Endometrial Intraepithelial Neoplasia Classification Research Articles

Functional PTEN mutations in progestin-resistant de novo endometrial intraepithelial neoplasia (119)

<b>Objectives:</b> Endometrial intraepithelial neoplasia (EIN), including simple hyperplasia and complex hyperplasia with atypia (CAH), is a precursor lesion for endometrial adenocarcinoma. Not all patients with EIN are eligible for or choose to have a hysterectomy and are typically treated with progestin. Depending on EIN classification and covariates like obesity, 25-50% of cases fail to respond to progestin therapy. We hypothesized that non-responders might have mutations in <i>PTEN</i> that affect function but not expression. <b>Methods:</b> This is a retrospective case-control study of 49 patients who had <i>de novo</i> endometrial biopsies with EIN (41 CAH and eight simple hyperplasia). Included cases required diagnoses confirmed by two pathologists and a history of oral or IUD progestin therapy. All the cases had at least 3-6 months of follow-up biopsies. Regions of interest containing EIN were sampled for DNA analysis using histologic sections and the commercially available GeneTrails^c solid tumor panel. Protein expression was measured in serial sections by Nanostring immunolabeling and GeoMx spatial profiling. Data were analyzed by Chi-square and unsupervised clustering with adjusted p-values. <b>Results:</b> Clinical follow-up revealed that 24 patients were progestin responders (eight simple hyperplasia and 16 CAH), and 25 were progestin non-responders (all with CAH). Those who did not respond to progestin either progressed to adenocarcinoma by three months or had persistent hyperplasia by six months. <i>PTEN</i> mutations above the variable allele frequency were identified in 19/25 of the progestin non-responders and 2/16 of the progestin responders yielding a likelihood ratio of 6 (2-23, p<0.001). Nanostring immunolabeling revealed no difference in <i>PTEN</i> expression between groups. <b>Conclusions:</b> Although there are no significant differences in <i>PTEN</i> expression in progestin non-responders compared with progestin responders for patients with EIN, there is a significantly increased frequency of <i>PTEN</i> functional mutations in the non-responders. This data suggests that genomic information, specifically <i>PTEN</i> mutations, predicts treatment response to progestin in EIN and has the potential to guide treatment decisions.

Comparison of endometrial cancer risk in patients with endometrial precancerous lesions: WHO 1994 vs EIN classification

Our aim was to investigate the frequency of concurrent endometrial cancer in patients with endometrial precancerous lesions (PCLs) using World Health Organization 1994 (WHO94) and endometrial intraepithelial neoplasia (EIN) systems. We retrospectively investigated patients that underwent surgery for endometrial PCLs according to WHO94 or EIN systems at Hacettepe University Gynecology Clinic between January 2002 and June 2014. Of the 267 patients, 189 (70.9%) were in the WHO94 group, 78 (29.2%) were in the EIN group. Mean age of patients was 50.2 years. Sixteen patients (8.5%) in WHO94 group and 15 (%19.2) patients in the EIN group had EC (p = 0.013). In WHO94 group, EC rate in patients with atypical EH (32.6%) was significantly more than patients with non-atypical EH (1.4%) (p < .001). Atypical EH and EIN are actual PCLs which could be accompanied by EC. Therefore, atypical EH and EIN should be treated surgically if there is no desire for fertility. IMPACT STATEMENT What is already known on this subject? Endometrial hyperplasias are precursors lesion in the pathogenesis of endometrium adenocarcinomas. There are two classification systems: World Health Organization System and endometrial intraepithelial neoplasia system (WHO and EIN). What do the results of this study add? In this paper, we report on endometrial precancerous lesions. Controversy continues over the endometrial precancerous lesion classification. We also share our experiences in this regard. We concluded that the EIN system was superior in determining concurrent cancer risk. What are the implications of these findings for clinical practice and / or further research? The paper should be of interest to readers in the areas of gynecology.It is important to clarify the classifications of precancerous lesions in order to guide clinicians in the treatment of patients with endometrial precancerous lesions. In this context, it could be suggested to use the EIN system more widely.

PAX2 in endometrial carcinogenesis and in differential diagnosis of endometrial hyperplasia: A systematic review and meta-analysis of diagnostic accuracy.

Benign and precancerous endometrial hyperplasias (EH) are differentiated according to two alternative histomorphologic classifications: World Health Organization (WHO) or endometrial intraepithelial neoplasia (EIN) system. The 2017 European Society of Gynaecological Oncology guidelines recommend paired box 2 protein (PAX2) immunohistochemistry to identify precancerous EH. However, methods for interpreting immunostaining and diagnostic accuracy are not defined, and the role of PAX2 in endometrial carcinogenesis is unclear. We aimed to assess: (a) PAX2 expression throughout endometrial carcinogenesis, from normal endometrium to benign EH, precancerous EH, and endometrial cancer (EC); (b) the diagnostic accuracy of PAX2 immunohistochemistry in diagnosing precancerous EH, defining criteria for its use. Electronic databases were searched for from their inception to July 2018. All studies evaluating PAX2 immunohistochemistry in normal endometrium, EH, and EC were included. Univariate comparisons of PAX2 expression were performed with Fisher's exact test (significant P<.05). Sensitivity, specificity, positive and negative likelihood ratio, diagnostic odds ratio (DOR), and area under the curve on summary receiver operating characteristic curves were calculated. Subgroup analyses were based on expression thresholds (decrease vs complete loss) and classifications used (WHO vs EIN). Six studies with 266 normal endometrium, 586 EH, and 114 EC were included. Both decrease and complete loss of PAX2 expression were significantly more common in EC and precancerous EH than benign EH. Diagnostic accuracy was moderate for both PAX2 complete loss and decrease (areas under the curve 0.829 and 0.876, respectively). PAX2 complete loss with EIN system showed the best results (sensitivity=0.72; specificity=0.95; DOR=43.13). PAX2 seems to behave as a tumor suppressor in endometrial carcinogenesis. PAX2 is an accurate marker of precancerous EH; complete loss of PAX2 and EIN classification appear as the optimal diagnostic criteria.

Loss of B-cell lymphoma 2 immunohistochemical expression in endometrial hyperplasia: A specific marker of precancer and novel indication for treatment: A systematic review and meta-analysis.

Endometrial hyperplasia is differentiated into benign or premalignant. Two histological classifications are used for this purpose: World Health Organization (WHO) classification, based on cytological atypia, disregarding glandular complexity, and endometrial intraepithelial neoplasia (EIN) classification, based on several different parameters. B-cell lymphoma 2 (Bcl-2) loss has been studied as immunohistochemical marker with the aim of improving the differential diagnosis between benign and premalignant hyperplasia. We aimed to evaluate: (A) Bcl-2 loss as marker of endometrial precancer, by assessing it in proliferative endometrium, benign hyperplasia, premalignant hyperplasia, and endometrial cancer; (B) the diagnostic accuracy of Bcl-2 in the differential diagnosis between benign and premalignant endometrial hyperplasia; (c) how the results change according to the histological classification and the thresholds of Bcl-2 expression used. Electronic databases were searched from their inception to March 2018. All studies assessing Bcl-2 immunohistochemistry in endometrial specimens were included. In total, 20 observational studies assessing 1,278 specimens were included. Bcl-2 loss rates were not significantly different between proliferative endometrium and benign hyperplasia (P=0.12) and between premalignant hyperplasia and endometrial cancer (P=0.53). Among hyperplasias, Bcl-2 loss was significantly associated with premalignancy, according to both the WHO (OR=4.39; P<0.00001) and EIN classifications (OR=6.07; P=0.01), and also with architecture complexity (OR=2.06; P=0.02). Using the WHO classification, Bcl-2 loss showed low diagnostic accuracy in detecting premalignant hyperplasia (area under the curve [AUC]=0.708), with a sensitivityof 0.41, a specificityof0.81, a positive likelihood ratioof3.22, and a negative likelihood ratioof 0.69. Using the EIN classification, accuracy was high (AUC=0.938), with a sensitivityof 0.18, a specificityof 0.97, a positive likelihood ratioof5.16 and a negative likelihood ratioof0.86. Thresholds of Bcl-2 expression not involving a complete loss showed lower diagnostic accuracy with a slight increase in sensitivity, but a severe decrease in specificity. B-cell lymphoma 2 loss is a marker of endometrial precancer, with a high specificity and high diagnostic accuracy if the EIN classification is used. Thresholds of Bcl-2 expression not involving a complete loss should not be considered. Bcl-2 loss in endometrial hyperplasia may be a novel indication for treatment when precancerous features are ambiguous in a histological examination. Bcl-2 loss correlates better with EIN classification than with the WHO classification, suggesting that glandular complexity is an important precancerous feature.

Can malignant potential of endometrial polyps be determined by incorporating the endometrial intraepithelial neoplasia (EIN) classification?

ObjectiveThe reported frequency of malignant or premalignant changes confined to endometrial polyps (EP) is 0.5–6%. The management of atypical endometrial hyperplasia (AEH) confined to EP is not yet established. Recently, an alternative pathological nomenclature has emerged using the term endometrial intraepithelial neoplasia (EIN) instead of atypia. The objective of this study was to evaluate the safety of conservative hysteroscopic resection of endometrial polyps with AEH or EIN. MethodsRetrospective cohort study of all cases of hysteroscopic resections of EP was performed at a single center between the years 2000–2011. All patients with a pathologic diagnosis of AEH in EP were included. A post-hoc revision of the pathologic specimens was made according to the EIN classification. ResultsOf the 32 patients with AEH in EP, 25 had normal endometrial curetting. Even with AEH confined to EP, 12 cases (48%) showed AEH (11 cases) or carcinoma (1 case) in the hysterectomy specimens. EIN in EP (14 cases) was correlated with 57% of diagnosis of EIN or carcinoma in the uterus; whereas in the absence of EIN in EP only 1 of 9 cases showed EIN in the final pathologic specimen (p=0.002), and none with carcinoma, which yields a PPV of 14% and a NPV of 100%. ConclusionThe diagnosis of EIN in EP may be a better predictor than AEH for endometrial involvement with malignant or pre-malignant neoplasms. The safety of conservative hysteroscopic resection of EP with AEH/EIN is questioned.

Reproducibility of current classifications of endometrial endometrioid glandular proliferations: further evidence supporting a simplified classification

To compare the reproducibility of the current (2003) World Health Organization (WHO), endometrial intraepithelial neoplasia (EIN) and European Working Group (EWG) classifications of endometrial endometrioid proliferations. Nine expert gynaecological pathologists from Europe and North America reviewed 198 endometrial biopsy/curettage specimens originally diagnosed as low-grade lesions. All observers were asked to classify the cases by using the categories described in each scheme: six for WHO, four for EIN, and three for EWG. The results were evaluated by kappa statistics for more than two observations. The analysis was repeated using only two major categories (benign versus atypical/carcinoma). Both the WHO and EIN classifications showed poor interobserver agreement (κ = 0.337 and κ = 0.419, respectively), whereas the EWG classification showed moderate agreement (κ = 0.530). Full agreement between pathologists occurred in only 28% for the WHO classification, 39% for the EIN classification, and 59% for the EWG classification. With only two diagnostic categories, kappa values increased in all classifications, but only the EWG classification reached a substantial level of agreement (κ = 0.621); similarly, full agreement among all pathologists increased to 70% for the WHO classification, 69% for the EIN classification, and 72% for the EWG classification. A two-tier classification of endometrial endometrioid proliferative lesions improves reproducibility, and should be considered for the diagnosis of endometrial biopsy/curettage specimens.

Prediction of coexistent carcinomas risks by subjective EIN diagnosis and comparison with WHO classification in endometrial hyperplasias

Endometrial intraepithelial neoplasia (EIN) classification is proposed as a new diagnostic system to resolve the limitations of the World Health Organization (WHO) classification in routine practice. Our aim was to find out whether EIN classification excels the WHO classification regarding the accurate prediction of coexisting endometrial carcinomas (EC) in biopsy specimens.We retrospectively re-classified 139 WHO-classified endometrial hyperplasia (EH) cases by subjective EIN diagnosis and compared the incidence of coexisting carcinomas using two classification systems by re-evaluating biopsy and corresponding hysterectomy specimens.Of 139 WHO-classified hyperplasia cases, 36 and 103 were classified as benign and EIN cases, respectively. Forty of 93 cases with atypical EH had EC at hysterectomy as compared with 2/46 cases without atypical EH, while EC was detected in 42/103 cases with EIN, and in 0 of 36 cases without EIN. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for atypical EH vs. non-atypical EH in biopsy specimen was 95.2%, 45.4%, 43.0% and 95.7%, respectively. For EIN vs. benign, the sensitivity was 100% and the specificity was 37.1%.The incidence of coexisting carcinomas in EIN cases was similar to that in atypical EH cases. However, regarding the exclusion of coexisting carcinomas, EIN criteria of benign lesions excelled the WHO criteria of non-atypical EH/CH.

Molecular biomarkers in endometrial hyperplasias predict cancer progression

The purpose of this study was to assess the value of the 2003 World Health Organization (WHO) and endometrial intraepithelial neoplasia (EIN) classifications, D-score, and molecular biomarkers in endometrial hyperplasia (EH) for cancer progression. We conducted a review of 307 endometrial hyperplasias for WHO and EIN classifications and an analysis of biomarkers, D-score, and cancer progression-free survival. The WHO, EIN, D-score, and many biomarkers were prognostic; 7.2% of the samples progressed to cancer. The WHO and EIN classifications correlated weakly with CK5/6 and p16. The D-score was strongest prognostically. When >1, it had the lowest false-negative progression rate of all features analyzed. COX2 negativity was the only other independent multivariate cancer progression predictor in endometrial hyperplasia, but only in cases with D-score <1. Eight of 13 cases (61%), with a combined D-score of <1 and negative COX2 progressed, which contrasted with 3 of 139 of all other cases (2.8%) (P < .0001; hazard ratio, 53.0). The biomarkers did not strengthen the prognostic value of the WHO or EIN classification. Combined D-score <1 and COX2 negativity strongly predict cancer progression in endometrial hyperplasias.

The molecular genetics and morphometry‐based endometrial intraepithelial neoplasia classification system predicts disease progression in endometrial hyperplasia more accurately than the 1994 World Health Organization classification system

The objective of this study was to compare the accuracy of disease progression prediction of the molecular genetics and morphometry-based Endometrial Intraepithelial Neoplasia (EIN) and World Health Organization 1994 (WHO94) classification systems in patients with endometrial hyperplasias. A multicenter, multivariate analysis was conducted on 477 patients with endometrial hyperplasia who were required to have a 1-year minimum disease-free interval from the time of the index biopsy (1-18 years of follow-up). The results from that analysis were compared with the results from 197 patients who had < 1 year of follow-up. Twenty-four of 477 hyperplasias (5.0%) progressed to malignant disease over an average of 4 years (maximum, 10 years). According to the WHO94 classification, 16 of 123 atypical hyperplasias (13%) and 8 of 354 nonatypical hyperplasias (2.3%) progressed (hazard ratio [HR] = 7). Twenty-two of 118 EINs (19%) and 2 of 359 non-EINs (0.6%) progressed (HR = 45). EIN was prognostic within each WHO94 subcategory. Progression rates were 3% in simple hyperplasias, 22% in complex hyperplasias, 17% in simple atypical hyperplasias, and 38% in complex atypical hyperplasias with EIN, compared with progression rates of 0.0-2.0% in all hyperplasias if EIN was absent. EIN detected precancerous lesions (sensitivity, 92%) better than WHO94 atypical hyperplasias collectively (67%) or complex atypical hyperplasias alone (46%). In a Cox regression analysis, EIN was the strongest prognostic index of future endometrial carcinoma. The same was true for patients with < 1 year of follow-up (HR for EIN, atypical hyperplasia, and complex atypical hyperplasia: 58, 7, and 8, respectively). The EIN classification system predicted disease progression more accurately than the WHO94 classification and identified many women with benign changes that would have been regarded as high risk according to the WHO94 classification system.