Endometrioid Neoplasia Research Articles

β-catenin, PAX2, and PTEN Aberrancy Across the Spectrum of Endometrioid Ovarian Lesions.

Endometriosis is a common condition, with the ovary being the most common anatomic site. Endometriosis-particularly in the ovary-is associated with a risk of malignant progression, with a histologic spectrum of lesions from benign to malignant. Recently, a panel of 3 markers consisting of β-catenin, PAX2, and PTEN has been described as a potentially useful diagnostic adjunct in the diagnosis of intrauterine endometrioid neoplasia, where aberrancy for one or more of the markers is strongly associated with neoplasia. Here, we applied the panel to ovarian endometrioid lesions, including endometriosis, endometriosis with flat cytologic atypia, endometrioid borderline tumors, and endometrioid adenocarcinoma (n=85 cases in total). The incidence of aberrancy for the 3 markers increased along this putative neoplastic spectrum, arguing for a role of each of the markers in the neoplastic transformation of ovarian endometriosis. Just 1/32 (3%) of cases of nonatypical endometriosis was marker-aberrant, and this case was aberrant only for PAX2. One of 5 cases (20%) of endometriosis with atypia was marker-aberrant (both PAX2 and PTEN), supporting prior findings that some cases of flat atypia may represent bona fide precursor lesions. Of 19 endometrioid borderline tumors, 10 (53%) were aberrant for one or more markers, with PAX2 being the most frequently aberrant. Of 29 endometrioid adenocarcinomas, 28 (96.6%) were aberrant for at least 1 marker, with PAX2 again the most frequently aberrant. Patterns of aberrancy were well-preserved in areas of nonatypical endometriosis adjacent to borderline tumor or adenocarcinoma, supporting a biological origin in a common marker-aberrant precursor. The findings show that the biomarker panel could be of some diagnostic utility in the characterization of ovarian endometrioid neoplasia, such as in the diagnosis of endometrioid borderline tumor, distinguishing endometrioid from nonendometrioid lesions, or in identifying other types of early precursors at a higher risk of malignant transformation.

Lesions sub-diagnostic of endometrioid intra-epithelial neoplasia/atypical hyperplasia: value of morphology and immunohistochemistry in predicting neoplastic outcome.

Areas of gland crowding that do not fulfil diagnostic criteria of endometrioid intra-epithelial neoplasia (EIN) are often encountered in endometrial biopsies. In this study, we document the prevalence of neoplastic outcome in patients with these subdiagnostic lesions (SL) and assess the utility of morphological features and a three-marker immunohistochemistry panel (PAX2, PTEN, beta-catenin) to predict outcome. Of 430 women with SL on endometrial sampling at Brigham and Women's Hospital between 2001 and 2021 with available follow-up biopsy, 72 (17%) had a neoplastic outcome (EIN or endometrioid carcinoma). Multilayered epithelium and mitoses in SL were statistically associated with a neoplastic outcome. Abnormal three-marker staining was observed in 93% (53 of 57) of SL with neoplastic outcome and 60% (37 of 62) of a control group with benign outcome. Among the 72 patients with neoplastic outcome, EIN/carcinoma tissue was available in 33; of these, 30 (91%) showed abnormal staining for one or more markers. Remarkably, in 84% of these cases the EIN/carcinoma had the aberrant expression seen in the preceding SL. Based on a prevalence of 17%, the positive and negative predictive values of abnormal staining in one or more markers were 24 and 97%, respectively. The presence of SL warrants clinical surveillance and repeat sampling because it is followed by endometrioid neoplasia in a significant subset of patients. Normal three-marker staining identifies women with a very low risk of neoplastic outcome. Conversely, abnormal staining is frequent in SL with benign outcome leading to poor specificity and positive predictive value.

Mesonephric-Like Adenocarcinoma of the Endometrium: Review of the Literature and Practical Diagnostic Recommendations

Abstract Mesonephric-like adenocarcinomas are endometrial and ovarian neoplasms of müllerian origin with morphologic, immunophenotypic, and molecular evidence of mesonephric-type transdifferentiation, as well as considerable homology with endometrioid tumors. First described in 2016, mesonephric-like adenocarcinomas are morphologically indistinguishable from “true” mesonephric adenocarcinomas of the uterine cervix, but the latter are distinguished by (1) primary localization to the cervical wall, (2) frequent association with mesonephric remnants, and (3) in some cases, lack of mucosal involvement. Despite an overall low-grade morphology, mesonephric-like adenocarcinoma follows an aggressive clinical course, characterized by frequent and early recurrences, most often in the lung. Accordingly, accurate distinction of mesonephric-like adenocarcinoma from morphologic mimics—especially low-grade endometrioid adenocarcinoma—is critical. However, available evidence indicates that endometrial mesonephric-like adenocarcinomas are significantly underdiagnosed, likely due to their relative novelty, rarity, and considerable overlap with endometrioid neoplasia. Prospective recognition of characteristic morphologic features, a low threshold for application of diagnostic immunohistochemistry, and judicious use of molecular studies will permit accurate diagnosis in almost all cases.

CTNNB1 Mutations and Aberrant β-Catenin Expression in Ovarian Endometrioid Carcinoma: Correlation With Patient Outcome.

CTNNB1 mutations and aberrant β-catenin expression have adverse prognosis in endometrial endometrioid carcinoma, and recent evidence suggests a prognostic role of β-catenin in ovarian endometrioid carcinoma. Thus, we aimed to determine the prognostic value of the CTNNB1 mutational status, and its correlation with β-catenin expression, in a well-annotated cohort of 51 ovarian endometrioid carcinomas. We performed immunohistochemistry for β-catenin and developed an 11-gene next-generation sequencing panel that included whole exome sequencing of CTNNB1 and TP53. Results were correlated with clinicopathologic variables including disease-free and disease-specific survival. Tumor recurrence was documented in 14 patients (27%), and cancer-related death in 8 patients (16%). CTNNB1 mutations were found in 22 cases (43%), and nuclear β-catenin in 26 cases (51%). CTNNB1 mutation highly correlated with nuclear β-catenin (P<0.05). Mutated CTNNB1 status was statistically associated with better disease-free survival (P=0.04, log-rank test) and approached significance for better disease-specific survival (P=0.07). It also correlated with earlier International Federation of Gynecology and Obstetrics stage (P<0.05). Nuclear β-catenin, TP53 mutations, age, ProMisE group, surface involvement, tumor grade and stage also correlated with disease-free survival. There was no association between membranous β-catenin expression and disease-free or disease-specific survival. CTNNB1 mutations and nuclear β-catenin expression are associated with better progression-free survival in patients with OEC. This relationship may be in part due to a trend of CTNNB1-mutated tumors to present at early stage. β-catenin immunohistochemistry may serve as a prognostic biomarker and a surrogate for CTNN1B mutations in the evaluation of patients with ovarian endometrioid neoplasia, particularly those in reproductive-age or found incidentally without upfront staging surgery.

Evidence for a Novel Endometrioid Carcinogenic Sequence in the Fallopian Tube With Unique Beta-Catenin Expression.

Epithelial proliferations in the fallopian tube have been characterized by some as stem cell outgrowths (SCOUTs) and divided into type I and type II. Type II SCOUTs exhibit diffuse cellular beta-catenin nuclear staining (β-catenin), implying a CTNNB1 mutation. SCOUTs are more common in perimenopausal and postmenopausal women and are associated with ovarian cancer but have not been linked directly to malignancy. We analyzed type II SCOUTs in various gynecologic conditions, and searched for endometrioid atypical hyperplasias (tubal endometrioid intraepithelial neoplasia) or adenocarcinomas in the tube. β-catenin SCOUT frequency in cases of neoplasia was 66.7% per case and 30.7% per nonfimbrial cross-section for uterine endometrioid carcinomas versus 25% and 13.3% for controls, respectively (P=0.02 and 0.09). Multiple (3 or more) β-catenin SCOUTs in a single section were uncommon; 6 of 9 were associated with a carcinoma or proliferative lesion in the endometrium. Tubal endometrioid intraepithelial neoplasia/atypical hyperplasia displayed complex growth, including focal cribriform growth patterns and squamous morules. Two cases of type II SCOUTs associated with tubal endometrioid intraepithelial neoplasia/atypical hyperplasia and/or adenocarcinomas in the fallopian tube were identified, both of which coexisted with a separate endometrioid adenocarcinoma, one with bilateral ovarian endometrioid adenocarcinomas. Both benign and neoplastic tubal lesions were β-catenin. This report is the first to link components of a unique β-catenin endometrioid carcinogenic sequence in the fallopian tube. It further emphasizes the multifocal nature of endometrioid neoplasia in the female genital tract and poses questions regarding the frequency and biologic underpinnings of β-catenin proliferations in the oviduct.

An immunohistochemical and molecular analysis of papillary proliferation of the endometrium

Papillary proliferations of the endometrium (PPEs) are uncommon lesions that are often associated with endometrial polyps. PPEs occasionally precede or co-exist with atypical endometrial hyperplasia or adenocarcinoma, but their pathogenesis and relationship to endometrial neoplasia is uncertain. In the present study 11 PPEs, including eight benign papillary proliferations (BPPs) and three complex papillary hyperplasias (CPHs) were examined immunohistochemically for expression of PAX2, BAF250a, p16, β-catenin and DNA mismatch repair (MMR) proteins. Molecular analysis was also performed on the CPHs using targeted next generation sequencing (NGS). All PPEs demonstrated at least one immunohistochemical abnormality with altered expression of p16 and PAX2 in nine and seven cases, respectively, and β-catenin in one case. However, none of the cases showed loss of BAF250a or MMR protein staining. All CPHs showed KRAS mutations with additional mutations in AKT1 and FBXW7 in one case each, and both PIK3CA and CTNNB1 in the remaining case. Therefore, PPEs demonstrate immunophenotypical and molecular overlap with endometrial endometrioid neoplasia, although loss of BAF250a and MMR protein function do not appear to contribute significantly to these lesions. KRAS mutations may be important drivers in CPHs but this finding needs to be confirmed in larger studies.

Frequency of “incidental” serous tubal intraepithelial carcinoma (STIC) in women without a history of or genetic risk factor for high-grade serous carcinoma: A six-year study

ObjectiveThe purpose of this study was to determine the prevalence of incidentally discovered serous tubal intraepithelial carcinoma in women without a genetic risk for or history of high grade serous carcinoma (HGSC) in the gynecologic tract. MethodsAll pathology reports at our institution that included bilateral salpingectomies from January 2006–December 2011 were examined in women >50years old in which the entire tube or the distal one-third was examined histologically with the complete (proximal and distal fallopian tube) or modified (distal one third of the tube) SEE-FIM protocol. Cases were divided into: Group 1, a history of or known risk factors (BRCA1 or BRCA2 mutations) for HGSC and Group 2, those without these attributes for whom a STIC would be unexpected (incidental). Women undergoing unspecified “risk-reducing” procedures were included in Group 1. ResultsOf 4051 identified total, 2268 had complete examination of the distal fallopian tube and were age 50 or above. Of these, 1747 were in group 2. Two STICs were identified (0.1%), one associated with a grade 2 endometrial endometrioid adenocarcinoma and one with a low-grade ovarian serous carcinoma in the setting of a serous borderline tumor. ConclusionsIncidental STICs in women over age 50 are uncommon. However, the significance of lesser tubal atypias (0.3% in this study), risk of STIC in women with no epithelial pathology and the risk imposed by coexisting endometrioid neoplasia are unclear and require further study.

Endometrioid adenocarcinoma of the ovary mimicking serous borderline tumor: report of a series of cases.

Ovarian endometrioid adenocarcinomas may have an extremely variable morphologic appearance and mimic a number of other epithelial malignancies as well as nonepithelial tumors. We report the clinicopathologic features of a small series of ovarian endometrioid adenocarcinomas (n=5), 4 of which were received in consultation, which were originally diagnosed as or were suspected to represent serous borderline tumor, with or without a component of low-grade serous adenocarcinoma. The patients were aged between 47 and 74 yr (mean, 60 yr), and all tumors were unilateral and Stage 1C. Serous borderline tumor was suspected on the basis of the predominant architectural pattern with prominent papillary formations consisting of rather bland epithelial cells covering stromal cores which projected into cystic spaces. In all cases, there were areas of typical endometrioid adenocarcinoma, although these foci were minor. Features useful in confirming an endometrioid neoplasm, not all of which were present in every case, were a monomorphous cell population, areas of cytoplasmic clearing, areas of more pronounced nuclear atypia, and mitotic activity than is typical of low-grade serous neoplasms, squamous elements, endometriosis and absent or only focal WT1 immunohistochemical staining. The close mimicry of a serous borderline tumor by an endometrioid adenocarcinoma is a diagnostic pitfall which has not been reported in the literature and represents yet another example of the propensity for ovarian endometrioid adenocarcinomas to mimic other neoplasms. Pathologists should consider an endometrioid adenocarcinoma when faced with a presumed serous borderline tumor with any of the features listed above. Extensive sampling may be of value in revealing more typical areas of endometrioid neoplasia and negative staining with WT1 of use in excluding a serous neoplasm.

Endometrioid Neoplasms With Clear Cells

The presence of clear cells in genital tract neoplasms often reflexly prompts the diagnosis of a clear cell tumor but clear cells may be seen in many other neoplasms. In one such, those of endometrioid type, they are well known and generally readily characterized when they have the secretory pattern that recapitulates the well-known morphology of early secretory endometrium. In this report, we describe various clear cell morphologies, some possibly related to the secretory variant, but others not, and all potentially the source of significant diagnostic difficulty. We reviewed 21 endometrioid tumors that occurred in patients from 27 to 88 (median 64) years. Most had an adnexal mass (13) or abdominal swelling (4), but 4 presented with vaginal bleeding. One tumor formed a cystic mass in the pelvis, 1 tumor involved the right fallopian tube, 1 the endometrium, and 18 the ovary. One tumor was a cystadenofibroma, 1 a borderline tumor, and 19 were adenocarcinomas. Twelve patients had stage I, 4 stage III, 1 stage IV, and 4 were unstaged. One patient who had a previous hysterectomy and salpingo-oophorectomy underwent resection of a cystic pelvic mass; others all were treated with abdominal hysterectomy and salpingo-oophorectomy. All the neoplasms had the typical architecture of endometrioid tumors but differed markedly in their cytoplasmic features. In 18 of the tumors at least one-third of the cells had clear cytoplasm and 3 had only clear cells. The clear cytoplasm varied from foamy to empty and the nuclei had a variable location, basilar, central, and apical. The clear cells were associated with squamous differentiation in only 1 case in which the change appeared hydropic. By immunohistocytochemistry, the clear cells were focally positive for epithelial markers in most cases but in some cases one or more of these immunostains were negative. Tubulocystic, solid, and papillary patterns of clear cell carcinoma were absent. Periodic acid-Schiff was focally positive for glycogen in the cytoplasm in 5 cases. Although a few cases had a focal slight resemblance to secretory endometrioid carcinoma most did not and the orderly morphology of classic secretory carcinoma was noteworthy for its absence. The nature of the cytoplasmic clarity is usually uncertain but is likely variably owing to lipid, mucin or glycogen accumulation, or is a hydropic change. The distinction from clear cell carcinoma depends on awareness of this unusual variant of endometrioid neoplasia and a lack of the distinctive patterns of clear cell carcinoma; at this time, special studies, including immunohistochemistry, do not aid significantly although certainly negative reactions, such as for thyroglobulin protein (arguing against clear cell struma ovarii) may play a role in some differential diagnostic considerations. There are prognostic and therapeutic implications in the distinction with clear cell carcinoma.

The histological diagnosis of endometrial hyperplasia. Is there a need to simplify?

The intra- and interobserver variability of the histological diagnosis of endometrial hyperplasia, including low-grade carcinomas, is high and thus often causes confusion in the dialogue between pathologists and clinicians. The current classification of the WHO, ISGP, and FIGO is not altogether successful in overcoming this difficulty. New approaches to resolve this unsatisfactory situation have been suggested by two recent simultaneous studies, one by a European group of experts (1999) and the other by Mutter and The Endometrial Collaborative Group (2000). Both studies suggest simplifying the WHO classification by reducing the present four categories to two. The European study names the new histological groups endometrial hyperplasia (EH) and endometrioid neoplasia (EN), while Mutter et al. call them endometrial hyperplasia (EH) and endometrial intraepithelial neoplasia (EIN). Differentiation between the two new categories can be made based on uncomplicated morphological concepts and confirmed morphometrically by the semiquantitative determination of the stromal volume in relation to total tissue volume (stroma+epithelium+gland lumen). This simplification has the advantage of a high degree of reproducibility of histological diagnoses while facilitating understanding by clinicians. Most importantly, there is no decrease in prognostic accuracy, since EH is a benign lesion, easily treated with hormones and almost without risk of progressing to cancer, while EIN/EN is a pre- or already malignant disease with a high risk of progression (approximately 30%) requiring a more radical treatment. This article summarizes the current discussion on this issue.

Prognostic aspects on endometrial hyperplasia and neoplasia.

There are various forms of endometrial hyperplasia which, in terms of prognosis and therapy, can be subdivided into those having cytological atypia and those lacking this feature. The former may progress into invasive endometrial malignancy through a transitional non-invasive stage. This is a continuous process and, as a result, the distinction between an atypical hyperplasia and an intraepithelial adenocarcinoma (IEA) or an adenocarcinoma with stromal invasion is not histologically reproducible. The concept of endometrioid neoplasia, which includes the entire spectrum of the aforementioned proliferating endometrial lesions, was introduced. Adenocarcinomas arising from an atypical hyperplasia are invariably of the endometrioid cell type, whereas those developing from an atrophic endometrium may be either of the endometrioid or of the non-endometrioid cell type. Endometrioid adenocarcinomas arising through the hyperplasia-neoplasia sequence are oestrogen induced and tend to be well differentiated and less invasive of the myometrium, lack lymphatic and metastatic involvement and have an excellent prognosis. Oestrogen-induced adenocarcinomas are also endometrioid, arising from an atrophic or a rather weakly proliferating endometrium, but these neoplasms are frequently of higher histological grade and have a somewhat less favourable prognosis. Finally, endometrial carcinomas of the non-endometrioid cell type, mainly serous papillary and clear cell carcinomas, are non-oestrogen induced, non-hyperplasia associated and show adverse aggressive histological features and an extremely poor prognosis. The antigenic characteristics and the molecular events associated with the development of these forms of endometrial malignancy are distinct and allow the description of, at least, two pathogenetic types of endometrial carcinoma.

Präkanzeröse Läsionen des Endometriums: Aspekte der molekularen Pathogenese und Probleme der Nomenklatur

Für das Endometriumkarzinom (EC), das häufigste Malignom des weiblichen Genitale, lassen sich bisher zwei unterschiedliche Pathogenesewege definieren, denen auch eine biologisch prognostische Bedeutung zukommt. Als Prototyp des sog. Typ- I-Karzinoms gilt das endometrioide Adenokarzinom als häufigster Vertreter des EC mit vergleichsweise deutlich besserer Prognose. Pathogenetisch zeigt das endometrioide Karzinom häufig eine Mikrosatelliteninstabilität sowie K-ras-Mutationen, die bereits auch in vorausgehenden Hyperplasien nachweisbar sind. Mikrosatelliteninstabile Tumoren weisen oft auch Mutationen des PTEN-Gens auf. Alterationen des p53-Gens werden nur bei 10 - 20 % beobachtet, präferenziell bei schlecht differenzierten (G3) Karzinomen. Endometrioide Karzinome sind östrogenabhängig und oft mit endometrialen Hyperplasien assoziiert. Die Nomenklatur dieser Hyperplasien ist derzeit im Fluss. Diskutiert wird eine Zweiteilung in Hyperplasien (glandulär-zystische Hyperplasie und komplexe Hyperplasie) und endometrioide Neoplasie (atypische Hyperplasie und gut differenziertes [G1] Karzinom) und das Konzept der endometrialen intraepithelialen Neoplasie (EIN). Derzeit sollten jedoch noch die Ergebnisse weiterer Studien abgewartet werden, bevor die WHO-Klassifikation der endometrialen Hyperplasien modifiziert wird, deren Änderung auf der Basis eines breiten internationalen Konsens erfolgen sollte. Beim Typ II des EC, dessen Prototyp das serös-papilläre Adenokarzinom ist, lassen sich in mehr als 90 % Mutationen des p53-Tumorsuppressorgens nachweisen, mit einer immunhistochemisch detektierbaren Akkumulation des (aberranten) p53-Onkoproteins intranukleär. Eine Mikrosatelliteninstabilität und K-ras-Mutationen sind seltene Ereignisse. Diese Karzinome mit sehr schlechter Prognose entstehen nicht selten in einem atrophen Endometrium, möglicherweise über eine flache Läsion, die als endometriales intraepitheliales Karzinom bezeichnet wird. Das klarzellige Adenokarzinom steht pathogenetisch dem serös-papillären Typ-II-Karzinom nahe, mit jedoch nachweisbaren Unterschieden.

Endometrioid neoplasia of the ovary: a reappraisal.

The emergence in recent years of new concepts and entities pertaining to ovarian endometrioid neoplasia has led to a reappraisal of the subject. In this reappraisal, the double listing of benign endometrioid lesions as both "tumors" and "tumor-like" lesions, as it appears in the World Health Organization (WHO) classification, is being avoided and they are all listed under one heading. Clear cell tumors, which, in the WHO classification, are not listed under endometrioid neoplasia, are included among the latter in the proposed classification. Recently described entities are reviewed, as are those previously listed but not well documented. Some of the WHO listed endometrioid tumors of low malignant potential are omitted from the present discussion, as histologic and clinical data pertaining to such neoplasms are still not available.