Endometrial Serous Adenocarcinoma Research Articles

Endometrial Serous Adenocarcinoma and Perineal Leiomyosarcoma: A rare case report of Synchronous Primaries

The simultaneous presentation of endometrial carcinoma and perineal leiomyosarcoma in a patient as a synchronous tumor is very rare.

Whole exome sequencing reveals novel candidate variants for endometriosis utilizing multiple affected members in a single family.

Endometriosis is an estrogen-dependent, chronic inflammatory disease that affects 10% of women during the reproductive ages. Despite the estimated 50% heritability for the condition, only 26% was associated with common genetic variants. Thus, necessity of identifying rare variants for the missing heritability is implicated in the literature. Therefore, our study aimed to identify novel rare genetic variants involved in the pathogenesis of endometriosis utilizing a family of multiple affected members. A family composed of four affected women along with their two unaffected mothers were recruited at a single gynecology and infertility clinic specialized in endometriosis. All patients presented with endometriomas, which was visualized by transvaginal ultrasonography. Two affected individuals had received laparoscopic endometrioma excision and therefore were diagnosed with recurrent disease. One mother had a history of endometrial serous adenocarcinoma (ESC) for which she underwent hysterectomy with bilateral oophorectomy. Three endometriosis cases were whole exome sequenced on Illumina NextSeq 550 platform with an average of 90% coverage. Candidate genes were confirmed by Sanger sequencing and followed-up with family segregation. Novel rare variants were identified in TNFRSF1B (NM_001066.3: c.1072G>A, p.(Ala358Thr)) and GEN1 (NM_001130009.3: c.1574C>T, p.(Ser525Leu)) as possible genetic causes of endometriosis. A third novel rare variant was identified in CRABP1 (NM_004378.3:c.54G>C, p.(Glu18Asp)) only on the mother with ESC history and her daughters. Novel candidate genetic variants that might contribute to endometriosis were suggested that need replication through independent cohorts or validation by functional studies. The family has also received genetic counseling and that the affected daughters are on clinical follow-up, accordingly.

ENDOMETRIALHYPERPLASIA AND ITS RELATIONSHIP WITH P16 STROMAL EXPRESSION OF ENDOMETRIAL POLYPS: REVIEW

Recently, p16 stromal expression has been reported in the examination of endometrial serous adenocarcinomas associated with endometrial polyps. Therefore, endometrial polyps are defined as preneoplastic formations in some textbooks. Due to these different expressions of stromal cells in endometrial polyps, we wanted to present the place of p16 expressions in stromal tissue in endometrial hyperplasia and endometrial polyps in the differential diagnosis in our review article.

Endometrial Serous Adenocarcinoma with Septate Uterus: A Rare Case Report

Abstract Introduction/Objective Congenital structural malformations of the uterus rarely coincide with uterine malignancies and can cause significant challenges to the detection of tumors originating from the uterine cavity. We report a case of delayed diagnosis of endometrial high-grade serous adenocarcinoma following an initial false-negative endometrial biopsy result. A septate uterus was discovered incidentally upon gross dissection, and it was recognized as the cause of the initial false-negative biopsy result. Exceptionally rare cases of uterine malformation combined with carcinoma have been reported in the literature and we are sharing this case to provide further awareness of such clinical scenario. Methods/Case Report A 67- year-old multigravida (G3P2103) female presented with postmenopausal bleeding. Initially, the patient underwent an endometrial biopsy revealing strips of benign glandular epithelium. Three months later endometrial biopsy showed high-grade serous carcinoma. A computed tomography scan (CT) of the abdomen and pelvis showed expanded and heterogeneously hypodense endometrium. The patient underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Gross examination of the specimen revealed a septate uterus with two cavities. Within the right cavity, there was an infiltrating polypoid mass and a superficial benign-appearing endometrial polyp was identified in the left cavity. After histologic examination of the right cavity mass, a diagnosis of endometrial high-grade serous adenocarcinoma was rendered. Results (if a Case Study enter NA) N/A Conclusion Congenital structural malformations of the uterus carry a higher risk of delayed or missed uterine cancer diagnosis. Septate uterus is associated with a higher chance of failed endometrial biopsy and can result in a false- negative outcome. The use of hysteroscopy, hysterosonography, and three-dimensional ultrasound could improve the diagnostic modality of malignant uterine tumors associated with structural malformations.

P-301 Exome sequencing reveals novel candidate variants for endometriosis and endometrial serous adenocarcinoma in a single family having multiple affected members

Abstract Study question Could genetic evaluation of a family, having multiple affected members with endometriosis, contribute to identifying novel rare variants for the missing heritability of the disease? Summary answer Two novel genetic variants one in each of TNFRSF1B and GEN1 genes detected only in all affected family members, suggesting potential new biomarkers forendometriosis. What is known already Endometriosis is an estrogen-dependent, chronic inflammatory disease that affects 10% of women during the reproductive ages. Despite the estimated 50% heritability for the condition, only 26% was associated with common genetic variants through GWAS studies. The necessity of identifying rare variants for the missing heritability is implicated in the literature. In this respect, only one familial study has suggested novel candidate variants utilizing whole exome sequencing (WES). Study design, size, duration A single family having 4 women diagnosed with endometriosis out of 6 were recruited for genetic delineation utilizing whole exome sequencing (WES). The average follow-up period of the patients were five years. Participants/materials, setting, methods Total of 6 women from the same family. Four women with endometriosis were diagnosed. WES was performed on these 3 women with endometriosis utilizing the Twist Core Exome Target Capture and Enrichment Kit on the Illumina Nextseq 550 platform with 50X coverage. Bioinformatics analyses along with variant prioritization at MAF <1% for all normal populations were performed on Genomize SEQ platform. Candidate genes were subjected to confirmation by Sanger sequencing followed by familial segregation. Main results and the role of chance All endometriosis patients presented with dysmenorrhea. Additionally, one of them reported having dyschezia, one had chronic pelvic pain and the other patient complained having dyspareunia. The 3 patients who underwent WES analysis were also under treatment for endometriosis related infertility. 2 out of these 3 patients had a positive history for endometriosis surgery and presented with recurrent endometriomas. Novel heterozygous missense variants one in each of TNFRSF1B and GEN1 genes were determined in all affected members, while a novel heterozygous missense variant in CRABP1 was detected only in daughters descending from the mother with cancer history. All variants were predicted to be deleterious by in silico tools Limitations, reasons for caution Our findings are limited to the family of interest and needs to be replicated in larger cohorts. Designation of the novel findings as causative mutations, functional validations need to be performed. Wider implications of the findings The novel genetic variants detected will help in providing genetic counseling to the family. Our findings, when replicated in larger cohorts and validated functionally, will provide significant contribution to the elucidation of the molecular mechanisms of the pertinent conditions. Trial registration number not applicable

Metastatic CD138+ Lobular Breast Carcinoma Mimicking a Plasma Cell Neoplasm

Abstract We present a case of an 85-year-old female who received a bone marrow biopsy for concern over myelodysplastic symptoms and was subsequently diagnosed with a CD138-positive metastatic lobular breast carcinoma that mimicked a plasma cell neoplasm. Her medical history included endometrial serous adenocarcinoma (pT1a N0), severe mitral regurgitation, and atrial fibrillation. She presented with a 3-month history of thrombocytopenia (60,000/mcL) and a down-trending macrocytic anemia (nidus hemoglobin: 6-7 g/dL) that prompted a bone marrow biopsy. The aspirate smears were aparticulate and hemodiluted, while the touch preparations revealed a homogeneous population of large, plasmacytoid cells. These were again seen filling the medullary cavity on the bone marrow biopsy with eccentrically placed nuclei containing nucleoli and abundant eosinophilic cytoplasm. The cells were CD138, cytokeratin 7 and 8/18, mammoglobulin, and GATA-3 positive. They were cytokeratin 20, TTF-1/Napsin, PAX-8, and uroplakin negative. Further testing revealed the cells to be estrogen receptor positive (strong, 90%+), progesterone negative, HER2 negative, p120 positive (strong cytoplasmic), and E-cadherin negative. The patient’s prior serous adenocarcinoma histomorphology was not consistent with the plasmacytoid cells. Prior literature revealed a case report on a metastatic lobular carcinoma to bone marrow and discussion on the morphologic similarities, but the case was CD138 negative. This case highlights that CD138 can be positive in certain carcinomas, some of which can have a plasmacytoid morphology. Suspicion should be raised in an elderly female population.

The impact of histological subtype in developing both ovarian and endometrial cancer: A longstanding nationwide incidence study

ObjectivesTo estimate the incidence of ovarian cancer (OC) and endometrial cancer (EC) separately, as well as double cancers diagnosed in the same calendar year, and to relate the occurrences to histological subtype. Study designAll cases of epithelial OC and EC diagnosed in the Netherlands in 1989–2009 were related to population data. Histologically specific associations were made using the ratio of observed and expected incidence numbers, calculated with age-specific incidence rates. Results25,489 OC and 32,729 EC were analyzed, and 649 OC/EC. Life-time risks for OC and EC were 1.8% and 2.4%. Among OC, adenocarcinoma (18%) and serous cancers (33%) were the most prevalent subtypes. In EC, adenocarcinoma (39%) and endometrioid cancer (37%) were highest, with hardly any serous cancers. The observed incidence of OC/EC was 50-fold higher than expected (95% CI, 46–54). For patients aged <55years, the O/E ratio was 274, for the elderly 32, both findings are significant. Of the 2345 OC endometrioid subtype, 294 had EC (12.5%), whereas 1.1 was expected. In EC patients, no particular histological subtype was distinguished with a highly elevated occurrence of OC. The 680 serous EC patients had 11 double cancers (1.6%), of which 8 with the ovarian serous subtype. ConclusionStrong relationships exist between malignancies in the ovary and a second primary malignancy in the endometrium, especially for the endometrioid subtype of ovarian cancer. Viewed from the endometrial site, no special subtype was noted, and the influence of endometrial serous adenocarcinoma in developing serous OC is not plausible.

Endometrial Cancer: Molecular and Cellular Basis of Tumor Development, Novel Biomarkers and Therapeutic Agents, and Innovative Research Approaches

Endometrial Cancer: Molecular and Cellular Basis of Tumor Development, Novel Biomarkers and Therapeutic Agents, and Innovative Research Approaches

Coordinate patterns of estrogen receptor, progesterone receptor, and Wilms tumor 1 expression in the histopathologic distinction of ovarian from endometrial serous adenocarcinomas

The purpose of this study is to assess whether composite or coordinate immunoexpression patterns of estrogen receptor (ER), progesterone receptor (PR), and Wilms tumor 1 (WT1) gene can significantly distinguish between endometrial serous carcinoma (ESC) and ovarian serous carcinoma (OSC). Immunohistochemical analyses were performed on whole tissue sections from 22 uterus-confined ESCs and on a tissue microarray of 140 high-grade, pan-stage OSCs, using antibodies to ER, PR, and WT-1. Estrogen receptor, PR, and WT1 expressions were present in 37%, 49%, and 81% of OSC, respectively, but these markers were also present in 18%, 27%, and 36% of ESC. The ER+/PR+/WT1+ coordinate profile was identified in 33.6% of OSC but in none of ESC (P = .0006), resulting in a calculated sensitivity and specificity of this profile for OSC of 33.6% and 100%, respectively. By contrast, the ER-/PR-/WT1- coordinate profile was identified in 41% of ESC but in only 6.4% of OSC (P = .0001), resulting in a calculated sensitivity and specificity of this profile for ESC of 50% and 94%. In summary, in the differential diagnosis between OSC and ESC, positivity for all 3 markers favors an extrauterine origin, whereas negativity for all 3 markers is supportive of an endometrial origin. The use of single markers for this purpose is not recommended, as each lacks optimal discriminatory power. Coordinate profiles, in general, have a high specificity but low sensitivity in this differential diagnosis.

The Oncoplacental Gene Placenta-Specific Protein 1 Is Highly Expressed in Endometrial Tumors and Cell Lines

Placenta-specific protein 1 (PLAC1) is a small secreted protein expressed exclusively in trophoblast cells in the mammalian placenta. PLAC1 is expressed early in gestation and is maintained throughout. It is thought to function in trophoblast invasion of the uterine epithelium and, subsequently, to anchor the placenta to the epithelium. In recent years, evidence has accumulated that PLAC1 is also expressed in a variety of human solid tumors, notably in breast cancers. We demonstrate for the first time that PLAC1 is ubiquitously expressed in tumors originating in uterine epithelium. Further, we find that PLAC1 expression is significantly higher in the more advanced, more aggressive endometrial serous adenocarcinomas and carcinosarcomas relative to endometrioid adenocarcinomas by more than 6-fold and 16-fold, respectively. We also show that PLAC1 is simultaneously transcribed from two promoters but that, in all cases, the more distal P1 promoter dominates the more proximal P2 promoter. While the function of the two PLAC1 promoters and their regulation are as yet unknown, overall expression data suggest that PLAC1 may serve as a biomarker for endometrial cancer as well as a potential prognostic indicator.

MicroRNA‐34b functions as a potential tumor suppressor in endometrial serous adenocarcinoma

Endometrial serous adenocarcinoma (ESC) is aggressive and carries a poor prognosis. p53 is frequently mutated in ESC. microRNAs (miRNAs) are a direct p53 target and have been implicated in cancer cell behavior. In this study, we compared miRNA expression levels in ESC with the levels in endometrial endometrioid adenocarcinoma (EEC) and normal endometria. Six miRNAs were identified as having aberrant down-regulation specific to ESC with miR-34b being most pronounced. miR-34b was found to have promoter hypermethylation, which when reversed, restored miR-34b expression in the cell lines treated with 5-aza-2' deoxycytidine (DAC). Ectopic expression of miR-34b in turn inhibited cell growth, migration and most notably invasion. Our findings suggest a relationship among p53 mutation, miR-34b promoter methylation and tumor cell behavior. These effects are likely mediated by the downstream target of miR-34b, the proto-oncogene mesenchymal-epithelial transition factor (MET), a known prognostic factor in endometrial carcinomas. The expression of MET was reduced following the restoration of miR-34b in cell lines. In summary, our data suggest that miR-34b plays a role in the molecular pathogenesis of endometrial cancer.

Global dysregulation of the chromosome 14q32 imprinted region in uterine carcinosarcoma

Uterine carcinosarcoma (UCS) is a rare but very aggressive cancer of the female reproductive tract with an extremely poor prognosis. With the goal of understanding the role of microRNA (miRNA) dysregulation in these tumors, we profiled the expression of 667 human miRNAs in a panel of eight UCS patients and five benign control primary tissue samples. These expression profiles revealed two important characteristics of UCS. First, compared with the two most common uterine cancers, endometrial endometrioid adenocarcinoma and endometrial serous adenocarcinoma, UCS samples display a virtually unique pattern of miRNA dysregulation with an overlap of only 5% among the three tumor types. In addition, nearly one-third of the miRNAs significantly dysregulated in UCS tissues compared with benign endometrium (32 of 114) lie in a single small (250-kb) imprinted region of chromosome 14q32. These data suggest that the presence of such a global, region-specific disruption substantially contributes to the unique histology and poor outcome of this type of cancer.

A case of minimal uterine serous carcinoma with distant lymph node metastasis without peritoneal dissemination

A 61-year old woman underwent total abdominal hysterectomy and pelvic lymph node dissection under the diagnosis of endometrial cancer. Although pelvic lymph nodes were positive for adenocarcinoma with psamomma bodies, no other lesion that was a primary lesion was verified. A postoperative study revealed the existence of para-aortic lymph node and supraclavicular lymph node metastases. Therefore, the endometrial biopsy specimen was reviewed. With the findings of p53 positivity by immunohistochemistry in the papillary part, the final histopathological diagnosis was changed to endometrial serous adenocarcinoma. Postoperative chemotherapy followed by radiotherapy for supraclavicular lymph node metastasis achieved complete response. This type of tumor must be considered in a differential diagnosis when metastatic papillary serous carcinoma is detected, but the primary site remains unknown.

Changes in microRNA expression levels correlate with clinicopathological features and prognoses in endometrial serous adenocarcinomas

This study aimed to determine the expression profiles of microRNAs (miRNAs) in endometrial serous adenocarcinoma and to examine the association between miRNA expression and clinical outcomes. Twenty-one patients diagnosed with endometrial serous adenocarcinoma between January 2001 and December 2006 were enrolled. miRNA expression profiles were examined using miRNA microarray and qRT-PCR. miRNA expression levels were correlated with clinicopathological variables and survival rates. A total of 120 miRNAs were differentially expressed in endometrial serous adenocarcinoma compared to normal endometria. Of these, 54 miRNAs were down-regulated (>2-fold), including miR-101, miR-10b*, miR-152, and miR-29b, and the remainder were up-regulated (>2-fold), including miR-200a, miR-200b, and miR-205. Decreased expression of miR-10b*, miR-29b, and miR-455-5p was correlated with vascular invasion (P = 0.048, P = 0.013, and P = 0.032, respectively). Univariate analysis revealed that lower expression of miR-101, miR-10b*, miR-139-5p, miR-152, miR-29b, and miR-455-5p was significantly correlated with poor overall survival (P < 0.05), and reduced expression of miR-152, miR-29b, and miR-455-5p was significantly correlated with poor disease-free survival (P < 0.05). Multivariate analysis demonstrated that decreased expression of miR-152 (P = 0.021) was a statistically independent risk factor for overall survival, and decreased expression levels of miR-101 (P = 0.016) and miR-152 (P = 0.010) were statistically independent risk factors for disease-free survival. In addition, transfection of miR-101 or miR-152 precursors into an endometrial serous carcinoma cell line inhibited cell growth (P < 0.0001 and P = 0.01, respectively). Moreover, strong positive immunoreactivity of cyclooxygenase-2 (COX-2) was significantly correlated with down-regulation of miR-101 (P = 0.035). These findings suggest that the dysregulation of miRNAs is associated with the poor prognosis in endometrial serous adenocarcinoma patients.

MSN-1 Antibody in the Evaluation of Female Genital Tract Adenocarcinomas

The reactivity of a new monoclonal antibody (MAb), MSN-1, raised against a human endometrial cancer cell line (SNG-II), was studied in a variety of endometrial, endocervical, and ovarian carcinomas as well as normal cycling endometrium. Moderate to strong reactivity (2-3+) was seen in six of nine normal secretory endometria (67%), one of 10 normal proliferative endometria (10%), 18 of 18 endometrial adenocarcinomas (100%), 10 of 11 endometrioid ovarian adenocarcinomas (91%), seven of nine clear cell ovarian adenocarcinomas (78%), one of 12 endometrial hyperplasias without atypia (9%), two of four endometrial hyperplasias with atypia (50%), zero of five endometrial serous adenocarcinomas, two of 17 serous ovarian adenocarcinomas (12%), zero of 10 intestinal-type mucinous ovarian adenocarcinomas, and zero of nine metastatic adenocarcinomas in ovary. Endocervical adenocarcinomas showed moderate to strong staining in 75% (six of eight). It is concluded that MSN-1 can be used to confirm endometrioid/clear cell differentiation in ovarian and endometrial tumors, cannot be used to discriminate endocervical from endometrial differentiation, cannot be used to discriminate atypical hyperplasia from carcinoma, and may be useful to distinguish between atypical (premalignant) endometrial hyperplasias and those without atypia.