Prospective endometrial assessment of breast cancer patients treated with third generation aromatase inhibitors

OBJECTIVE: A prospective evaluation of the effects on endometrium of third generation aromatase inhibitors (AIs), administered as adjuvant up-front therapy or switched therapy in menopausal patients suffering from breast cancer. METHODS: Forty-five patients suffering from estrogen-receptor positive breast cancer were treated with AIs as adjuvant endocrine therapy; 27 patients switched from tamoxifen to AIs (group 1) due to adverse medical events related to tamoxifen intake (22 patients) or to an extended endocrine treatment after 60 months of tamoxifen therapy (5 patients); whereas 18 patients received AIs as up-front adjuvant therapy (group 2). All patients underwent endometrial investigation before the start of AIs therapy and, thereafter, at 12 month intervals. Endometrial assessment was based on Transvaginal Ultrasonography (TU), followed by hysteroscopy and endometrial biopsy when a double layered endometrial stripe above 4 mm was measured on the longitudinal plane of uterine scanning. Six patients, showing endometrial hyperplasia before the start of AIs therapy, underwent hysteroscopy on a yearly basis, disregarding the endometrial thickness measured by TU. Histopathologic results on endometrial biopsies represented the reference test in order to estimate the prevalence of endometrial morbidity. RESULTS: Demographic and clinical variables evaluated (age, parity, age at menarche and menopause, Body Mass Index, previous chemotherapy and radiotherapy) did not differ in groups 1 and 2. The average period of endometrial surveillance after the start of AIs therapy was 24.8 +/-10.8 months for group 1 and 21.4 +/- 11.5 months for group 2. A progressive decrease of endometrial thickness, from 8.2 +/- 5.0 to 3.0 +/- 1.2 in group 1 and from 4.7 +/- 4.3 to 1.9 +/- 0.3 in group 2, was found before the start and after 36-48 months of AIs therapy. The second line endometrial investigations' rate dropped from 70.3% to 12.5% in group 1 and from 27.7% to 0.0% in group 2, at baseline and after 36-48 months of AIs therapy, respectively. We found baseline endometrial abnormalities in 25.9% and in 22.2% of patients in groups 1 and 2 (P = 0.4), respectively. During AIs administration, an endometrial pathology was found in 1 patient of group 1 and in 3 patients of group 2. In 3 patients, the abnormality consisted of simple hyperplasias and in all these patients an abnormal endometrium (1 complex atypical hyperplasia and 2 simple hyperplasias) was already detected at baseline assessment. Only in 1 patient (2.2%) of group 2 did we find an emerging pathology, consisting of adenosarcoma harbored within an endometrial polyp, detected after 12 months of therapy with letrozole. In 3 out of 5 patients showing simple hyperplasia and in 1 patient showing atypical hyperplasia before the start of AIs therapy, we observed a reversal to normal endometrium and to simple hyperplasia, respectively, after 12 months of therapy with anastrozole. CONCLUSIONS: AIs delivered as up-front therapy for breast cancer have no effects on unspecific endometrial thickening. When administered as switched therapy after tamoxifen withdrawal, AIs may reverse tamoxifen-associated endometrial thickening. As a consequence, we reduced unnecessary second-line endometrial investigations. A low rate of emerging endometrial pathology was found during AIs therapy.     

Pretreatment and prospective assessment of endometrium in menopausal women taking tamoxifen for breast cancer

OBJECTIVES: To estimate the pretreatment incidence of endometrial pathology and to prospectively assess the endometrial morbidity emerging during tamoxifen intake for breast cancer. STUDY DESIGN: One-hundred and forty-six menopausal breast cancer patients, candidate to receive tamoxifen underwent endometrial assessment by Transvaginal Ultrasonography (TU) before the start of therapy. A double-layered endometrial stripe measuring more than 4mm indicated hysteroscopy and endometrial biopsy. Endometrial abnormalities detected before the start of tamoxifen were treated by operative hysteroscopy or by hysterectomy; no therapy and yearly hysteroscopic follow-up was scheduled for patients showing non-atypical hyperplasias. All women were asked to undergo TU on a yearly basis; during the follow-up period, indication for hysteroscopy and endometrial biopsy were the following: (i) an endometrial lining measured above 4mm at the first time, (ii) at least a 50% increase of endometrial thickness since the last finding in patients previously assessed by hysteroscopy, (iii) a recorded vaginal bleeding, and (iv) previous findings of endometrial hyperplasia. Histopathologic result from biopsy or hysterectomy was the reference test to establish the baseline prevalence of endometrial pathology and the emerging prevalences of morbidity after 12, 24, 36, 48 and 60 months of tamoxifen therapy. RESULTS: One-hundred and five patients were followed for 60 months, whereas 113, 126, 137 and 141 patients were evaluated up to 48, 36, 24 and 12 months, respectively. In 44 out of 146 patients, pretreatment TU showed an endometrium thicker than 4mm and in 31 (21.2%) of these patients abnormalities consisting of 16 endometrial polyps, seven polyps harboring simple hyperplasia, four simple hyperplasias, three atypical hyperplasias and one adenocarcinoma were found. During tamoxifen intake benign endometrial abnormalities were detected in 36 out of 114 assessable patients showing normal endometrium before the start of tamoxifen therapy (31.5%) and in seven out of 27 patients with baseline endometrial abnormalities (25.9%). Overall, an endometrial pathology emerged in 30.4% of patients during tamoxifen administration and in no patients we found an atypical lesion. CONCLUSIONS: In menopausal breast cancer patients the incidence of endometrial abnormalities before the start of tamoxifen therapy is high and includes 2.7% of atypical pathology. After the diagnosis and treatment of baseline atypical lesions were accomplished, no atypical endometrial lesion emerged after the start of tamoxifen administration. Based on these findings, we believe that pretreatment assessment of endometrium is recommended in all menopausal women candidate to receive tamoxifen therapy.     

Baseline endometrial assessment before tamoxifen for breast cancer in asymptomatic menopausal women

OBJECTIVE: The aim of this study is to estimate the prevalence of endometrial pathology before the start of tamoxifen therapy in menopausal breast cancer patients. METHODS: Ninety-one gynecologically asymptomatic patients, suffering from estrogen receptor-positive breast cancer and scheduled for adjuvant tamoxifen, underwent pretreatment endometrial assessment. In all patients, a transvaginal ultrasonography was carried out; a double-layered endometrial stripe measuring above 4 mm was considered as abnormal. In these patients, outpatient hysteroscopy and endometrial biopsy were performed. Pathologic findings were considered the reference test in estimating the prevalence of endometrial morbidity. RESULTS: In 34 patients (37.3%) a thickened endometrium was an indication for hysteroscopic and pathologic assessment. Endometrial polyps, simple hyperplasias, and complex atypical hyperplasias were found in 10 (10.9%), 4 (4.3%), and 3 (3.2%) patients, respectively, leading to an overall prevalence of baseline endometrial morbidity of 18.6%. Established individual risk factors for development of endometrial pathology, such as body mass index, age at menarche and menopause, and parity, did not significantly differ in patients with and without endometrial abnormalities. Only patients' age (63.8 +/- 8.6 and 52.2 +/- 11.8; P = 0.03) and endometrial thickness (10.5 +/- 3.5 and 3.9 +/- 3.0; P > 0.001) were significant predictive factors of endometrial pathology. CONCLUSIONS: Menopausal women with estrogen receptor-positive breast cancer appear to have high risk of baseline subclinical endometrial abnormalities; therefore, an endometrial assessment, before the start of tamoxifen therapy, is always recommended in such patients.     

他莫昔芬对乳腺癌患者子宫内膜影响的前瞻性临床病理研究

目的:前瞻性研究他莫昔芬对乳腺癌患者子宫内膜的影响。方法:对2005年1月~2008年10月于温州医学院附属第二医院乳腺外科手术的155例乳腺癌患者进行随访,以阴道B超、宫腔镜及子宫内膜活检评价服用他莫昔芬前后子宫内膜情况。结果:可评价患者共135例,其中绝经前46例,绝经后89例。服用他莫昔芬后,未绝经组36例(78.26%)出现异常阴道流血,9例(19.56%)出现子宫内膜病变,绝经组22例(24.72%)发生异常阴道流血,出现子宫内膜病变29例(32.60%),其中术前绝经组18例(18/59,30.51%),化疗后绝经组11例(11/30,36.67%)。阴道B超对绝经后子宫内膜病变诊断的灵敏度为52.3%,特异度为90.2%,宫腔镜诊断相应的灵敏度为81.8%,特异度为100%。结论:他莫昔芬导致绝经后妇女子宫内膜病变发生增加,对绝经前妇女的影响还不确定。阴道B超可作为初步检测手段,宫腔镜检查可提高诊断的准确率。     

Ovarian cysts in postmenopausal tamoxifen-treated breast cancer patients with endometrial thickening detected by transvaginal sonography

OBJECTIVE: To investigate the frequency of ovarian cysts in tamoxifen-treated postmenopausal breast cancer patients with endometrial thickening detected by transvaginal sonography. METHODS: Medical records and transvaginal sonographies of 38 postmenopausal women treated for breast cancer with adjuvant tamoxifen therapy who had undergone endometrial sampling due to abnormal endometrial thickness were reviewed retrospectively. RESULTS: During the study period five of 38 tamoxifen-treated postmenopausal patients (13.2%) had ovarian cysts. The mean tamoxifen treatment interval of the patients with an ovarian cyst was 22.4 +/- 18.4 months (p = 0.17). The mean endometrial thickness of the patients with an ovarian cyst was 12.6 +/- 5.9 mm (p = 0.17). Endometrial biopsy detected six cases of abnormal endometria, including endometrial carcinoma (n = 1), endometrial polyp (n = 1) and simple endometrial hyperplasia without atypia (n = 4). Three patients with ovarian cysts underwent laparatomy revealing simple cysts on histopathological examination. Two patients with ovarian cysts declined laparatomy and are currently under follow-up. CONCLUSION: Ovarian cysts a common side-effect of tamoxifen treatment in postmenopausal tamoxifen-treated breast cancer patients. Transvaginal sonography should be performed to detect any concomitant endometrial pathology.     

Antiestrogenic therapy in breast cancer and endometrial modifications

The aim of this retrospective study was to detect endometrial lesions in tamoxifen breast cancer users (menopausal state related). The meaning of genital bleeding during the treatment and the actual incidence of benign and malignant pathology of the endometrium related to length of treatment was also evaluated. Tamoxifen (TMX) is a nonsteroidal triphenylene derivate with clear antiestrogenic properties on the breast which is used as adjuvant treatment for breast cancer; potential adverse effects include endometrial lesions. Three hundred and sixty-six breast cancer patients were enrolled in this study; 292 patients were treated with 20 mg/daily of TMX as adjuvant therapy and the remaining 74 did not receive therapy. All patients were subdivided in premenopausal and postmenopausal, asymptomatic and symptomatic groups. All patients underwent ultrasound scans (to examine endometrial thickness) and hysteroscopic examinations before treatment and after one, three and five years. Endometrial biopsy under direct hysteroscopic vision was systematically performed. The pathological histology reports were classified under polyps, simple hyperplasia, complex hyperplasia, atypical hyperplasia, and carcinoma. A higher incidence of endometrial pathology was found only in symptomatic postmenopausal TMX treated patients (27.2% vs 19.5%) between the third and fifth year of treatment.     

Descriptive epidemiology of endometrial hyperplasia in patients with abnormal uterine bleeding

PURPOSE OF INVESTIGATION: To evaluate the prevalence and epidemiologic characteristics of endometrial hyperplasias in women with abnormal uterine bleeding. METHODS: We performed a retrospective analysis on data gained from 294 patients with histologically documented endometrial hyperplasia (with or without atypia), detected among 1,469 women who underwent fractional dilatation and curettage in our department due to abnormal uterine bleeding from 1986 to 1998. Epidemiologic characteristics were abstracted from the patients' medical charts. RESULTS: 294/1469 women were found with endometrial hyperplasia (258 without atypia and 36 atypical hyperplasias). Thirty-six of them were under 40 years of age. Four of the detected endometrial hyperplasias progressed to endometrial carcinoma (one with simple hyperplasia, two with complex and one with atypical hyperplasia). Obesity and hypertension were justified as risk factors in our study population. CONCLUSIONS: The prevalence of endometrial hyperplasia according to our data was 20%. There were statistically significant differences in most epidemiologic parameters between the two types of hyperplasia. The progression of four endometrial hyperplasias to endometrial adenocarcinoma indicates the need for intense follow-up even in cases where patients undergo conservative therapy.     

Liquid-based endometrial cytology: its possible value in postmenopausal asymptomatic women

The incidence of endometrial adenocarcinoma in asymptomatic women is low. Nevertheless, some of these women might require endometrial surveillance. In this study, we evaluated the accuracy of liquid-based endometrial cytology compared to biopsy in asymptomatic postmenopausal women. Three hundred twenty women scheduled for hysteroscopy were enrolled for this study. After hysteroscopy, patients were submitted to endometrial cytology and to biopsy. Two hundred ninety-three (92%) women had sonographically thickened endometrium (>5 mm), 53 (17%) were on tamoxifen, and 16 (5%) were on hormonal substitutive treatment. The evaluation of the biopsies determined that six (2%) women had adenocarcinoma, one (<1%) had adenomatous atypical hyperplasia, and eight (3%) had simple nonatypical hyperplasia. Endometrial cytology evidenced 5 (2%) neoplastic cases, 2 (<1%) hyperplastic with atypia cases, and 25 (8%) hyperplastic without atypia cases. Two hundred twenty-two biopsies (69%) and 17 (5%) cytologies were inadequate. One adenocarcinoma and one simple nonatypical hyperplasia were underrated by cytology resulting, respectively, as atypical hyperplasia and as negative. Four cases were false positive (simple nonatypical hyperplasias on cytology, negative on biopsy). The sensitivity and specificity were estimated, respectively, at 94% and 95%; the positive and negative predictive value were estimated, respectively, at 80% and 99%. Endometrial cytology provided sufficient material more often than biopsy (P < 0.01). We suggest to introduce liquid-based endometrial cytology in the management of some subpopulations of asymptomatic postmenopausal women. Particularly, the combination of liquid-based endometrial cytology and transvaginal sonography may improve their diagnostic accuracy and reduce unnecessary more invasive and expensive procedures.     

Endometrial lesions in patients undergoing tamoxifen therapy.

Forty-six nonhysterectomized women treated with tamoxifen during 6-36 months as adjuvant therapy for breast cancer underwent a hysteroscopy to assess the endometrial effects of this drug. Whereas the endometrium was normal among 23 patients, 13 presented with endometrial polyps, 8 with hyperplasia and 2 with adenocarcinoma. The rate of endometrial lesions was directly related to the cumulative dose of tamoxifen but it was not statistically different among patients receiving progestational therapy compared to patients who did not receive this therapy.     

Endokrine Therapie des Endometriumkarzinoms und seiner Präkanzerosen

Endometrial cancer is, apart from breast cancer, the most common gynecologic malignancy in western industrialized countries with a mortality rate of ca 20–25%. Estrogen-associated endometrial cancer (type 1) has a favourable prognosis, but the non-estrogen-related type 2 tends to have a poor outcome. Endometrial hyperplasias without atypia can be safely treated with endocrine interventions. Conservative treatment of atypical endometrial hyperplasias should be reserved for women who wish to preserve their fertility, provided a thorough histological follow-up is possible. The cornerstone of the treatment of invasive endometrial cancer is radical surgery including complete pelvic and para-aortic lymphonodectomy in tumors larger than stage 1a or with other risk factors. The routine use of adjuvant teletherapy is not indicated when correct surgical staging has been performed. There are no evidence based recommendations for adjuvant hormonal or chemotherapy. In patients with disseminated endometrial cancer, endocrine therapy is a reasonable initial approach. Palliative chemotherapy is indicated after the failure of an endocrine treatment, in patients with receptor-negative tumors, or when life-threatening tumor manifestations require a fast response.     

Resectoscopic surgery may be an alternative to hysterectomy in high-risk women with atypical endometrial hyperplasia

STUDY OBJECTIVE: Endometrial hyperplasia is found in 2% to 10% of women with abnormal uterine bleeding (AUB). Up to 43% of patients with cytologic atypia harbor coexisting adenocarcinoma, and approximately 20% to 52% of atypical hyperplasias, if untreated, progress to cancer. The objective of this study was to estimate the incidence of atypical endometrial hyperplasia encountered during routine resectoscopic surgery in women with AUB and to evaluate the role of resectoscopic surgery in the management of women with AUB and atypical endometrial hyperplasia who refused and/or were at high risk for hysterectomy. DESIGN: Prospective cohort study (Canadian Task Force classification II-3). SETTING: University-affiliated teaching hospital. PATIENTS: From January 1990 through December 2005, the senior author (GAV) performed primary resectoscopic surgery in 3401 women with AUB. Among these, there were 22 women with atypical (17 complex, 5 simple) endometrial hyperplasia. INTERVENTIONS: All women underwent hysteroscopic evaluation and partial (n = 3) or complete (n = 19) endometrial electrocoagulation and/or resection. Subsequently, 6 women had hysterectomy and bilateral salpingo-oophorectomy (BSO). MEASUREMENTS AND MAIN RESULTS: The median (range) for age, parity, and body mass index were 55 years (24-78 years), 2 (0-4), and 30.1 kg/m2 (22.5-52.2 kg/m2), respectively. Among the 3401 women, there were 22 cases of atypical endometrial hyperplasia, 12 of which were incidentally diagnosed at the time of hysteroscopy (complex 10, simple 2, incidence 0.35%). After hysteroscopic diagnosis or confirmation of diagnosis, 6 women underwent hysterectomy and BSO. Of the remaining 16 women, followed for a median of 5 years (range 1.5-12 years), 1 was lost to follow-up, 1 had only a biopsy to preserve fertility, 1 died from lung cancer after 4 years, and 1 died from colon cancer after 5 years. One patient developed endometrial cancer after 10.5 years with postmenopausal bleeding. She remains alive and well 3.5 years after hysterectomy and BSO. The remaining 11 patients are amenorrheic at a median follow-up of 6 years (range 1.5-12 years). CONCLUSIONS: Resectoscopic surgery in 3391 women with AUB detected 12 incidental cases of atypical endometrial hyperplasia (incidence 0.35%). Skillful resectoscopic surgery may be an alternative to hysterectomy in women with AUB and atypical endometrial hyperplasia, who refuse or are at high-risk for hysterectomy and who are compliant with regular and long-term follow-up.     

Accuracy of hysteroscopic diagnosis of endometrial hyperplasia: a retrospective study of 323 patients

STUDY OBJECTIVE: To evaluate the diagnostic accuracy of hysteroscopic view in endometrial hyperplasia. DESIGN: Retrospective study (Canadian Task Force classification II-2). SETTING: Public hospital in northern Italy. PATIENTS: Three hundred twenty-three patients suffering from endometrial hyperplasia out of 2251 women (1119 premenopausal and 1132 postmenopausal) who underwent office-based hysteroscopy from January 1996 through May 2004. INTERVENTION: Review of 2251 outpatient hysteroscopies carried out with 5- to 6-mm sheathed hysteroscopes and accomplished with blind or hysteroscopically targeted endometrial biopsies. MEASUREMENTS AND MAIN RESULTS: The pathologic report was considered the reference test. Hysteroscopic detection of focal or extensive endometrial thickening, irregular vascular network, architectural distortion and crowding of gland openings, and gland cyst formation were considered endoscopic features consistent with hyperplasia. Overall sensitivity, specificity, negative predictive values (NPV), and positive predictive values (PPV) of hysteroscopy in order to foresee a diagnosis of hyperplasia were calculated. These figures were calculated both in premenopausal and postmenopausal patients. Histopathology yielded a diagnosis of simple, complex, and atypical hyperplasia in 247, 51, and 25 patients, respectively. Hysteroscopy foresaw hyperplasia in 38.4% of patients with simple hyperplasia and in 58.9% of patients with complex or atypical hyperplasia. Normal hysteroscopic findings underestimated simple hyperplasia in 34 patients (13.7%) and complex or atypical hyperplasias in 1 patient (1.3%) (p <.01). To predict the diagnosis of hyperplasia, hysteroscopy showed an overall sensitivity, specificity, NPV, and PPV of 63.7%, 91.7%, 91.3%, and 64.7%, respectively. Among premenopausal patients, hyperplasia was diagnosed in 134 women (11.9%); in this group, hysteroscopy showed sensitivity, specificity, NPV, and PPV of 65.6%, 88.5%%, 93.5%, and 50.5%, respectively. In postmenopausal patients, we found endometrial hyperplasia in 189 women (16.6%); sensitivity, specificity, NPV, and PPV of hysteroscopic view to anticipate hyperplasia were 61.6%, 95.2%, 89.3%, and 79.4%, respectively. A significantly better PPV to foresee hyperplasia was found in postmenopausal women compared with premenopausal patients (p <.01). CONCLUSIONS: Current hysteroscopic criteria suggesting endometrial hyperplasia are inaccurate; in order to exclude hyperplasia, a pathologic assessment is warranted in all hysteroscopies showing an irregularly lined or thick endometrium.     

Endometriumhyperplasie und -karzinom

Endometrial hyperplasia can cause bleeding disorders and some are also precancerous lesions of an endometrial cancer. Vaginal sonography plays an important role in the diagnosis of endometrial hyperplasia. This can be combined with a sonographically supported progestin test for further differential diagnosis. For a definitive diagnosis, hysteroscopy and curettage is the method of choice. An exact histological classification of endometrium hyperplasia is necessary. For medical treatment of endometrial hyperplasia without atypia, cyclic or continuous treatment with an oral progestin or alternatively intrauterine progestin treatment by a levonorgestrel intrauterine system (LNG-IUS) may be useful. After treatment of complex or atypical hyperplasia, control of histological specimen is necessary. In atypical hyperplasia or early stage of endometrial cancer in patients who desire a pregnancy, conservative therapy should be used cautiously and only in combination with strict clinical and sonographical controls.     

Clinicopathological analysis in cases with glandular and atypical glandular hyperplasia treated with gestagens

Many of the cases with endometrial adenocarcinoma of the endometrium are proceeded of glandular and atypical glandular hyperplasia with different risk of progression to neoplasia. Two hundred and eighty cases with glandular and atypical glandular hyperplasia were examined in order to assess the risk of their progression into endometrial cancer. The hyperplasias were evaluated separately for their likelihood of progression to cancer in patients treated and not treated with progestogen therapy. In all cases a fractional re-curreting was performed in order to evaluate the stage of the disease. The leading symptom was the vaginal bleeding in 70% of the cases in the postmenopause. Seventy eight percent of the patients were with obesity (BMI > 30 mg/m2), twenty six percent were with exogenous use of estrogens. 4% of the cases with glandular hyperplasia progressed into cancer and in 13% into atypical grandular hyperplasia. 55% of the atypical glandular hyperplasias progressed into cancers. In the cases with progestogen treatment 70% of the cases showed remission confirmed by re-curetting compared with 23% of the cases without hormonal treatment. The grandular hyperplasia without atypia responded to hormonal therapy. In the postmenopausal patients the atypical glandular hyperplasia should be treated with surgery--total hysterectomy.     

Reproductive tract pathology in asymptomatic women treated with tamoxifen

PURPOSE: To determine the long-term effects of tamoxifen on the female reproductive tract in patients with breast cancer. METHODS: Forty-nine patients with breast cancer receiving tamoxifen longer than two years were analyzed. All the patients underwent pelvic examination, pap smear, transvaginal ultrasonography, serum CA 125 and dilatation and curettage. RESULTS: There were 16 patients with genital system pathology. Three of them had atypical Pap smears, one with cervical carcinoma and the other two with chronic cervicitis. Two significant ovarian pathologies were found. These were ovarian fibroma, and unilateral dermoid cyst. There were three patients with endometrial hyperplasia without atypia. Uterine myoma was encountered in seven of the cases. Only one patient had elevated CA 125 levels despite normal genital examination findings. CONCLUSION: Since no significant genital pathology attributable to tamoxifen therapy could be detected, the follow-up for gynecologic pathologies in breast cancer patients receiving tamoxifen therapy may be individualized.     

Molecular analysis of endometrial hyperplasia in HNPCC-suspicious patients may predict progression to endometrial carcinoma.

Women predisposed to hereditary nonpolyposis colorectal cancer are at high risk of developing endometrial carcinoma at a young age. Hereditary nonpolyposis colorectal cancer-associated endometrial carcinomas are of the endometrioid type, usually arise from complex atypical hyperplasia, and often show microsatellite instability. To identify occult hereditary nonpolyposis colorectal cancer individuals among endometrial carcinoma patients, we examined complex atypical hyperplasias and endometrial carcinomas of 60 women < or =50 years of age (mean age: 35.7 years) using microsatellite instability, immunohistochemistry, and DNA sequence analysis. Three patient groups were recruited: group 1, patients with complex atypical hyperplasia exclusively (n = 27); group 2, patients with complex atypical hyperplasia and synchronous or metachronous endometrial carcinoma (n = 15); group 3, patients with endometrial carcinoma only (n = 18). Overall, 13 of 33 endometrial carcinomas (39%) displayed high-level microsatellite instability. None of the complex atypical hyperplasias in group 1 had high-level microsatellite instability or loss of hMLH1/hMSH2 protein expression. In group 2 patients, 33% of complex atypical hyperplasias and 53% of endometrial carcinomas had high-level microsatellite instability. Loss of hMSH2 protein expression was found in six endometrial carcinoma patients, five of them with verified hMSH2 germline mutations, including four patients with high-level microsatellite instability in complex atypical hyperplasia. Among group 3 patients, 28% of endometrial carcinomas displayed high-level microsatellite instability; three of those five endometrial carcinomas were from patients with multiple extrauterine hereditary nonpolyposis colorectal cancer-associated tumors. We conclude that young women (< or =50 years of age) with concurrent complex atypical hyperplasia and multiple hereditary nonpolyposis colorectal cancer-associated carcinomas are at risk of developing high-level microsatellite instability endometrial carcinoma. Combined microsatellite instability and immunohistochemistry analysis allows the identification of a high proportion of hereditary nonpolyposis colorectal cancer patients among young women with endometrial carcinoma and complex atypical hyperplasia. All complex atypical hyperplasias with high-level microsatellite instability progressed to endometrial carcinoma. Only one third of the complex atypical hyperplasias with microsatellite stability progressed to high-level microsatellite instability endometrial carcinoma, while seven complex atypical hyperplasias progressed to microsatellite stability endometrial carcinoma. Microsatellite analysis of complex atypical hyperplasia in young patients may therefore be a useful prognostic marker for predicting possible progression to high-level microsatellite instability endometrial carcinomas.     

Hysteroscopic evaluation of endometrial polyps.

OBJECTIVE: To establish the validity of hysteroscopy for predicting cancer in endometrial polyps based on their number, size and hysteroscopic appearance. METHOD: Retrospective observational study of 653 women diagnosed hysteroscopically as having endometrial polyps. After outpatient or surgical hysteroscopic resection or resection following hysterectomy, the diagnosis was confirmed by histological examination. The incidence of cancer in women who had polyps was determined in the light of menopausal status, symptoms, size, number and appearance of the polyps. RESULT: Carcinoma was found in only 3.9% of the women who consulted for menopausal metrorrhagia and were diagnosed as having a polyp. Hysteroscopy had a sensitivity of 36% and a specificity of 98% for a diagnosis of cancerous polyp or atypical hyperplasia. CONCLUSION: The appearance and number of endometrial polyps seen by hysteroscopy may be useful in predicting cancer in the polyps, although resection and histological examination will still be necessary to confirm the diagnosis.     

Recurrent endometrial polyps in postmenopausal breast cancer patients on tamoxifen

OBJECTIVES: Endometrial polyps are the most common endometrial pathology described in association with postmenopausal tamoxifen exposure, with an incidence of up to 10.7% of malignancy. Some women tend to develop recurrent polyps. However, no one has yet described any risk factors for the development of recurrent endometrial polyps in postmenopausal breast cancer tamoxifen-treated patients. METHODS: We compared various clinical features of 64 postmenopausal breast cancer tamoxifen-treated patients with a primary endometrial polyp (Group I), with those of 27 similar patients with recurrent polyps (Group 2). RESULTS: Previous exposure to hormone replacement therapy was significantly more common and duration of tamoxifen treatment, up to the diagnosis of primary endometrial polyp, was significantly shorter in Group II patients (P = 0.0217 and P = 0.0148, respectively). Logistic regression analysis revealed that the combination of shorter tamoxifen exposure before the diagnosis of primary polyp, lower parity, lower menopausal age at the diagnosis of primary polyp, and higher years of tamoxifen treatment was found to increase significantly the risk of developing recurrent endometrial polyps. Any additional year of tamoxifen treatment may increase by fivefold the risk of developing recurrent polyps. There was no significant difference in ultrasonographic endometrial thickness measured before resection of the primary polyps in both groups and before the resection of recurrent polyps in Group II. CONCLUSIONS: Previous use of HRT, shorter duration of tamoxifen exposure, and additional years of tamoxifen treatment may significantly increase the risk of developing recurrent endometrial polyps in postmenopausal breast cancer tamoxifen-treated patients.     

Effects of tamoxifen on the human female genital tract: review of the literature

Tamoxifen is a non-steroidal triphenylethylene derivate, with clear antioestrogenic effects on the breast, that is orally administrated for the treatment of breast cancer and its prevention in a high-risk population. This article analyzes the effects of tamoxifen on the adult human female genital tract and considers its carcinogenicity in the gynaecological reproductive organs. It has been found that tamoxifen causes oestrogenic changes of the vaginal and cervical squammous epithelium and increases the incidence of cervical and endometrial polyps. The action of tamoxifen on the human endometrium in postmenopausal women is connected with simple oestrogenic effects including hyperplasia, while in others with endometrial cystic atrophy. In cases where tamoxifen induces endometrial polyps and hyperplasia, the extensive fibrosis accounts for difficulties in obtaining endometrial biopsy or resecting the polyps. In premenopausal patients tamoxifen disrupts the menstrual cycles and causes ovarian cysts, while in postmenopausal patients it induces ovarian cystic tumors and endometriomas. Also, postmenopausal patients treated with tamoxifen may develop endometriosis, adenomyosis and leiomyomata. In addition, randomized trials have shown a link between tamoxifen use in breast cancer patients and the development of endometrial carcinomas. Moreover, of note is the fact that the association of tamoxifen therapy with uterine mesenchymal neoplasms is higher than expected. In conclusion, the most worrying gynaecological side-effect of tamoxifen is the well-known increased risk of endometrial carcinomas. Women with breast cancer treated with tamoxifen should undergo annual gynaecological examination, but endometrial sampling should be obtained only in the event of endometrial bleeding.     

Histopathologic features and risk factors for benignity,hyperplasia, and cancer in endometrial polyps

OBJECTIVE: The purpose of this study was to determine the rate of benign, hyperplastic, and malignant endometrial polyps and whether clinical data can predict histopathologic outcome. STUDY DESIGN: Five hundred nine patients with endometrial polyps who consecutively underwent hysteroscopic removal of endometrial polyps over 48 months were identified from our gynecologic oncology surgical database. Medical reports provided clinical data. Statistical analysis was performed. RESULTS: Histologically, 358 polyps (70.3%) were benign; 131 polyps (25.7%) had simple or complex endometrial hyperplasia, 16 polyps (3.1%) had hyperplasia with atypia, and 4 polyps (0.8%) were cancerous. Polyps were divided into group A and group B, according to the risk of malignancy (group A, benign; group B, atypical hyperplastic and cancerous). Age, menopause status, and hypertension were associated significantly with group B. CONCLUSION: Endometrial polyps rarely become malignant, but hyperplastic changes are more common. Age, menopause status, and hypertension may increase the risk of premalignant and malignant polyps. To achieve complete removal of the polyp and a reliable histologic analysis, operative hysteroscopy should be offered to symptomatic patients or to patients with risk factors.