Primary Endometrioid Carcinoma Research Articles

Single-cell RNA sequencing in endometrial cancer: exploring the epithelial cells and the microenvironment landscape.

Single-cell RNA sequencing (scRNA-seq) technology has emerged as a powerful tool for dissecting cellular heterogeneity and understanding the intricate biology of diseases, including cancer. Endometrial cancer (EC) stands out as the most prevalent gynecological malignancy in Europe and the second most diagnosed worldwide, yet its cellular complexity remains poorly understood. In this review, we explore the contributions of scRNA-seq studies to shed light on the tumor cells and cellular landscape of EC. We discuss the diverse tumoral and microenvironmental populations identified through scRNA-seq, highlighting the implications for understanding disease progression. Furthermore, we address potential limitations inherent in scRNA-seq studies, such as technical biases and sample size constraints, emphasizing the need for larger-scale research encompassing a broader spectrum of EC histological subtypes. Notably, a significant proportion of scRNA-seq analyses have focused on primary endometrioid carcinoma tumors, underscoring the need to incorporate additional histological and aggressive types to comprehensively capture the heterogeneity of EC. By critically evaluating the current state of scRNA-seq research in EC, this review underscores the importance of advancing towards more comprehensive studies to accelerate our understanding of this complex disease.

Patterns of spread and genetic alterations of primary endometrioid carcinomas of the ovary

ObjectiveThe primary objective was to characterize the rate of lymph node involvement in a cohort of patients with primary ovarian endometrioid adenocarcinoma. Additionally, we sought to quantify the recurrence rate,...

Patterns of spread and genetic mutations of primary endometrioid carcinomas of the ovary (168)

<b>Objectives:</b> Primary endometrioid carcinoma of the ovary is rare and comprises approximately ten percent of all primary ovarian carcinomas. Less is known about their pattern of spread and genetic alterations. Thus, the objective of this study was to characterize patterns of spread, rate of recurrence, and genetic mutations in a cohort of patients with primary endometrioid ovarian carcinoma. <b>Methods:</b> After obtaining institutional review board approval, all patients diagnosed with primary endometrioid adenocarcinoma of the ovary between January 1, 2012, and May 11, 2021, we re identified from an institutional pathology database. All tissue diagnoses were subject to expert pathologic review to confirm accuracy. Patients with co-existing neoplasms were excluded. Demographic and disease-related data were collected from pathology reports and clinical records, and time to recurrence and death were calculated if applicable. Statistical analyses were performed using SAS statistical software version 9.4. <b>Results:</b> Sixty-three patients were identified for analysis. Median age at diagnosis was 60 years (range: 22-90) and the median CA-125 at presentation was 133 U/mL (mean: 1140 U/mL, range: 7-21,545 U/mL). Assigned FIGO stage after surgery included IA in 17 (27%), IC in 24 (38%), II in 17 (27%), III in four patients (6%), and assigned histologic grades were: grade 1 in 32%, grade 2 in 43%, and grade 3 in 25% of patients. The mean ovarian tumor size was 12.7cm (range: 4.1-22cm). At either primary or re-staging surgery, 41 (65%) patients had pelvic lymph node sampling, and 33 (52%) had para-aortic lymph node sampling. The median number of pelvic lymph nodes removed was 12 (mean: 13.1; range: 1-46), and the median number of paraaortic lymph nodes removed was six (mean: 8.7; range: 1-46). All assessed lymph nodes were negative for metastases. Twenty-eight patients had germline mutational status documented. Only two patients had pathologic mutations identified - one in <i>BRCA1</i> and one in <i>BRCA2</i>. One additional patient was found to have two variants of unknown significance (VUS) in the <i>BRCA2</i> gene. Two further patients were negative for germline <i>BRCA</i> mutations but had a positive HRD score on tumor analysis. Median follow-up for patients alive at the time of data cutoff was 42 months (range: 4-70). The median progression-free survival (PFS) and overall survival (OS) for the cohort of patients who completed primary therapy were 42 and 44 months, respectively. Ten out of 63 patients (16%) experienced recurrence(s) with a median time to recurrence of 25 months. Four patients died of disease with a median OS of 31 months. <b>Conclusions:</b> No nodal metastases were identified in a cohort of comprehensively surgically staged patients with primary endometrioid ovarian carcinoma. Surgeons may consider omitting re-staging operations in patients with partially-staged but completely resected endometrioid carcinoma, regardless of grade. Germline <i>BRCA1</i> and <i>BRCA2</i> mutations were seen less frequently compared to high-grade serous carcinomas.

Primary endometrioid carcinoma of the uterosacral ligament arising from deep infiltrating endometriosis 6\u2009years after bilateral salpingo-oophorectomy due to atypical proliferative endometrioid tumor of the ovary: a rare case report

BackgroundEndometriosis can potentially lead to the development of a malignant tumor. Most malignant tumors arising from the endometriosis originate from the ovarian endometrioma, whereas those arising from extragonadal lesions are rare. We report a rare case of endometrioid carcinoma that developed from deep infiltrating endometriosis in the uterosacral ligament 6 years after treatment for atypical proliferative endometrioid tumor of the ovary in a 48-year-old woman.Case presentationSix years ago, the patient underwent laparoscopic bilateral salpingo-oophorectomy for her right ovarian tumor with atypical proliferative (borderline) endometrioid tumor accompanied by ovarian endometrioma. The solid tumor in the cul-de-sac was detected during follow-up using magnetic resonance imaging. Positron emission tomography/computed tomography revealed an abnormal accumulation of 18F-fluorodeoxyglucose at the tumor site. Thus, tumor recurrence with borderline malignancy was suspected. The patient underwent diagnostic laparoscopy followed by hysterectomy and partial omentectomy. Retroperitoneal pelvic lymphadenectomy and para-aortic lymphadenectomy were also performed. The cul-de-sac tumor at the left uterosacral ligament was microscopically diagnosed as invasive endometrioid carcinoma arising from deep infiltrating endometriosis. The final diagnosis was primary stage IIB peritoneal carcinoma. The patient received six courses of monthly paclitaxel and carboplatin as adjuvant chemotherapy. The patient showed no evidence of recurrence for 2 years after the treatments.ConclusionThis study reports a rare case of metachronous endometriosis-related malignancy that developed 6 years after treatment for borderline ovarian tumor. If endometriosis lesions remain after bilateral salpingo-oophorectomy, the physician should keep the malignant nature of endometriosis in mind.

A Comparative Analysis of Immunohistochemical Profile of Primary and Metastatic Endometrial Endometrioid Carcinoma

Abstract Introduction/Objective Beta catenin plays an important role in cancer tumorigenesis and have been found to be associated with metastasis in a variety of tumors. Analyzing TCGA data, we found that 30% of endometrial endometrioid carcinoma cases have beta-catenin mutations. We hypothesize that beta-catenin mutation may be associated with metastasis of endometrial endometrioid carcinoma. ER and PR expression was also compared to determine any changes after metastasis. Methods Retrospective institutional review of all endometrial endometrioid carcinoma (192 cases) between 2011 to 2018 was performed, including 149 cases of FIGO grade I, 38 cases of FIGO grade II and 5 cases of FIGO grade III. 19 cases with paired primary and metastatic specimen were identified. Immunohistochemistry staining (IHC) was carried out for ER, PR and beta-catenin. Results Median patient age was 56 years. The most common metastatic site was vagina, accounting for 68% of metastasis (14/19), followed by bladder (3/19), lung (2/19) and rectum (1/19). The primary and metastatic carcinoma of all 19 cases exhibit very similar morphology. All of those cases were positive and concordant for ER and PR in primary and metastatic endometrioid carcinoma. On the other hand, nuclear beta-catenin staining caused by mutation was positive in 5 metastatic carcinoma but not in primary carcinoma. Conclusion IHC expression of ER and PR remains unchanged between primary and metastatic carcinoma, demonstrating the reliability of ER and PR to confirm the origin of metastatic carcinoma. 26% of the metastatic carcinoma (5/19) exhibit nuclear beta-catenin staining but not in primary carcinoma, suggesting the possible role of beta-catenin in metastasis of endometrial endometrioid carcinoma.

Colorectal Carcinoma Presenting as Ovarian Metastasis: A Case Report

There is a common occurrence of colorectal adenocarcinoma metastasis to the ovary and in rare circumstances, these cases may present clinically as primary ovarian cancer and histologically as primary endometrioid carcinoma of the ovary. Approximately 3.6% to 7.4% of patients with colon cancer have ovarian metastasis at the time of initial presentation, of which, 45% are mistaken for primary ovarian tumors. The author reports the case of a 60-year-old female presenting with fatigue and pelvic pain secondary to a pelvic mass. Computed tomography (CT) revealed a lobulated, heterogeneous pelvic mass measuring 11.1 × 10.5 × 9.8 cm, and ultrasound (US) showed complex 13.8 × 8.2 × 12.3 cm mass posterior to the uterus. Upon examination of the specimen following debulking procedure, endometrioid carcinoma of the ovaries was initially considered. However, immunohistochemical stains were performed and showed malignant cells positive for cytokeratin (CK) 20, caudal type homeobox (CDX) 2, and specific AT-rich sequence binding (SATB) protein 2, consistent with metastatic colorectal carcinoma. This report highlights the diagnostic challenges arising with differentiation between primary endometrioid ovarian carcinoma and metastatic colorectal adenocarcinoma to the ovary and the potential clinical consequences of misdiagnosis.

Isolated primary endometrioid carcinoma of the ovary an unusual case of malignancy

Endometrioid tumors tend to be malignant in most cases and accounts for roughly 20.0% of all cases of ovarian cancer. This form of ovarian epithelial carcinoma tends to simulate atypical endometrial glands. As the tumor grows, it infiltrates into the surrounding tissues and organs, allowing the tumor to feed with greater ease and become more solid. Survival after the appearance of an endometrioid tumor of the ovary depends upon the stage and grade of the tumor at the time of diagnosis and the treatment modality followed. Because of the high possibility of malignancy, aggressive chemotherapeutic regimen and possibly extensive surgery should commence as soon as possible. If the tumor is diagnosed early and successfully treated, patients have a five-year survival rate of 75.0%. We report an unusual case of isolated primary endometrioid carcinoma of the ovary in a 55-year-old woman, who presented with dull aching pain and lump in the right lower abdomen for the last 3 months. Keywords: Endometrioid carcinoma, Ovary, Histopathology, Immunohistochemistry.

Analysis of mutational signatures in primary and metastatic endometrial cancer reveals distinct patterns of DNA repair defects and shifts during tumor progression

ObjectiveMutational signatures provide insights into the biological processes shaping tumor genomes and may inform patient therapy. We sought to define the mutational signatures of i) endometrioid and serous endometrial carcinomas (ECs), stratified into the four molecular subtypes, ii) uterine carcinosarcomas, and iii) matched primary and metastatic ECs. MethodsWhole-exome sequencing MC3 data from primary endometrioid and serous carcinomas (n = 232) and uterine carcinosarcomas (n = 57) from The Cancer Genome Atlas (TCGA), and matched primary and metastatic ECs (n = 61, 26 patients) were reanalyzed, subjected to mutational signature analysis using deconstructSigs, and correlated with clinicopathologic and genomic data. ResultsPOLE (ultramutated) and MSI (hypermutated) molecular subtypes displayed dominant mutational signatures associated with POLE mutations (15/17 cases) and microsatellite instability (55/65 cases), respectively. Most endometrioid and serous carcinomas of copy-number low (endometrioid) and copy-number high (serous-like) molecular subtypes, and carcinosarcomas displayed a dominant aging-associated signature 1. Only 15% (9/60) of copy-number high (serous-like) ECs had a dominant signature 3 (homologous recombination DNA repair deficiency (HRD)-related), a prevalence significantly lower than that found in high-grade serous ovarian carcinomas (54%, p < 0.001) or basal-like breast cancers (46%, p < 0.001). Shifts from aging- or POLE- to MSI-related mutational processes were observed in the progression from primary to metastatic ECs in a subset of cases. ConclusionsThe mutational processes underpinning ECs vary even among tumors of the same TCGA molecular subtype and in the progression from primary to metastatic ECs. Only a minority of copy-number high (serous-like) ECs display genomics features of HRD and would likely benefit from HRD-directed therapies.

285 An Uncommon Presentation of Extragenital Carcinosarcoma

Carcinosarcoma, or malignant mixed Müllerian tumor, comprises less than 5% of all uterine malignancies. It is extremely uncommon to diagnose carcinosarcoma outside of the genital tract. Here, we present a 56-year-old woman who was being evaluated for an endometrial polyp. Endometrial curettage was performed. Microscopy showed fragments of an endometrial polyp with focal well differentiated endometrioid endometrial carcinoma, arising in a background of complex endometrial hyperplasia with atypia. She then underwent a total hysterectomy with bilateral salpingo-oophorectomy. Histological evaluation revealed a well differentiated endometrioid adenocarcinoma limited to the endometrium, with no protrusion into the uterine wall, extension into the adnexae, or lymphovascular invasion. At nine months status post total hysterectomy, the patient presented to her clinician with new onset vaginal bleeding, rectal bleeding. Radiological investigations revealed two 7 cm pelvic masses. Biopsy of the mass revealed highly atypical glands in a desmoplastic stroma and necrosis with features consistent with adenocarcinoma of Müllerian origin. Given the recent history of endometrial adenocarcinoma, the mass was suspected to have an endometrial origin. An exploratory laparotomy with resection of the pelvic mass, omentectomy, pelvic and para-aortic lymphadenectomies, low anterior bowel resection, ileo-cecectomy, partial vaginectomy, and left parametrial resection was performed. Histological evaluation demonstrated a fragmented carcinosarcoma; the carcinomatous component comprised predominantly endometrioid carcinoma and the sarcomatous component comprised endometrial stromal sarcoma. All lymph nodes were negative for malignancy. Immunohistochemical studies confirmed the morphological findings. Extensive sampling of the mass also showed foci of endometriosis. We present this case to highlight that a high index of suspicion and attention to morphologic details are paramount to arrive at an accurate diagnosis. It is most likely that the carcinosarcoma arose from the endometriosis rather than metastatic deposits from the previously known primary endometrioid carcinoma.

Synchronous Primary Ovarian Mucinous Carcinoma and Endometrioid Endometrial Carcinoma : A rare case report.

Introduction: Synchronous tumours of female genital tract are a rare . The most common organs involved are ovary and endometrium. Endometrioid carcinoma is the most common malignancy detected in majority of cases . Synchronous cancers with dissimilar histology are a very rare phenomenon . We report a case of 51 year old lady with synchronous primary mucinous carcinoma of ovary and primary endometrioid endometrial carcinoma . Case report: a 51 year old lady presented with post menopausal bleeding and foul smelling vaginal discharge of 1 month duration . Her CA125 was elevated. Magnetic resonance imaging showed increased endometrial thickness and a12.5x10x9.3cm mass in the fundus of uterus suggestive of a leiomyoma along with and a 13.8x11.5x11cm mass in the left adnexa. Endometrial aspiration done showed Complex Hyperplasia with Atypia. Total abdominal hysterctomy and bilateral salphingoophorectomy along with lymphnode sampling was performed . The adnexal mass was pT1a pN0 cM0 grade 2 invasive mucinous carcinoma. The endometrial lesion was pT1b pN0 cM0 FIGO grade 2 endometrioid endometrial adenocarcinoma. Conclusion : Synchronous ovarian tumours of dissimilar histology is extremely rare and there are only a few reports of ovarian mucinous carcinoma with endometrioid endometrial carcinoma. DOI: 10.21276/APALM.1295

Follicular Lymphoma mimicking Metastatic Nodes on the F-18 FDG PET/CT and MRI for Staging of Endometrial Cancer.

A 53-year-old woman was diagnosed with endometrial carcinoma by vaginal bleeding. F-18 fluorodeoxy glucose positron emission tomography PET/CT (F-18 FDG PET/CT) scan for staging showed intense focal FDG uptake in the endometrium suggesting endometrial malignancy. PET/CT showed multiple node uptakes in the pericaval region, paraaortic region, common iliac, and both internal iliac and external iliac regions suggesting multiple pelvic and retroperitoneal node metastases. MRI showed multiple metastatic lymphadenopathy in the retroperitoneum and pelvic cavity. Pathologic diagnosis performed with dissected pelvic and paraaortic nodes was confirmed as a follicular malignant lymphoma positive for B-cell lymphoma-2(Bcl-2) stain, not the metastatic node of primary endometrioid carcinoma.

The antitumor effect of metformin with and without carboplatin on primary endometrioid endometrial carcinoma in vivo

ObjectivesNew treatment options for advanced and recurrent endometrial carcinoma (EC) are necessary. Epidemiological studies showed that diabetic patients using metformin have reduced risks of endometrial cancer (EC) incidence. Moreover, pre- and clinical studies demonstrated an antitumor effect by metformin, with and without additional treatments, for different solid malignancies. However, cancer cell-autonomous effects of metformin on EC have not been fully characterized yet. The aim of this study was to investigate the effect of metformin, with or without carboplatin, on patient-derived primary endometrioid EC cells xenografted in nude mice, to assess its ability to reduce or impair growth in already established tumors. MethodsTwo xenograft models were established by subcutaneous inoculation of primary endometrioid EC cell suspensions. Tumors were allowed to grow and then mice were treated with metformin (250mg/kg, daily, p.o.), carboplatin (50mg/kg, 1×/week, i.p.), or the combination of both compounds at the same concentration as single treatment, for three weeks. Effects of metformin treatment on the tumor mass were determined by tumor growth follow-up. Metformin influences on AMPK/mTOR cell signaling were evaluated by investigating AKT, AMPK and S6 phosphorylation levels. ResultsIn vivo, metformin did not affect the growth of EC tumors established from patient-derived primary cultures and the phosphorylation of AKT, AMPK and S6. In addition, no enhanced antitumor effect was determined by combining metformin and carboplatin treatments. ConclusionsMetformin, at clinically relevant concentrations, did not show effects on the growth of already established tumors. Adding metformin to carboplatin did not have synergistic effects.

Dual blockade of PI3K/AKT/mTOR (NVP-BEZ235) and Ras/Raf/MEK (AZD6244) pathways synergistically inhibit growth of primary endometrioid endometrial carcinoma cultures, whereas NVP-BEZ235 reduces tumor growth in the corresponding xenograft models

ObjectivesEndometrial carcinoma (EC) is the most common gynecological cancer in the Western World. Treatment options are limited for advanced and recurrent disease. Therefore, new treatment options are necessary. Inhibition of the PI3K/AKT/mTOR and/or the Ras/Raf/MEK pathways is suggested to be clinically relevant. However, the knowledge about the effect of combination targeted therapy in EC is limited. The aim of this study was to investigate the effect of these therapies on primary endometrioid EC cell cultures in vitro and in vivo. MethodsPrimary endometrioid EC cell cultures were incubated with Temsirolimus (mTORC1 inhibitor), NVP-BKM120 (pan-PI3K inhibitor), NVP-BEZ235 (pan-PI3K/mTOR inhibitor), or AZD6244 (MEK1/2 inhibitor) as single treatment. In vitro, the effect of NVP-BEZ235 with or without AZD6244 was determined for cell viability, cell cycle arrest, apoptosis induction, and cell signaling. In vivo, the effect of NVP-BEZ35 was investigated for 2 subcutaneous xenograft models of the corresponding primary cultures. ResultsNVP-BEZ235 was the most potent PI3K/AKT/mTOR pathway inhibitor. NVP-BEZ235 and AZD6244 reduced cell viability and induced cell cycle arrest and apoptosis, by reduction of p-AKT, p-S6, and p-ERK levels. Combination treatment showed a synergistic effect. In vivo, NVP-BEZ235 reduced tumor growth and inhibited p-S6 expression. The effects of the compounds were independent of the mutation profile of the cell cultures used. ConclusionsA synergistic antitumor effect was shown for NVP-BEZ235 and AZD6244 in primary endometrioid EC cells in vitro. In addition, NVP-BEZ235 induced reduction of tumor growth in vivo. Therefore, targeted therapies seem an interesting strategy to further evaluate in clinical trials.

Target-Enriched Next-Generation Sequencing Reveals Differences between Primary and Secondary Ovarian Tumors in Formalin-Fixed, Paraffin-Embedded Tissue

Differentiating primary endometrioid or mucinous ovarian tumors from secondary ovarian tumors can be challenging. We compared somatic mutation profiles of primary and secondary ovarian cancers to investigate if these profiles can help diagnose ovarian tumors. Cancer-related genes (n = 115) were screened by target-enriched next-generation sequencing in formalin-fixed, paraffin-embedded tumor tissue from 43 primary endometrioid and mucinous ovarian carcinomas and 28 proven colorectal cancer metastases to the ovary. Results were validated by high-resolution melting curve analysis and Sanger sequencing. TP53, NOTCH1, PIK3CA, and FAT4 versus APC, TP53, KRAS, and FAT4 mutations were the most common in the primary ovarian tumors and ovarian colorectal cancer metastases, respectively. An inactivating APC mutation was found in 4.7% of primary ovarian tumors (2 of 43; 95% CI, 1.6%-10.9%). In contrast, inactivating APC mutations were identified in 71% of colorectal cancer metastases (20 of 28; 95% CI, 55%-88%) (P < 0.001; sensitivity: 71.4%, 95% CI, 51.1%-86.0%; specificity: 95.4%, 95% CI, 82.9%-99.1%). Loss of heterozygosity and APC promoter hypermethylation did not differ significantly between the primary and secondary ovarian tumors. NOTCH1 mutations were observed specifically in primary ovarian tumors, although at a low frequency, but not in metastases (6 of 41; 14.6%; 95% CI, 3.8%-25.4%). APC mutation analysis can be used to differentiate primary endometrioid and mucinous ovarian tumors from colorectal cancer metastases to the ovary.

Stromal signatures in endometrioid endometrial carcinomas

The pattern of myometrial invasion in endometrioid endometrial carcinomas varies considerably; ie, from widely scattered glands and cell nests, often associated with a fibromyxoid stromal reaction (desmoplasia) and/or a lymphocytic infiltrate, to invasive glands with little or no stromal response. Recently, two distinct stromal signatures derived from a macrophage response (colony-stimulating factor 1, CSF1) and a fibroblastic response (desmoid-type fibromatosis, DTF) were identified in breast carcinomas and correlated with clinicopathologic features including outcome. In this study, we explored whether these stromal signatures also apply to endometrioid carcinomas and how their expression patterns correlated with morphologic changes. We studied the stromal signatures both by immunohistochemistry and in situ hybridization in 98 primary endometrioid carcinomas with (87 cases) and without (11 cases) myometrial invasion as well as in the corresponding regional lymph nodes metatases of 9 myoinvasive tumors. Desmoplasia correlated positively with the DTF expression signature. Likewise, mononuclear infiltrates were found in the stroma of tumors expressing CSF1. Twenty-four out of eighty-seven (27%) myoinvasive endometrioid carcinomas were positive for the macrophage signature and thirteen out of eighty-seven (15%) expressed the fibroblast signature. Eleven additional cases were positive for both DTF and CSF1 signatures (11/87; 13%). However, over half of the cases (39/87; 45%) and the majority of the non-myoinvasive tumors (8/11; 73%) failed to express any of the two stromal signatures. The macrophage response (CSF1) was associated with higher tumor grade, lymphovascular invasion, and PIK3CA mutations (P<0.05). There was a concordance in the expression of the CSF1 signature in the primary tumors and their corresponding lymph node metastases. This study is the first characterization of stromal signatures in endometrioid carcinomas. Our findings shed new light on the relationship between genetically different endometrioid carcinomas and various stromal responses. Preservation of the CSF1 macrophage stromal response in the metastases leds support to targeting the CSF1 pathway in endometrioid endometrial carcinomas.

Primary Endometrioid Carcinoma of the Broad Ligament: A Rare Case Report

Although secondary involvement of the broad ligament by malignant tumours arising elsewhere in the abdomen is common, primary tumours in this location are rare. Most neoplasms in this region whether benign or malignant usually present clinically with vague symptoms and are often discovered either during a routine gynaecological examination or on abdominal exploration because of the presence of a pelvic mass and vague lower abdominal discomfort or pain [1]. The present case which was diagnosed clinically as left ovarian tumour and histopathologically as endometrioid carcinoma of the broad ligament is reported for its rarity and for the unique histological finding of transitional cell differentiation associated with the primary tumour.

AURKA and BRCA2 expression highly correlate with prognosis of endometrioid ovarian carcinoma

Aurora kinase A (AURKA), a serine/threonine kinase, has been shown to regulate the cell cycle checkpoint and maintain genomic integrity. AURKA is overexpressed in various carcinomas. Breast cancer 2, early onset (BRCA2) has an important role in maintaining genomic stability and acts as a tumor suppressor. Our recent study suggested that AURKA regulates genomic instability and tumorigenesis through cell cycle dysregulation and suppression of BRCA2 expression. However, the expression of AURKA, BRCA2 and their clinical significance is unknown in endometrioid ovarian cancer. In this study, we determined AURKA and BRCA2 expression in endometrioid ovarian carcinoma and correlated them with clinicopathologic characteristics and patient survival. Immunohistochemical staining was performed in 51 primary endometrioid ovarian carcinoma tumor samples, using tissue microarray. We then analyzed the associations between AURKA and BRCA2 expression and clinical factors (tumor grade, disease stage, surgical type, clinical response, and relapse) and overall and disease-free survival durations. AURKA and BRCA2 expression were found in 48 and 29% of the samples, respectively. The results of Fisher's exact test suggested that AURKA expression was significantly associated with no family history of ovarian cancer (P=0.03) and that BRCA2 expression was associated with early-stage disease (P=0.03), low ascites incidence (P=0.03), younger age (<60) at diagnosis (P=0.03), and low-grade tumors (P<0.01). The nuclear BRCA2 score was negatively correlated with AURKA score (P=0.019, two-tailed Pearson correlation). A log-rank test demonstrated that AURKA expression was associated with shorter overall (P=0.001) and disease-free (P=0.009) survival durations, and that BRCA2 expression was associated with longer overall (P=0.000) and disease-free (P=0.002) durations. Patients with BRCA2-positive and AURKA-negative tumors had higher overall (P=0.001) and disease-free (P=0.001) survival rates than did patients with AURKA-positive and BRCA2-negative tumors. Our results demonstrate that a negative regulatory loop exists between AURKA and BRCA2 expression in the ovarian endometrioid carcinoma. AURKA expression is an unfavorable prognostic factor in patients with endometrioid ovarian cancer and BRCA2 is favorable, combination of these two markers may better predict the prognosis of patients with endometrioid ovarian carcinoma than individual marker alone.

Myometrial Invasion and Lymph Node Metastasis in Endometrioid Carcinomas: Tumor-associated Macrophages, Microvessel Density, and HIF1A Have a Crucial Role

Myometrial invasion is an independent prognostic parameter of the endometrioid carcinomas which correlates with the risk of metastasis to pelvic and/or paraaortic lymph nodes. Recognition of myometrial invasion is sometimes difficult. In fact, myoinvasion is overdiagnosed in routine practice in as many as 25% of the cases. Recently, it has been observed that tumor-associated macrophages stimulate angiogenesis and promote cancer dissemination. Tumor macrophages (CD163), microvessel density (CD31), and hypoxia inducible factor 1 α subunit (HIF1A) were investigated in 64 primary endometrioid carcinomas with (50 cases) and without (14 cases) myometrial invasion as well as in the corresponding regional lymph nodes metastases of 20 of the myoinvasive tumors. Endometrioid carcinomas with myometrial invasion showed higher number of CD163-tumor macrophages and greater microvessel density than endometrioid carcinomas without myometrial invasion (P=0.000 and P=0.000, respectively). In carcinomas confined to the corpus uteri (stage I), expression of HIF1A was associated with deep myoinvasion (stage IC) (P=0.006). There was a significant relationship between microvessel density and CD163-macrophages both in the myoinvasive and nonmyoinvasive tumors. On the other hand, high-grade endometrioid carcinomas had more macrophage infiltrates and microvessels than low-grade tumors (P=0.03 and P=0.07). Also, there was a positive correlation between CD163-macrophages and microvessel density in the primary tumors and their corresponding regional lymph node metastases. These findings link increased microvessel proliferation to stromal macrophage infiltrate and suggest that enhanced tumor angiogenesis, triggered by stromal macrophages, regulates the progression of endometrioid carcinomas. The identical stroma microenvironment found in the primary and the corresponding metastatic tumor suggests that tumor stroma response is determined by the intrinsic biology of the tumor.

The Association between Primary Endometrioid Carcinoma of the Ovary and Synchronous Malignancy of the Endometrium

Objective. Ovarian and endometrial cancers coincide rather frequently in the same patient. Few data are available on the involvement of the specific morphological subtypes. To identify histological pathways in the synchronous occurrence, a population-based study was performed in The Netherlands. Methods. Using the national pathology database (PALGA) information of ovarian cancers and of earlier or later cancer in the endometrium was obtained. 5366 Patients were identified with primary malignant epithelial or borderline malignancy. Results. In 157 cases (2.9%) a new primary malignancy in the endometrium was diagnosed (146 within 1 year). The ratio of observed versus expected number of synchronous malignancy in the endometrium was estimated at 3.6 (95% CI: 2.7–4.7). Among 460 ovarian endometrioid carcinoma patients 53 cases showed a second primary endometrial cancer; 40 out of these 53 cases (75.5%) showed at both organ sites an endometrioid adenocarcinoma. Conclusion. These findings suggest an important role for the endometrioid subtype and prompt to mechanism-based studies incorporating molecular techniques.

Overexpression of kallikrein 10 (hK10) in uterine serous papillary carcinomas

Kallikrein 10 is a secreted serine protease recently implicated in the growth and invasion of several human tumors. The goal of this study was to investigate the expression and secretion levels in vitro and in vivo of kallikrein 10 in uterine serous papillary carcinoma, a highly aggressive variant of endometrial tumor. Human kallikrein 10 gene expression levels were evaluated in 11 snap-frozen uterine serous papillary carcinoma biopsies and 6 normal endometrial cell biopsies by real-time polymerase chain reaction. Secretion of kallikrein 10 protein by 10 primary tumor cultures including 3 uterine serous papillary carcinomas, 2 endometrioid carcinomas, and 5 ovarian serous papillary tumors was measured using a sensitive ELISA. Finally, kallikrein 10 concentration in 75 serum and plasma samples from 22 healthy women, 20 women with benign diseases, 21 women with endometrioid carcinomas, and 12 uterine serous papillary carcinoma patients was studied. Kallikrein 10 gene expression levels were significantly higher in uterine serous papillary carcinoma when compared with normal endometrial cell biopsies (mean copy number by real time polymerase chain reaction = 743 versus 1.4; uterine serous papillary carcinoma versus endometrioid carcinoma: P < .02). In vitro kallikrein 10 secretion was detected in all primary uterine serous papillary carcinoma cell lines tested (mean = 2.7 microg/L), and the secretion levels were not significantly different to those found in primary ovarian serous papillary tumor cultures (mean 4.2 microg/L). In contrast, no kallikrein 10 secretion was detectable in primary endometrioid carcinomas. Kallikrein 10 serum and plasma concentrations (microg/L; mean +/- SEM) among normal healthy females (0.6 +/- 0.04), patients with benign diseases (0.6 +/- 0.06), and patients with endometrioid carcinomas (0.7 +/- 0.06) were not significantly different. In contrast, serum and plasma kallikrein 10 values in uterine serous papillary carcinoma patients (1.2 +/- 0.1) were significantly higher than those in the non-cancer group (P = .002), benign group (P = .002), and endometrioid carcinoma patients (P = .005). Kallikrein 10 is highly expressed in uterine serous papillary carcinoma, and it is released in the plasma and serum of uterine serous papillary carcinoma patients. Kallikrein 10 may represent a novel biomarker for uterine serous papillary carcinoma.