Programmed death-ligand 1 (PD-L1) is a biomarker that may predict the response to anti-programmed death 1/PD-L1 immunotherapy. We evaluated the expression of PD-L1 in carcinoma cells (Ca) and immune ...cells (ICs) across histopathologic and The Cancer Genome Atlas (TCGA) molecular subgroups of endometrial carcinoma (EC). Our study included 842 patients with EC. Direct sequencing of polymerase epsilon (POLE) exonuclease domain hot spots and conventional immunohistochemistry (MLH1, PMS2, MSH2, MSH6, p53) were conducted to identify TCGA classification–based molecular subgroups of ECPOLE-mutated, mismatch repair deficient, no specific molecular profile, and p53 aberrant. Multiplex immunohistochemistry was performed to evaluate PD-L1 expression in Ca and tumor-infiltrating ICs. PD-L1 expression in Ca and in ICs was detected in 8.6% and 27.7% of the cases, respectively. A combined positive score (CPS) was ≥1% in 19.4% of the samples. PD-L1 positivity in Ca and ICs, and CPS correlated with tumor T-cell density (P<0.001). POLE-mutated and mismatch repair-deficient tumors were more likely to present PD-L1-expressing ICs, CPS positivity, and abundant tumor-infiltrating lymphocytes compared with other TCGA subgroups (P<0.001). No differences existed in Ca-PD-L1 expression (P=0.366). Within various histotypes, non-endometrioid carcinomas displayed the highest Ca-PD-L1, ICs, and CPS (P<0.03). Advanced cancers showed more frequent Ca-PD-L1 positivity (P=0.016), and CPS (P=0.029) and IC≥1% (P=0.037) positivity compared with early disease. In conclusion, PD-L1 expression profiles differ between molecular subclasses, histologic subtypes, and disease stage of EC. Prospective studies are needed to explore the predictive value of various PD-L1 scoring systems within the subgroups of EC. CPS presents methodological advantages over cell type–specific scoring systems.
Do the uterine leiomyoma driver events - mediator complex subunit 12 (
) mutations, high mobility group AT-hook (HMGA2) overexpression, and fumarate hydratase (FH) inactivation - also contribute to ...the development of uterine adenomyomas?
mutations and FH deficiency occur in a subset of uterine adenomyomas, but at lower frequencies than in leiomyomas.
Uterine adenomyomas are benign tumours with clinical features very similar to uterine leiomyomas. Mutations affecting
,
and
account for up to 80-90% of leiomyomas, but their contribution to adenomyomas is not known.
Formalin-fixed paraffin-embedded adenomyoma samples from 21 patients operated on during 2012-2014 were collected at the pathology department's archives and analysed for uterine leiomyoma driver events.
Adenomyoma diagnoses were verified by a specialized pathologist and representative areas were marked on haematoxylin-eosin slides. DNA was extracted from the tissue samples and sequenced to detect mutations in
. Expression levels of HMGA2 and 2SC, a robust indirect method to detect FH inactivation, were analysed by immunohistochemistry (IHC). The coding region of
was sequenced in one adenomyoma sample showing strong 2SC staining as well as in the same patient's normal tissue sample. All patients' medical histories were collected and reviewed.
mutation c.131G > A, p.G44D, the most common mutation in uterine leiomyomas, was identified in two samples (2/21; 9.5%). One adenomyoma displayed strong 2SC positivity and subsequent sequencing revealed a frameshift
mutation c.911delC, p.P304fs in the tumour. The mutation was also present in the patient's normal tissue sample, indicating that she has a hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. HMGA2 protein expression was normal in all adenomyomas.
Restricted sample size limits the determination of exact mutation frequencies of the studied aberrations in adenomyomas.
Uterine leiomyoma driver mutations do contribute to the development of some adenomyomas. We also report an adenomyoma in the context of hereditary HLRCC syndrome. Despite clinical similarities, the pathogenic mechanisms of adenomyomas and leiomyomas are likely different. Large-scale genomic analyses are warranted to elucidate the complete molecular background of adenomyomas.
This study was supported by The Academy of Finland, the Sigrid Jusélius Foundation, and the Cancer Society of Finland. The authors declare no conflict of interest.
Abstract Objective To assess the stage distribution and stage‐related disease‐specific survival rates for endometrial cancer using the FIGO (the International Federation of Gynecology & Obstetrics) ...2009 and 2023 staging systems. Further, we sought to evaluate the prognostic utility of additional covariates beyond the FIGO 2023 stage. Methods Endometrial carcinomas were molecularly classified by the Proactive Molecular Risk Classifier for Endometrial Cancer and staged according to FIGO 2009 and 2023 criteria. Disease‐specific survival was calculated as the time from surgery to death from endometrial cancer. Results Data from 604 patients were analyzed. Median follow‐up time was 81 months. A total of 118 stage shifts (19.5%) occurred between the FIGO 2009 and FIGO 2023 systems, with upshifts accounting for 107 (90.7%) of these changes. Within the FIGO 2023 system, molecular classification resulted in restaging of 69 patients (11.4%). Shifts that could alter adjuvant therapy decisions were identified in 23 patients (3.8%). The FIGO 2023 system effectively categorized endometrial cancers into prognostic subgroups. The FIGO 2023 stage, tumor size, positive peritoneal cytology, and mismatch repair deficiency were associated with disease‐specific survival in a multivariable analysis, whereas age and adjuvant therapy were not. Conclusion The FIGO 2023 staging system for endometrial cancer appears highly prognostic. Prognostic assessment of the patients can be further enhanced by readily accessible covariates. A stage shift between the FIGO 2009 and 2023 systems occurs in about one‐fifth of patients. The implementation of molecular classification within the FIGO 2023 system bears implications for decisions regarding adjuvant therapy.
Synopsis The FIGO 2023 staging system for endometrial cancer alters stage distribution compared with the FIGO 2009 system, and bears implications for decisions regarding adjuvant therapy.
The role of clinicopathological factors and molecular markers in prognostic classification of endometrioid ovarian carcinoma (EnOC) is not established. Tumor grade is used in risk assessment, but the ...role of current 3-tier grading system has been challenged.
Clinicopathological factors and 12 immunohistochemical biomarkers (PR, ER, β-catenin, vimentin, ARID1A, HNF1-β, p53, p16, MIB-1, E-cadherin, c-erb-B2 and L1CAM) were analyzed as regards patient outcome in 215 contemporarily classified EnOCs.
Of clinical parameters, grade and stage appeared as strong independent prognostic factors both for disease-free and disease-specific overall survival. Grades 1–3 distinguished clearly from each other in the survival analysis, whereas stages I-II and stages III-IV clustered with each other. PR, ER, nuclear β-catenin and vimentin positivity were associated with favorable overall outcome and clinical parameters, whereas abnormal expression of p53, overexpression of p16 and L1CAM positivity were associated with aggressive disease characteristics and poor survival. The frequency of good-prognosis markers PR and β-catenin gradually decreased and poor-prognosis markers p53, p16 and L1CAM gradually increased from grade 1–3. However, vimentin and ER were expressed at similar frequencies across different grades and presented with independent prognostic significance.
We found histological grade and disease stage, but not residual tumor, to be independent clinical prognostic factors in EnOC. A set of good-prognosis markers (PR, ER, β-catenin and vimentin) and poor-prognosis markers (p53, p16 and L1CAM) were identified. Our findings support continuation of the use of the 3-tier grading system for EnOC and provide clinically feasible IHC biomarkers for prognostic profiling.
•Disease stage and grade are independent clinical prognostic factors in endometrioid ovarian carcinoma.•3-tier grading system is supported by distinct survival and gradual change of markers between grades.•Markers of favorable outcome were PR, ER, nuclear β-catenin and vimentin positivity.•Abnormal expression of p53, overexpression of p16 and L1CAM positivity were associated with aggressive disease.
Clear cell and endometrioid ovarian carcinomas (OCC and OEC, respectively) have a presumed origin in endometriosis and share molecular alterations with each other and with their endometrial ...counterparts. The Cancer Genome Atlas (TCGA)-based molecular classification stratifies endometrial carcinomas into four categories: POLE mutated (POLEmut), mismatch repair deficient (MMRd), p53 abnormal (p53abn) and no specific molecular profile (NSMP) with divergent prognoses. The subsequent studies are indicative that this TCGA classification has some value in OEC, but the knowledge related to OCC is limited.
Endometrial carcinoma molecular classification was evaluated and compared in a large series of OCCs (n = 115) and OECs (n = 158). POLE mutation analysis and tissue microarray-based immunohistochemistry for mismatch repair and p53 proteins were performed.
The distribution to the molecular groups was as follows: POLEmut 0.9%/3.2%, MMRd 3.5%/6.3%, p53abn 20%/30%, and NSMP 76%/60% in OCCs/OECs, respectively. The proportion of NSMP tumors was the largest in both histological types and significantly higher in OCC than OEC (p = 0.009). The molecular classification correlated significantly with DSS in both OCCs and OECs (p < 0.001 and p = 0.009, respectively), and with DFS in OCCs (p = 0.001). POLEmut and MMRd OCCs carried excellent prognosis, whereas MMRd OECs presented with poorer outcome. The p53abn group was associated with the poorest prognosis in both tumor types, particularly emphasized in OCCs.
TCGA molecular classification associated with patient outcome in both histotypes, and the difference in prognosis between the molecular groups was even more marked in OCC. The large amount of NSMP tumors highlights the need for further studies.
•The molecular classification of endometrial carcinoma shows prognostic value in endometriosis-associated ovarian cancers.•The difference in patient outcome between the molecular groups was more distinct in ovarian clear cell carcinoma.•POLE mutated and MMR deficient ovarian clear cell carcinomas were uncommon, but carried an excellent prognosis.•The p53 abnormal group had the poorest prognosis in both histotypes, which was particularly emphasized in clear cell tumors.•No specific molecular profile (NSMP) was the largest group in both histotypes.
Highlights • L1CAM predicts poor outcome in endometrioid, but not in clear cell ovarian carcinoma. • Our findings are similar to those previously observed in endometrial carcinoma. • L1CAM associates ...with poor outcome in grade 1–2 endometrioid ovarian carcinoma. • L1CAM predicts poor prognosis in concurrent ovarian and endometrial carcinomas.
Abstract
Glycodelin is a lipocalin protein mainly expressed in well-differentiated epithelial cells in reproductive tissues, including endometrium and seminal vesicles. Previously, glycodelin has ...been shown to induce differentiation of endometrial carcinoma cells, which was associated with reduced xenograft tumor growth. Glycodelin is highly expressed in secretory endometrium, but not in proliferative or postmenopausal endometrium. While glycodelin is weakly, if at all, expressed in cancer tissues and, when expressed, associated with better prognosis, results regarding the expression of glycodelin in endometrial carcinoma are discordant. Therefore, we studied the expression of glycodelin in endometrial carcinoma and hyperplasia by immunohistochemical staining using highly validated antibody developed in house. Furthermore, the levels of mRNA were addressed utilizing in silico transcriptomics databases.
Glycodelin transcripts were more abundant in normal uterus than in uterine carcinomas. Glycodelin staining in endometrial carcinoma sections was also much lower than that in secretory phase endometrium. Interestingly, in some endometrial hyperplasia samples glycodelin levels were much lower in hyperplastic regions of the sample as compared to those having normal histology.
In conclusion, our data show that glycodelin is not highly expressed, if at all, in endometrial carcinoma tissues. This is in keeping with the reduced expression of glycodelin in postmenopausal endometrium and association of glycodelin in epithelial differentiation.
Citation Format: Hannu Koistinen, Annukka Pasanen, Laura Hautala. Glycodelin expression in endometrial carcinoma. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 436.
Uterine leiomyoma (UL) is a common benign neoplasm which can sometimes be difficult to differentiate from the uterine inflammatory myofibroblastic tumor (IMT) based on morphology alone. IMT is a ...myofibroblastic/fibroblastic neoplasm which has typically been considered to be rare in the uterus. Its clinical behavior is usually indolent although aggressive variants exist. The majority of IMTs harbor genomic rearrangement ofanaplastic lymphoma kinase(ALK), whileALKfusion has not been thus far detected in ULs. We analyzed 2263 ULs of which 9 (0.4%) had tyrosine-kinase activation. Seven of the samples were ALK immunopositive: 6 had anALKfusion gene and 1 overexpressed anALKtranscript skipping exons 2 to 3, Moreover, 1 sample had aRET, and 1 aPDGFRBfusion gene. While no recurrent somatic mutations were found, 1 patient had anALKgermline mutation. Seven tumors showed leiomyoma-like morphology, 1 tumor had slightly loose, and 1 fibrous growth pattern. Six tumors had mild to moderate lymphocyte infiltration, while no immune cell infiltration was detected in 3 cases. None of the tumors showed aggressive behavior. Except for strong ALK positivity (7/9 tumors) the protein expression profile of the tumors was identical to ULs and distinct from other mesenchymal uterine tumors. In gene expression level, these tumors and the known UL subclasses did not separate perfectly. However, vitamin C metabolism and epithelial-mesenchymal transition pathways were uniquely enriched in these lesions. The overall similarity of the analyzed tumors to UL raises the question whether an UL diagnosis would be more proper for a subset of uterine IMTs.
One in four women suffers from uterine leiomyomas (ULs)-benign tumours of the uterine wall, also known as uterine fibroids-at some point in premenopausal life. ULs can cause excessive bleeding, pain ...and infertility
, and are a common cause of hysterectomy
. They emerge through at least three distinct genetic drivers: mutations in MED12 or FH, or genomic rearrangement of HMGA2
. Here we created genome-wide datasets, using DNA, RNA, assay for transposase-accessible chromatin (ATAC), chromatin immunoprecipitation (ChIP) and HiC chromatin immunoprecipitation (HiChIP) sequencing of primary tissues to profoundly understand the genesis of UL. We identified somatic mutations in genes encoding six members of the SRCAP histone-loading complex
, and found that germline mutations in the SRCAP members YEATS4 and ZNHIT1 predispose women to UL. Tumours bearing these mutations showed defective deposition of the histone variant H2A.Z. In ULs, H2A.Z occupancy correlated positively with chromatin accessibility and gene expression, and negatively with DNA methylation, but these correlations were weak in tumours bearing SRCAP complex mutations. In these tumours, open chromatin emerged at transcription start sites where H2A.Z was lost, which was associated with upregulation of genes. Furthermore, YEATS4 defects were associated with abnormal upregulation of bivalent embryonic stem cell genes, as previously shown in mice
. Our work describes a potential mechanism of tumorigenesis-epigenetic instability caused by deficient H2A.Z deposition-and suggests that ULs arise through an aberrant differentiation program driven by deranged chromatin, emanating from a small number of mutually exclusive driver mutations.
Preoperative or intraoperative risk assessment models are used to stratify patients with endometrial carcinoma to lymphadenectomy. Our aim was to determine whether preoperative analysis of L1 cell ...adhesion molecule (L1CAM) can improve risk assessment.
Immunohistochemical L1CAM staining was performed on endometrial biopsies of 241 patients and paired hysterectomy samples of 75 patients. Risk assessment models based on preoperative histologic type and grade, myometrial invasion, and/or tumor diameter and alternative models incorporating preoperative L1CAM were compared with regard to their capability of predicting lymph nodal or distant metastasis. Soluble L1 levels were measured by enzyme-linked immunosorbent assay in serum samples of 40 patients with endometrial carcinoma.
The concordance rate between L1CAM staining results of preoperative and hysterectomy samples was moderate (κ = 0.586, P < 0.0001). Preoperative L1CAM expression was associated with nonendometrioid histology, lymph node involvement, advanced stage, and positive peritoneal cytology. Receiver operating characteristic curve analyses showed that L1CAM did not significantly improve risk stratification algorithms based on traditional risk factors. Intraoperative tumor diameter was an effective surrogate for myometrial invasion. There was no statistical difference between L1 serum levels of patients with an L1CAM-positive or L1CAM-negative endometrial carcinoma (P = 0.786).
L1 cell adhesion molecule expression in endometrial biopsy correlates with high-risk features of endometrial carcinoma but does not significantly improve risk stratification algorithms based on traditional factors. Soluble L1 detected in the serum of patients with endometrial carcinoma does not correlate with tumoral L1CAM expression.
PDF
