High-grade Endometrial Carcinomas Research Articles

Molecular Classification Outperforms Histologic Classification in Prognostication of High-grade Endometrial Carcinomas With Undifferentiated and Sarcomatous Components.

Since the establishment of 4 molecular subgroups of endometrial carcinoma (EC), there has been significant interest in understanding molecular classification in the context of histologic features and diagnoses. ECs with undifferentiated, spindle, and/or sarcomatous components represent a diagnostically challenging subset of tumors with overlapping clinical and histologic features. We examined the clinicopathologic, morphologic, immunohistochemical, and molecular features of these tumors identified in our institutions' pathology databases using immunohistochemistry and targeted sequencing. Disease-specific survival (DSS) and progression-free survival (PFS) were analyzed using Kaplan-Meier curves and log-rank tests. One hundred sixty-two ECs were included: carcinosarcomas (UCS; n=96), dedifferentiated/undifferentiated EC (DDEC/UDEC; n=49), and grade 3 endometrioid EC with spindled growth (GR3spEEC) (n=17). All molecular subgroups were represented in all histologic subtypes and included 12 (7%) POLE-mutated (POLEmut), 43 (27%) mismatch repair-deficient (MMRd), 77 (48%) p53-abnormal (p53abn), and 30 (19%) no specific molecular profile (NSMP) tumors. However, the molecular classification (irrespective of histologic diagnosis) was a significant predictor for both DSS (P=0.008) and P≤0.0001). POLEmut EC showed an excellent prognosis with no recurrences or deaths from the disease. MMRd tumors also showed better outcomes relative to NSMP and p53abn tumors. In conclusion, molecular classification provides better prognostic information than histologic diagnosis for high-grade EC with undifferentiated and sarcomatous components. Our study strongly supports routine molecular classification of these tumors, with emphasis on molecular group, rather than histologic subtyping, in providing prognostication.

Abstract B018: MYC is sufficient to generate mid-life high-grade serous ovarian and serous endometrial carcinomas in a BRCA wild type p53-R270H mouse model

Abstract Genetically engineered mouse models (GEMM) have fundamentally changed how cancer etiology, early detection, and treatment can be understood. Mouse models have been developed that support the fallopian tube as the origin of some ovarian cancers. However, serous endometrial cancer is a much rarer gynecologic cancer with fewer models available. The genetics of serous endometrial cancer are very similar that of high-grade serous ovarian cancer. The most common mutation found in both high-grade serous ovarian cancer and serous uterine cancer is p53 and in humans, MYC is amongst the most amplified genes in both tyeps of cancer. We developed a GEMM of high-grade serous ovarian cancer by using a fallopian tube epithelium specific promoter Ovgp1 to express MYC and dominant negative mutant p53-R270H. Female mice developed lethal cancer at an average of 15.1 months. Histopathological examination of mice revealed HGSOC characteristics including nuclear p53 and nuclear MYC in clusters of cells within the fallopian tube epithelium and ovarian surface epithelium. Unexpectedly, nuclear p53 and MYC clustered cell expression was also identified in the uterine luminal epithelium, possibly from intraepithelial metastasis from the fallopian tube epithelium. Extracted tumor cells exhibited strong loss of heterozygosity at the p53 locus, leaving the mutant allele. Copy number alterations in these cancer cells were prevalent, disrupting a large fraction of genes. Transcriptome profiles most closely matched human HGSOC and serous endometrial cancer. Histological and transcriptomic findings are consistent with the hypothesis that serous uterine cancer may originate from the fallopian tube epithelium. Citation Format: Alexandra Blackman, Amy Rees, Rob Bowers, Christian Jones, Silvia Vaena, Shelby Carter, Evan Villamor, Della Evans, George Fullbright, David Long, Laura Spruill, Martin Romeo, Kristi Helke, Anthony Emanuel, Joe Delaney. MYC is sufficient to generate mid-life high-grade serous ovarian and serous endometrial carcinomas in a BRCA wild type p53-R270H mouse model [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B018.

Practice patterns, time trends and quality of care of uterine cancer in Belgium: An analysis of the EFFECT database

ObjectivesTo investigate the practice patterns and quality of care for uterine cancer on a national level in Belgium, including trends in practice over the period 2012–2016. MethodsQuality indicators were measured using the EFFectiveness of Endometrial Cancer Treatment (EFFECT) database. Multivariable logistic mixed regression was used to test for associations between the quality indicators and year of diagnosis, adjusted for potential confounders and intra-cluster correlations. ResultsThe EFFECT database includes 4178 patients diagnosed with uterine cancer in the period 2012–2016. Minimally invasive surgery (laparoscopic or robotic-assisted) was applied in 61.6% of patients who had surgery for clinical stage I endometrial carcinoma (EC), increasing from 52.9% in 2012 to 66.4% in 2016. At least pelvic lymph node staging was performed in 69.0% of patients with clinical stage I, high-grade EC; and in 63.9% of patients with clinical stage I-II serous carcinoma, clear cell carcinoma or carcinosarcoma. The latter increased from 48.8% in 2012 to 77.2% in 2016. Adjuvant radiotherapy (external beam and/or brachytherapy) was offered to 33.5% of patients who had surgery without lymph node staging for pathological stage I EC at high-intermediate or high risk of recurrence. Adjuvant chemotherapy was administered to 64.4% of patients with pathological stage III-IVA EC. ConclusionsStudy results indicate an overall good quality of care for patients with uterine cancer in Belgium. Treatment areas with potential room for improvement include the use of minimally invasive surgery, comprehensive surgical staging and adjuvant therapy, which confirms the remaining controversies in uterine cancer treatment and the need for further research.

In Vivo Intra-Uterine Delivery of TAT-Fused Cre Recombinase and CRISPR/Cas9 Editing System in Mice Unveil Histopathology of Pten/p53-Deficient Endometrial Cancers.

Phosphatase and TENsin homolog (Pten) and p53 are two of the most frequently mutated tumor suppressor genes in endometrial cancer. However, the functional consequences and histopathological manifestation of concomitant p53 and Pten loss of function alterations in the development of endometrial cancer is still controversial. Here, it is demonstrated that simultaneous Pten and p53 deletion is sufficient to cause epithelial to mesenchymal transition phenotype in endometrial organoids. By a novel intravaginal delivery method using HIV1 trans-activator of transcription cell penetrating peptide fused with a Cre recombinase protein (TAT-Cre), local ablation of both p53 and Pten is achieved specifically in the uterus. These mice developed high-grade endometrial carcinomas and a high percentage of uterine carcinosarcomas resembling those found in humans. To further demonstrate that carcinosarcomas arise from epithelium, double Pten/p53 deficient epithelial cells are mixed with wild type stromal and myometrial cells and subcutaneously transplanted to Scid mice. All xenotransplants resulted in the development of uterine carcinosarcomas displaying high nuclear pleomorphism and metastatic potential. Accordingly, in vivo CRISPR/Cas9 disruption of Pten and p53 also triggered the development of metastatic carcinosarcomas. The results unfadingly demonstrate that simultaneous deletion of p53 and Pten in endometrial epithelial cells is enough to trigger epithelial to mesenchymal transition that is consistently translated to the formation of uterine carcinosarcomas in vivo.

ARID1B Immunohistochemistry Is an Important Test for the Diagnosis of Dedifferentiated and Undifferentiated Gynecologic Malignancies.

Dedifferentiated and undifferentiated endometrial and ovarian carcinomas (DDC/UDC) are aggressive malignancies defined by morphologic and molecular undifferentiation, and associated with core SWI/SNF deficiency. Their main differential diagnoses include high-grade endometrial and ovarian carcinomas that often show overlapping morphologic and molecular profiles. Loss of cell lineage markers expression by immunohistochemistry (IHC) is commonly used to assist diagnosis, but it has poor specificity, while core SWI/SNF deficiency is much more specific. Approximately half of SWI/SNF-deficient DDC/UDC are associated with loss of ARID1B expression, yet, unlike the other core SWI/SNF proteins (SMARCA4 and SMARCB1), this test is rarely available, even in tertiary centers. Mutational testing for ARID1B is increasingly common among targeted DNA sequencing panels, but it is difficult to interpret in the absence of IHC results. Overall, the importance of including ARID1B IHC as part of the routine panel for undifferentiated gynecologic malignancies should be emphasized, especially as SWI/SNF inactivation is becoming a necessary biomarker for diagnostics, clinical management, and clinical trial enrollment.

HER2 Genetic Intratumor Heterogeneity Is Associated With Resistance to Trastuzumab and Trastuzumab Emtansine Therapy in Recurrent High-Grade Endometrial Cancer

Anti-HER2 targeted therapies have recently demonstrated clinical activity in the treatment of high-grade endometrial carcinomas (ECs), particularly serous carcinomas with HER2 amplification and/or overexpression. Intratumor heterogeneity of HER2 amplification or HER2 genetic intratumor heterogeneity (G-ITH) has been associated with resistance to anti-HER2 therapies in breast and gastroesophageal cancers; however, its clinical relevance in EC is unknown. To characterize HER2 G-ITH in EC, archival specimens from a clinically annotated cohort of 57 ECs treated with trastuzumab or trasutuzmab emtansine in the recurrent (n = 38) or adjuvant (n = 19) setting were subjected to central pathology review, HER2 assessment by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), and next-generation sequencing. HER2 G-ITH, defined as HER2 amplification in 5% to 50% of tumor cells examined by FISH, was identified in 36% (19/53) of ECs and was associated with lower HER2 copy number and levels of protein expression. HER2 IHC revealed spatially distinct areas of strong expression juxtaposed with areas of low/absent expression in tumors with the “cluster” pattern of G-ITH, whereas the “mosaic” pattern was typically associated with a diffuse admixture of cells with variable levels of HER2 expression. HER2 G-ITH was frequently observed in cases with IHC/FISH or FISH/next-generation sequencing discrepancies and/or with an equivocal/negative FISH result (9/13, 69%). Although the objective response rate to anti-HER2 therapy in recurrent ECs was 52% (13/25) for tumors lacking HER2 G-ITH, none (0%, 0/10) of the patients with HER2 G-ITH achieved a complete or partial response (P = .005). HER2 G-ITH was significantly associated with worse progression-free survival (hazard ratio, 2.88; 95% CI, 1.33-6.27; P = .005) but not overall survival. HER2 IHC score, HER2/CEP17 ratio, HER2 copy number, histologic subtype, and other genetic alterations, including PIK3CA hotspot mutations, were not significantly associated with therapeutic response or survival outcomes. Treatment responses were not restricted to serous carcinomas, supporting consideration of anti-HER2 therapy in patients with HER2-positive high-grade ECs of non-serous histology. Our results demonstrate that HER2 G-ITH is an important determinant of response to trastuzumab and trastuzumab emtansine in EC, providing a rationale for the development of novel therapeutic strategies to target HER2-nonamplified resistant tumor subpopulations, such as HER2 antibody-drug conjugates with bystander effects.

A novel prognostic model for high-grade endometrial cancer using combined neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR).

e17622 Background: Endometrial carcinoma (EC) as a common malignant tumor of the female reproductive system, posing a serious threat to the health of women. Compared to low-grade EC, high-grade EC has more rapid progression and a worse prognosis. Among the high-grade EC, grade3 endometrioid carcinoma, serous carcinoma, and clear cell carcinoma were the most common. Neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) are potential biomarkers of the systemic inflammatory response, and the correlation with prognosis of high-grade EC remains unclear. We want to evaluate the predictive significance of NLR and PLR in the prognosis of high-grade endometrial carcinoma and to establish a predictive model combining clinical factors. Methods: This multicenter retrospective cohort study included 910 high-grade epithelial endometrial carcinoma patients from the Chinese Endometrial Carcinoma Consortium database who underwent initial surgical treatment between January 1, 2005, and December 31, 2019. Univariable Cox survival analysis(the 2-sided Log-rank test) was used to assess each factor. Then the least absolute shrinkage and selection operator (LASSO) method was used to select the independent risk factors for DFS (disease-free survival) and OS (overall survival) from the outcomes of the univariate analysis to proceed with model fitting. Cox proportional hazard regression models were developed to predict the risk of recurrence and death at 3, 5, and 10 years, and the models were validated and calibrated. The area under the curve was used to measure the predictive performance of the model. The decision curve analysis was used to explore the clinical net benefit of the nomograms. Results: NLR and PLR were risk factors for recurrence, and NLR was a risk factor for death. We established models for predicting death and recurrence. In the training cohort, the AUC of recurrence model at 3, 5 and 10-year was 0.85, 0.85 and 0.86. And for the death model, the AUC at 3, 5 and 10-year was 0.83, 0.84 and 0.86. In the validation cohort, the AUC of recurrence model at 3,5 and 10-year was 0.72, 0.77 and 0.77. And for death model was 0.72, 0.81 and 0.84. Kaplan–Meier survival analysis showed a significant difference between low-risk and high-risk groups. The calibration curve also revealed excellent predictive accuracy both in the training and validation cohort. Conclusions: NLR and PLR are risk factors affecting the prognosis of high-grade endometrial carcinoma patients. Combining NLR/PLR and clinicopathological factors, we established a novel and more comprehensive prognostic model for patients to achieve risk stratification. This prognosis predictive model has the potential to offer risk scores and precise risk stratification for patients with high-grade endometrial cancer.

The predictive value of CA-125 for radiologic evidence of metastatic disease in type 2 endometrial cancers.

e17610 Background: Type 2 endometrial cancers encompass histologic variants that are more aggressive and have a higher incidence of extrauterine disease at the time of presentation than their type 1 counterparts. For high grade endometrial carcinomas, current National Comprehensive Cancer Network (NCCN) guidelines propose the "consideration of chest, abdomen and pelvis CT to evaluate for metastatic disease." We sought to investigate the predictive value of serum CA-125 for radiographic evidence of metastatic disease in patients with type 2 endometrial cancers. Methods: An IRB-approved, retrospective study investigating patients diagnosed with endometrial cancers between 2000-2020 at an urban, multi-site health system was conducted. Only patients with type 2 endometrial cancers and both pre-operative computed tomography scans of the chest, abdomen, and pelvis (CT CAP) and serum CA-125 results were included. A Youden’s index was used to calculate the optimal CA-125 cutoff. The sensitivity and specificity of CA-125 in predicting radiographic evidence of extrauterine disease was then calculated using this pre-determined CA-125 cutoff. Results: In total, 2,227 patients diagnosed with endometrial cancer (types 1 and 2) between 2000-2020 were identified. 1,932 cases were excluded due to low grade disease and/or the absence of pre-operative imaging and CA-125 results. Ultimately, 295 cases were included in analyses. A receiver operating characteristic (ROC) curve was used to generate Youden’s index which established the optimal CA-125 cutoff as 68 U/mL (P=0.0005). Using this cutoff, the specificity and sensitivity were determined to be 92.45% and 63.86%, respectively. The positive predictive value was 76.81% and the negative predictive value was 86.73%. Conclusions: According to current NCCN guidelines, pre-operative imaging and CA-125 should be considered if extrauterine disease is suspected in the setting of endometrial cancer. Although the role of serum CA-125 in monitoring clinical response is well documented, the utility of this test in stratifying patients who should undergo further radiologic evaluation is uncertain. Our results suggest that a CA-125 cutoff of > 68 U/mL is predictive of radiographic evidence of metastatic disease and, thus, can be used to determine which patients should receive pre-operative CT CAP.

Preoperative CA125 Significantly Improves Risk Stratification in High-Grade Endometrial Cancer.

Patients with high-grade endometrial carcinoma (EC) have an increased risk of tumor spread and lymph node metastasis (LNM). Preoperative imaging and CA125 can be used in work-up. As data on cancer antigen 125 (CA125) in high-grade EC are limited, we aimed to study primarily the predictive value of CA125, and secondarily the contributive value of computed tomography (CT) for advanced stage and LNM. Patients with high-grade EC (n = 333) and available preoperative CA125 were included retrospectively. The association of CA125 and CT findings with LNM was analyzed by logistic regression. Elevated CA125 ((>35 U/mL), (35.2% (68/193)) was significantly associated with stage III-IV disease (60.3% (41/68)) compared with normal CA125 (20.8% (26/125), [p < 0.001]), and with reduced disease-specific-(DSS) (p < 0.001) and overall survival (OS) (p < 0.001). The overall accuracy of predicting LNM by CT resulted in an area under the curve (AUC) of 0.623 (p < 0.001) independent of CA125. Stratification by CA125 resulted in an AUC of 0.484 (normal), and 0.660 (elevated). In multivariate analysis elevated CA125, non-endometrioid histology, pathological deep myometrial invasion ≥50%, and cervical involvement were significant predictors of LNM, whereas suspected LNM on CT was not. This shows that elevated CA125 is a relevant independent predictor of advanced stage and outcome specifically in high-grade EC.

Single brain metastasis as onset of stage I endometrial carcinoma in patient affected by multiple sclerosis: the first case in literature

Brain metastases in any gynecological cancer are a rare occurrence. Even more so, it is extremely rare for a gynecological malignancy to manifest itself with symptoms indicative of cerebral involvement. Literature regarding the association between MS and cancer is conflicting. We herein report a rare presentation of single metastasis of endometrial carcinoma in a 59-year-old woman affected by Primary Progressive Multiple Sclerosis (PPMS). A head CT scan was performed, which revealed the presence of an expansive lesion in the left parietal region. After careful assessment, a high-grade endometrial carcinoma was diagnosed and a decision was made to remove both the primary lesion and the brain metastasis in one sitting, through a conjoined surgery session involving neurosurgeons and gynecologists. The postoperative course was free from complications up until a few days after being transferred to a rehabilitation center, where she died following respiratory complications.

Magnetic resonance imaging-radiomics in endometrial cancer: a systematic review and meta-analysis

ObjectiveEndometrial carcinoma is the most common gynecological tumor in developed countries. Clinicopathological factors and molecular subtypes are used to stratify the risk of recurrence and to tailor adjuvant treatment. The...

Undifferentiated-dedifferentiated endometrial carcinoma; the reappearance of an old friend with insights into the new data.

Endometrial carcinoma is a common malignancy in women and shows increasing incidence. Except for its two main pathogenetic types I and II, the continuing evolution on molecular genetics have led to a new classification system (TCGA), that includes four main molecular subtypes: (i) POLE-mutant (ultramutated), (ii) hypermutated (MSI), (iii) copy-number low/MSS (p53wt) and (iv) copy-number high/serous-like (p53mut). The undifferentiated and dedifferentiated endometrial carcinomas are rare and clinically aggressive variants, comprising about 10% of the high-grade endometrial carcinomas and 2% of the endometrial carcinomas in general. Until recently, they were under-recognized and not fully described morphologically and immunohistochemically/molecularly. Their recognition diagnostically is crucial because of their poor prognosis; approximately 40% of patients with these subtypes will die within 0.5-20 months after diagnosis, so additional therapeutic strategies are important for an effective management. Because of their rarity, the responsiveness to other than conventional treatment, such as immunotherapy, has not been sufficiently investigated yet. The aim of this review is to provide an update on the knowledge about these two uncommon subtypes according to the current literature.

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.

Classification of high-grade endometrium carcinomas using molecular and immunohistochemical methods.

As a result of the integration of molecular changes into the histological classification of cancers, which increases diagnostic repeatability, the differences between the groups become more prominent and targeted therapies gain significance. The most comprehensive molecular study regarding endometrial carcinomas (EC) is The Cancer Genome Atlas (TCGA) project. According to TCGA, endometrial carcinomas are classified into four molecular prognostic subgroups: copy-number-low/p53-wild-type (p53wt), DNA polymerase epsilon (POLE)-mutated/ultramutated (POLEmt), microsatellite-instability/hypermutated (MSI), and copy-number-high/p53-mutated (p53mt). In this study, we aim to apply the molecular classification to our high-grade endometrial cancer patients, and particularly, to identify our overtreated patients. Ninety-seven patients diagnosed with high-grade EC in Selcuk University, Faculty of Medicine between 2009-2018 were retrospectively evaluated and classified into four subgroups. Primary outcomes of overall and progression-free survival were evaluated for clinical, pathological, and molecular features. Further, all molecular groups were divided into endometroid and non-endometrioid groups, and disease-free survival (DFS) and overall survival (OS) were investigated across groups. According to molecular classification, 23 patients (23.7%) were assigned to the MSI group, 21 (21.6%) to the POLEmt group, 40 (41.2%) to the p53mt group, and 13 (13.4%) to the p53wt group. Patients' DFS (p = 0.001) and OS rates (p = 0.001) were significantly different according to their molecular classification. The results of our analyses determined that, in the molecular classification of high-grade ECs, the p53mt group had the poorest prognosis and the POLEmt group had the best prognosis. Tumor size, myometrial invasion, lymphovascular space invasion (LVSI), lymph node metastasis, cervical invasion, ovarian invasion and stage showed statistically significant differences based on molecular classification (p < 0.05). The use of molecular classification in the clinical practice will allow more accurate prognostic prediction and more appropriate treatment planning, particularly as high-grade ECs constitute a heterogenous group with poor prognosis.

High grade endometrial carcinoma: 4 common issues

Classification of high grade endometrial carcinoma is a daunting task. Morphologic overlap, non-descript histology, overlapping immunohistochemical staining results and a flood of new molecular tests can make this relatively common task incredibly difficult. This case based talk will address such topics as the presence of severe nuclear atypia, solid growth patterns, clear cell carcinoma and the ever growing field of immunohistochemical and molecular testing in these tumours. A histologic and immunohistochemistry based approach to diagnosis, underpinned by recent molecular findings, will be presented to help ease the classification of these difficult lesions.

Incorporating Molecular Classification When Stratifying the Survival Risk of Patients with High-Grade Endometrial Carcinomas.

Assessing survival risk in patients with high-grade endometrial carcinomas has remained challenging. We aimed to investigate the distribution of molecular subtypes and assess their prognostic role in a large cohort of 355 patients with high-grade endometrial carcinoma. Molecular classification was determined using DNA polymerase epsilon (POLE) sequencing as well as immunohistochemical staining for p53 and mismatch repair (MMR) proteins. Endometrial carcinomas were stratified into four subtypes: POLE ultramutated, MMR-deficient, non-specific molecular profile (NSMP), and p53-mutant. This study included 177 and 178 patients with endometrioid and non-endometrioid carcinomas, respectively. Forty-two patients (11.8%) were categorized as POLE ultramutated, 106 (29.9%) as MMR-deficient, 128 (36.1%) as p53-mutant, and 79 (22.2%) as NSMP. Patients of different molecular subtypes had distinct survival times; molecular classification, but not histotype, was significantly associated with survival outcomes. When incorporating molecular classification into the stratification model, 52 patients (15.5%) switched risk groups, with 40 (11.9%) shifting to a lower risk for having a POLE mutation and 12 (3.6%) shifting to a higher risk owing to p53-mutant status. Molecular classification may provide more accurate prognostic information among patients with high-grade endometrial carcinomas and improve their stratification for purposes of clinical management.

The statuses of HER2 expression and mismatch repair in endometrial clear cell carcinoma.

High-grade endometrial carcinomas (HGEC) are difficult to classify. With the current use of HER2-based therapy in serous carcinoma, a diagnosis of clear cell carcinoma (CCC) has the potential to exclude patients from receiving therapy. Therefore, we examined HER2 expression in our CCC patients. The preparations of 8 patients with CCC who underwent hysterectomy, bilateral salpingo-oophorectomy, and lymph node dissection were re-evaluated. Patients did not have any prior treatment. Histopathologic parameters that were evaluated include cytoplasmic clearing, nuclear atypia, mitotic activity, hobnail architecture, hyalinized cores, hyaline globules, stratification of epithelial lining papillae, or glandular structures, and highly atypical cell layers. Immunohistochemically, HER2, ER, PR, HNF1β, Napsin A, MLH1, MSH2, MSH6 and PMS2 were applied. HER2 staining pattern, ASCO/CAP protocol used for endometrial carcinom was used. HER2 was positive in 3 of our 8 CCC patients (37.5%). While all of our HER2+cases were Napsin A and HNF1β positive, MMR proteins were intact and ER and PR were negative. Two patients had wild type p53 and 1 patient had aberrant p53 staining. Considering that there is not always a consensus between SC and CCC, even among gynecopathologists, tumor heterogeneity and different tumor components may exist, and while patients may be diagnosed with CCC and benefit from HER2 therapy, there is also a possibility that they may not benefit from the treatment. The fact that 37.5% of our CCC cases were HER2+is a finding with strong implications for the therapeutic approach. As a result of our study, in patients with CCC, if MMR is intact and ER-PR is negative, regardless of the p53 staining pattern, HER2 testing may be an objective screening method for patients who are likely to benefit from HER-targeted therapy. Consequently, patients with a diagnosis of CCC can be candidates for future clinical trials of HER2-targeted therapy.

Correlative Assessment of p53 Immunostaining Patterns and TP53 Mutation Status by Next-Generation Sequencing in High-Grade Endometrial Carcinomas.

TP53 mutations are frequently identified in the copy number-high molecular subgroup of endometrial carcinomas (ECs). P53 immunohistochemistry (IHC) is a widely used surrogate marker reflecting the mutational status of TP53 , and recent reports have shown ~95% concordance between the two methods in ECs. While these results are promising, studies evaluating the correlation between different p53 IHC staining patterns and comprehensive next-generation sequencing results are still limited. We compared the p53 IHC staining patterns, scored as wild-type, diffuse nuclear overexpression, null/complete absence, and cytoplasmic, to next-generation sequencing results reported by FoundationOneCDx in 43 high-grade ECs: 20 serous ECs, 9 mixed ECs with a serous component, 4 carcinosarcomas with a serous component, and 10 grade 3 endometrioid ECs. The concordance of p53 IHC and TP53 mutation status was 100% (43/43) overall, including 100% (33/33) concordance in tumors with a serous component and 100% (10/10) in endometrioid ECs. Among the 35 tumors with aberrant p53 expression the most commonly observed pattern was diffuse nuclear overexpression seen in 69% (24/35), followed by cytoplasmic staining in 17% (6/35), and complete absence of staining (null) in 14% (5/35) of tumors. Of the 6 tumors with cytoplasmic staining, 4 corresponded to missense mutations within the DNA binding domain (V157F in 2 tumors, and S127P and R280S, in 2 tumor each), while 2 corresponded to nonsense mutations in the tetramerization domain (p.E339*). Our results further support that p53 IHC can serve as an accurate predictor of TP53 alterations in ECs to aid the molecular-based tumor classification and the distinction between tumor histotypes, both of which play an important role in the assessment of clinical prognosis and therapeutic decision making. In addition, our data suggest, that the type and position of TP53 mutation may not directly correlate with the observed p53 IHC pattern in all tumors, and that there may be alternative mechanisms for cytoplasmic localization (other than mutations involving the nuclear localization domain), possibly due to conformational changes or posttranslational modifications of the aberrant p53 protein.

A Large High-Grade Endometrial Serous Carcinoma with Yolk Sac Tumor Differentiation in a Post- Menopausal Woman: Case Report

Abstract Introduction/Objective Yolk sac tumors are germ cell tumors mostly arising in the ovary or vagina, with cases reported throughout the gynecological tract. Only few cases were reported to arise in the endometrium and even fewer admixed with a conventional carcinoma especially in postmenopausal women. Yolk sac tumor-like areas are considered a form of retro-differentiation. Here we report a case of high-grade serous carcinoma of the endometrium with yolk sac differentiation in a postmenopausal woman. Methods/Case Report An 82-year-old Caucasian female presented with postmenopausal bleeding and a 17.6 cm endometrial mass. Total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed. A large markedly necrotic friable mass occupied the entire endometrial cavity. Microscopic examination revealed a noninvasive carcinoma arising within a polyp. Tumor cells showed two different distinct morphologic patterns, including a predominantly high-grade serous carcinoma with scant foci of clear cell component, admixed with areas of squamous/eosinophilic-like morphological pattern. The latter was diffusely positive for p53, p16, AE1/AE3 and CK7, focally positive for CK5/6, GATA3, HepPar1 , AFP , PLAP , PAX8, CD30 and SALL4 , while negative for desmin, ER, PR, Napsin A, HCG, p40, p63, C-Kit, HMB45, S100, and Melan A. Mismatch repair proteins expression was intact throughout the entire tumor. Serum AFP level measured three weeks after surgery was within normal range. Results (if a Case Study enter NA) NA Conclusion Highlighting the yolk sac tumor differentiation in endometrial carcinoma is very challenging and requires a thorough immunohistochemical evaluation combined with morphologic assessment.

Nuclear β-Catenin Expression in the Context of Abnormal p53 Expression Indicates a Nonserous Histotype in Endometrial Carcinoma.

The interobserver reproducibility is poor for histotyping within the p53-abnormal molecular category of endometrial carcinomas (ECs); therefore, biomarkers that improve histologic classification are useful. β-catenin has been proposed to have prognostic significance in specific clinicopathologic and molecular contexts. The diagnostic utility for β-catenin expression patterns in determining the histotype of p53-abnormal ECs has not been well studied. We identified ECs molecularly classified as "p53-abnormal." The p53-abnormal classification was assigned when (1) no POLE exonuclease domain hotspot mutations identified, (2) mismatch-repair protein expression was retained, and (3) abnormal p53 expression (null or overexpression) was present. Morphology was re-reviewed and β-catenin immunohistochemistry was scored as abnormal (nuclear) or normal (membranous, non-nuclear). Eighty ECs were identified in the "p53-abnormal" category; 27 (33.75%) were uterine serous carcinomas, and 53 were of nonserous histotype: 28 uterine carcinosarcomas (35%), 16 endometrioid carcinomas (20%), 2 clear cell carcinomas (2.5%), and 7 high-grade EC with ambiguous morphology (8.75%). All 27 uterine serous carcinomas demonstrated membranous β-catenin staining. Of the 53 nonserous ECs, 11 (21%) showed abnormal β-catenin expression: 6 endometrioid carcinomas, 4 uterine carcinosarcoma, and 1 high-grade EC with ambiguous morphology. The specificity of abnormal β-catenin expression for nonserous EC is high (100%) but the sensitivity is low (21%) with positive and negative predictive values of 100% and 60%, respectively. Our data shows that abnormal β-catenin expression in the context of p53-abnormal EC is highly specific, but not sensitive, for nonserous ECs and may be of value as part of a panel in classifying high-grade EC, particularly to exclude uterine serous carcinoma when nuclear staining is present.