Endometrial Intraepithelial Neoplasia Research Articles

New WHO Classification of Endometrial Hyperplasias.

Endometrioid endometrial carcinoma, the most common form of endometrial cancer, usually develops out of a typical sequence of endometrial hyperplasias. The underlying cause of these hyperplasias is a relative predominance of estrogen combined with insufficient progesterone levels. Typical causes include corpus luteum insufficiency/anovulatory cycles (premenopause), polycystic ovary syndrome and obesity with metabolic syndrome (aromatase conversion of ovarian androgens in adipose tissue), inappropriate hormone therapy post menopause (insufficient dosage of gestagens) or an estrogen or androgen-producing tumor 1. Even in patients with Lynch syndrome (formerly known as HNPCC), tumorigenesis of hereditary endometrioid carcinoma usually follows the usual progression with development of the respective hyperplasias 1. Up to now, the correct clinical evaluation of endometrial hyperplasias was made more difficult by the different classification systems still in use: in Germany hyperplasias are sometimes still differentiated according to the classification “glandular-cystic hyperplasia” and “adenomatous hyperplasia grade I to III”. In 1994, the WHO classified endometrial hyperplasias into 4 categories: simple hyperplasia without atypia, complex hyperplasia without atypia, simple atypical hyperplasia, complex atypical hyperplasia 1, 2. While categories 1, 2 and 4 were generally accepted, pathologists continued to debate the existence of group 3-type hyperplasias. Hyperplasias without atypia (categories 1 and 2) are considered benign pathologies which will regress with conservative treatment (oral gestagens, gestagen IUD, elimination of the cause of anovulation/corpus luteum insufficiency) 1. A large percentage (up to 60 %) 3 of atypical endometrial hyperplasias (categories 3 and 4) are found to be coexistent with invasive endometrial carcinoma or develop into invasive endometrial carcinoma within the space of just a few years 1, 2, 4. Hysterectomy (total hysterectomy, not supracervical hysterectomy!) is therefore the treatment of choice for atypical endometrial hyperplasia 4 or – in selected patients, i.e. younger patients wanting to have children – high-dose gestagen therapy with appropriate close histological monitoring 1, 4. The WHO classification of 1994 and even more so the parallel use of the older classification system led to confusion among clinicians. The consequence of this was inadequate diagnosis, with hysterectomies performed for hyperplasias without atypia or gestagens administered in HRT dosages for atypical hyperplasia. Pathologists also experienced difficulties with categorization. This was made even more difficult by the development and parallel use of a further classification system: benign hyperplasia and endometrial intraepithelial neoplasia (EIN) 2. In its latest classification 5 published in 2014, the WHO has clarified the matter: it now only differentiates between 2 categories of endometrial hyperplasia: hyperplasia without atypia atypical hyperplasia/endometrioid intraepithelial neoplasia (Table 1). Table 1 New WHO classification of endometrial hyperplasias 5. This reduction to 2 categories was not only due to the need to do away with the confusing multitude of terms currently in use. Rather, it reflects a new understanding of molecular genetic changes. Hyperplasias without atypia exhibit no relevant genetic changes. They are benign changes and will regress again after the endocrine milieu (physiological gestagen levels) has normalized. In a few cases (1–3 %), progression to invasive disease may occur if the endocrine disorder (long-term estrogen dominance or relative or absolute gestagen deficiency) persists over the long term. Atypical endometrial hyperplasias exhibit many of the mutations typical for invasive endometrioid endometrial cancer 7. In up to 60 % of cases, patients have coexisting invasive cancer or are at extremely high risk of developing invasive cancer (Table 1). The implications for treatment are obvious: hyperplasias without atypia should generally be treated conservatively (normalization of the cycle through weight loss, metformin; oral contraceptives; cyclical gestagens; gestagen IUD). Preventive hysterectomy should only be considered in exceptional cases (e.g., extreme obesity without any prospect of weight loss) 1, 4. The surgery should be done as a total hysterectomy, i.e., it must include removal of the cervix 4. Treatment of atypical hyperplasia/endometrioid intraepithelial neoplasia should generally consist of total (not supracervical) hysterectomy 1, 4. Conservative treatment with high-dose gestagens and close histological monitoring should only be considered in exceptional cases (when the patient wants to have children, satisfactory compliance) 1, 4, 6.

Safety of same day discharge in patients undergoing laparoscopic hysterectomy for endometrial intraepithelial neoplasia (EIN) and malignancy

Objectives: The approach to hysterectomy for the treatment of endometrial cancer has recently shifted toward laparoscopic surgical techniques without increased intraoperative or post-operative complications. While patients undergoing laparoscopic hysterectomy have traditionally been hospitalized post-operatively, same-day discharge (SDD) has been demonstrated to be safe, cost saving, and acceptable to patients undergoing hysterectomy for benign indications. Gynecologic oncologists in our institution began implementing SDD for patients undergoing laparoscopic hysterectomy for endometrial cancer or EIN in 2011, and it has become the norm for these patients, providing a unique opportunity to evaluate the safety and feasibility of outpatient hysterectomy in this population.

The Role of Frozen-Section in the Surgical Management of Patients with Endometrial Intraepithelial Neoplasia.

Patients with endometrial intraepithelial neoplasia may have concurrent endometrial cancer if managed surgically or develop cancer in time if managed conservatively. Therefore, intraoperative assessment of the uterus may be helpful if a surgical approach is decided on. Our study aimed to investigate the role of frozen-section examination in patients with endometrial intraepithelial neoplasia. Patients with endometrial intraepithelial neoplasia who were subjected to hysterectomy with intraoperative frozen-section assessment were included. Main outcome measures were the rates of concurrent endometrial cancer and concurrent high-risk endometrial cancer as well as the efficacy of frozen-section in the detection of concurrent invasive disease and in the designation of low-risk and high-risk features. The study group consisted of seventy-three patients. Permanent pathology revealed endometrial adenocarcinoma in 19.2% whereas only one patient (1.4%) had high-risk disease necessitating surgical staging. Frozen-section diagnoses were consistent with final pathology in 93.2% of patients in terms of the presence or absence of co-existent carcinoma. When frozen-section reports were further evaluated in terms of the presence or absence of high-risk endometrial carcinoma, consistency with the final pathology was seen in 98.6% of patients. Co-existent endometrial cancer is not uncommon in endometrial intraepithelial neoplasia. Intraoperative frozen-section evaluation should therefore be considered whenever possible. Frozen-section is effective in the detection of coexistent invasive disease and in the designation of low-risk features. Although coexistent high-risk cancer is extremely rare, frozen-section assessment is not successful in determining high-risk features. Therefore, a re-staging surgery may be required on rare occasions.

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.

The malignant potential of endometrial polyps can be determined by incorporating the Endometrial Intraepithelial Neoplasia (EIN) classification

Objectives: The reported frequency of malignant or pre malignant changes confined to endometrial polyp is 0.5–6%. The management of Atypical Endometrial Hyperplasia (AEH) confined to endometrial polyp (EP) is not yet established. Recently, an alternative pathological nomenclature has emerged, using the term Endometrial Intraepithelial Neoplasia (EIN) instead of term the atypia. The objective of this study was to evaluate the safety of conservative hysteroscopic resection of endometrial polyps with AEH or EIN.

Endometrial Intraepithelial Neoplasia

Developed in conjunction with molecular and progression data, the sequence classification schema for endometrial intraepithelial neoplasia (EIN)/benign hyperplasia (BH) provides an easy to adopt and reproducible method for classification of endometrial biopsies. To review current data supporting the use of BH/EIN to classify endometrial biopsies, and to discuss the hormone-driven endometrial sequence from anovulation/disordered proliferative endometrium through BH and EIN and their diagnostic difficulty. A comprehensive review of EIN literature based on literature indexed by PubMed (National Library of Medicine) and Google Scholar. The BH/EIN schema is gaining wider acceptance among pathologist and clinicians. The research leading to the EIN criteria is based on molecular and progression data. The BH/EIN schema has better reproducibility among pathologists, is intuitively easy to use, and requires understanding of endometrial physiology and neoplasia.

Current Issues in Gynecologic Pathology

Current Issues in Gynecologic Pathology

NF-κB and COX-2 Expression in Nonmalignant Endometrial Lesions and Cancer

To examine the immunohistochemical expression of cyclooxygenase-2 (COX-2) and nuclear factor-κB (NF-κB) in benign endometrial polyps (EPs), endometrial hyperplasia (EH), endometrial intraepithelial neoplasia (EIN), and endometrioid endometrial cancer (EC). The immunohistochemical expression of COX-2 and NF-κB was performed using an Aperio Scanscope XT automated system in 218 patients with endometrioid EC and 107 patients with nonmalignant endometrial lesions: 53 with benign EPs, 37 with EH, and 17 with EIN. COX-2 and NF-κB p50 expression were significantly lower in EC compared with nonmalignant lesions. We observed significant decreased NF-κB p65 expression in EC vs EPs (P < .001) and EH (P = .014) as well as in EIN vs. EPs (P = .01). For patients with EC, COX-2 correlated positively with NF-κB p65 and NF-κB p50 (P < .001). Grade 3 tumors had a higher mean expression of NF-κB p65 (P = .03). NF-κB p50, NF-κB p65, and COX-2 expression had no impact on survival. We conclude that COX-2 and NF-κB expression are lower in EC compared with nonmalignant endometrial lesions. COX-2 and NF-κB expression have no prognostic value in EC.

Endometrial Intraepithelial Neoplasia (EIN) in Endometrial Biopsy Specimens Categorized by the 1994 World Health Organization Classification for Endometrial Hyperplasia

Our study is to determine the presence of endometrial intraepithelial neoplasia (EIN) in endometrial biopsy specimens classified by the 1994 World Health Organization (WHO) criteria for endometrial hyperplasia. Endometrial biopsy specimens that were stained with hematoxylin and eosin (HE) were examined and categorized by the WHO 1994 criteria and for the presence of EIN as defined by the International Endometrial Collaborative Group. β-catenin expression was examined by immunohistochemistry. A total of 474 cases of HE stained endometrial biopsy tissues were reviewed. There were 379 cases of simple endometrial hyperplasia, 16 with simple atypical endometrial hyperplasia, 48 with complex endometrial hyperplasia, and 31 with complex atypical endometrial hyperplasia. Among the 474 endometrial hyperplasia cases, there were 46 (9.7%) that were classified as EIN. Of these 46 cases, 11(2.9%) were classified as simple endometrial hyperplasia, 1 (6.3%) as simple atypical endometrial hyperplasia, 6 (12.5%) as complex endometrial hyperplasia, and 28 (90.3%) as complex atypical endometrial hyperplasia. EIN was associated with a higher rate of β-catenin positivity than endometrium classified as benign hyperplasia (72% vs. 22.5%, respectively, P < 0.001), but a lower rate than endometrial adenocarcinoma (72% vs. 96.2%, respectively, P < 0.001). In benign endometrial hyperplasia, high β-catenin expression was noted in the cell membranes, whereas in EIN and endometrial adenocarcinoma high expression was noted in the cytoplasm. In conclusion, EIN is more accurate than the WHO classification for the diagnosis of precancerous lesions of the endometrium.

Delayed Diagnoses of Cervical Intraepithelial Neoplasia and Cancer After Negative Evaluation for Atypical Glandular Cell Pap Smear

At initial evaluation, 1 in 6 women with atypical glandular cells (AGCs) on Pap smear has cervical intraepithelial neoplasia (CIN) or cancer. Years later, a greater-than-expected incidence of "significant delayed diagnoses" has been reported in women who had negative initial evaluation results. This study aimed to test the premise that AGC represents a lesser future risk for CIN 2/CIN 3/carcinoma in situ (CIS) and cancer after negative evaluation results in a population diagnosed at a young age (<35 years). Cohort study consists of 43,000 community health center patients who had 83,542 Pap smears (1997-2010); 213 were diagnosed with AGC, and 117 met inclusion criteria. Completed evaluation was consistent with American Society for Colposcopy and Cervical Pathology guidelines without finding CIN 2/CIN 3/CIS or cancer. Follow-up lasted for longer than 1 year. Categorical data were evaluated with χ. During the follow-up period that averaged for 85.3 months, the cohort had 4.5 mean Pap smears and reported 46 cytological diagnoses of low-grade squamous intraepithelial lesions, 3 diagnoses of high-grade squamous intraepithelial lesions, and 10 repeated diagnoses of AGCs. Two CIN 2/CIN 3/CIS lesions, 1 cervical cancer, and 1 endometrial intraepithelial neoplasia were confirmed on biopsy. Average age of patients at index Pap smear was 34.2 years (range = 15-64 years). Compared with a published report where the average age at index Pap smear was 41.5 years, our cohort developed a total of 4.3% significant delayed diagnoses versus 10.8% (significant difference, p = .046). During a 7-year follow-up, this cohort of 117 women with AGC and negative initial evaluation findings developed fewer significant delayed diagnoses than expected when compared with an older reported group and had no new extragynecological cancers. Age seems to be a risk factor for delayed diagnoses in patients with AGC.

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.

Endometrial intraepithelial neoplasia with secretory differentiation: diagnostic features and underlying mechanisms

Endometrial intraepithelial neoplasia (EIN) with secretory differentiation and ordinary EIN occurring in a secretory context are rare but recognized findings. We determined how often secretory differentiation in EIN was associated with evidence of circulating progestins in the background endometrium, and studied clinical characteristics and clinical outcomes of affected patients. We selected 41 patients with secretory differentiation in either the EIN itself (n=31) and/or background endometrium (n=38). Most (90%, 28/31) secretory EINs were associated with circulating progestins. Rare exceptions were observed, suggesting that secretory EIN may occur as a hormone-independent phenomenon. Circulating progestins are not sufficient, however, to induce EIN secretory differentiation, as 26% (10/38) of EIN within a secretory background were of the ordinary (non-secretory) type. EIN patients with secretory endometrium in the background are younger (averaging 45 years) than the aggregate group of all patients with EIN (53 years in previously published studies) and are often premenopausal with a cyclical source of endogenous progestins. Involution of EIN during follow-up was more frequent (81%, 17/21) for those with a secretory background at the time of initial EIN diagnosis compared with historical averages (25%, 36/142). These results suggest a potential role for endogenous progesterone, as well as therapeutic progestins, in modulating EIN outcomes.

Utility of PAX2 as a Marker for Diagnosis of Endometrial Intraepithelial Neoplasia

Diagnosis of endometrial intraepithelial neoplasia (EIN) requires learning new criteria. Two trainees rendered diagnoses based on biopsy findings, and then measured the effect of reviewing PAX2 on their interpretation. Fifty-two endometrial biopsy specimens diagnosed as having EIN were evaluated using EIN criteria. Background endometrial pattern, altered differentiation, and any features complicating diagnosis were noted. PAX2 stains were scored as confusing, helpful, or noncontributory. Fifty-two cases generated 104 passes; 82% were rediagnosed as EIN. The diagnosis was complicated because of altered differentiation (14%), EIN and background separation (13%), large lesions lacking background (11%), and secretory background (8%). PAX2 was most helpful in cases with secretory backgrounds and when EIN lacked adjacent normal tissue, and most confusing when scoring was ambiguous (14%). The diagnosis of EIN can be difficult when: (1) the lesion cannot be easily compared with background; (2) there is a confounding process; and (3) gland differentiation is altered. PAX2 can be of assistance in delimiting EIN lesions.

Management of Endometrial Precancers

In the United States, endometrial cancer is the most commonly diagnosed cancer of the female reproductive system. Strategies to sensitively and accurately diagnose premalignant endometrial lesions are sorely needed. We reviewed studies pertaining to the diagnostic challenges of endometrial precancers, their predictive value, and evidence to support management strategies. Currently, two diagnostic schemas are in use: the four-class 1994 World Health Organization hyperplasia system, based on morphologic features of architectural complexity and nuclear atypia and, more recently, the two-class endometrial intraepithelial neoplasia system, which is quantitative. Diagnosis should use criteria and terminology that distinguish between clinicopathologic entities that can be managed differently. In some instances, such as for women with hereditary nonpolyposis colon cancer, biomarkers may aid in diagnosis, but the clinical utility of biomarkers has yet to be determined. Total hysterectomy is curative for atypical endometrial hyperplasia or endometrial intraepithelial neoplasia, and provides a definitive standard for assessment of a concurrent carcinoma, when clinically appropriate. If hysterectomy is performed for atypical endometrial hyperplasia or endometrial intraepithelial neoplasia, then intraoperative assessment of the uterine specimen for occult carcinoma is desirable, but optional. Nonsurgical management may be appropriate for patients who wish to preserve fertility or those for whom surgery is not a viable option. Treatment with progestin therapy may provide a safe alternative to hysterectomy; however, clinical trials of hormonal therapies for atypical endometrial hyperplasia or endometrial intraepithelial neoplasia have not yet established a standard regimen. Future studies will need to determine the optimal nonsurgical management of atypical endometrial hyperplasia or endometrial intraepithelial neoplasia, standardizing agent, dose, schedule, clinical outcomes, and appropriate follow-up.

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.

Reproducibility of endometrial intraepithelial neoplasia diagnosis is good, but influenced by the diagnostic style of pathologists

AbstractEndometrial intraepithelial neoplasia (EIN) applies specific diagnostic criteria to designate a monoclonal endometrial preinvasive glandular proliferation known from previous studies to confer a 45-fold increased risk for endometrial cancer. In this international study we estimate accuracy and precision of EIN diagnosis among 20 reviewing pathologists in different practice environments, and with differing levels of experience and training. Sixty-two endometrial biopsies diagnosed as benign, EIN, or adenocarcinoma by consensus of two expert subspecialty pathologists were used as a reference comparison to assess diagnostic accuracy of 20 reviewing pathologists. Interobserver reproducibility among the 20 reviewers provided a measure of diagnostic precision. Before evaluating cases, observers were self-trained by reviewing published textbook and/or online EIN diagnostic guidelines. Demographics of the reviewing pathologists, and their impressions regarding implementation of EIN terminology were recorded. Seventy-nine percent of the 20 reviewing pathologists' diagnoses were exactly concordant with the expert consensus (accuracy). The interobserver weighted κ values of 3-class EIN scheme (benign, EIN, carcinoma) diagnoses between expert consensus and each of reviewing pathologists averaged 0.72 (reproducibility, or precision). Reviewing pathologists demonstrated one of three diagnostic styles, which varied in the repertoire of diagnoses commonly used, and their nonrandom response to potentially confounding diagnostic features such as endometrial polyp, altered differentiation, background hormonal effects, and technically poor preparations. EIN diagnostic strategies can be learned and implemented from standard teaching materials with a high degree of reproducibility, but is impacted by the personal diagnostic style of each pathologist in responding to potential diagnostic confounders.

Endometrial Intraepithelial Neoplasia Terminology in Practice

An alternative WHO classification system for endometrial precancers and hyperplasia separates a lesion called endometrial intraepithelial neoplasia (EIN) from diffuse hormonal effects and cancer, resulting in a 3-category system. EIN is a localized lesion with objective histologic criteria, characterized by monoclonal growth of mutated cells, and associated with a 45-fold elevated cancer risk. This study summarizes our department's experience with EIN diagnoses in the 4 years since conversion to the new terminology. We identified all reports from endometrial samples diagnosed as EIN or including the terms "gland crowding" or "atypia" since conversion and obtained follow-up information from subsequent pathology specimens or clinic notes (82%). The diagnoses were reported by a mixture of pathologists, the majority of whom are not subspecialized to gynecologic pathology and the slides were not reviewed. Overall, 17.1% of women with EIN had carcinoma and 34.9% had either carcinoma or persistent EIN. The proportion of women with EIN or cancer on follow-up did not trend with years since adoption of EIN terminology. The median age at the time of diagnosis was 55 years in an overall population of women who underwent sampling at a median age of 47 years. The median follow-up time was 4 months. All cancers were of endometrioid histology; all but 2 were International Federation of Gynecology and Obstetrics grade 1. In comparison with a previous reproducibility study among expert pathologists on a comparable population from our department, these results for general pathologists show a higher false positive rate for subsequent cancer.

The Selective Expression of Ret Finger Protein in Endometrial Cancer: Can RFP be a Marker of Serous Carcinomas?

Endometrial cancer is a common malignancy of the gynecological system and has been classified into two major groups, Types I and II. Type I tumors are estrogen-related, low-grade endometrioid tumors, whereas type II tumors are aggressive, high-grade non-endometrioid tumors. Ret finger protein is a nuclear transcription factor with a tripartite motif that is highly expressed in different tumor cells. To analyze the expression of ret finger protein in endometrial tissues and cancer, 18 cases of secretory and proliferative endometrium, endometrial polyp, endometrial hyperplasia and endometrial intraepithelial neoplasia and 21 cases of types I and II endometrial carcinoma were evaluated immunohistochemically. Although rare cases of secretory endometrium showed a weak focal nuclear positivity, remaining proliferative endometrium, endometrial hyperplasia and type I endometrioid cancer cases were negative. In contrast, all cases of serous cancers showed strong nuclear positivity. After these strong positive results for serous endometrial cancer, 12 more cases of ovarian and endometrial serous carcinoma cases were added to the study. All of the additional cases were also strongly positive for ret finger protein. We suggest that ret finger protein might play a role in the carcinogenesis of the serous tumors of gynecological system and can be used to differentiate serous carcinomas from other epithelial tumors.

Molecular pathogenesis of endometrial and ovarian cancer.

Pregnancy, breastfeeding, and oral contraceptive pill use interrupt menstrual cycles and reduce endometrial and ovarian cancer risk. This suggests the importance of turnover within Mullerian tissues, where the accumulation of mutations in p53 and PTEN has been correlated with number of cycles. The most common type of endometrial cancer (Type I) is endometrioid and molecular abnormalities include mutations in PTEN, KRAS and β-catenin. The Type I precursor is Endometrial Intraepithelial Neoplasia which displays PTEN defects. Type II endometrial cancer (whose precursors are less clear) includes serous and clear cell tumors and the most common alteration is p53 mutation. For ovarian cancer, histopathologic types parallel endometrial cancer and include serous, mucinous, endometrioid, and clear cell; some molecular features are also shared. The most frequent type of ovarian cancer is high grade serous that often displays p53 mutation and its precursor lesions may originate from normal-appearing fallopian tube epithelium that contains a p53 "signature". Mutations in KRAS, BRAF and PTEN are described in mucinous, endometrioid and low grade serous cancers and these may originate from ovarian cortical inclusion cysts. A consideration of molecular and other pathogenetic features, like epidemiology and histopathology, may provide a better understanding of endometrial and ovarian cancer.

Endometrial intraepithelial neoplasia vs. World Health Organization classification of endometrial hyperplasia does not improve reliability of diagnosis or prediction of outcome in premenopausal women with preinvasive endometrial pathology undergoing progestin treatment

Endometrial intraepithelial neoplasia vs. World Health Organization classification of endometrial hyperplasia does not improve reliability of diagnosis or prediction of outcome in premenopausal women with preinvasive endometrial pathology undergoing progestin treatment