Cases Of Proliferative Endometrium Research Articles

Expression of PAX2 and PTEN in Oestrogen-Driven Endometrial Hyperplasia and Neoplasia

Endometrial hyperplasia is of paramount clinical implication as it is usually seen to precede endometrioid adenocarcinoma. However, clinicians and pathologists have always been uncertain about the distinction between innocuous hyperplasia from their sinister counterparts. This has serious implications, for the latter lesion has a greater propensity for progressing into adenocarcinoma and needs deft clinical intervention in the form of adequate progestational exposure or surgery. Thirty cases diagnosed as endometrial hyperplasia on endometrial biopsies were retrieved from the archives and reclassified as per the EIN criteria. Thirty cases each of proliferative endometrium and endometrioid carcinoma were also included. Immunohistochemistry with antibodies against PAX2 and PTEN was performed, and the extent of loss of expression was scored. A total of ten cases of EIN were identified, all of whom were initially diagnosed as complex hyperplasia with atypia. All cases of proliferative endometrium showed retained expression of PAX2 and PTEN. In contrast, all cases of endometrioid carcinoma showed complete loss of PAX2 and PTEN. The EIN cases showed partial loss of both PAX2 and PTEN expression. Loss of PAX2 expression in EIN showed a specificity and positive predictive value of 90% and 83.33%, respectively. The advent of the EIN criteria has made identification of clinically significant endometrial precancerous lesion more acceptable and reproducible. However, in cases of ambiguity, the use of antibodies against certain protein molecules which reflect the genes involved in the stepwise carcinogenesis would be of great utility in the hands of the pathologist. In comparison with PTEN, the use of PAX2, which gives a crisp nuclear positivity and has a lower percentage of loss of expression in normal endometrium, can be used as part of the algorithm in accurately identifying the precancerous endometrium.

Assessment of the Predictability of Pipelle Biopsy in Detecting Endometrial Pathology

Objective: To assess the predictability of pipelle biopsy in detecting endometrial pathology in patients with heavy menstrual bleeding and its verification by uterine histopathology at hysterectomy.
 Methods: A validation study inclusive of 50 patients, aged 35-55 years, sampled through convenience sampling technique, diagnosed with abnormal uterine bleeding and belonging to the peri-meno- pausal age group was carried out in obstetrics and gynaecology department Karachi, from January 2015 to June 2015. The patients included in the research investigation, were scheduled for hysterec- tomy, and got their endometrial sampling done through pipelle technique. The data collected were then sent for histopathology analysis. The final findings of histopathology were then verified by means of histopathology report. Patients having previous experience of D&C within the last four weeks or with uterus size greater than sixteen weeks were excluded. Inferential analysis was performed using Wilcoxon signed sum rank test. Kappa analysis was also done to measure the degree of agreement between pipelle and histopathological outcomes.
 Result: The results of the study showed the mean age of sample as 45.94 ± 7.92 years. Medical his- tory for the sample has been shown and revealed that 14% of the sample had menopause. KAPPA analysis was conducted to compare the degrees of acknowledgement for histopathology and pipelle outcomes. The analysis showed that there was a 76.6% positive agreement observed in between the two techniques, with p-value results significant (<0.01). The study reported 14% cases of proliferative endometrium, while 4% cases of endometrial hyperplasia and 4% cases of endometritis and en- dometrial polyps have been diagnosed in the given sample.
 Conclusion: The results of the study has shown that pipelle biopsy is a significant methodology used to assess the endometrial pathology among the patients with heavy menstrual bleeding, as verified by histopathology reports after assessment through hysterectomy.

The impact of examining VEGF-C expression, D2-40 based detection of LVI, and LVD on the Prediction of Lymph Node Metastasis in Endometrial Carcinoma.

Background: Background: Lymph node metastasis (LNM) is a main route of endometrial carcinoma (EC) spread and it plays a chief prognostic role. Our objective is to find LMN predictors through investigating lymph vessel invasion (LVI), and lymphatic vessel density (LVD), in addition to VEGF-C expression in the primary tumor site of the EC. Material and Methods: A retrospective Immunohistochemical study applying VEGF-C and D2-40 antibodies on 40 EC cases, in addition to 20 cases of proliferative endometrium, and 20 cases with atypical endometrial hyperplasia as control groups. The studied cases were screened for expression of VEGF-C, D2-40- LVI, and LVD. Statistical analysis with the correlation of the findings to various clinicopathological parameters were achieved. Results: Expression of VEGF-C was moderate to high in 87.5% of EC cases, only mild to moderate focal staining in atypical hyperplasia cases, and exclusively negative in proliferative endometrium cases. VEGF-C expression could independently predict LNM with sensitivity, specificity , PPV, NPV, and accuracy of (100, 51.6, 62.5, 100, 62.5%)respectively. D2-40-LVI detection system is more sensitive in predicting LNM in EC than routine H&E stained section. It was detected in 9/9of EC with LNM cases ,(sensetivity100%) compared to 7/9 cases detected by H&E staining (sensetivity77.8%). D2-40 -LVI detection system could predict LNM with sensitivity, specificity, PPV, NPV, and accuracy of (100, 67.7, 47.4, 100, 75%. )respectively. D2-40-LVI ,Peritumoral LVD, and VEGF-C expression showed a significant correlation to LNM (p

Altered PTEN expression as a diagnostic marker for the earliest endometrial precancerous changes

Introduction: Study was planned to investigate PTEN gene expression in endometrial hyperplasia and carcinoma as analyzed by immunohistochemistry. Material and Method: This study was conducted on 80 endometrial samples in the Department of Pathology, Gandhi Medical College, Bhopal (January 2012 to August 2016) Results: 5 out of 5 cases of proliferative endometrium, 3 out of 5 cases of secretory endometrium, 37 [84%] out of 44 cases of simple and complex endometrial hyperplasia without atypia, 8 out of 15 cases of simple and complex endometrial hyperplasia with atypia and 3 out of 11 cases of endometrial carcinoma showed positive PTEN expression. Conclusion: PTEN is a major gene involved in the pathogenesis of endometrial carcinoma. Our data suggest that decreased PTEN expression was a marker of earliest endometrial pre-cancer lesion and we propose that use of PTEN immunostaining in a clinical setting may be informative in identifying premalignant lesions that are likely to progress to carcinoma.

Randomized trial of medroxyprogesterone acetate for the prevention of endometrial pathology from adjuvant tamoxifen for breast cancer: SWOG S9630.

The proliferative effect of adjuvant tamoxifen on the endometrium can potentially result in endometrial abnormalities, including cancer in postmenopausal women. We conducted a randomized, controlled trial to assess endometrial pathological diagnoses in postmenopausal women with early stage, ER-positive breast cancer without endometrial pathology at baseline. They were assigned to tamoxifen alone versus tamoxifen plus cyclical medroxyprogesterone acetate (MPA 10 mg for 14 days every 3 months) for 5 years. Endovaginal sonograms (EVS) +/− endometrial biopsies (EMB) were required at baseline, 2 and 5 years. Of 313 patients registered, 296 were eligible and 169 (57%; 89, tamoxifen; 80, tamoxifen+MPA) were evaluable (completed year-2 EVS, with an EMB if stripe width was ⩾5 mm). Sixty (67%) of these in the tamoxifen arm had an endometrial stripe width ⩾5 mm (and underwent subsequent EMB) compared with 48 (60%) in the tamoxifen+MPA arm (P=0.40). There were four cases of proliferative endometrium and one simple hyperplasia on the tamoxifen arm (6% (95% confidence interval (CI): 2–13%) among evaluable patients and one proliferative endometrium on the tamoxifen+MPA arm (P=0.11). The overall fraction with benign endometrial abnormalities at year 2 was 3.6% (6/169; 95% CI: 1.3–7.6%), with only 1 (of 102) new benign proliferative event at year 5. The event rate in both arms was much lower than projected, making treatment arm comparisons less informative. A normal endometrium prior to tamoxifen may provide reassurance regarding future endometrial events. However, validation in a larger trial is needed before changing practice in asymptomatic, postmenopausal women.

UbcH10 Expression in Benign, Hyperplastic, and Malignant Endometrial Curetted Materials

The aim of this study was to investigate the role of UbcH10 expression in the differential diagnosis of benign, hyperplastic, and malignant endometrial tissues and also the relationship of UbcH10 with the clinicopathologic parameters of malignant cases. A tissue microarray was performed for 81 endometrial curettage biopsies, which histological diagnosis had demonstrated to be 13 cases of proliferative endometrium, 7 cases of disordered proliferative endometrium, 5 cases of complex atypical hyperplasia, 24 cases of nonatypical hyperplasia, and 32 cases of endometrioid adenocarcinoma. Expression of UbcH10 was assessed by immunohistochemistry. When groups were compared according to UbcH10 percentages and scores, a statistically significant difference was found only between the carcinoma group and the other groups, except the complex atypical hyperplasia group (P < .05). In the malignant group, UbcH10 percentages and scores were only significantly related to age. There was no significant association between UbcH10 expression and tumor grade and stage. Overexpression of UbcH10 may be a useful indicator of endometrial carcinoma. UbcH10 also deserves further evaluation in the detection of prognostic mean and also for its role in endometrial carcinogenesis.

Nuclear features in endometrial cytology: Comparison of endometrial glandular and stromal breakdown and endometrioid adenocarcinoma grade 1

This study was to clarify the nuclear features of "condensed clusters of stromal cells (EGBD-stromal cells)" and "metaplastic clumps with irregular protrusions (EGBD-metaplastic cells)" which may be recognized in endometrial glandular and stromal breakdown (EGBD) cases in liquid-based cytologic (LBC) preparations of endometrial brushings. The material consists of cytologic smears of 20 cases of proliferative endometrium (PE), 20 cases of EGBD, and 20 cases of endometrioid adenocarcinoma grade 1 (G1) for which histopathological diagnosis was obtained by endometrial curettage. Nuclear findings were examined in PE cells, EGBD-stromal cells, EGBD-metaplastic cells, and G1 cells, respectively. It was examined about the following items: (1) Nuclear shape; (2) A long/minor axis ratio in cell nuclei; (3) An area of cell nuclei; (4) Overlapping nuclei; (5) The distribution pattern of nuclei within cell clusters. The following observations were made: (1) In PE cells, round-oval nuclei appeared to predominate, overlapping nuclei were not observed, and a slightly abnormal distribution pattern of nuclei was recorded; (2) In EGBD-stromal cells, reniform nuclei were characteristically observed, nuclei had small size and a generally elongated appearance, overlapping nuclei were recognized, and a remarkable abnormal distribution pattern of nuclei was found; (3) In EGBD-metaplastic cells, spindle nuclei were a characteristic feature, nuclei were larger in size and had a bipolar appearance, overlapping nuclei with moderately abnormal distribution pattern of nuclei were identified; (4) In G1 cells round-oval nuclei predominated, overlapping nuclei with moderately abnormal distribution pattern of nuclei were found. The study demonstrates that the analysis of selected nuclear findings appears to be very useful in the cytopathological assessment of endometrial lesions in LBC samples, especially for the discrimination of EGBD and G1.

Utility of thin-layer preparations in the endometrial cytology

The purpose of the current study was to examine the use of thin-layer cytologic (TLC) preparation compared to conventional cytologic preparation (CCP) in the normal endometrium (proliferative, secretory, atrophic) and endometrial glandular and stromal breakdown (EGBD). During a 6-month period, we compiled 158 cases by collecting a direct endometrial sample using the Uterobrush. The material comprised 40 cases of proliferative endometrium, 42 cases of secretory endometrium, 46 cases of atrophic endometrium, and 30 cases of EGBD. The following points were investigated: (1) number of endometrial epithelial cell clumps; (2) presence of TLC > CCP cases on number of epithelial cell clumps; (3) number of condensed cluster of stromal cells; (4) presence of TLC > CCP cases on number of condensed cluster of stromal cells; (5) presence of metaplastic clumps with irregular protrusion-containing condensed stromal cluster; (6) presence of a clear background; (7) presence of blood vessel in TLC; (8) presence of blood vessel of length more than diameter of a field in object x20 glasses in TLC. (1) In all phases, the number of epithelial cell clumps per a unit area of a preparation of TLC is greater than in CCP. (2) Cells (condensed cluster of stromal cells and metaplastic clumps with irregular protrusion-containing condensed stromal cluster) of useful and adequate numbers for a diagnosis of EGBD were observed in TLC. (3) In all phases, TLC was significantly higher than CCP on the appearance of a clear background. (4) The proliferative endometrium and secretory endometrium were highly significant in comparison with atrophic endometrium and EGBD, respectively, in terms of the occurrence of a blood vessel of length more than diameter of a field in object x20 glasses. Although the preparation area of TLC is smaller than that of CCP, the preparation has a clean background so that an accurate report on the patient's condition is possible. Therefore, TLC preparation is a useful tool for the accurate and reliable diagnosis of normal endometrial phase and EGBD, because the preparation area is confined and identification of the target cell clumps is easy.

Adverse effects of a SERM (Levormeloxifene): Safety parameters and bone mineral density 12 months after treatment withdrawal

Objective: Levormeloxifene is a selective estrogen receptor modulator (SERM). The development of the drug was discontinued due to intolerable adverse effects. This paper follow-up on the adverse events in a group of 234 women that was followed for 12 months without treatment after 12 months of treatment with levormeloxifene. Methods: Adverse events were recorded at all clinical visits. The double-layer thickness of the uterine endometrium was determined by transvaginal ultrasonography. Endometrial biopsies were obtained by pipelle. The biopsies taken at the entrance to the follow-up phase were taken under hysteroscopy-guidance. Bone mineral density of the total body, lumbar spine (L1–L4), hip and forearm was measured by dual-energy X-ray absorptiometry. Results: The most prominent adverse event was increased endometrial thickness over the pre-defined threshold of 8 mm. No cases of proliferative endometrium were reported. Following withdrawal of treatment the mean endometrial thickness approached baseline levels in a dose dependent manner. Hysteroscopic examinations showed that levormeloxifene was related to increased incidence of edema, vascularization and cysticity. In the levormeloxifene groups, a total of eight women had utero-vaginal prolapse and five women reported urinary incontinence (including worsening of a previously existing condition). Bone density in the spine and hip approached baseline levels during the 12 months of follow-up without treatment. Conclusion: Endometrial thickening, seen in association with the use of some SERM's, may lead to harmful adverse effects more than 12 months after treatment is initiated. Levormeloxifene prevents the postmenopausal bone loss, but the lowest effective dose is unknown.

Ultrasonographic endometrial monitoring during continuous–sequential hormonal replacement therapy regimen in postmenopausal women

Objective: To evaluate the endometrial thickness in different periods of a continuous–sequential HRT regimen and to correlate the ultrasonographic findings with the histological patterns. Methods: The study was structured in two phases. In the 1st phase, 37 postmenopausal women (group A) treated by at least 6 months with a conventional continuous–sequential hormonal replacement therapy (cs–HRT) regimen were enrolled. In all patients, the endometrial thickness was measured at the 7th, 14th, 21st and 25th day of the cycle using transvaginal ultrasonography (TV-USG). In the 2nd phase of the study, other 41 postmenopausal women (group B) were enrolled and treated with the same sc-HRT regimen. At entry and after six cycles of cs–HRT, an endometrial biopsy was performed. The endometrial pattern was related with endometrial thickness. Either the evaluations were performed immediately after progestogen withdrawal bleeding, as showed by 1st phase results. Results: The results of the 1st phase of the study showed a mean endometrial thickness significantly lower at 7th day of the cycle compared to 14th, 21st and 25th day (4.3±1.2 versus 6.6±2.9, 7.8±4.2 and 7.4±4.6 mm±SD, respectively). After six cycles of cs–HRT (2nd phase of the study), the mean endometrial thickness was significantly increased in comparison with basal values (4.2±1.5 versus 2.8±1.2 mm±SD; P<0.05). Endometrial biopsies showed 13 cases (39.4%) of atrophy and 20 cases (60.6%) of proliferative endometrium. Mean endometrial thickness in case of atrophy was lower than in presence of a proliferative endometrium (3.7±1.2 versus 4.4±1.4 mm±SD; not significant). Endometrial thickness was <4 mm in 16 cases (11 of atrophic and five of proliferative endometrium), between 4 and 5 mm in 15 cases (13 of proliferative and two of atrophic endometrium) and between 5 and 6 mm in two cases (either case of proliferative endometrium). Conclusions: The best timing for monitoring endometrial thickness during cs–HRT regimens is the period immediately after withdrawal bleeding improving the reliability of the ultrasonographic exam to identify endometrial pathologies.

Endometrial safety of continuous combined hormone replacement therapy with 17 β-oestradiol (1 or 2 mg) and dydrogesterone

Objectives: To determine the endometrial safety of oral 17 β-oestradiol combined continuously with dydrogesterone in preventing endometrial proliferation. Methods: The low dose group comprised three 52-week (13 cycles of 28 days) studies (two of which were double blind) using a 17 β-oestradiol dose of 1 mg daily combined with dydrogesterone 2.5, 5, 10 or 20 mg daily. The high dose group comprised two 24-week double-blind studies using a 17 β-oestradiol dose of 2 mg daily combined with dydrogesterone 2.5, 5, 10 or 15 mg daily. Endometrial safety was verified by aspiration endometrial biopsies. Inadequate progestational response was defined as proliferative endometrium, endometrial polyp, hyperplasia and carcinoma. Results: Data was evaluable from 650 healthy postmenopausal women in the low dose group and 310 in the high dose group. Endometrial protection was achieved with dydrogesterone at doses of 5 mg or higher combined with 1 or 2 mg 17 β-oestradiol. The success rate was 97%, 97% and 98% in women receiving 1/5, 1/10 and 1/20 mg, respectively, and 95%, 98% and 91% in women receiving 2/5, 2/10 and 2/15 mg, respectively. A lower success rate was achieved with the 2.5 mg dydrogesterone dosage (93% in the 1/2.5 mg group and 85% in the 2/2.5 mg group) due to more cases of proliferative endometrium. None of the women in the low dose group developed hyperplasia or carcinoma; five (0.7%) had endometrial polyps. In the high dose group, one woman given 2.5 mg dydrogesterone developed hyperplasia; there were no cases of carcinoma. Conclusion: 5 mg daily dydrogesterone appears to be the lowest effective dose to ensure endometrial safety in a continuous combined regimen with 1 or 2 mg 17 β-oestradiol.

Continuous combined hormone replacement therapy compared with tibolone

Objective: To compare relief of vasomotor symptoms, changes in lipoproteins, and bleeding patterns in postmenopausal women receiving either continuous combined hormone replacement therapy (HRT) of estradiol valerate and norethisterone or tibolone 2.5 mg/day. Methods: In a multicenter, randomized, open-label study, 235 postmenopausal women received one of the above-mentioned treatments. Fasting lipoproteins were measured at baseline and at 3, 6, and 12 months. At each visit, participants completed Greene climacteric questionnaires and recorded any bleeding episodes. Data are presented as mean ± standard deviation if normally distributed, median and interquartile range if non-normally distributed, or as frequency count. For menopausal symptoms and diary card data, the differences were tested by Wilcoxon rank-sum test. Results: One hundred sixteen women received continuous combined HRT and 119 women received tibolone; 72 and 76 women, respectively, completed 12 months of therapy. Both treatments effectively relieved vasomotor symptoms and reduced serum total cholesterol. Continuous combined HRT, but not tibolone, significantly reduced low-density lipoprotein levels. Both treatments reduced high-density lipoprotein levels, but the effect was more profound with tibolone. The initial bleeding score was higher for women taking continuous combined HRT; however, by the end of the study, the percentages of amenorrheal women were comparable. Endometrial histology was similar for both treatments at the end of the study, although two cases of proliferative endometrium were found in the tibolone group. Conclusion: Estradiol valerate–norethisterone continuous combined HRT controls symptoms and is associated with a safe lipid profile.

Bcl-2 protein expression in endometrial carcinoma: the lack of correlation with p53

bcl-2 expression was examined on paraffin-embedded specimens in proliferative, hyperplastic, and neoplastic human endometrium by immunohistochemistry. The results of bcl-2 immunostaining in endometrial carcinomas were compared with clinicopathological indicators as well as with p53 accumulation. The streptavidin-peroxidase detection system was used and the intensity and the distribution of immunostaining was evaluated semiquantitatively by counting H-score values. Expression of the bcl-2 protein was found in 2 out of 5 cases of proliferative endometrium (mean H-score 0.4, range 0.35–0.45), 4 out of 5 cases of simple hyperplasia (mean H-score 1.23; range 1.0–1.4), 4 out of 5 cases of complex hyperplasia (mean H-score 1.1; range 0.7–1.2) and in 7 out of 25 cases of endometrial carcinoma (mean H-score 0.48; range 0.35–0.65). All bcl-2 positive slides were obtained from patients who had endometrial cancer and who were in the early (stage I due to FIGO) clinical stage of the disease. bcl-2 expression was not related to age, surgical stage or histopathological features, and neither was there an inverse correlation between bcl-2 immunostaining and p53 expression reported in the study of neoplastic endometrium. Our data indicate that mechanisms other than p53 may play a role in the regulation of bcl-2 expression in endometrial carcinomas.

Relationship Between Circulating Estradiol Levels, Body Mass Index, and Breakthrough Bleeding in Postmenopausal Women Receiving Hormone Replacement Therapy

The purpose of this prospective study was to investigate the association of breakthrough bleeding with circulating estradiol levels and obesity in postmenopausal women receiving hormone replacement therapy. Fifty postmenopausal women receiving 0.625 mg conjugated estrogen with 2.5 mg medroxyprogesterone acetate were included in the study. Patients are recalled at 1st, 5th and 9th weeks for the measurements of the serum estradiol levels. Twenty women (40%) had a bleeding episode within 9 weeks of therapy. Of the 25 women who had a body mass index (BMI) of > 25, 13 (52%) had bleeding. Of the 25 women who had a BMI of < 25, 7 (28%) had bleeding. There was a trend toward a relation between BMI and breakthrough bleeding, although the relation did not achieve significance (p = 0.14). Serum estradiol levels of both bleeders and nonbleeders remained similar throughout the study. Endometrial histology revealed proliferative endometrium in two cases and secretory endometrium in one case at baseline; two cases of proliferative endometrium were found during bleeding. The remaining samples revealed atrophy. No relation was found between serum estradiol levels and breakthrough bleeding. Nevertheless, increased BMI may have an impact on breakthrough bleeding in postmenopausal women receiving hormone replacement therapy.

DNA Ploidy, Cell Cycle Kinetics, and Low Versus High Grade Atypia in Endometrial Hyperplasia

There have been few studies of DNA ploidy and cell cycle kinetics in endometrial hyperplasia. The authors studied archival cases of proliferative endometrium, simple, complex and atypical endometrial hyperplasia and well, moderately, and poorly differentiated endometrial adenocarcinoma by flow cytometry and also evaluated the significance of the degree of cytologic atypia (low versus high) in endometrial hyperplasia relative to the occurrence of carcinoma. All proliferative endometria, all types of hyperplasia and well and moderately differentiated carcinomas were diploid. Two-thirds of poorly differentiated adenocarcinomas were aneuploid. Neither S-phase fractions or proliferative fractions (S+G2M) could distinguish among the different types of hyperplasia or predict which hyperplasias were associated with carcinomas. The degree of cytologic atypia in atypical hyperplasia was not predictive of the occurrence of carcinoma. Poorly differentiated carcinomas showed significant differences in DNA ploidy, S-phase, and proliferative fractions from endometrial hyperplasia and lower grade carcinoma. These results support the concept that there are two fundamentally different types of endometrial carcinoma.

Presence of cells with argyrophil granules in normal, hyperplastic, and neoplastic endometrium.

Cells with argyrophil granules were searched for in 131 consecutive specimens obtained from endometrial curettage. Particular care was taken with the fixation methods to avoid a false positivity to the silver impregnation according to Grimelius. We did not consider the grossly argyrophilic positivity on the cellular apex or of the whole cytoplasm, which was partially reduced by diastase digestion and probably due to the presence of glycogen and secretory mucoproteins. Cells with thin argyrophilic granules similar to those observed in endocrine APUD cells were present among glandular cells and/or among stromal cells in 15 of 131 examined specimens. They concerned 5 cases of proliferative endometrium, 3 of secretive endometrium, 5 of hyperplasia, and 2 of carcinoma. In 8 of the 15 cases with argyrophilic cells, immunohistochemical studies with the PAP method showed cells with the presence of FSH, S-100 protein, somatostatin, vasoactive intestinal peptide (VIP), gastrin, and neuron-specific enolase (NSE). The significance and origin of these cells in normal and neoplastic endometrium are discussed.