High-grade Endometrioid Carcinoma Research Articles

Immunohistochemical Expression of Cyclooxygenase-2 in endometrioid carcinoma

Background and objectives: Cyclooxygenase-2 functions as an enzyme which synthesize prostaglandins from Arachidonic acid Cyclooxygenase -2 is one of the important factors in maintaining the endometrium during menstrual cycle. The Aim of this study was to assess expression of Cyclooxygenase-2 in endometrioid carcinoma by immunohistochemistry to explore association between Cyclooxygenase-2 expression and a certain number of clinicopathologic variables. Methods: A retrospective study was carried out for seventy-eight blocks that were preseved in formalin and embedded in paraffin of endometrioid carcinoma were obtained and randomly selected from a private laboratory in Erbil city during October 2020 to October 2022. COX-2 rabbit monoclonal antibody was used to satin slides obtained from endometrioid carcinoma blocks and the expression was scored by multiplying the number of stained cells by the intensity of staining. Results: Cyclooxygenase-2 expressed in 15.4% of cases of study cases. It is down-expressed in high grade endometrioid carcinoma while over-expressed in cases with myometrial invasion ?50%. Regarding other clinicopathological parameters like, lymphovascular invasion, tumor stage and lymphnode status, Cyclooxygenase-2 showing down-expression, there is no existence of notable link between the expression of Cyclooxygenase-2 and clinicopathological parameters, including: Age(p=0.197), Tumor grade(p=0.069), Myometrial invasion(p=0.261), Lympho vascular invasion(p=0.516), Lymph node status(p=1000) and Tumor stage(p=0.872). Conclusion: Cyclooxygenase-2 is expressed in a limited number of endometrioid carcinoma and there is lack of significant association between Cyclooxygenase-2 expression and clinicopathological parameters

Molecular classification of ovarian high-grade serous/endometrioid carcinomas through multi-omics analysis: JGOG3025-TR2 study.

Considerable interobserver variability exists in diagnosis of ovarian high-grade endometrioid carcinoma (HGEC) and high-grade serous carcinoma (HGSC) due to histopathological similarities. While homologous recombination deficiency (HRD) correlates with drug sensitivity in HGSC, the molecular features of HGEC are unclear. Fresh-frozen samples from 15 ovarian HGECs and 274 ovarian HGSCs in the JGOG-TR2 cohort were submitted to targeted DNA sequencing, RNA sequencing, DNA methylation array, and SNP array. We additionally analyzed 555 ovarian HGSCs from TCGA-OV and 287 endometrial high-grade carcinomas from TCGA-UCEC. Unsupervised clustering using copy number signatures identified four distinct tumor groups (C1, C2, C3 and C4). C1 (n = 41) showed CCNE1 amplification and poor survival. C2 (n = 160) and C3 (n = 59) showed high BRCA1/2 alteration frequency with low and moderate ploidy, respectively. C4 (n = 22) was characterized by favorable outcome, higher HGEC proportion, no BRCA1/2 alteration or CCNE1 amplification, and low levels of HRD score, ploidy, intra-tumoral heterogeneity, cell proliferation rate, and WT1 gene expression. Notably, C4 exhibited a normal endometrium-like DNA methylation profile, thus, defined as "HGEC-type" tumors, which were also identified in TCGA-OV and TCGA-UCEC. Ovarian "HGEC-type" tumors present a non-HRD status, favorable prognosis, and endometrial differentiation, possibly constituting a subset of clinically diagnosed HGSCs.

High-grade endometrioid carcinoma in the abdominal wall after cesarean section—Case report and review of the literature

High-grade endometrioid carcinoma in the abdominal wall after cesarean section—Case report and review of the literature

Endometrial endometrioid adenocarcinoma with a malignant squamous component: is the unusual metastatic pattern unique of these tumors?

The FIGO scheme is currently applied for tumor grading of endometrioid adenocarcinoma. The current report presents a series of ten cases of endometrioid carcinomas that when applying the FIGO grading does not fully convey the true biological nature of the disease. The squamous component of these tumors is malignant; it constitutes the predominant invasive component, and it often metastasizes to unconventional sites. Half of the cohort developed distant disease recurrence within 2 years, even those with early-stage disease. Somatic mutations were analyzed, targeting 101 genes in all ten cases, and mutations in PTEN, MMR, PIK3CA, ATM, RB1, and TP53 genes were detected, often multiple mutations in the same case. None of the cases revealed unique molecular signatures or previously unreported gene mutations. Immunohistochemical staining for beta-catenin showed aberrant nuclear staining in eight of ten cases and remaining two showed cytoplasmic and membranous staining. Aggressive behavior and unusual sites of metastases are observed in this series even in low-grade tumor. The FIGO grading on smaller samples may be deceptive for these cases. Even if FIGO is applied, the pathology report should emphasize the malignant squamous component and its potential significance so that the gynecologic oncology team can formulate appropriate adjuvant treatment upfront. This case series argues that this histology should be regarded as a high-grade endometrioid carcinoma and can show unusual metastatic patterns. Further research is needed with more cases within this histologic subtype to guide recommendations on adjuvant therapies for this aggressive tumor type.

Complexity of the Genetic Background of Oncogenesis in Ovarian Cancer-Genetic Instability and Clinical Implications.

Ovarian cancer is a leading cause of death among women with gynecological cancers, and is often diagnosed at advanced stages, leading to poor outcomes. This review explores genetic aspects of high-grade serous, endometrioid, and clear-cell ovarian carcinomas, emphasizing personalized treatment approaches. Specific mutations such as TP53 in high-grade serous and BRAF/KRAS in low-grade serous carcinomas highlight the need for tailored therapies. Varying mutation prevalence across subtypes, including BRCA1/2, PTEN, PIK3CA, CTNNB1, and c-myc amplification, offers potential therapeutic targets. This review underscores TP53's pivotal role and advocates p53 immunohistochemical staining for mutational analysis. BRCA1/2 mutations' significance as genetic risk factors and their relevance in PARP inhibitor therapy are discussed, emphasizing the importance of genetic testing. This review also addresses the paradoxical better prognosis linked to KRAS and BRAF mutations in ovarian cancer. ARID1A, PIK3CA, and PTEN alterations in platinum resistance contribute to the genetic landscape. Therapeutic strategies, like restoring WT p53 function and exploring PI3K/AKT/mTOR inhibitors, are considered. The evolving understanding of genetic factors in ovarian carcinomas supports tailored therapeutic approaches based on individual tumor genetic profiles. Ongoing research shows promise for advancing personalized treatments and refining genetic testing in neoplastic diseases, including ovarian cancer. Clinical genetic screening tests can identify women at increased risk, guiding predictive cancer risk-reducing surgery.

Drug-Resistant Epithelial Ovarian Cancer: Current and Future Perspectives.

Epithelial ovarian cancer (EOC) is a complex disease with diverse histological subtypes, which, based on the aggressiveness and course of disease progression, have recently been broadly grouped into type I (low-grade serous, endometrioid, clear cell, and mucinous) and type II (high-grade serous, high-grade endometrioid, and undifferentiated carcinomas) categories. Despite substantial differences in pathogenesis, genetics, prognosis, and treatment response, clinical diagnosis and management of EOC remain similar across the subtypes. Debulking surgery combined with platinum-taxol-based chemotherapy serves as the initial treatment for High Grade Serous Ovarian Carcinoma (HGSOC), the most prevalent one, and for other subtypes, but most patients exhibit intrinsic or acquired resistance and recur in short duration. Targeted therapies, such as anti-angiogenics (e.g., bevacizumab) and PARP inhibitors (for BRCA-mutated cancers), offer some success, but therapy resistance, through various mechanisms, poses a significant challenge. This comprehensive chapter delves into emerging strategies to address these challenges, highlighting factors like aberrant miRNAs, metabolism, apoptosis evasion, cancer stem cells, and autophagy, which play pivotal roles in mediating resistance and disease relapse in EOC. Beyond standard treatments, the focus of this study extends to alternate targeted agents, including immunotherapies like checkpoint inhibitors, CAR T cells, and vaccines, as well as inhibitors targeting key oncogenic pathways in EOC. Additionally, this chapter covers disease classification, diagnosis, resistance pathways, standard treatments, and clinical data on various emerging approaches, and advocates for a nuanced and personalized approach tailored to individual subtypes and resistance mechanisms, aiming to enhance therapeutic outcomes across the spectrum of EOC subtypes.

High-grade Serous Carcinoma can Show Squamoid Morphology Mimicking True Squamous Differentiation.

Tubo-ovarian high-grade serous carcinoma (HG-SC) and ovarian endometrioid carcinoma (EC) can show overlapping morphologic features, such as glandular and solid patterns. The differential diagnosis of these subtypes is thus sometimes difficult. The existence of "squamous differentiation" tends to lead to a diagnosis of EC rather than HG-SC. We noticed that HG-SC can contain a "squamoid component," but its nature has been poorly investigated. This study was thus established to clarify the nature of this "squamoid component" in HG-SC by investigating its frequency and immunohistochemical features. We reviewed hematoxylin and eosin-stained slides of 237 primary untreated cases of tubo-ovarian HG-SC and identified 16 cases (6.7%) of HG-SC with "squamoid component." An immunohistochemical staining panel (CK5/6, CK14, CK903, p40, p63, WT1, ER, and PgR) was used to analyze all of these 16 cases. We also selected 14 cases of ovarian EC with "squamous differentiation" as a control. The "squamoid component" in HG-SC was completely p40-negative and showed significantly lower expression of CK5/6, CK14, CK903, and p63 than the "squamous differentiation" in EC. The immunophenotype of the "squamoid component" in HG-SC was concordant with the conventional HG-SC component (WT1-positive/ER-positive). Furthermore, all 16 tumors were confirmed to be truly "HG-SC" by the findings of aberrant p53 staining pattern and/or WT1/p16 positivity, and the lack of mismatch repair deficiency and POLE mutation. In conclusion, HG-SC can on rare occasions show a "squamoid component" mimicking "squamous differentiation." However, the "squamoid component" in HG-SC does not represent true "squamous differentiation." The "squamoid component" is one part of the morphologic spectrum of HG-SC, which should be interpreted carefully for the differential diagnosis of HG-SC and EC. An immunohistochemical panel including p40, p53, p16, and WT1 is a useful adjunct to achieve a correct diagnosis.

A phase II trial of palbociclib combined to letrozole after progression on second-line chemotherapy for women with ER/PR-positive high-grade serous or endometrioid ovarian, fallopian tube, or peritoneal cancer: LACOG 1018.

5514 Background: Treatment options for patients with high-grade ovarian serous (HGSC) or endometrioid carcinoma (HGEC) who progress after receiving chemotherapy for recurrence are limited. Methods: LACOG 1018, a phase II, single-arm, multicenter trial evaluated the efficacy of letrozole 2.5mg/day po continuously plus palbociclib 125mg/day po for 21 days in 28-day cycles in patients with histologically proven ovarian HGSC or HGEC, fallopian tube or peritoneal cancer who had progressed on prior chemotherapy for locoregional recurrence or metastatic disease (at least one platinum-based regimen). Patients had centrally confirmed ER and/or PR positivity (> 10% by immunohistochemistry) and ECOG PS 0-2. The primary endpoint was progression-free survival (PFS) at 12 weeks by RECIST 1.1. Secondary endpoints were overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR) and safety. Tumor evaluations were performed every 6 weeks until week 24. Sample size was calculated as 31 patients for the primary endpoint (90% power to detect a two-sided significance level of 5%, 45% PFS at 12 weeks) and 39 patients for secondary endpoints considering 10% drop-out. NCT03936270. Results: A total of 41 eligible patients were included in five Brazilian centers between Feb2020-Jan2022 (table). The PFS-week12 rate was 63.4% (95%CI 46.8 – 76.1). At the time of analysis (cut-off date Jan 18th, 2023) median follow-up was 18.1 months (95%CI 12.9 – 24.3), and 37 PFS events had occurred. Median PFS was 4.2 months (95%CI 2.7 – 5.5) and median OS was 13.4 months (95%CI 10.4 – 20.1). The ORR was 7.7% (N=3 PR) and the CBR was 71.8%. Treatment-related adverse event rates of any grade and grade 3-4 were 95.1 % and 51.2 %, respectively. Grade 3-4 neutropenia was reported in 17 (41.5%) patients, and febrile neutropenia in 1 (2.4%). Only one patient (2.4 %) discontinued the treatment due to toxicity. At the cut-off date, three patients remained on treatment. Conclusions: Palbociclib combined to letrozole demonstrated a significant efficacy in terms of PFS rate at 12 weeks (63.4%) and CBR (71.8%), with no new safety concerns in women with recurrent advanced and metastatic hormone receptor-positive ovarian cancer. These results warrant further investigation of palbociclib plus letrozole in high-grade ovarian cancer. Clinical trial information: NCT03936270 . [Table: see text]

An Expanded Series of Pilomatrix-like High-grade Endometrioid Carcinoma (PiMHEC), Including Both MMR Deficient and MMR Proficient Cases.

An Expanded Series of Pilomatrix-like High-grade Endometrioid Carcinoma (PiMHEC), Including Both MMR Deficient and MMR Proficient Cases.

Deregulated Metabolic Pathways in Ovarian Cancer: Cause and Consequence.

Ovarian cancers are tumors that originate from the different cells of the ovary and account for almost 4% of all the cancers in women globally. More than 30 types of tumors have been identified based on the cellular origins. Epithelial ovarian cancer (EOC) is the most common and lethal type of ovarian cancer which can be further divided into high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous carcinoma. Ovarian carcinogenesis has been long attributed to endometriosis which is a chronic inflammation of the reproductive tract leading to progressive accumulation of mutations. Due to the advent of multi-omics datasets, the consequences of somatic mutations and their role in altered tumor metabolism has been well elucidated. Several oncogenes and tumor suppressor genes have been implicated in the progression of ovarian cancer. In this review, we highlight the genetic alterations undergone by the key oncogenes and tumor suppressor genes responsible for the development of ovarian cancer. We also summarize the role of these oncogenes and tumor suppressor genes and their association with a deregulated network of fatty acid, glycolysis, tricarboxylic acid and amino acid metabolism in ovarian cancers. Identification of genomic and metabolic circuits will be useful in clinical stratification of patients with complex etiologies and in identifying drug targets for personalized therapies against cancer.

HER2 IHC Expression and Gene Amplification in p53-aberrant High-grade Endometrial Endometrioid Carcinoma Suggests That This Population May Benefit From HER2 Testing and Targeted Therapy.

Among gynecologic cancers, uterine serous carcinoma (USC) has been shown to be human epidermal growth factor receptor 2 (HER2) amplified and trastuzumab has been included in the recent National Comprehensive Cancer Network (NCCN) guidelines for treatment of advanced stage or recurrent USC with HER2 overexpression/amplification. There is limited literature suggesting that a subset of high-grade endometrioid carcinomas with aberrant p53 expression may also be HER2 amplified and these patients could benefit from the addition of targeted therapy. We identified 59 p53-aberrant (mismatch repair proficient) FIGO 3 endometrioid carcinomas of the uterus. HER2 immunohistochemistry was performed in all 59 tumors and HER2 fluorescence in situ hybridization (FISH) was performed in 52 of the 59 cases. Four of the 59 cases were HER2 3+ by immunohistochemistry (6.7%), using the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2007, 2013, and 2018 criteria. HER2 FISH was performed in 3 of the 4 cases and was amplified in all 3. Nine, 8, and 7 tumors showed 2+ HER2 staining when applying 2018, 2013, and 2007 criteria, respectively, FISH was performed in 7 tumors and none were amplified. An additional 4 cases did not perfectly meet the 2018 ASCO/CAP criteria but were assigned a score of 2+, none were amplified by HER2 FISH. The remaining 42 cases showed 1+ or no staining for HER2, FISH was successfully performed in 38 tumors and none showed amplification. Approximately half of the tumors fulfilled criteria for HER2-low or HER2-very low (10 HER2-low and 20 HER2-very low). Our data shows that a subset of p53-aberrant high-grade endometrial endometrioid carcinoma express HER2 and these patients may benefit from the addition of targeted therapy. The role of targeted therapy in HER2-low gynecologic carcinoma is currently unexplored.

Investigating the suitability of in vitro cell lines as models for the major subtypes of epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most fatal gynaecological malignancy, accounting for over 200,000 deaths worldwide per year. EOC is a highly heterogeneous disease, classified into five major histological subtypes-high-grade serous (HGSOC), clear cell (CCOC), endometrioid (ENOC), mucinous (MOC) and low-grade serous (LGSOC) ovarian carcinomas. Classification of EOCs is clinically beneficial, as the various subtypes respond differently to chemotherapy and have distinct prognoses. Cell lines are often used as in vitro models for cancer, allowing researchers to explore pathophysiology in a relatively cheap and easy to manipulate system. However, most studies that make use of EOC cell lines fail to recognize the importance of subtype. Furthermore, the similarity of cell lines to their cognate primary tumors is often ignored. Identification of cell lines with high molecular similarity to primary tumors is needed in order to better guide pre-clinical EOC research and to improve development of targeted therapeutics and diagnostics for each distinctive subtype. This study aims to generate a reference dataset of cell lines representative of the major EOC subtypes. We found that non-negative matrix factorization (NMF) optimally clustered fifty-six cell lines into five groups, putatively corresponding to each of the five EOC subtypes. These clusters validated previous histological groupings, while also classifying other previously unannotated cell lines. We analysed the mutational and copy number landscapes of these lines to investigate whether they harboured the characteristic genomic alterations of each subtype. Finally we compared the gene expression profiles of cell lines with 93 primary tumor samples stratified by subtype, to identify lines with the highest molecular similarity to HGSOC, CCOC, ENOC, and MOC. In summary, we examined the molecular features of both EOC cell lines and primary tumors of multiple subtypes. We recommend a reference set of cell lines most suited to represent four different subtypes of EOC for both in silico and in vitro studies. We also identify lines displaying poor overall molecular similarity to EOC tumors, which we argue should be avoided in pre-clinical studies. Ultimately, our work emphasizes the importance of choosing suitable cell line models to maximise clinical relevance of experiments.

Impact of neoadjuvant chemotherapy duration on the survival of patients with advanced stage high-grade serous or endometrioid ovarian carcinoma (359)

Impact of neoadjuvant chemotherapy duration on the survival of patients with advanced stage high-grade serous or endometrioid ovarian carcinoma (359)

Overall survival in endometrial cancer in women with ovarian conservation surgery (484)

Objectives: To compare overall survival (OS) in women with endometrial cancer who received hysterectomies with and without oophorectomies. Methods: Data were obtained from the Surveillance, Epidemiology, and End Results Program (SEER) Research Plus dataset. The sample included endometrial cancer women aged 18 and above diagnosed between 2014 to 2018 (n=52,680) who had hysterectomies with oophorectomies (ovary removed) and without oophorectomies (ovary retained). Histology of endometrial cancer included low-grade and high-grade endometrioid carcinoma, papillary serous carcinoma, clear cell carcinoma, carcinosarcoma, and mixed type. Kaplan-Meier curves, log-rank comparisons, and Cox regression analyses were used to evaluate OS. Results: There were 97.4% patients (n=51,324) who had oophorectomies while 2.6% (n=1,356) did not. Mean age was 62.7 years; the majority were White (79.6%, n=41,941), stage I (78.8%, n=41,496), and endometrioid type (78.1%, n=41,142). Adjuvant therapies were radiation (28.3%, n=14,893), chemotherapy (22.6%, n=11,930), and combined radiation/chemotherapy (12.5%, n=6,598). There were 5,051 deaths (9.6%) among which 119 deaths (0.2%) were in the ovary retained group while 4,943 deaths (9.4%) were in the ovary removed group. In the whole sample, OS did not differ between the two groups (p=0.14). In those with late-stage endometrial cancer (stages III and IV), there were lower hazards for OS (HR:0.75, 95% CI: 0.58-0.97, p=0.03) in the ovary removed group. In those with early-stage endometrial cancer (stages I and II), the OS did not differ between the two groups (p=0.21). Conclusions: Oophorectomy in late-stage endometrial cancer patients who received hysterectomy was associated with improved OS. However, oophorectomy in early-stage endometrial cancer patients was not associated with improved OS. Fertility-sparing surgery may be considered for those in early-stage endometrial cancer who desire to preserve ovary function. Further studies are needed to confirm when oophorectomy is indicated in endometrial cancer patients with ovarian activity. Objectives: To compare overall survival (OS) in women with endometrial cancer who received hysterectomies with and without oophorectomies. Methods: Data were obtained from the Surveillance, Epidemiology, and End Results Program (SEER) Research Plus dataset. The sample included endometrial cancer women aged 18 and above diagnosed between 2014 to 2018 (n=52,680) who had hysterectomies with oophorectomies (ovary removed) and without oophorectomies (ovary retained). Histology of endometrial cancer included low-grade and high-grade endometrioid carcinoma, papillary serous carcinoma, clear cell carcinoma, carcinosarcoma, and mixed type. Kaplan-Meier curves, log-rank comparisons, and Cox regression analyses were used to evaluate OS. Results: There were 97.4% patients (n=51,324) who had oophorectomies while 2.6% (n=1,356) did not. Mean age was 62.7 years; the majority were White (79.6%, n=41,941), stage I (78.8%, n=41,496), and endometrioid type (78.1%, n=41,142). Adjuvant therapies were radiation (28.3%, n=14,893), chemotherapy (22.6%, n=11,930), and combined radiation/chemotherapy (12.5%, n=6,598). There were 5,051 deaths (9.6%) among which 119 deaths (0.2%) were in the ovary retained group while 4,943 deaths (9.4%) were in the ovary removed group. In the whole sample, OS did not differ between the two groups (p=0.14). In those with late-stage endometrial cancer (stages III and IV), there were lower hazards for OS (HR:0.75, 95% CI: 0.58-0.97, p=0.03) in the ovary removed group. In those with early-stage endometrial cancer (stages I and II), the OS did not differ between the two groups (p=0.21). Conclusions: Oophorectomy in late-stage endometrial cancer patients who received hysterectomy was associated with improved OS. However, oophorectomy in early-stage endometrial cancer patients was not associated with improved OS. Fertility-sparing surgery may be considered for those in early-stage endometrial cancer who desire to preserve ovary function. Further studies are needed to confirm when oophorectomy is indicated in endometrial cancer patients with ovarian activity.

The role of socioeconomic status in mediating Black-White racial disparities in endometrial cancer incidence and survival (421)

The role of socioeconomic status in mediating Black-White racial disparities in endometrial cancer incidence and survival (421)

Discovery of novel RNA transcripts for endometrial cancer with copy-number high alterations using pan-cancer analysis of whole genomes (PCAWG) endometrial cancer dataset (275)

<b>Objectives:</b> Uterine serous carcinoma is an aggressive type of endometrial cancer that has a propensity for metastatic spread and disproportionately affects Black women. Several new drugs are being evaluated in clinical trials for uterine serous carcinoma, including trastuzumab, pembrolizumab - lenvatinib combination, and adavosertib. However, additional treatment options are greatly needed. The Cancer Genome Atlas (TCGA) endometrial cancer project has shown that endometrial cancer can be broadly divided into four molecular classifications. Within the four molecular subtypes, the copy-number high group consists of high-grade endometrioid carcinoma and uterine serous carcinoma, which are characterized by frequent <i>TP53</i> mutation and somatic copy number alterations. To better understand the biology of this aggressive subset of endometrial cancer, we have performed bioinformatic analysis using the dataset from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and TCGA. <b>Methods:</b> To better understand the biology of uterine serous carcinoma, we sought to identify novel or poorly characterized genes using the PCAWG dataset. We analyzed the RNA sequencing data from the TCGA endometrial cancer dataset, focusing on the copy-number high group. Genes that are highly expressed in the copy-number high endometrial cancer were identified by comparing the gene expression profiles between the copy-number high endometrial cancer dataset to genes expressed in normal endometrium obtained from the PCAWG project. Survival outcomes for genes of interest were evaluated using Kaplan-Meier Plotter, containing survival data extracted from the TCGA endometrial cancer dataset. <b>Results:</b> RNA transcripts that were significantly upregulated in copy-number high endometrial cancer were identified. Three of the most significantly upregulated transcripts were claudin-6 (<i>CLDN6</i>), cancer-testis antigen <i>MAGEA9B</i>, and long non-coding RNA <i>LINC01833</i>. Kaplan-Meier analysis of overall survival showed that high <i>CLDN6</i> expression was associated with worse overall survival when compared to low <i>CLDN6</i> expression (HR: 2.04 in White patients, p=0.0037; HR: 7.35 in Black patients, p=0.0002). High expression of <i>MAGEA9B</i> was also associated with worse overall survival than low <i>MAGEA9B</i> expression (HR: 1.78 in White patients, p=0.022; HR: 5.69 in Black patients, p=0.000033). In contrast, high expression of long non-coding RNA <i>LINC02159</i> was not associated with significant alteration in overall survival (HR: 1.28 in White patients, p=0.34, HR: 0.52 in Black patients, p=0.17). <b>Conclusions:</b> Integrated genomic analysis of the TCGA endometrial cancer dataset led to the identification of several novels, previously uncharacterized RNA transcripts that are associated with poor prognosis in copy-number high endometrial cancer. Further characterization of these transcripts in uterine serous carcinoma will improve our understanding of the biology of this disease and lead to novel therapeutic options.

Clinical implications of tumor-based next-generation sequencing in ovarian cancer.

5545 Background: Epithelial ovarian cancer is genetically heterogeneous, both among and within histologic subtypes. Advances in next-generation sequencing have made it feasible to ascertain the somatic genetic signature of each patient, however, critical analysis of population-level sequencing results is required to maximize the potential of this technology. Here, we aimed to assess the clinical relevance of tumor-based next-generation sequencing (tbNGS) in a large cohort of patients with high-grade epithelial ovarian cancer. Methods: Our study population comprised patients with high-grade serous (n = 972), clear cell (n = 33), endometrioid (n = 28), mucinous (n = 4), and mixed (n = 34) or unspecified (n = 21) epithelial ovarian carcinoma diagnosed between April 2013 and September 2021. tbNGS results were identified within the electronic medical record using optical character recognition and natural language processing. Genetic, clinical, and demographic information was collected for patients who had undergone tbNGS. Progression-free survival (PFS) and overall survival (OS) were calculated from date of first treatment to date of first recurrence and date of death, respectively. Data were analyzed using descriptive statistics, univariate and multivariate Cox regression models, and clustering analyses. Results: Of 1092 patients in the described population, 409 (37.5%) had tbNGS results identified. Nearly all (96.1%) revealed one or more genetic aberrations. Most patients (74.6%) had an actionable mutation, defined as relaying eligibility for a targeted treatment or clinical trial. The most frequent alterations were TP53, PIK3CA, and NF1 mutations; and CCNE1 amplification. Ten different targeted institutional and commercial panels were employed, covering a range of 35 to 600+ gene loci. The median time from diagnosis to testing was 14.5 months, likely corresponding to time of recurrence. Though no standalone alterations were significantly related to survival, multivariate and clustering analyses identified several genetic patterns which corresponded to patient outcomes. Mutation of BRAF, PIK3R1, NOTCH3, MET, and/or ATR was correlated with shorter PFS (HR 1.84, p = 0.001); mutation of ATM, RB1, CDKN2A, FGFR1, and/or FGFR2 was associated with improved PFS (HR 0.64, p = 0.04), as was mutation of NBN and/or ATRX (HR 0.54, p &lt; 0.05). MYC, NOTCH3, and/or CREBBP mutations were significantly correlated with worse OS (HR 1.95, p = 0.02). In our population, 40 patients (9.78%) were enrolled in genotypically-relevant clinical trials. Conclusions: tbNGS is prevalent at our institution, and often yields actionable information. We identified several mutational patterns that correlate to patient survival. Detailed analysis of population-level tumor genomics may help to identify therapeutic targets and guide development of clinical decision support tools.

Clinical analysis of 23 cases with simultaneous double primary gynecological malignant tumors

Objective: To investigate the clinicopathological features, diagnosis, treatment and prognosis of simultaneous double primary gynecological malignant tumors. Methods: A total of 23 patients with simultaneous double primary malignant tumors of female reproductive system primarily treated in Beijing Obstetrics and Gynecology Hospital, Capital Medical University from January 1, 2010 to December 31, 2020 were retrospectively collected. The age, symptoms, tumor stage, tumor type, treatment and prognosis of patients were collected and followed up. Results: (1) The number of patients with gynecological tumors in our hospital increased year by year in the past 11 years. A total of 8 987 patients with gynecological malignant tumors were firstly diagnosed and cured in our hospital, including 3 474 cases of cervical cancer, 3 484 cases of endometrial cancer, 1 329 cases of ovarian malignancies, 171 cases of fallopian tube cancer, 182 cases of uterine sarcoma, 42 cases of vaginal cancer, 192 cases of vulvar cancer, 110 cases of trophoblastic tumor and 3 cases of other gynecological malignancies. The top three cancers were endometrial cancer, cervical cancer and ovarian malignancies. (2) There were 23 patients identified with simultaneous double primary gynecological tumors in the past 11 years, accounting for 0.26% (23/8 987) of female malignant tumors. There were 3 cases of cervical cancer complicated with endometrial cancer, 3 cases of cervical cancer complicated with ovarian cancer, 16 cases of endometrial cancer combined with ovarian cancer, and 1 patient with endometrial cancer combined with fallopian tube cancer. (3) All 23 patients underwent surgical treatment. According to the first diagnosis of the tumor, the surgical methods included cervical cancer radical surgery, endometrial cancer staging surgery and ovarian cancer cytoreductive surgery. After operation, radiotherapy and chemotherapy were supplemented according to the results of pathological examination and tumor staging. (4) The age of 23 patients ranged from 28 to 66 years, with an average age of (49.4±9.7) years. All patients had vaginal bleeding or conscious pelvic mass as their main clinical manifestation. The clinical stage was found in 7 patients (30%, 7/23) with advanced gynecological cancer (stage Ⅲ-Ⅳ), and 16 patients (70%, 16/23) with early stage gynecological cancer (stage Ⅰ-Ⅱ). According to the nonspecific tumor markers, 13 patients (57%, 13/23) had elevated CA125 and CA199. (5) Among the 23 patients, 1 case was uncontrolled and 3 cases recurred during the follow-up period, and the sites of uncontrolled or recurred were all located in the abdominopelvic cavity. Three cases died. Among the 3 patients who died, 1 patient was an uncontrolled patient, whose tumor type was cervical adenosquamous cell carcinoma combined with ovarian clear cell adenocarcinoma. The overall survival time was 19 months with postoperative supplementary radiotherapy and chemotherapy. There were 2 recurrent patients, and the tumor types were endometrioid carcinoma complicated with high-grade serous ovarian carcinoma and ovarian endometrioid carcinoma, respectively. After surgery, all patients received supplementary chemotherapy and recurred 60 and 21 months after surgery, respectively, and the overall survival time was 78 and 28 months, respectively. Another patient recurred 43 months after surgery, and survived with tumor for 14 months after recurrence. The remaining 19 patients were tumor-free and were still being followed up. Conclusions: There are no specific markers for simultaneous double primary gynecological malignant tumors. The most common clinical symptoms are vaginal bleeding or pelvic mass. The treatment principle of simultaneous double primary gynecological malignant tumor is the same as that of single gynecological malignant tumor, but need to be taken into account the characteristics of two tumors. Surgery is the main treatment method, and radiotherapy and chemotherapy play an important auxiliary role. The prognosis of simultaneous double primary gynecological malignancies is related to the late stage of the two malignancies.

CTNNB1 -mutated High-grade Endometrioid Carcinoma With Extensive Squamous and Shadow Cell Differentiation Can Mimic Pilomatrix Carcinoma.

CTNNB1 -mutated High-grade Endometrioid Carcinoma With Extensive Squamous and Shadow Cell Differentiation Can Mimic Pilomatrix Carcinoma.

High-grade endometrial carcinomas: Morphologic spectrum and molecular classification.

High-grade endometrial carcinoma (HGEC) is a heterogeneous group of tumors with various morphologic, genetic, and clinical characteristics. Morphologically, HGEC includes high-grade endometrioid carcinoma, serous carcinoma, clear cell carcinoma, undifferentiated/dedifferentiated carcinoma, and carcinosarcoma. The morphologic classification has been used for prognostication and treatment decisions. However, patient management based on morphologic classification is limited by suboptimal interobserver reproducibility, variable clinical outcomes observed within the same histotype, and frequent discordant histotyping/grading between biopsy and hysterectomy specimens. Recent studies from The Cancer Genome Atlas (TCGA) Research Network established four distinct molecular subtypes: POLE-ultramutated, microsatellite unstable, copy number high, and copy number low groups. Compared to histotyping, the TCGA molecular classification appears superior in risk stratification. The best prognosis is seen in the POLE-ultramutated group and the worst in copy number high group, while the prognosis in the microsatellite unstable and copy number low groups is in between. The TCGA subtyping is more reproducible and shows a better concordance between endometrial biopsy and resection specimens. It has now become apparent that the molecular classification can supplement histotyping in patient management. This article provides an overview of the pathologic diagnosis/differential diagnosis of HGEC and the TCGA classification of endometrial cancers, with the clinical significance and applications of TCGA classification briefly discussed when appropriate.