Risk Of Endometrial Carcinoma Research Articles

PHENOTYPIC FEATURES OF ENDOMETRIAL CANCER AND MSI IN COLON AND BLOOD SERUM

Since the end of the last century an upward trend regarding hormone-dependent tumours of the reproductive system, including endometrial cancer (EC) has been observed, with one of the trend reasons being increased number of mutations, in particular, microsatellite instability (MSI) – the consequence of unpaired nucleotides repair system gene inactivation (MSH2, MSH3, MSH6, MLH1,PMS2, EXO1).This molecular genetic phenomenon may also be characteristic of certain colon cancer forms, while being detectable not only in the tumour but also in blood, which may be of clinical interest as regards either determining risk groups in terms of other localization malignant tumours development, especially colon cancer, or early diagnostics of the said diseases. However, relationship between clinical, phenotypic and molecular risk factors for EC and colon cancer needs further studying.The aim of research – to estimate MSI frequency in blood serum and colonic mucosal lining in patients with EC.Materials and methods. 342 patients with I – IV stage EC aged between 30 and 80 underwent MSI determining in tumour tissue, blood serum and colonic mucosa by means of polymerase chain reaction method using primers for microsatellite sequence (ВАТ-25, ВАТ-26). Colonic mucosal lining samples were obtained by colonoscopy prior to surgical intervention.Genomic DNA purification from blood serum was performed using DNA purification kit produced by Silex M Scientific and Production Company (Russia), in accordance with manufacturer's instructions. PCR was performed by the standard procedure using Tertsik-2 programmable thermal cycler produced by DNA – Technology LTD, Russia. The studies were carried out at Virola laboratory at Kharkiv Medical Academy of Postgraduate Education. Ethics and Bioethics Committee permit (minutes No.4 of 18.04.2013, Kharkiv Medical Academy of Postgraduate Education). The obtained digital study results were processed by means of conventional variation statistics methods using the χ2 criterion.Results. Estimation of MSI occurrence frequency in the colon tissue showed that MSI- colonic tissue is significantly more frequent (93.9 %) compared to MSI+ (6.1 %), p<0.01.Analysis of MSI occurrence frequency in case of EC showed that MSI is significantly more frequently observed in blood serum (10.8 % of cases) than in the colonic tissue (mucosal lining) (6.1 %). A similar pattern was observed also in cases with MSI+ tumour phenotype (MSI frequency in colonic mucosal lining made 12.2 %, whereas in blood serum – 29.6 %, p <0.01).Analysis of indices in cases with MSI- tumour phenotype demonstrated inverse relation, i.e. genome microsatellite instability was more frequently observed in the colonic mucosal lining than in blood serum (p<0.05).We have carried out analysis of the MSI occurrence frequency in colonic tissue depending on the EC phenotypic traits and risk factors. The obtained data on the MSI disorder occurrence frequency in colonic tissue in case of EC depending on the endometrial carcinoma risk factors demonstrated correlation with the majority of criteria, thus verifying the literature data on the presence of common pathogenetic mechanisms in case of EC and colon cancer.Conclusions. 1. MSI disorders in the colonic mucosal lining and blood serum are more frequently observed in case of EC MSI + phenotype.2. Similarity of pathogenesis in terms of EC and colon cancer is affected by similar phenotypic traits of patients as well as by MSI development.

Cost-effectiveness analysis of treatment modalities for women with high-intermediate risk endometrial carcinoma: Should Gynecologic Oncology Group (GOG) 249 have included a chemotherapy-only arm?

Objectives: GOG 249 was developed to determine if the combination of vaginal brachytherapy (BT) and three cycles of paclitaxel and carboplatin (PC) are superior to whole pelvic radiation therapy (WPRT) in terms of disease-free survival for high-intermediate risk (H-IR) endometrial cancer (EMCA) patients. Accordingly, we estimated the costs and outcomes of four treatment modalities used for the management of H-IR EMCA.

Cigarette smoking and endometrial carcinoma risk: the role of effect modification and tumor heterogeneity

The inverse relationship between cigarette smoking and endometrial carcinoma risk is well established. We examined effect modification of this relationship and associations with tumor characteristics in the National Institutes of Health-AARP Diet and Health Study. We examined the association between cigarette smoking and endometrial carcinoma risk among 110,304 women. During 1,029,041 person years of follow-up, we identified 1,476 incident endometrial carcinoma cases. Multivariable Cox proportional hazards regression models were used to estimate relative risks (RRs) and 95 % confidence intervals (CIs) for the association between smoking status, years since smoking cessation, and endometrial carcinoma risk overall and within strata of endometrial carcinoma risk factors. Effect modification was assessed using likelihood ratio test statistics. Smoking associations by histologic subtype/grade and stage at diagnosis were also evaluated. Reduced endometrial carcinoma risk was evident among former (RR 0.89, 95 % CI 0.80, 1.00) and current (RR 0.65, 95 % CI 0.55, 0.78) smokers compared with never smokers. Smoking cessation 1-4 years prior to baseline was significantly associated with endometrial carcinoma risk (RR 0.65, 95 % CI 0.48, 0.89), while cessation ≥ 10 years before baseline was not. The association between smoking and endometrial carcinoma risk was not significantly modified by any endometrial carcinoma risk factor, nor did we observe major differences in risk associations by tumor characteristics. The cigarette smoking-endometrial carcinoma risk relationship was consistent within strata of important endometrial carcinoma risk factors and by clinically relevant tumor characteristics.

Does HBV Infection Increase Risk of Endometrial Carcinoma?

Connections between chronic inflammation and tumor development and progression are now generally accepted. Recent evidence indicates that hepatitis B is associated with several types of cancer, but whether endometrial carcinoma (EC) is included has not been reported. We analyzed HBV serum marker status in 398 patients with endometrial cancer, comparing them to 788 control women undergoing health examination. The total prevalence of HBsAg tested positive in cancer group was significantly higher than the control group (12.8% vs 6.0%, P=0.001), while positive HBsAb was significantly lower (41.2% vs 68.5%, P=0.001). Hepatitis B carriers in endometrial cancer group were also more frequent than in the control group (9.3% vs 5.5%, P=0.013). Interestingly, in the endometrial cancer group, 147 cases were HBV serum marker negative, which was also higher than in the control group (36.9% vs 15.6%, P=0.001). There may be a correlation between HBV infection and endometrial carcinoma.

Endometrial carcinoma in high‐risk populations: is it time to consider a screening policy?

Endometrial carcinoma (EC) is the leading female genital tract malignancy in industrialized countries. It will become an important public health problem in the coming years in the USA and Europe, where its incidence is increasing, and next-generation interventions should include periodical screening in high-risk women. In this review, we discuss the importance to gynaecologists of detecting women at high risk and offering an adequate screening programme. Screening for EC is particularly challenging and there is currently no proven programme for the surveillance of women estimated to be at an increased risk of developing this form of cancer. The data in the literature, including this and previous issues of Cytopathology, and personal experience suggest that endometrial liquid-based cytology (LBC) might play an essential role in a screening policy for EC. LBC may enable practitioners to reduce age-adjusted mortality for women at high risk for EC.

Lhermitte-Duclos disease: A case report

A 43-year-old female with a past history of breast carcinoma presented with headaches and dizziness concerning for metastatic disease. An MRI showed a large non-enhancing right cerebellar mass. Microscopic examination of the subsequent biopsy showed fragments of cerebellar parenchyma with disorganised collections of atypical ganglion cells of variable size consistent with dysplastic gangliocytoma/Lhermitte-Duclos disease (LDD). LDD is a rare, slow growing benign lesion of the cerebellum. The histogenesis remains uncertain as it is not clear whether it represents a hamartomatous or neoplastic process. Grossly there is enlargement and coarsening of the cerebellar folia. Histologically there is relative preservation of architecture with diffuse enlargement of the molecular and internal granular layers which contain atypical ganglion cells of various size and reduced numbers of purkinje cells. Adult onset of LLD is pathognomonic of Cowden syndrome a hamartoma/cancer syndrome associated with a germline loss of function mutation of the PTEN gene resulting in an increased risk of breast, thyroid, endometrial, colorectal and renal cell carcinoma. While LDD is a slow growing lesion without reported malignant potential, the association with Cowden syndrome and subsequent increased risk of epithelial malignancy warrants referral for genetic counselling.

Polycystic ovarian disease in adult and perimenopausal women

Polycystic ovarian disease (PCOD) is most common endocrine disorder in women. Symptoms are variable and often involve more than one body function. The major clinical features are hirsutism, menstrual irregularities, obesity, insulin resistance, hyperinsulinemia, polycystic ovaries (PCO). Other characteristics include malepattern balding, acanthosis negricans, sleep apnea with increased risk for hypertension, cardiovascular disease, diabetes mellitus, endometrial carcinoma, and overproduction of ovarian androgens and luteinizing hormone. While some believe that PCOD disappears after menopause, symptoms can persist after menopause. The cause of PCOD is still unknown. Genetic studies suggest that transmission is autosomal dominant with decreased penetrance because of hypersensitive intra-ovarian-insulin-androgen signaling with disturbances in gonadotropin levels, hyperandrogenism, and reduced insulin sensitivity. Hyperinsulinaemia frequently stimulates lipid storage with alterations in lipoproteins, cholesterol, hyperlipidaemia obesity. Anti-Mullerian hormone might be responsible for these abnormalities. Information on PCOD in adult perimenopausal women is scarce as it may be difficult to diagnose, since one marker is irregular menstruation. PCO, a common feature of PCOD, may occur with or without other disorders and the associated obesity is of android (central) type with a waist-hip ratio (WHR) of > 0.8. Fasting glucose insulin ratio (FGI) has become a popular diagnostic criteria. Triglycerides, low-density lipoprotein (LDL), and cholesterol are elevated with decreased levels of sex hormone binding globulin (SHBG) due to hyperinsulinemia. The elevated levels of serum leptin and insulin and their linkage to obesity suggest the potentially complicated implications for obese patients. Preventative measures for PCOD are limited. Clinical management is primarily focused on treating symptoms and manifestations and preventing long-term complications. Oral contraceptive pills (OCP) have several benefits, including treatment of irregular menstruation. Insulin-sensitizing agents can ameliorate insulin resistance, endocrine, and metabolic reproductive abnormalities. Metformin has been extensively used and is not associated with an increase in insulin secretion or risk of hypoglycaemia. The weight loss that accompanies protracted therapy may account for some of the beneficial effects. Long-term follow-up is needed to determine the effectiveness in changing the metabolic outcomes without causing other complications, such as reducing hair growth. Management should include patient education, with particular attention to diabetes, cardiovascular risk, obesity and endometrial cancer.

Abstract B51: Effect modification of the relationship between cigarette smoking and endometrial carcinoma risk

Abstract Introduction: Epidemiological studies have consistently observed inverse associations between cigarette smoking and endometrial carcinoma risk. However, effect modification of this relationship by other endometrial carcinoma risk factors and relationships with tumor characteristics are unclear. Methods: We examined the association between cigarette smoking and endometrial carcinoma risk among 110,304 women enrolled in the National Institutes of Health-AARP Diet and Health Study. During 1,029,041 person years of follow-up, we identified 1,476 incident endometrial carcinoma cases. Multivariable Cox proportional hazards regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for the association between smoking status, years since smoking cessation, and endometrial carcinoma risk. Potential effect modification by other endometrial carcinoma risk factors was assessed using likelihood ratio test statistics. Smoking associations by histologic subtype (Type I vs. Type II) and stage at diagnosis (in situ/localized vs. regional/distant) were also evaluated. Results: Reduced endometrial carcinoma risk was evident among former (RR: 0.88, 95% CI 0.79, 0.98) and current (RR: 0.67, 95% CI 0.55, 0.81) smokers compared with never smokers. Number of years since smoking cessation was significantly related to endometrial carcinoma risk: smoking cessation 1-4 years prior to baseline was associated with reduced endometrial carcinoma risk (RR: 0.66, 95% CI 0.49, 0.89) whereas smoking cessation 10 or more years before baseline was not significantly associated with risk (RR: 0.94, 95% CI 0.84, 1.06). The association between smoking status and endometrial carcinoma risk was modified by body mass index (BMI, pinteraction=0.02) and menopausal status (pinteraction=0.08). Among obese women (BMI > 30 kg/m2), former (RR: 0.78, 95% CI 0.68, 0.92) and current smoking (RR: 0.59, 95% CI 0.42, 0.82) were inversely related to endometrial carcinoma risk. Smoking status was not associated with risk among overweight women (BMI 25-30 kg/m2); however, among normal-weight women (BMI <25 kg/m2), current (RR: 0.59, 95% CI 0.42, 0.85) but not former smoking (RR: 1.04, 95% CI 0.85, 1.27) was related to endometrial carcinoma risk. Opposite associations for pre- and postmenopausal women were observed, with current smoking being inversely related to endometrial carcinoma risk in postmenopausal women (RR: 0.61, 95% CI 0.50, 0.74) but positively associated with endometrial carcinoma risk in premenopausal women (RR: 1.47, 95% CI 0.75, 2.88). No other endometrial carcinoma risk factors, including menopausal hormone use, parity, oral contraceptive use, or diabetes significantly modified the smoking-endometrial carcinoma risk relationship. We did not observe major differences in associations between smoking status and endometrial carcinoma risk by tumor characteristics. Conclusion: Our results demonstrate that endometrial carcinoma risk is influenced by current as well as recent smoking history; however, associations did not vary meaningfully by endometrial tumor characteristics. Effect modification by some hormone-associated risk factors (e.g. menopausal status and obesity) but not others (e.g. menopausal hormones and oral contraceptive use) might suggest that smoking reduces endometrial carcinoma risk through multiple biological mechanisms. Citation Format: Ashley S. Felix, Hannah P. Yang, Gretchen L. Gierach, Yikyung Park, Louise A. Brinton. Effect modification of the relationship between cigarette smoking and endometrial carcinoma risk. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr B51.

Ovarian granulosa cell tumor and increased risk of breast cancer

Granulosa cell tumor of the ovary (GCT) is a rare neoplasm. The tumor often secretes estrogens and then presents at an earlier stage due to hormone-related symptoms. GCT women are at increased risk of endometrial carcinoma, but there is only limited information about GCTs and potential association to other hormone-related neoplasms such as breast cancer. We conducted a retrospective follow-up study on 163 women with GCT. Medical records and histological sections were reviewed and a search in the pathology registry performed. Eight [95% confidence interval (CI); 3.4-15.8] GCT women were diagnosed with a breast neoplasm; one with Paget's disease of the nipple and seven with breast carcinoma. Based on calculations using incidence rates on breast cancer among Danish women, we would have expected 2.5 cases of breast cancer. The odds ratio was 3.3 (95% CI, 1.6-6.6), suggesting an increased risk of breast cancer in GCT women.

Risk of Incidental Finding of Endometrial Cancer at the Time of Hysterectomy for Benign Condition

Study ObjectiveTo assess the risk of unanticipated endometrial carcinoma during hysterectomy to treat a presumed benign condition. DesignRetrospective analysis (Canadian Task Force classification II-2). SettingTertiary referral center, university hospital. PatientsAll women who underwent hysterectomy to treat presumed benign indications at our center from January 2000 to December 2011 were identified. We analyzed all pathologic reports and identified cases of unexpected endometrial carcinoma. InterventionsHysterectomy by any approach to treat presumed benign indications. Measurements and Main ResultsAt our institution, 2179 hysterectomies were performed to treat presumed benign indications. Nine (0.4%) revealed unexpected endometrial carcinoma (95% confidence interval, 0.2–0.7). ConclusionOur data suggest that the rate of unanticipated endometrial carcinoma during hysterectomy to treat benign conditions is low.

Overexpression of the Insulin Receptor Isoform A Promotes Endometrial Carcinoma Cell Growth

Epidemiological studies have demonstrated that type 2 diabetes mellitus (T2DM) and hyperinsulinemia are associated closely with endometrial carcinoma risk, although the molecular mechanism remains unclear. Insulin receptor isoformA expression is upregulated in many cancer cells and tissues, which suggests that IR-A-mediated signaling pathways may have important implications for cancer pathogenesis. We measured the expression of insulin receptor isoforms (IR-A and IR–B in the normal endometrium tissues, the endometrial carcinoma tissues and the endometrial carcinoma cell lines. We found that the total insulin receptor (IR) and IR-A expression mRNA levels and the ratio of IR-A to total IR in endometrial carcinoma specimens were significantly higher than them in control endometrial tissue specimens(P<0.05). Further analysis indicated that the tendency was more prominently in patients with T2DM. IR-A mRNA was differentially expressed in four endometrial carcinoma cell lines (Ishikawa, KLE, RL95-2 and HEC-1-A. RL95-2 cells have a low endogenous IR-A expression, and these were used to construct a stable cell line overexpressing IR-A. We found that IR-A overexpression significantly increased cell proliferation, the proportion of cells in S phase, activation of the Akt pathway and tumorigenicity of xenografts in nude mice. In contrast, there was no significant difference in the the percentage of apoptotic cells between cells overexpressing IR-A and control cells. Moreover, levels of phosphorylated ERK1/2 protein were significantly decreased in cells overexpressing IR-A relative to controls. These findings reveal the pivotal role of IR-A in endometrial cancer carcinogenesis, and suggest that the association of elevated IR-A levels with cell proliferation and tumorigenicity may be causally linked to its effect on the proportion of cells in S phase and the activation of the Akt pathway.

Ultra-low-dose vaginal estrogen tablets for the treatment of postmenopausal vaginal atrophy

ABSTRACTVaginal atrophy is a common chronic condition affecting up to 57% of postmenopausal women. The decrease in estrogen following cessation of menses can lead to bothersome symptoms that include vaginal dryness and irritation, pain and burning during urination (dysuria), urinary tract infections, and pain (dyspareunia) and bleeding during sexual activities. These symptoms can be safely and effectively managed with the use of local estrogen therapy, which reduces the risks associated with long-term systemic hormone therapy. The ultra-low-dose 10 μg estradiol vaginal tablet is the lowest approved dose available and has an annual estradiol exposure of only 1.14 mg. Its development addresses recommendations from regulatory agencies and women's health societies regarding the use of the lowest hormonal dose. The 10 μg vaginal tablet displays minimal estradiol absorption, causes no increased risk of endometrial hyperplasia or carcinoma, and provides significant symptom relief. The clinical evidence presented here may offer greater reassurance to health-care professionals and postmenopausal women that vaginal atrophy can be treated safely and effectively.

Effects of insulin, insulin-like growth factor-I and -II on proliferation and intracellular signaling in endometrial carcinoma cells with different expression levels of insulin receptor isoform A

Background Hyperinsulinemia, insulin-like growth factor (IGF)-I and -II (IGF-II) are associated with increased risk of endometrial carcinoma. Insulin receptor isoform A (IR-A) is more frequently expressed in endometrial carcinoma than in normal endometrial tissues. To better understand their roles in endometrial carcinoma, we investigated the effects of insulin, IGF-I, and IGF-II in endometrial carcinomas cells with different IR-A expression levels. Methods To explore the role of IR-A in mediating the activity of IGF-I, IGF-II, and insulin, we investigate the cellular proliferation of endometrial carcinoma cell lines RL95-2 and RL95-2-IR-A by MTS assays. Then we examined the protein kinase Akt phosphorylation and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in both cell lines by Western blotting. The effect of IGF-II and AG1024 on cell cycle progression and apoptosis was assessed by flowcytometry. To examine whether the effects of IGFs were mediated by IR-A, we blocked IGF-I receptor (IGF-IR) in both cell lines using AG1024, an IGF-IR-specific inhibitor. Results IGF-I and IGF-II significantly enhanced proliferation of both cell lines (P &lt;0.05). By contrast, insulin significantly increased proliferation of RL95-2-IR-A cells only (P &lt;0.05). IGF-I and IGF-II significantly increased pAkt levels in RL95-2 cells and pERK1/2 levels in RL95-2-IR-A cells (all, P &lt;0.05). Insulin increased pERK1/2 levels in RL95-2-IR-A cells only (P &lt;0.05). LY294002 and PD98059 inhibited the specific signaling activities and cellular proliferation. After AG1024 pretreatment, neither IGF-I nor IGF-II affected pAkt levels in RL95-2 cells. IGF-II, but not IGF-I, increased pERK1/2 levels in RL95-2-IR-A cells. After AG1024 pretreatment, the proliferation rate and DNA content corresponding to the S phase increased and apoptosis decreased significantly in IGF-II-treated RL95-2-IR-A cells only (P &lt;0.05). Conclusions The proliferation effect of insulin is mediated by IR-A. When IR-A dominates in a cell line, IGF-II activated cell proliferation mainly through the ERK1/2 pathway. On the other hand, IGF-II activated cell proliferation mainly through the Akt pathway. IR-A can at least partly mediate the proliferative and anti-apoptotic effects of IGF-II through the ERK1/2 pathway.

Histologic Evaluation of Prophylactic Hysterectomy and Oophorectomy in Lynch Syndrome

Women with Lynch syndrome (LS) are at increased risk for endometrial (EC) and ovarian carcinoma (OC). Current surveillance recommendations for detection of EC and OC in LS patients are not effective. Small studies have shown that prophylactic hysterectomy and bilateral salpingo-oophorectomy (P-TH-BSO) are the most effective and least expensive preventive measures in these patients. Data regarding histologic findings in prophylactic specimens in these patients are lacking. All LS patients who underwent P-TH-BSO at the Memorial Sloan-Kettering Cancer Center from 2000 to 2011 were identified. Slides were evaluated for the presence of endometrial hyperplasia (EH), EC, OC, or any other recurrent histologic findings. Twenty-five patients were identified, with an age range of 36 to 61 years. Fifteen patients had a synchronous or prior colorectal carcinoma, and 2 patients had a history of sebaceous carcinoma. Focal FIGO grade 1 endometrioid ECs were detected in 2 patients; 1 was 54 years of age (MSH2 mutation; superficially invasive), and the other was 56 years of age (MLH1 mutation; noninvasive). Focal complex atypical hyperplasia, unassociated with carcinoma, was seen in 3 patients, ages 35 and 45 (MLH1 mutations) and 53 years (MSH2 mutation). One patient (44 y, with MSH2 mutation) was found to have a mixed endometrioid/clear cell OC and simple EH without atypia. The OC was adherent to the colon but did not show distant metastasis. In our study, P-TH-BSOs performed because of the presence of LS revealed incidental EC and/or EH in 24% of cases and OC in 4%. The ECs were low grade, confined to the endometrium, and seen in patients older than 50 years. Prophylactic hysterectomy allows detection of early lesions in LS; these lesions appear to be small and focal. This small series of prophylactic hysterectomies may provide some clues about LS-associated endometrial carcinogenesis.

Retrospective analysis of prognostic variables and clinical outcomes in surgically staged intermediate risk endometrial carcinoma

ObjectiveTo identify independent prognostic variables for surgically staged intermediate risk endometrial carcinoma as defined by the Gynecologic Oncology Group 99 (GOG99) criteria. Study designRetrospective study of 239 patients with FIGO stage IB-occult IIB endometrioid type endometrial cancer, who were primarily treated with comprehensive staging surgery. Data were collected on clinicopathological variables, extent of primary surgery, postoperative adjuvant treatment, and patterns of recurrences. Kaplan–Meier survival curves were used to estimate disease free survival (DFS) and overall survival (OS), and multivariate Cox regression models were used to identify independent prognostic variables. The median follow-up time was 67 months (range, 12–183 months). ResultsThe 5-year DFS and OS were 91.0% and 93.0%, respectively. On univariate Kaplan–Meier analysis, age>60 years, deep myometrial invasion (MI), presence of lymph vascular invasion (LVSI), and negative progesterone receptor (PR) status were significantly associated with diminished 5-year DFS and OS. The univariate analysis on patterns of failures demonstrated that patients with older age or positive LVSI were more inclined to develop locoregional recurrence, while PR status and the depth of MI had a statistically significant impact on distant failure. On multivariate analysis, PR status, age, and the depth of MI were independent prognostic variables for 5-year DFS, and age was the only independent prognostic variable for 5-year OS. LVSI and age were independent prognostic variables for locoregional recurrence, while PR status and depth of MI were independent prognostic variables for distant recurrence. ConclusionsAge, depth of MI, PR status and presence of LVSI are of independent prognostic value for intermediate risk endometrial cancer. The presence of these variables warrants consideration when deciding upon treatment strategies.

Papillary Proliferation of the Endometrium

Papillary proliferation of the endometrium (PPE) without cytologic atypia is uncommon and has only been studied in detail by Lehman and Hart in 2001. On histologic examination, PPE ranges from simple papillae with fibrovascular cores, often involving the surface of endometrial polyps, to complex intracystic proliferations; some consider the latter to be analogous to nonatypical complex hyperplasia. To further characterize PPE, with emphasis on the risk of and features associated with concurrent or subsequent neoplasia, the clinicopathologic features of 59 cases without cytologic atypia were studied. The cases were classified into 2 groups according to the degree of architectural complexity and extent of proliferation. Group 1 consisted of those with localized simple papillae. Simple papillae were defined as those with short, predominantly nonbranching stalks; those with occasional secondary branches and/or detached papillae were also included in this group. Localized proliferations were those with 1 or 2 foci involving the surface or the subjacent glands of polyps or nonpolypoid endometrium. Group 2 consisted of those with complex papillae and/or those with diffuse and crowded intracystic papillae. Complex papillae were those with either short or long stalks, with frequent secondary and complex branches. Diffuse proliferation was defined as presence of 3 or more foci within a specimen or involvement of >50% of the endometrial polyp by simple or complex PPE. Any coexistent or subsequent hyperplasia of conventional type (World Health Organization classification) or adenocarcinoma was recorded. The age of patients ranged from 23 to 82 years (median, 53 y); 36 (61%) were postmenopausal. The majority presented with abnormal vaginal bleeding. Sixteen patients (27%) were receiving hormonal preparations including 5 who were treated with a progestogen for preexisting endometrial hyperplasia or low-grade endometrioid adenocarcinoma. The histologic diagnosis of PPE was made in 49 biopsies and in 10 hysterectomy specimens. Thirty-six cases (61%) were classified as group 1 and 23 (39%) as group 2. In 47 cases (80%), there was a coexisting endometrial polyp, 39 (66%) of which were involved by the PPE. Fifty-three cases (90%) had coexisting epithelial metaplastic changes, 41 (77%) of which were involved by the PPE. The most common type of metaplasia was mucinous (41 of 59 cases, or 69%). Follow-up information was known for 46 patients (78%). Coexistent or subsequent nonatypical and atypical hyperplasia was found in 8 (17%) and 6 cases (13%), respectively. In 6 of the 46 cases (13%), a low-grade endometrioid adenocarcinoma was present either in the original specimen or during follow-up. In contrast to group 1 PPE, those with group 2 features were significantly associated with concurrent or subsequent premalignant lesions (nonatypical and atypical hyperplasia) or carcinoma (P<0.0001). This study indicates that localized and architecturally simple PPEs confined to a completely removed polyp are usually associated with a benign outcome and may be appropriately labeled as "benign papillary proliferation of the endometrium." Lesions with architecturally complex papillae, especially when extensive, have an increased risk of concurrent or subsequent endometrial hyperplasia and carcinoma and should probably be regarded as analogous to atypical complex hyperplasia, and the term "complex papillary hyperplasia" is appropriate. As the distinction between simple and complex PPE may be difficult in small endometrial aspirational samples, consideration for curettage should be given to ascertain whether the lesion has been completely removed.

LAPTM4B gene polymorphism and endometrial carcinoma risk and prognosis

A novel gene called LAPTM4B (lysosome-associated protein transmembrane 4 beta) plays several crucial roles in carcinogenesis. In this case-control study, we investigated the relationship between LAPTM4B gene polymorphism and susceptibility to endometrial carcinoma (EC). In an adjusted multivariate logistic regression analyses, subjects with the LAPTM4B*1/2 and *2/2 genotypes respectively exhibited 1.572-fold (95% confidence interval (CI) = 1.041–2.375) and 2.335-fold (95% CI = 1.365–3.995) increases in the risk of developing EC relative to those carrying LAPTM4B*1/1. Patients with LAPTM4B *2 had both significantly shorter overall survival (OS) and shorter disease-free survival (DFS) (both p < 0.001). Multivariate analysis showed that LAPTM4B genotype is an independent prognostic factor for OS and DFS (both p < 0.001). These results suggest that LAPTM4B polymorphisms might play an important role in the aetiology of EC.

No association between the GSTM1 and GSTT1 polymorphism and endometrial cancer risk: A meta-analysi

Purpose: A number of case-control studies have been conducted to investigate the association of glutathione S-transferase (GST) genetic polymorphisms and endometrial carcinoma risk. However, these studies have yielded contradictory results. We therefore performed a meta-analysis to derive a more precise estimation of the association between polymorphisms on GSTM1, GSTT1 and endometrial carcinoma. Methods: Identification of relevant studies was carried out through a search in the following databases Medline, EMbase andChinaNational Knowledge International (CNKI) up to March. 2013. All case-control studies that investigated the association between GS-TM1 and GSTT1 gene polymorphisms and risk of endometrial cancer were included in the study. The pooled odds ratio (OR) was used for analyses of results and the corresponding 95% confidence intervals (CI) were estimated. Result: Six published case-control studies of association between the GSTM1 and GSTT1 polymorphism and endometrial cancer risk covering 3558 subjects were included in the metaanalysis, but the results indicated that the null genotypes of GSTM1 and GSTT1 polymorphisms were not associated with a significantly increased risk of endometrial cancer (for GSTM1: OR = 0.99; 95% CI, 0.86 - 1.4; for GSTT1: OR = 0.96; 95% CI, 0.80 - 1.14, respectively). Conclusion: This meta-analysis suggests that GSTM1 and GSTT1 polymorphism may not be associated with increased risk of endometrial cancer. To validate the association between polymorphism and endometrial cancer, further studies with larger numbers of participants worldwide are needed.

Clinical and histopathological characteristics in patients with postmenopausal bleeding

Background: Incidence of endometrial carcinoma in Vojvodina is 15-20/100 000. In 75% cases, endometrial carcinoma is diagnosed in postmenopausal period. In 90 % of patients, the first clinical sign is postmenopausal bleeding. The aim of the study was to investigate clinical and histopathological characteristics in patients with postmenopausal bleeding. Methods: The study included 122 patients with postmenopausal bleeding. All of these patients underwent gynecological examination and vaginal ultrasound. We obtained materials for histopathological analysis by fractionate explorative curettage. Once we had definitive histopathological findings, we divided patients in two groups A (endometrial carcinoma) and B (benign changes). Results: We confirmed significant statistical differences between examined group A and B, including age (64.49 compared with 58.81 years), postmenopausal period (13.67 instead 9.11 years), and length of uterine corpus (6.41 instead 5.25 cm). Conclusion: Elderly women with longer postmenopausal interval and postmenopausal bleeding had increased risk for endometrial carcinoma. Measurement of endometrial thickness by transvaginal ultrasound appeared to be insufficient parameter for differentiating the benign from the malignant changes of endometrium. Patients with endometrial carcinoma had significantly longer corpus of uterus comparing to patients with benign changes. Body mass index was not found to be significant risk factor in development of endometrial carcinoma in the examined groups. Obesity was diagnosed in both groups, suggesting that increased body mass index is a risk factor for development of pathological changes in endometrium, which could lead to postmenopausal bleeding.

Importance of revealing a rare case of breast cancer in a female to male transsexual after bilateral mastectomy

The incidence of breast carcinoma following prophylactic mastectomy is probably less than 2%. We present a 43-year-old female to male transsexual who developed breast cancer 1 year after bilateral nipple- sparing subcutaneous mastectomy as part of female to male gender reassignment surgery. In addition to gender reassignment surgery, total abdominal hysterectomy with bilateral salpingo-oophorectomy (to avoid the patient from entering menopause and to eliminate any subsequent risk of iatrogenic endometrial carcinoma), colpocleisys, metoidioplasty, phalloplasty, urethroplasty together with scrotoplasty/placement of testicular prosthesis and perineoplasty were also performed. Before the sex change surgery, the following diagnostic procedures were performed: breast ultrasound and mammography (which were normal), lung radiography (also normal) together with abdominal ultrasound examination, biochemical analysis of the blood and hormonal status.According to medical literature, in the last 50 years only three papers have been published with four cases of breast cancer in transsexual female to male patients. All hormonal pathways included in this complex hormonal and surgical procedure of transgender surgery have important implications for women undergoing prophylactic mastectomy because of a high risk of possible breast cancer.