diagnosed with a non-invasive well-differentiated endometrial carcinoma confined to a hyperplastic endometrial polyp. Analysis of the ovarian tissue by FISH confirmed mosaicism: 45,X0/46,XX/47,XXX. CONCLUSION(S): The endogenous estrogen secretion from the ovaries might have caused malignancy in this case. Patients with Turner's syndrome with spontaneous menarche might carry a higher risk of endometrial carcinoma.     

Hematometra after Radiotherapy for Cervical Carcinoma

The development of a hematometra after radiotherapy for cervical carcinoma is often related to recurrent disease. We present two cases in which a hematometra developed during the use of estrogen replacement therapy. This development was related to regained endometrial activity in combination with fibrosis and obliteration of the upper vagina and/or cervix. In one patient a dilatation and curettage could be performed; in the other a hysterectomy was necessary in order to exclude recurrent disease. These two cases show once more that endometrium can regain its proliferative activity after radiotherapy for cervical cancer. Estrogen replacement therapy in these patients should include the use of a progestagen agent in order to avoid continuous unopposed endometrial stimulation. In the absence of progesterone withdrawal bleeding the uterine cavity should be routinely examined for the development of a hematometra.     

Endometrial cancer associated with feminizing ovarian tumor and polycystic ovarian disease.

Feminizing ovarian tumors and polycystic ovarian disease may cause endometrial cancer by abnormal, unopposed endogenous estrogenic stimulation. We reviewed the clinical course of 72 endometrial cancer patients with a concomitant feminizing ovarian tumor or polycystic ovarian disease and compared tumor characteristics and treatment results with those exhibited by 523 patients treated for endometrial cancer alone. With functioning ovarian tumor and with polycystic ovaries, the cancer tended to be more often low-grade, low-stage, and superficial than did endometrial cancer alone. The high 5-year and 10-year survival rates observed in our functioning ovarian tumor-polycystic ovary patients support the conclusion that endometrial carcinoma with a coexistent endogenous estrogenic stimulus has a more favorable prognosis (P less than 0.01) than endometrial carcinoma alone.