Endometrial Intraepithelial Carcinoma Research Articles

Serous Endometrial Intraepithelial Carcinoma with High-Grade Serous Ovarian Carcinoma: A Synchronous Presentation

Serous Endometrial Intraepithelial Carcinoma with High-Grade Serous Ovarian Carcinoma: A Synchronous Presentation

Serous endometrial intraepithelial carcinoma (SEIC) with metachronous umbilical cutaneous, pleural, and peritoneal metastases: Case report and literature review

Serous endometrial intraepithelial carcinoma (SEIC) with metachronous umbilical cutaneous, pleural, and peritoneal metastases: Case report and literature review

Localized Endometrial Proliferations of Pregnancy are Clonal Glandular Outgrowths Characterized by PTEN Loss and PIK3CA Pathogenic Variants

Gestational endometrium can demonstrate a spectrum of atypical but benign changes. One such lesion is localized endometrial proliferation of pregnancy (LEPP), first described in a series of 11 cases. To understand its biological and clinical importance, we explore the pathologic, immunophenotypic, and molecular features of this entity. Nine cases of LEPP identified in 15 years were retrieved from departmental archives and reviewed. Immunohistochemistry and next-generation sequencing using a comprehensive 446-gene panel were performed when the material was available. Eight cases were identified in curettage specimens performed after first-trimester pregnancy loss, and 1 in the basal plate of a mature placenta. The mean patient age was 35 (range 27–41) years. The mean lesion size was 6.3 (range 2–12) mm. Architectural patterns, often coexisting in the same case, included cribriform (n = 7), solid (n = 5), villoglandular (n = 2), papillary (n = 2), and micropapillary (n = 1). Cytologic atypia was mild in 7 cases and moderate in 2. Mitotic activity was low (up to 3 per 2.4 mm2). All lesions were associated with neutrophils. Background Arias–Stella phenomenon was present in 4 cases. Immunohistochemistry was performed in 7 LEPP, all of which demonstrated wildtype p53, retained MSH6 and PMS2, membranous beta-catenin, and positive estrogen receptor (mean 71%) and progesterone receptor (mean 74%). All were negative for p40 except 1 case (focal weak positivity). PTEN was markedly reduced in background secretory glands in all cases; in 5/7, LEPP foci showed a complete absence of PTEN expression. PIK3CA pathogenic variants were identified in 4/4 cases sequenced; 3/4 had inactivating PTEN mutations. Follow-up, available in 8 patients (mean length = 51 months, range 7–161), was conservative with observation only and showed no persistence or adverse outcomes. LEPP is characterized by intraglandular cribriform/solid architecture, positive estrogen receptor/progesterone receptor, PTEN loss, and PIK3CA and PTEN mutations. Although our findings indicate that LEPP is neoplastic, for now, we advise against diagnosing LEPP as endometrial carcinoma or hyperplasia because LEPP has a particular clinicopathologic context (concurrent gestation), distinct morphology (purely intraepithelial complex growth), and indolent outcome. Thus, it should be distinguished from endometrial intraepithelial neoplasia and carcinoma for which therapeutic interventions are indicated.

Serous endometrial intra-epithelial carcinoma: an observational study

BackgroundSerous endometrial intra-epithelial carcinoma is described as a malignant, superficial spreading lesion with risk of extra-uterine spread at time of diagnosis, and poor outcome.ObjectiveTo evaluate the surgical management of patients...

Minimally Invasive Technique Not Associated with Worse Prognosis in Patients with Stage I Uterine Papillary Serous Carcinoma (UPSC)

Study Objective To determine the role of surgical technique in increasing risk of recurrence in patients with stage I UPSC. Design Using a prospective database and billing records, all cases of UPSC were identified from 2006 through 2021. Standard statistical analysis related the impact of surgical technique and BTL on recurrence risk and progression free survival (PFS) in patients with stage I UPSC. Setting N/A. Patients or Participants All patients with UPSC diagnosed at our center 2006-2021. Interventions N/A. Measurements and Main Results A total of 225 total cases of UPSC were identified, including 118 pts with stage I disease. Six patients (5%) had endometrial intraepithelial carcinoma (EIC), 98 (83%) were stage IA, and 14 (12%) were stage IB. A history of BTL was obtained in 25 pts (21%). Minimally invasive hysterectomy was performed in 99 (84%; 31% robot, 53% laparoscopy). Adjuvant chemotherapy was given to 83 patients (72%) with 31 (256%) receiving 3 cycles or less and 54 (46%) receiving 4-7 cycles. Additionally, 22 (19%) received vaginal brachytherapy and 9 (8%) received whole pelvic radiation. Seventeen patients (14%) experienced recurrence after treatment and 8 (7%) died of disease. No differences in PFS or outcomes were noted between open and minimally invasive methods (P=0.76). Patients who underwent BTL prior to diagnosis were found to have a recurrence rate of 28% vs. 11% in patients without history of BTL (P = 0.03). A multivariate model incorporating known risk factors for recurrence, including use of radiation, chemotherapy, depth of invasion, and LVSI, confirmed that BTL remained a significant predictor of recurrence (OR 3.18; 95% CI 1.02-9.96, P = 0.046). Conclusion No differences in progression free survival were noted between patients who underwent minimally invasive vs. open surgeries in patients with stage I UPSC. However, BTL does not appear to be protective against extra-uterine spread and may change the presenting stage of biologically more aggressive tumors. To determine the role of surgical technique in increasing risk of recurrence in patients with stage I UPSC. Using a prospective database and billing records, all cases of UPSC were identified from 2006 through 2021. Standard statistical analysis related the impact of surgical technique and BTL on recurrence risk and progression free survival (PFS) in patients with stage I UPSC. N/A. All patients with UPSC diagnosed at our center 2006-2021. N/A. A total of 225 total cases of UPSC were identified, including 118 pts with stage I disease. Six patients (5%) had endometrial intraepithelial carcinoma (EIC), 98 (83%) were stage IA, and 14 (12%) were stage IB. A history of BTL was obtained in 25 pts (21%). Minimally invasive hysterectomy was performed in 99 (84%; 31% robot, 53% laparoscopy). Adjuvant chemotherapy was given to 83 patients (72%) with 31 (256%) receiving 3 cycles or less and 54 (46%) receiving 4-7 cycles. Additionally, 22 (19%) received vaginal brachytherapy and 9 (8%) received whole pelvic radiation. Seventeen patients (14%) experienced recurrence after treatment and 8 (7%) died of disease. No differences in PFS or outcomes were noted between open and minimally invasive methods (P=0.76). Patients who underwent BTL prior to diagnosis were found to have a recurrence rate of 28% vs. 11% in patients without history of BTL (P = 0.03). A multivariate model incorporating known risk factors for recurrence, including use of radiation, chemotherapy, depth of invasion, and LVSI, confirmed that BTL remained a significant predictor of recurrence (OR 3.18; 95% CI 1.02-9.96, P = 0.046). No differences in progression free survival were noted between patients who underwent minimally invasive vs. open surgeries in patients with stage I UPSC. However, BTL does not appear to be protective against extra-uterine spread and may change the presenting stage of biologically more aggressive tumors.

Serous endometrial intraepithelial carcinoma coexistence with atypical polypoid adenomyoma in a young woman: a rare case

Serous endometrial intraepithelial carcinoma coexistence with atypical polypoid adenomyoma in a young woman: a rare case

Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis

TP53 and ARID1A are frequently mutated across cancer but rarely in the same primary tumor. Endometrial cancer has the highest TP53-ARID1A mutual exclusivity rate. However, the functional relationship between TP53 and ARID1A mutations in the endometrium has not been elucidated. We used genetically engineered mice and in vivo genomic approaches to discern both unique and overlapping roles of TP53 and ARID1A in the endometrium. TP53 loss with oncogenic PIK3CAH1047R in the endometrial epithelium results in features of endometrial hyperplasia, adenocarcinoma, and intraepithelial carcinoma. Mutant endometrial epithelial cells were transcriptome profiled and compared to control cells and ARID1A/PIK3CA mutant endometrium. In the context of either TP53 or ARID1A loss, PIK3CA mutant endometrium exhibited inflammatory pathway activation, but other gene expression programs differed based on TP53 or ARID1A status, such as epithelial-to-mesenchymal transition. Gene expression patterns observed in the genetic mouse models are reflective of human tumors with each respective genetic alteration. Consistent with TP53-ARID1A mutual exclusivity, the p53 pathway is activated following ARID1A loss in the endometrial epithelium, where ARID1A normally directly represses p53 pathway genes in vivo, including the stress-inducible transcription factor, ATF3. However, co-existing TP53-ARID1A mutations led to invasive adenocarcinoma associated with mutant ARID1A-driven ATF3 induction, reduced apoptosis, TP63+ squamous differentiation and invasion. These data suggest TP53 and ARID1A mutations drive shared and distinct tumorigenic programs in the endometrium and promote invasive endometrial cancer when existing simultaneously. Hence, TP53 and ARID1A mutations may co-occur in a subset of aggressive or metastatic endometrial cancers, with ARID1A loss promoting squamous differentiation and the acquisition of invasive properties.

Clear cell endometrial carcinoma precursors: presentation of two cases and diagnostic issues

BackgroundThe precursors of clear cell endometrial carcinoma (CC-EC) are still undefined. Here, we deal with the diagnostic issues related to CC-EC precursors by presenting a morphological, immunophenotypical and molecular study of two representative cases and discussing the relevant literature.Case presentationOur and previous cases suggest that clear cell endometrial intraepithelial carcinoma (CC-EIC) is a real entity, which may be distinguished from metaplastic/reactive changes and from its serous counterpart. CC-EIC appears associated with atrophic polyps and may be diagnosed based on morphological and immunophenotypical features of CC-EC in the absence of invasive disease. We described a p53-mutant putative precursor characterized by high-grade nuclei in the absence of other distinctive features. Two putative low-grade precursors resembled atypical tubal metaplasia and endometrial intraepithelial neoplasia, although immunohistochemistry could not support their relationship with CC-EC.ConclusionsIn conclusion, pathologists should be aware of the existence of CC-EIC, since its correct diagnosis may be crucial for a correct patient management. Although several putative earlier precursors have been described, they does not show univocal features that allow their recognition in the common practice. Further studies are necessary in this field.

Serous endometrial intraepithelial carcinoma (SEIC): Current clinical practice in The Netherlands

IntroductionSerous endometrial intraepithelial carcinoma (SEIC) is a rare diagnosis, defined as an intraepithelial lesion with cells identical to serous type endometrial carcinoma. SEIC is considered to be potentially metastatic, however clear and robust data on prognosis are lacking, potentially leading to variability in clinical management. Objective: The aim is to establish the opinion of gynecologists on the optimal management of patients with SEIC. Methods: An online questionnaire with 15 multiple choice questions was sent to all gynecologists with expertise in gynecological oncology in 19 expert centers in The Netherlands. Results: A total of 24 gynecologists participated. The majority of respondents (n = 18/24, 75%) do not consult a guideline regarding the treatment of SEIC. In current practice, 14 of the 24 respondents perform surgical staging in women with SEIC (58.3%) while seven choose hysterectomy with bilateral salpingo-oophorectomy (29.2%), and three (12.5%) have no firm preference. Eleven of the 14 respondents who perform a surgical staging procedure believe that this is certainly the optimal treatment. The majority of respondents have no firm opinion on whether lymph node sampling or lymph node dissection is preferable during surgical staging (n = 15/23, 65.2%). Most respondents do not give adjuvant therapy (n = 15/24, 62.5%), 25.0% recommend brachytherapy (n = 6/24). Follow-up is for 5 years in almost all cases (n = 23/24). Conclusion: There is no consensus on the optimal surgical treatment and the use of adjuvant therapy for patients with SEIC. Our research team is therefore conducting a nationwide cohort study in which treatment modality, morbidity and survival will be evaluated.

Serous endometrial intraepithelial carcinoma: A clinico-pathological study of 48 cases and its association with endometrial polyps – A tertiary care oncology centre experience

BackgroundEndometrial serous carcinoma (ESC) is an aggressive neoplasm wherein the recent studies have shown that it arises from its putative precursor namely the serous endometrial intraepithelial carcinoma (SEIC). SEIC usually arises in inactive/ atrophic endometrium but surprisingly is frequently associated endometrial polyps (EPs). The aim of this study was to assess the incidence of SEIC with or without invasion, its clinical behaviour and association with endometrial polyp. Materials and MethodsAfter Institutional review board approval, a total of 205 samples (belonging to 120 patients); diagnosed as ESC from January 2009 to December 2015 were retrieved and reviewed for presence of in situ carcinoma and also for associated endometrial polyp. ResultsThe mean age at diagnosis was 62.40 years with postmenopausal bleeding being the most common presenting symptom. The incidence of SEIC with or without invasive tumor was 40% (48/120). Of these 48 cases; 25 cases were associated with in-situ carcinoma arising in the EPs which amounted to 52% of the total cases. The overall three year survival and disease free survival in SEIC with or without invasion were 1.9% and 0.25%, indicating the aggressive nature of the disease. ConclusionSEIC is a difficult histopathological diagnosis and one should carefully look for these lesion, especially in the EPs which are frequently associated with them. Extensive sampling of the EP will be helpful to pick up in-situ carcinoma arising in EP. SEIC is an aggressive disease on its own with a propensity to develop distant metastasis even in the absence of myometrial invasion and hence should be treated with optimum surgical staging and if indicated aggressive adjuvant treatment protocols.

A case of synchronous serous ovarian cancer and uterine serous endometrial intraepithelial carcinoma

BackgroundSerous endometrial intraepithelial carcinoma (SEIC) is now considered to represent an early stage of uterine serous carcinoma (USC). It is an intraepithelial lesion but has been reported to cause extrauterine metastases. We report a case of SEIC with serous ovarian carcinoma and lymph node metastasis.Case presentationA 57-year-old post-menopausal woman (gravida 3, para 2, SA1) was referred to our hospital with lower abdominal pain. An ultrasound and MRI showed that the ovary had swollen to 8 cm in size and had a solid lesion. The uterus was normal. The patient underwent exploratory laparoscopy on the suspicion of torsion of the ovarian tumor. Intraoperative findings showed a right ovarian tumor, but no ovarian tumor torsion was observed. A small amount of bloody ascites was found in the Douglas fossa, and bleeding was observed from the tumor itself. A right salpingo-oophorectomy was then performed. Histopathological results revealed a high-grade serous carcinoma. Forty days after the first surgery, we performed a staging laparotomy: a total abdominal hysterectomy, left salpingo-oophorectomy, systematic pelvic and paraaortic lymphadenectomy, and a partial omentectomy. A complete cytoreduction was achieved. In the pathological examination, the invasion of the serous carcinoma was observed in the left ovarian ligament, and lymph node metastasis was found in the paraaortic lymph nodes. Atypical columnar cells formed irregular papillary lesions which had proliferated in the endometrium, and this was diagnosed as SEIC. The final diagnosis was serous ovarian cancer, FIGO stage IIIA1(ii), pT2bN1M0, with SEIC.ConclusionWe report a case of SEIC with synchronous serous carcinoma of the adnexa uteri. Both were serous carcinomas and, thus, it was difficult to identify the primary lesion. The distinction between metastatic cancer and two independent primary tumors is important for an accurate diagnosis and tumor staging. Histological diagnostic criteria remain controversial, and further development of a method for differentiating between both diseases is required.

Proteomic Analysis of Pre-Invasive Serous Lesions of the Endometrium and Fallopian Tube Reveals Their Metastatic Potential.

Serous endometrial cancer (SEC) and high grade serous ovarian cancer (HGSOC) are aggressive gynecological malignancies with high rates of metastasis and poor prognosis. Endometrial intraepithelial carcinoma (EIC), the precursor for SEC, and serous tubal intraepithelial carcinoma (STIC), believed to be the precursor lesion for HGSOC, can also be associated with intraabdominal spread. To provide insight into the etiology of these precancerous lesions and to explore the potential molecular mechanisms underlying their metastatic behavior, we performed a proteomic mass spectrometry analysis in a patient with synchronous EIC and STIC. Through histological and molecular identification of precancerous lesions followed by laser capture microdissection, we were able to identify over 450 proteins within the precancerous lesions and adjacent healthy tissue. The proteomic analysis of STIC and EIC showed remarkable overlap in the proteomic patterns, reflecting early neoplastic changes in proliferation, loss of polarity and attachment. Our proteomic analysis showed that both EIC and STIC, despite being regarded as premalignant lesions, have metastatic potential, which correlates with the common presentation of invasive serous gynecological malignancies at advanced stage.

Fallopian tube abnormalities in uterine serous carcinoma

ObjectiveUterine serous carcinoma (USC) is presumed to arise from endometrial intra-epithelial carcinoma (EIC), whereas tubo-ovarian high-grade serous carcinomas have similar precursor lesions in the Fallopian tube, i.e. serous tubal intra-epithelial carcinoma (STIC). The presence of Fallopian tube abnormalities and their clonal relationship to the concurrent USC was investigated. MethodsIn this multicenter study, all patients treated for USC between 1992 and 2017 were retrospectively identified. Histopathological diagnosis of USC, EIC and STIC was revised by an expert pathologist. Additionally, all Fallopian tube sections were immunohistochemically stained (p53 and Ki-67). Fallopian tube abnormalities were classified as either p53 signature, serous tubal intra-epithelial lesion (STIL) or STIC. The USCs and Fallopian tube abnormalities were analyzed by targeted next-generation sequencing. ResultsIn 168 included patients, Fallopian tube abnormalities were found in 27.4% (46/168): p53-signatures in 17.9% (30/168), STILs in 3.0% (5/168) and STICs in 6.5% (11/168). In subgroup analysis, STICs were found in 9.5% (11/115) of patients with at least one section of the fimbriated end embedded. Next-generation sequencing showed identical TP53-mutations in the STIC and corresponding USC. ConclusionsIn conclusion, the presence of Fallopian tube abnormalities was shown in a high percentage of patients with USC, representing either true precursor lesions or metastasized disease.

漿液性子宮内膜上皮内癌（serous endometrial intraepithelial carcinoma）3症例の報告と内膜細胞診の役割について

漿液性子宮内膜上皮内癌（serous endometrial intraepithelial carcinoma）3症例の報告と内膜細胞診の役割について

Distinct Histologic, Immunohistochemical and Clinical Features Associated With Serous Endometrial Intraepithelial Carcinoma Involving Polyps.

The origin of serous endometrial intraepithelial carcinoma (SEIC) is debated, due to its premalignant and independently malignant nature. It often arises next to endometrial serous carcinoma (ESC), with a propensity for polypoid growth. We aimed to better characterize this discrepancy by analyzing the clinical, histologic, and immunohistochemical features of polypoid carcinoma associated with SEIC (P-SEIC), and compared them with usual endometrial serous carcinoma without SEIC (UESC). Consecutive patients with P-SEIC were recruited and compared with UESC controls from our institutional research center. Clinical, histologic, and immunohistochemical (IHC, ER, PR, P53, Napsin-A, WT1, P16) were analyzed. BRCA testing results and familial history were also extracted from clinical databases. Welch T test, Pearson χ, and Fisher exact test were performed in SPSS version 23. A total of 37 P-SEIC and 25 UESC were the basis of a case-control study. P-SEIC was associated with more bilateral ovarian involvement (P=0.026), yet showed lower rates of myometrial invasion (P=0.002). P-SEIC showed a statistically different IHC profile: p53+, p16+, ER+, PR+, and WT-1+, and high rates of Napsin-A, while UESC was p53+, p16+, WT-1-, Napsin-A-, with lower rates of ER and PR. We also identified 2 patients who received prophylactic salpingo-oophorectomy for BRCA mutations and who subsequently developed P-SEIC with its unique IHC pattern. Our results suggest different underlying expression profiles and possibly diverging molecular signatures between both P-SEIC and UESC. If confirmed in further molecular studies, it could lead to a distinct molecular subclass.

Pathologic quiz case: a 70-year-old woman with postmenopausal bleeding. Endometrial intraepithelial carcinoma, clear cell type.

Pathologic quiz case: a 70-year-old woman with postmenopausal bleeding. Endometrial intraepithelial carcinoma, clear cell type.

Serous endometrial intraepithelial carcinoma diagnosed by hysteroscopic transcervical resection

Serous endometrial intraepithelial carcinoma diagnosed by hysteroscopic transcervical resection

Risk of malignancies among asymptomatic postmenopausal women with thickened endometrium: A cohort study.

The risk of malignancies and related factors among asymptomatic postmenopausal women with thickened endometrium in transvaginal sonography (TVS) are unclear.In this longitudinal study at a tertiary teaching hospital, all medical records of hysteroscopy were searched and retrospectively reviewed according to age, TVS results and diseases coded as International Classification of Diseases version 10. Asymptomatic postmenopausal women with endometrial thickness ≥5 mm from January 2006 to January 2016 were included. A follow-up was provided up to January 2017.Four hundred eighty-eight patients were included with a median endometrial thickness of 8 mm (range 5–30) in TVS. The most common pathologic findings were polyps (51.0%) and normal endometrium (34.2%). Fifteen (3.1%) and 10 cases (2.0%) had endometrial intraepithelial neoplasia (EIN) and carcinoma. Patients with carcinoma had significantly more abnormal serum CA125, thicker endometrium, and more lesions with positive Doppler flow signals. In receiver operating characteristic curve analysis, endometrial thickness of 12 mm had the best predictive ability for malignancies. In multivariate analysis, endometrial lesion with positive Doppler flow signals in TVS was the only independent factor for EIN/carcinoma (odds ratio [OR] 8.0, 95% confidence interval [CI] 1.4–45.1) and for carcinoma (OR 16.0, 95% CI 1.3–192.8). After a median follow-up of 45 months, carcinoma occurred in 1 of 35 (2.8%) women with repeated thickened endometrium.Among asymptomatic postmenopausal women with thickened endometrium, the risk of EIN and malignancy was minimal but worth of long-term follow-up. Endometrial lesions with positive Doppler flow signals in TVS suggested a high risk of malignancy.

Uterine serous carcinoma accompany with serous endometrial intraepithelial carcinoma and papillary proliferation of the endometrium: report of a case

目的： 探讨Ⅱ型子宫内膜癌的临床病理特点。 方法： 回顾性分析2018年5月就诊于浙江大学医学院附属妇产科医院的1例子宫浆液性癌伴浆液性子宫内膜上皮内癌及子宫内膜乳头状增生的临床病理资料。 结果： HE染色以及免疫组织化学提示该肿瘤同时具有子宫浆液性癌、浆液性子宫内膜上皮内癌及子宫内膜乳头状增生的病理形态特点。子宫内膜乳头状增生伴发于子宫浆液性癌及浆液性子宫内膜上皮内癌。 结论： 子宫内膜性癌伴浆液性子宫内膜上皮内癌及子宫内膜乳头状增生兼具3种病理形态特点。.

Controversies in Gynecologic Cancer Staging: An AJCC Cancer Staging Manual, Eighth Edition Perspective

Abstract Staging systems provide a common language to support clinical research and decision making in patients with cancer. The eighth edition of the AJCC Cancer Staging Manual incorporates updates that reflect evolving clinical practices and scientific insights. The present article summarizes changes that have been made for gynecologic subsites and outlines continued challenges. Gynecologic American Joint Committee on Cancer/International Union Against Cancer staging continues to conform closely to current International Federation of Obstetrics and Gynecology staging. The eighth edition is aligned with the major revision made to International Federation of Obstetrics and Gynecology staging of ovarian cancer in 2014 and contains a unified staging system for ovarian, fallopian tube, and primary peritoneal cancer. Continuing challenges for ovarian cancer include determining the relative significance of intraoperative rupture, surface involvement, and positive washings, which are rank ordered in the new staging system. Another challenge is assignment of a tubal versus ovarian primary site for high-grade serous carcinoma, which cannot be done in a reliable way. In uterine carcinoma, endometrial intraepithelial carcinoma is now recognized as a T1 cancer, and nodal micrometastases have been defined with their own N stage. Also, isolated tumor cells in lymph nodes have been incorporated in the staging of all gynecologic carcinomas. The staging of uterine sarcoma is largely unchanged. Future revisions may consider grouping these tumors with soft tissue sarcomas at large. Staging of cervical cancer is largely unchanged. Nomenclature of early invasive carcinoma and the challenges in defining tumor dimension in cervical carcinoma are discussed. The nodal staging of vulvar cancer now incorporates a vocabulary for isolated tumor cells and micrometastases. Despite the current interest in molecular staging, the eighth edition expert panel did not identify any specific biomarkers for inclusion in stage classification, but several are recommended for collection as ancillary data elements, including p16 status in vulvar, vaginal, and cervical tumors. In the eighth edition, as in the seventh, anatomic factors remain the cornerstone of gynecologic cancer staging.