Implications for management of ovarian cancer in a transgender man: Impact of androgens and androgen receptor status.

A 36-year-old transgender man (assigned female at birth) on exogenous testosterone therapy was found to have stage IIA ovarian endometrioid carcinoma, and underwent adjuvant chemotherapy. Diffuse androgen receptor expression in the tumor initiated a multidisciplinary discussion regarding the safety of continuing exogenous testosterone as gender-affirming hormone therapy.

Clinico-pathologic comparison of type II endometrial cancers based on tamoxifen exposure.

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.

Hormone therapy and different ovarian cancers: a national cohort study.

Postmenopausal hormone therapy use increases the risk of ovarian cancer. In the present study, the authors examined the risks of different histologic types of ovarian cancer associated with hormone therapy. Using Danish national registers, the authors identified 909,946 women who were followed from 1995-2005. The women were 50-79 years of age and had no prior hormone-sensitive cancers or bilateral oophorectomy. Hormone therapy prescription data were obtained from the National Register of Medicinal Product Statistics. The National Cancer and Pathology Register provided data on ovarian cancers, including information about tumor histology. The authors performed Poisson regression analyses that included hormone exposures and confounders as time-dependent covariates. In an average of 8.0 years of follow up, 2,681 cases of epithelial ovarian cancer were detected. Compared with never users, women taking unopposed oral estrogen therapy had increased risks of both serous tumors (incidence rate ratio (IRR) = 1.7, 95% confidence interval: 1.4, 2.2) and endometrioid tumors (IRR = 1.5, 95% confidence interval: 1.0, 2.4) but decreased risk of mucinous tumors (IRR = 0.3, 95% confidence interval: 0.1, 0.8). Similar increased risks of serous and endometrioid tumors were found with estrogen/progestin therapy, whereas no association was found with mucinous tumors. Consistent with results from recent cohort studies, the authors found that ovarian cancer risk varied according to tumor histology. The types of ovarian tumors should be given attention in future studies.

Endometriosis-associated intestinal tumours: a consequence of long-term unopposed oestrogen?

A case of malignant transformation in an extra-ovarian site, 13 years after total abdominal hysterectomy and bilateral salpingo-oophorectomy, is discussed in a patient on long-term oestrogen implants, which highlights the potential risks surrounding the use of long-term oestrogen replacement therapy.

Endometrial effects of tibolone in elderly, osteoporotic women.

OBJECTIVE: To investigate endometrial effects of tibolone administered to postmenopausal women for 3 years. METHODS: Postmenopausal women (N=3,519) aged 60-85 years (mean 68 years) with a uterus and with osteoporosis were randomly assigned to receive tibolone orally, 1.25 mg per day, or identical placebo. We evaluated effects on endometrial thickness in all women, and examined endometrial histology in 635 participants considered to be at increased risk for abnormalities (with unexpected vaginal bleeding or endometrial thickness more than 4 mm). RESULTS: During the first year of study, mean endometrial thickness increased 1 mm in women receiving tibolone (P<.001), but no further increases were noted during the next 2 years. Diagnostic biopsies among 499 women receiving tibolone and 136 who were receiving placebo showed cumulative incidences of endometrial hyperplasia less than 1%. Among the 15% of women whose biopsy showed an endometrial polyp (similar rate in tibolone and placebo), those receiving tibolone were more than twice as likely to show hyperplasia within the polyp. A marginal increase in grade 1 endometrioid adenocarcinoma (P=.06 compared with placebo) was found among women receiving tibolone. Prevalences of vaginal bleeding during the study were 10.8% in the tibolone group and 2.8% in the placebo group (P<.001). CONCLUSION: Tibolone treatment during 3 years minimally increased endometrial thickness, hyperplastic polyps, endometrial carcinoma, and vaginal bleeding.

Clinicopathological and molecular analysis of endometrial carcinoma associated with tamoxifen.

Use of tamoxifen for treatment and prevention of breast cancer is becoming increasingly common. Tamoxifen has been associated with increased risk of endometrial carcinoma, although the exact mechanism of action is unknown. The aim of our study was to seek a possible correlation between endometrial carcinoma, tamoxifen exposure and MSI, PTEN, beta-catenin and K-ras abnormalities. A group of 18 patients with endometrial carcinoma following treatment with tamoxifen were selected. A control group included 15 patients with endometrial carcinoma and associated ovarian hyperthecosis and one patient with endometrial carcinoma and adult granulosa cell tumor of the ovary, chosen because both conditions are associated with increased production of estrogen and increased risk of endometrial carcinoma development. The second control group included 27 randomly selected consecutive patients with endometrial carcinoma without identifiable associated conditions. Immunostaining for beta-catenin was performed on all cases; DNA was extracted and amplified by PCR with primers for beta-catenin, K-ras and PTEN genes. BAT-25 and BAT-26 were analyzed to assess for MSI. There were 16 endometrioid endometrial carcinomas, one mixed carcinoma and one clear cell carcinoma among patients in the tamoxifen group. All patients with ovarian hyperthecosis and adult granulosa cell tumor had endometrioid endometrial carcinoma. In the random control group, there were 26 endometrioid endometrial carcinomas and one carcinosarcoma. Immunohistochemical and mutational analysis for beta-catenin showed abnormalities in 4/11 (36%) and 3/10 (30%) informative cases in the tamoxifen group; 7/16 (44%) and 4/15 (27%) informative cases, respectively in the ovarian hyperthecosis group and 1/27 random control cases (4%) (P<0.05). Patients with tamoxifen exposure had more K-ras mutations and fewer PTEN mutations and MSI as opposed to controls, but the results were not statistically significant. In conclusion, there was a direct relationship between tamoxifen exposure and overexpression of beta-catenin oncoprotein, which is known to play a major role in the pathogenesis of estrogen-driven, type I endometrial adenocarcinoma.

[Postmenopausal malignant transformation of extragenital endometriosis. A case report]. / Transformation maligne postménopausique d'une endométriose extragénitale. A propos d'un cas.

Malignant transformation of endometriosis is a rare event. The ovaries are the most common sites reported in the literature. Postmenopausal cancer arising in extragenital endometriosis is still more exceptional. Hormone replacement therapy and perhaps, to a lesser extent, Tamoxifen could be risk factors for the malignant transformation of endometriosis. We herein report the case of a patient who has developed, after 11 years of hormone replacement therapy, an extragenital endometrioid carcinoma in the vesico-uterine pouch.

Surveillance for endometrial cancer in women on tamoxifen: the role of liquid-based endometrial cytology - cytohistological correlation in a population of 168 women.

AIMS: The aim of this study was to evaluate the utility of liquid-based cytology for endometrial surveillance in patients receiving tamoxifen. METHODS: One hundred and sixty-eight women scheduled for hysteroscopy were enrolled in the study. The women sequentially underwent hysteroscopy, endometrial cytology and biopsy. RESULTS: Endometrial biopsy only was inadequate in 112 (67%) patients, both endometrial biopsy and cytology were inadequate in 19 (11%) patients, endometrial cytology only was inadequate in 4 (2%) patients, and both endometrial biopsy and cytology were adequate in 33 (20%) patients. Overall, endometrial biopsy was inadequate in 131 (78%) patients and endometrial cytology in 23 (14%) patients. Endometrial cytology provided sufficient material for diagnosis more often than endometrial biopsy (p < 0.05). In the series of 33 patients (20%) in whom both endometrial cytology and biopsy were adequate, there was a 100% correlation between the endometrial cytology and biopsy results. CONCLUSIONS: For the first time, this study shows the diagnostic efficacy of liquid-based endometrial cytology in the follow-up of women receiving tamoxifen. It could be applied solely or in conjunction with ultrasonography.

Expression of the epidermal growth factor system in endometrial cancer after adjuvant tamoxifen treatment for breast cancer.

The aim of our study was to describe the expression of cerbB-1, cerbB-2, cerbB-3 and cerbB-4 in endometrial cancer tissue and its correlation with clinicopathologic features and prognosis of endometrial cancer patients diagnosed during or after tamoxifen treatment for breast cancer. Thirteen tamoxifen-related endometrial cancers were identified from the archives of the Department of Obstetrics and Gynecology of the University of Patras, Medical School. Tissue specimens from endometrial lesions were immunostained for cerbB-1, cerbB-2, cerbB-3 and cerbB-4. For cerbB-1, five cases were positive and eight were negative. For cerbB-2, ten cases were positive and three were negative. For cerbB-3, nine cases were positive and four were negative. For cerbB-4, eight cases were positive and five were negative. However, a limitation of our study is that the number of cases was small, and further investigations are necessary to allow a more focused evaluation of cerbB-1, cerbB-2, cerbB-3 and cerbB-4 status, as a prognostic factor for endometrial cancer after tamoxifen treatment.

Endometrial adenocarcinoma following insertion of the levonorgestrel-releasing intrauterine system (mirena) in a 36-year-old woman.

The levonorgestrel-releasing intrauterine system (LNG-IUS), commonly referred to as mirena, is an effective form of contraception, which is widely used as an intrauterine device. It has a 32-mm long-shaped plastic frame that holds a reservoir (on the vertical stem) of 52 mg of levonorgestrel mixed with polydimethylsiloxane to allow a steady release of 20 mug of levonorgestrel per day within the endometrial cavity through a rate-limiting surface membrane. Apart from contraceptive purpose, it is also now commonly used in the management of heavy menstrual blood loss. This study included a 36-year old woman who developed endometrial cancer following the insertion of the LNG-IUS. Her main presentation was irregular vaginal bleeding, which is a common finding in women using this form of contraception. Although we would advice caution in investigating such women, the LNG-IUS remains a relatively safe method of contraception.

Molecular genetic characterization of tamoxifen-associated endometrial cancer.

OBJECTIVES: The non-steroidal, selective estrogen receptor modulator tamoxifen is currently the most extensively used hormonal agent for the prevention and treatment of estrogen receptor-positive breast cancer. Epidemiologic studies and clinical trials have shown an increased risk of endometrial cancer with tamoxifen exposure; however, few studies have examined these tumors on a molecular level. We sought to elucidate the molecular genetic alterations found in tamoxifen-associated endometrial cancer. METHODS: Twenty-nine breast cancer patients with a history of tamoxifen use who subsequently developed endometrial cancer were retrospectively identified and matched for endometrial histologic subtype and grade to 29 endometrial cancers from breast cancer patients never exposed to tamoxifen. Endometrial tumor tissue was microdissected and genomic DNA extracted for each case. Direct DNA sequencing of the most commonly mutated genes in sporadic endometrial cancer, PTEN, K-RAS, TP53, and CTNNB1, was performed in addition to microsatellite instability (MI) studies. Fisher's Exact Test was utilized for statistical analyses. RESULTS: Of 29 tamoxifen-associated cancers, 10 (34.5%) contained PTEN mutations compared to 13 (44.8%) of the non-tamoxifen-associated cancers (P = 0.59). All PTEN mutations were found in tumors with endometrioid histology, reflecting what is seen in sporadic endometrial cancers. Mutations of K-RAS, TP53, and microsatellite instability were present in similar frequencies between the two breast cancer groups, and moreover, these were similar to mutational frequencies found in sporadic endometrial cancer. CONCLUSION: Tamoxifen and non-tamoxifen-associated endometrial carcinomas arising in women with breast cancer contain similar genetic alterations to those of sporadic endometrial carcinomas.

Perineal talc exposure and epithelial ovarian cancer risk in the Central Valley of California.

Perineal talc use has been suggested as a possible risk factor for ovarian cancer based on its structural similarity to asbestos, a known human carcinogen. A population-based epidemiologic case-control study of epithelial ovarian cancer (EOC) was conducted in 22 counties of Central California that comprise the reporting area for 2 regional cancer registries. Telephone interviews were conducted with 256 cases diagnosed in the years 2000-2001 and 1,122 controls frequency-matched on age and ethnicity. The interview obtained information on demographic factors, menstrual and reproductive experience, exogenous hormone use, surgical history and family history of cancer. Questions on perineal talc use included frequency of use, duration of use and specific years when talc was used. Multivariate-adjusted odds ratio (OR) and 95% confidence intervals (CI) were derived from unconditional logistic regression. The OR for ever use of talc was 1.37 (CI = 1.02-1.85) compared to never users. However, no dose response association was found. Tubal ligation (TL) modified the effect of talc on EOC such that women with TL had an OR of 0.88 (CI = 0.46-1.68) associated with perineal talc use, whereas women with no TL had an OR of 1.54 (CI = 1.10-2.16). Talc use and EOC risk was highest in women with serous invasive tumors (OR = 1.77; CI = 1.12-2.81). This study provides some support for the hypothesis that perineal talc use is associated with an increased risk of EOC.

Ovarian endometrioid adenocarcinoma arising from an endometriotic cyst in a postmenopausal woman under tamoxifen therapy for breast cancer: a case report.

BACKGROUND: Ovarian cancer arising from an endometriotic cyst in a postmenopausal woman under tamoxifen therapy is rare. CASE: We herein report the case of a 67-year-old woman with a history of breast cancer, taking tamoxifen citrate 20 mg/day for 4 years, who underwent an operation for left ovarian tumor. The postoperative histological diagnosis was endometrioid adenocarcinoma in an endometriotic cyst with a gradual transition of the degree of cellular atypia noted from typical endometriotic epithelium, to atypical endometriosis, and finally to adenocarcinoma. CONCLUSION: Tamoxifen may cause malignant transformation of endometriosis through atypical endometriosis even in the postmenopausal state. Atypical endometriosis may act as a precancerous lesion in the process of tamoxifen-induced malignant transformation of endometriosis.

Phytoestrogen supplementation and endometrial cancer.

BACKGROUND: Phytoestrogens are increasingly used by patients as "natural" alternatives to hormone replacement. Attention in scientific and lay literature has focused on their potential to prevent menopausal symptoms, bone loss, heart disease, or breast cancer. Less is known about effects on the endometrium, specifically, whether prolonged exposure to phytoestrogens could promote hyperplasia or neoplasia, as does unopposed estrogen. CASE: We report the case of a woman diagnosed with grade 1 endometrioid adenocarcinoma of the endometrium whose history was notable for extensive use of supplemental phytoestrogens. CONCLUSION: The effects of phytoestrogens on endometrial tissue are not known. Given their increasing popularity and availability in concentrated form as dietary supplements, additional research is warranted before we can counsel our patients regarding the safety of such supplements.

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.

Benign, borderline, and malignant endometrioid neoplasia arising in endometriosis in association with tamoxifen therapy.

Tamoxifen therapy may result in a variety of endometrial proliferative lesions, including adenocarcinoma, and as recently suggested, proliferative changes within endometriosis. This report describes an endometrioid adenocarcinoma arising in ovarian endometriosis in a patient taking tamoxifen. There were also foci of benign and borderline endometrioid adenofibroma in the same ovary and a synchronous endometrioid endometrial adenocarcinoma in the uterus. The spectrum of benign, borderline, and malignant endometrioid neoplasia arising within endometriosis suggests that tamoxifen, as a result of its estrogenic effects, may cause proliferative and, in rare instances, malignant changes in endometriosis.

Effects of tamoxifen on cervicovaginal smears from patients with breast cancer.

OBJECTIVE: To evaluate the effect of tamoxifen on cervicovaginal epithelium and determine the value of cervicovaginal smears in identifying patients at risk for endometrial carcinoma. STUDY DESIGN: A group of 48 women with prior breast cancer were divided into three groups: A, tamoxifen-treated patients who developed endometrial carcinoma (n = 20); B, patients with endometrial cancer not treated with tamoxifen (n = 22); and C, tamoxifen-treated patients with no endometrial carcinoma (n = 16). A total of 114 cervicovaginal smears from these patients were evaluated for maturation index, histiocytes, benign and malignant endometrial cells, reactive cellular changes and microorganisms. All patients treated with tamoxifen had received doses of 10 mg twice daily. RESULTS: The maturation index was increased in tamoxifen-treated patients (A and C) versus nontreated patients (B) P < or = .001). The number of cases with endometrial cells was significantly higher in smears of treated patients who developed endometrial cancer (A) as compared to groups B and C (P = .01 and .02, respectively). Histiocytes were also significantly increased in the two groups that subsequently developed endometrial carcinoma (A and B) as compared to the group that did not (group C) (P = .02). There was no significant difference in the presence of reactive cellular changes between the three groups. CONCLUSION: Patients treated with tamoxifen exhibited a partial estrogenic effect in their smears regardless of whether they developed endometrial cancer. However, the presence of endometrial cells in the smears indicated a higher risk of endometrial adenocarcinoma.