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Endometrial Cancer: Old Questions and New Perspectives
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Endometrial Cancer: Old Questions and New Perspectives

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (20 February 2023) | Viewed by 45193

Special Issue Editors

Dr. Pierandrea De Iaco

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Guest Editor
Oncologic Gynecology Unit, Azienda Ospedaliero-Universitaria di Bologna, via Massarenti 9, Bologna, Italy
Interests: gynecologic oncology; minimally invasive surgery; molecular classification; fertility sparing treatment; medical treatment; radiotherapy; quality of life; palliative treatment; imaging
Special Issues, Collections and Topics in MDPI journals
Dr. Anna Myriam Perrone

E-Mail Website
Guest Editor
Oncologic Gynecology Unit, Azienda Ospedaliero-Universitaria di Bologna, via Massarenti 9, 40138 Bologna, Italy
Interests: gynecologic oncology; minimally invasive surgery; molecular classification; fertility sparing treatment; medical treatment; radiotherapy; quality of life; palliative treatment; imaging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Endometrial cancers are a common neoplasia accounting for approximately 6% of all malignancies in women and are a very heterogeneous group. Pre-operative diagnosis (ultrasound and RMI) is often very difficult due to the wide histopathological spectrum of lesions, and the correct therapeutic approach is very complex; for this reason, endometrial cancer should be addressed to reference centers. Hysterectomy represents the therapeutic mainstay for localized disease, but despite radical surgery, the risk of recurrence remains consistent, ranging between 15% and 20%. Laparoscopy is the preferred approach, but recent data on cervical cancer surgery (LAAC trial) require a thorough reassessment. The role of lymphadenectomy and of sentinel lymph node procedures is under evaluation. If diagnosis is performed in childbearing age, fertility preservation remains controversial, and chemotherapy and radiotherapy as adjuvant treatment are unresolved issues. 

In this Special Issue, experts in this field will discuss the current approaches to the management of patients with endometrial cancer: surgical treatment, the role of laparoscopic surgery, sentinel node procedure, and fertility sparing surgery. They will also focus on the molecular and pathological aspects of this heterogeneous group of neoplasms and the role of medical treatments and radiotherapy and the difficult role of imaging in the pre-operative setting.

Dr. Pierandrea De Iaco
Dr. Anna Myriam Perrone
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Endometrial cancer
  • minimally invasive surgery
  • sentinel node
  • fertility sparing
  • radiotherapy
  • medical treatment
  • imaging
  • molecular analysis
  • quality of life
  • palliative treatment

Published Papers (19 papers)

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10 pages, 1764 KiB  
Article
The Risk of Recurrence in Endometrial Cancer Patients with Low-Volume Metastasis in the Sentinel Lymph Nodes: A Retrospective Multi-Institutional Study
by Alessandro Buda, Cristiana Paniga, Salih Taskin, Michael Mueller, Ignacio Zapardiel, Francesco Fanfani, Andrea Puppo, Jvan Casarin, Andrea Papadia, Elena De Ponti, Tommaso Grassi, Jessica Mauro, Hasan Turan, Dogan Vatansever, Mete Gungor, Firat Ortag, Sara Imboden, Virginia Garcia-Pineda, Stefan Mohr, Franziska Siegenthaler, Stefania Perotto, Fabio Landoni, Fabio Ghezzi, Giovanni Scambia, Cagatay Taskiran and Robert Fruscioadd Show full author list remove Hide full author list
Cancers 2023, 15(7), 2052; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15072052 - 30 Mar 2023
Cited by 2 | Viewed by 1919
Abstract
The aim of this study was to assess the impact of low-volume metastasis (LVM) on disease-free survival (DFS) in women with apparent early-stage endometrial cancer (EC) who underwent sentinel lymph node (SLN) mapping. Patients with pre-operative early-stage EC were retrospectively collected from an [...] Read more.
The aim of this study was to assess the impact of low-volume metastasis (LVM) on disease-free survival (DFS) in women with apparent early-stage endometrial cancer (EC) who underwent sentinel lymph node (SLN) mapping. Patients with pre-operative early-stage EC were retrospectively collected from an international collaboration including 13 referring institutions. A total of 1428 patients were included in this analysis. One hundred and eighty-six patients (13%) had lymph node involvement. Fifty-nine percent of positive SLN exhibited micrometastases, 26.9% micrometastases, and 14% isolated tumor cells. Seventeen patients with positive lymph nodes did not receive any adjuvant therapy. At a median follow-up of 33.3 months, the disease had recurred in 114 women (8%). Patients with micrometastases in the lymph nodes had a worse prognosis of disease-free survival compared to patients with negative nodes or LVM. The rate of recurrence was significantly higher for women with micrometastases than those with low-volume metastases (HR = 2.61; p = 0.01). The administration of adjuvant treatment in patients with LVM, without uterine risk factors, remains a matter of debate and requires further evaluation. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
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11 pages, 2023 KiB  
Article
HER2 Amplification in p53-Mutated Endometrial Carcinomas
by Ambre Balestra, Denis Larsimont and Jean-Christophe Noël
Cancers 2023, 15(5), 1435; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15051435 - 24 Feb 2023
Cited by 2 | Viewed by 1900
Abstract
p53-mutated endometrial carcinomas tend to recur and develop distant metastases. Therefore, the detection of new potential therapeutic targets such as HER2 is particularly interesting. In this retrospective study, which considered over 118 endometrial carcinomas, the p53 mutation was detected in 29.6% of cases. [...] Read more.
p53-mutated endometrial carcinomas tend to recur and develop distant metastases. Therefore, the detection of new potential therapeutic targets such as HER2 is particularly interesting. In this retrospective study, which considered over 118 endometrial carcinomas, the p53 mutation was detected in 29.6% of cases. In these cases, the HER2 protein profile was studied via immunohistochemistry, and an overexpression of HER2 protein (++ or +++) was noted in 31.4%. The CISH technique was used in these cases to determine if gene amplification was present. In 18% of cases, the technique was not conclusive. Amplification of the HER2 gene was observed in 36.3% of cases and 36.3% of cases showed a polysomal-like aneusomy for centromere 17. Amplification was found in serous carcinomas, clear cell carcinomas and carcinosarcomas, highlighting the future potentiality of HER2-targeted therapies in these variants of aggressive carcinomas. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
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16 pages, 1640 KiB  
Article
Effects of Weight Status and Related Metabolic Disorders on Fertility-Sparing Treatment Outcomes in Endometrial Atypical Hyperplasia and Endometrial Cancer: A Retrospective Study
by Sijia Liu, Lulu Wang, Pengfei Wu, Shuhan Luo, Weiwei Shan, Xiaojun Chen and Xuezhen Luo
Cancers 2022, 14(20), 5024; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14205024 - 14 Oct 2022
Cited by 2 | Viewed by 1438
Abstract
Background: Although obesity was an independent risk factor for fertility-sparing treatment in endometrial atypical hyperplasia (EAH) and endometrioid endometrial cancer (EEC), the roles of other weight statuses and related metabolism were unclear. This study aimed to investigate the body mass index (BMI) interval [...] Read more.
Background: Although obesity was an independent risk factor for fertility-sparing treatment in endometrial atypical hyperplasia (EAH) and endometrioid endometrial cancer (EEC), the roles of other weight statuses and related metabolism were unclear. This study aimed to investigate the body mass index (BMI) interval that produced optimal treatment efficacy and the effects of related metabolic disorders in EAH/EEC patients. Methods: A total of 286 patients (including 209 EAH and 77 well-differentiated EEC) under progestin therapy were retrospectively analyzed. The cumulative complete response (CR) rate, relapse rate, and fertility outcomes were compared among different weight or metabolic statuses. Results: Underweight and overweight/obese status significantly decreased the cumulative 16-week and 32-week CR rate (p = 0.004, p = 0.022, respectively). The highest 16-week CR rate was observed at a BMI of 21–22 kg/m2 in the overall population (p = 0.033). Obesity (HR 0.37, 95%CI 0.15–0.90, p = 0.029) and PCOS (HR 0.55, 95%CI 0.31–0.99, p = 0.047) were associated with lower 16-week CR rate. Hyperuricemia (HR 0.66, 95%CI 0.45–0.99, p = 0.043) was associated with lower 32-week CR rate. The 16-week and 32-week CR rate (p = 0.036, p = 0.008, respectively) were significantly lower in patients exhibiting both obesity and hyperuricemia. Conclusions: The optimal fertility-sparing treatment efficacy was observed at a BMI of 21–22 kg/m2 in EAH/EEC. Hyperuricemia was an independent risk factor for long-term treatment outcomes. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
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15 pages, 2324 KiB  
Article
Biomarkers Associated with Lymph Nodal Metastasis in Endometrioid Endometrial Carcinoma
by Mathilde Mairé, Aurélien Bourdon, Isabelle Soubeyran, Carlo Lucchesi, Frédéric Guyon, Guillaume Babin, Anne Floquet, Adeline Petit, Jessica Baud, Valérie Velasco, Denis Querleu and Sabrina Croce
Cancers 2022, 14(9), 2188; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092188 - 27 Apr 2022
Cited by 3 | Viewed by 2184
Abstract
Introduction. Lymph node metastasis is determinant in the prognosis and treatment of endometrioid endometrial cancer (EEC) but the risk–benefit balance of surgical lymph node staging remains controversial. Objective. Describe the pathways associated with lymph node metastases in EEC detected by whole RNA sequencing. [...] Read more.
Introduction. Lymph node metastasis is determinant in the prognosis and treatment of endometrioid endometrial cancer (EEC) but the risk–benefit balance of surgical lymph node staging remains controversial. Objective. Describe the pathways associated with lymph node metastases in EEC detected by whole RNA sequencing. Methods. RNA-sequencing was performed on a retrospective series of 30 non-metastatic EEC. N+ and N− patients were matched for tumoral size, tumoral grade and myometrial invasion. Results. Twenty-eight EECs were analyzable (16 N+ and 12 N−). Bioinformatics Unsupervised analysis revealed three patterns of expression, enriched in N+, mix of N+/N− and enriched in N−, respectively. The cluster with only N+ patient overexpressed extra cellular matrix, epithelial to mesenchymal and smooth muscle contraction pathways with respect to the N− profile. Differential expression analysis between N+ and N− was used to generate a 54-genes signature with an 87% accuracy. Conclusion. RNA-expression analysis provides a basis to develop a gene expression-based signature that could pre-operatively predict lymph node invasion. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
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10 pages, 590 KiB  
Article
Fertility-Sparing Treatment for Endometrial Cancer: Oncological and Obstetric Outcomes in Combined Therapies with Levonorgestrel Intrauterine Device
by Ida Pino, Anna Daniela Iacobone, Ailyn Mariela Vidal Urbinati, Maria Di Giminiani, Davide Radice, Maria Elena Guerrieri, Eleonora Petra Preti, Silvia Martella and Dorella Franchi
Cancers 2022, 14(9), 2170; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092170 - 26 Apr 2022
Cited by 5 | Viewed by 1806
Abstract
Background: The prevalence of reaches up to 5% in women younger than 40 years. Therefore, the fertility preservation should be the goal of the clinical practice in women with desire of pregnancy and low-risk features. The aim of this study is to compare [...] Read more.
Background: The prevalence of reaches up to 5% in women younger than 40 years. Therefore, the fertility preservation should be the goal of the clinical practice in women with desire of pregnancy and low-risk features. The aim of this study is to compare oncological and reproductive outcomes of different hormonal therapies in FST of EC. Methods: A retrospective single-center study recruiting patients with presumed FIGO STAGE IA endometrioid G1 EC from 2005 to 2020 was performed. We assessed outcomes for three different therapeutic options: GnRHa + LNG-IUD vs. MA + LNG-IUD vs. MA + LNG-IUD + MET. Results: In total, 75 patients were enrolled and followed up for a median of 45 months. Complete response (CR) was achieved in 75% of patients at 12 months. Although not statistically significant, we reported an increasing rate of CR from the regimen with GnRHa to the one with MA + MET (65% vs. 83%). We showed a statistically significant lower risk of recurrence in women treated with MA + LNG-IUD + MET, when compared to GnRHa + LNG-IUD regimen. The pregnancy rate was 74% and live birth rate was 42%, with no differences among regimens. Conclusions: FST is a safe and effective option in women who desire to preserve fertility. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
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13 pages, 2279 KiB  
Article
Predictors for the Recurrence of Clinically Uterine-Confined Endometrial Cancer and the Role of Cytokeratin Immunohistochemistry Stain in the Era of Sentinel Lymph Node Mapping
by Wan-Hua Ting, Shu-Wei Hsieh, Hui-Hua Chen, Ming-Chow Wei, Ho-Hsiung Lin and Sheng-Mou Hsiao
Cancers 2022, 14(8), 1973; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14081973 - 13 Apr 2022
Viewed by 1748
Abstract
Background: The primary objective of this study was to elucidate the predictors for cancer recurrence in women with clinically uterine-confined endometrial cancer in the era of sentinel lymph node (SLN) mapping. Methods: All consecutive women with clinically determined uterine-confined endometrial cancer who had [...] Read more.
Background: The primary objective of this study was to elucidate the predictors for cancer recurrence in women with clinically uterine-confined endometrial cancer in the era of sentinel lymph node (SLN) mapping. Methods: All consecutive women with clinically determined uterine-confined endometrial cancer who had lymph node assessment by either SLN mapping or traditional pelvic lymphadenectomy were reviewed. Results: Women in the SLN mapping group had lower total dissected pelvic nodes, lower incidence of para-aortic lymph node dissection, less intraoperative blood loss and lower complication rates, but a longer operation time compared to the traditional lymphadenectomy group. Para-aortic lymph node metastasis (hazard ratio = 7.60, p = 0.03) was the sole independent predictor for recurrence-free survival. In addition, the utilization of cytokeratin immunohistochemistry stain detected more lymph node metastases (adjusted odds ratio = 3.04, p = 0.03). Recurrence-free survival did not differ between SLN mapping and traditional lymphadenectomy groups (p = 0.24). Conclusions: Para-aortic lymph node metastasis is an important predictor of cancer recurrence. Women with negative hematoxylin and eosin stain should undergo cytokeratin immunohistochemistry stain to increase the detection rate of positive lymph node metastasis. Besides, the probabilities of recurrence seem to be similar between SLN mapping and traditional lymphadenectomy groups in women with clinically uterine-confined endometrial cancer. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
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15 pages, 1626 KiB  
Article
Survival Analysis in Endometrial Carcinomas by Type of Surgical Approach: A Matched-Pair Study
by Pluvio J. Coronado, Agnieszka Rychlik, Laura Baquedano, Virginia García-Pineda, Maria A. Martínez-Maestre, Denis Querleu and Ignacio Zapardiel
Cancers 2022, 14(4), 1081; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14041081 - 21 Feb 2022
Cited by 5 | Viewed by 1700
Abstract
(1) Background: This study aimed to analyze the impact of surgical approach on survival rates in women diagnosed with endometrial cancer. (2) Methods: A retrospective multicenter cohort of 1382 women diagnosed with EC was performed. A total of 684 (49.5%) women underwent minimally [...] Read more.
(1) Background: This study aimed to analyze the impact of surgical approach on survival rates in women diagnosed with endometrial cancer. (2) Methods: A retrospective multicenter cohort of 1382 women diagnosed with EC was performed. A total of 684 (49.5%) women underwent minimally invasive surgery, 233 (34%) underwent robotic-assisted laparoscopy (RAL), 451 (66%) underwent conventional laparoscopy (LPS), and 698 (50.5%) underwent open surgery (OP). Sociodemographic features, tumor characteristics, and survival rates were analyzed in the whole sample and in a matched-pair model. (3) Results: Women operated on by OP were significantly older, presented more comorbidities, and had more aggressive tumors. Disease-free (DFS), overall (OS), and specific survival related to EC (SS) amounts were significantly higher for MIS compared to OP (p < 0.001). When matched by age, body mass index, comorbidities, ASA score, histological type, grade, myometrial invasion, and FIGO stage, 798 patients were selected. DFS, OS, and SS amounts were similar between the MIS and OP groups. (4) Conclusions: The surgical approach for women with EC does not impact DFS or OS amounts when matched by homogeneous groups. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
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14 pages, 1419 KiB  
Article
Prognosis Stratification Tools in Early-Stage Endometrial Cancer: Could We Improve Their Accuracy?
by Jorge Luis Ramon-Patino, Ignacio Ruz-Caracuel, Victoria Heredia-Soto, Luis Eduardo Garcia de la Calle, Bulat Zagidullin, Yinyin Wang, Alberto Berjon, Alvaro Lopez-Janeiro, Maria Miguel, Javier Escudero, Alejandro Gallego, Beatriz Castelo, Laura Yebenes, Alicia Hernandez, Jaime Feliu, Alberto Pelaez-García, Jing Tang, David Hardisson, Marta Mendiola and Andres Redondo
Cancers 2022, 14(4), 912; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14040912 - 12 Feb 2022
Cited by 3 | Viewed by 2417
Abstract
There are three prognostic stratification tools used for endometrial cancer: ESMO-ESGO-ESTRO 2016, ProMisE, and ESGO-ESTRO-ESP 2020. However, these methods are not sufficiently accurate to address prognosis. The aim of this study was to investigate whether the integration of molecular classification and other biomarkers [...] Read more.
There are three prognostic stratification tools used for endometrial cancer: ESMO-ESGO-ESTRO 2016, ProMisE, and ESGO-ESTRO-ESP 2020. However, these methods are not sufficiently accurate to address prognosis. The aim of this study was to investigate whether the integration of molecular classification and other biomarkers could be used to improve the prognosis stratification in early-stage endometrial cancer. Relapse-free and overall survival of each classifier were analyzed, and the c-index was employed to assess accuracy. Other biomarkers were explored to improve the precision of risk classifiers. We analyzed 293 patients. A comparison between the three classifiers showed an improved accuracy in ESGO-ESTRO-ESP 2020 when RFS was evaluated (c-index = 0.78), although we did not find broad differences between intermediate prognostic groups. Prognosis of these patients was better stratified with the incorporation of CTNNB1 status to the 2020 classifier (c-index 0.81), with statistically significant and clinically relevant differences in 5-year RFS: 93.9% for low risk, 79.1% for intermediate merged group/CTNNB1 wild type, and 42.7% for high risk (including patients with CTNNB1 mutation). The incorporation of molecular classification in risk stratification resulted in better discriminatory capability, which could be improved even further with the addition of CTNNB1 mutational evaluation. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
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10 pages, 1052 KiB  
Article
Prognostic Role of the Removed Vaginal Cuff and Its Correlation with L1CAM in Low-Risk Endometrial Adenocarcinoma
by Enrico Vizza, Valentina Bruno, Giuseppe Cutillo, Emanuela Mancini, Isabella Sperduti, Lodovico Patrizi, Camilla Certelli, Ashanti Zampa, Andrea Giannini and Giacomo Corrado
Cancers 2022, 14(1), 34; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010034 - 22 Dec 2021
Cited by 5 | Viewed by 2229
Abstract
Objective: The aim of our study was to investigate the role of the excised vaginal cuff length as a prognostic factor in terms of DFS and recurrence rate/site, in low-risk endometrial cancer (EC) patients. Moreover, we correlated the recurrence with the expression of [...] Read more.
Objective: The aim of our study was to investigate the role of the excised vaginal cuff length as a prognostic factor in terms of DFS and recurrence rate/site, in low-risk endometrial cancer (EC) patients. Moreover, we correlated the recurrence with the expression of L1CAM. Material and Methods: From March 2001 to November 2016, a retrospective data collection was conducted of women undergoing surgical treatment for low-risk EC according to ESMO-ESGO-ESTRO consensus guidelines. Patients were divided into three groups according to their vaginal cuff length: V0 without vaginal cuff, V1 with a vaginal cuff shorter than 1.5 cm and V2 with a vaginal cuff longer than or equal to 1.5 cm. Results: 344 patients were included in the study: 100 in the V0 group, 179 in the V1 group and 65 in the V2 group. The total recurrence rate was 6.1%: the number of patients with recurrence was 8 (8%), 10 (5.6%) and 3 (4.6%), in the V0, V1 and V2 group, respectively. No statistically significant difference was found in the recurrence rate among the three groups. Although the DFS was higher in the V2 group, the result was not significant. L1CAM was positive in 71.4% of recurrences and in 82% of the distant recurrences. Conclusions: The rate of recurrence in patients with EC at low risk of recurrence does not decrease as the length of the vaginal cuff removed increases. Furthermore, the size of the removed vaginal cuff does not affect either the site of recurrence or the likelihood of survival. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
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15 pages, 2040 KiB  
Article
A Personalized Neoantigen Vaccine in Combination with Platinum-Based Chemotherapy Induces a T-Cell Response Coinciding with a Complete Response in Endometrial Carcinoma
by Alexandre Harari, Apostolos Sarivalasis, Kaat de Jonge, Anne-Christine Thierry, Florian Huber, Caroline Boudousquie, Laetitia Rossier, Angela Orcurto, Martina Imbimbo, Petra Baumgaertner, Michal Bassani-Sternberg and Lana E. Kandalaft
Cancers 2021, 13(22), 5801; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225801 - 18 Nov 2021
Cited by 4 | Viewed by 2545
Abstract
Endometrial cancer (EC) is a common gynecological malignancy and the fourth most common malignancy in European and North American women. Amongst EC, the advanced serous, p53-mutated, and pMMR subtypes have the highest risk of relapse despite optimal standard of care therapy. At present, [...] Read more.
Endometrial cancer (EC) is a common gynecological malignancy and the fourth most common malignancy in European and North American women. Amongst EC, the advanced serous, p53-mutated, and pMMR subtypes have the highest risk of relapse despite optimal standard of care therapy. At present, there is no standard of care maintenance treatment to prevent relapse among these high-risk patients. Vaccines are a form of immunotherapy that can potentially increase the immunogenicity of pMMR, serous, and p53-mutated tumors to render them responsive to check point inhibitor-based immunotherapy. We demonstrate, for the first time, the feasibility of generating a personalized dendritic cell vaccine pulsed with peptide neoantigens in a patient with pMMR, p53-mutated, and serous endometrial adenocarcinoma (SEC). The personalized vaccine was administered in combination with systemic chemotherapy to treat an inoperable metastatic recurrence. This treatment association demonstrated the safety and immunogenicity of the personalized dendritic cell vaccine. Interestingly, a complete oncological response was obtained with respect to both radiological assessment and the tumor marker CA-125. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
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16 pages, 608 KiB  
Article
Does Clinical and Biochemical Thyroid Dysfunction Impact on Endometrial Cancer Survival Outcomes? A Prospective Database Study
by Chloe E. Barr, Kelechi Njoku, Leo Hotchkies, Neil A. J. Ryan, Y. Louise Wan, David A. Davies, Salman Razvi and Emma J. Crosbie
Cancers 2021, 13(21), 5444; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215444 - 29 Oct 2021
Cited by 6 | Viewed by 2161
Abstract
Endometrial cancer is the commonest gynaecological malignancy in developed countries, and women presenting with high risk or advanced disease have poor outcomes. Thyroid hormones play a key role in cellular metabolism and can influence cancer growth and invasion. Our aim was to evaluate [...] Read more.
Endometrial cancer is the commonest gynaecological malignancy in developed countries, and women presenting with high risk or advanced disease have poor outcomes. Thyroid hormones play a key role in cellular metabolism and can influence cancer growth and invasion. Our aim was to evaluate the association between clinical and biochemical thyroid dysfunction and endometrial cancer survival outcomes. This was a prospective cohort study of women treated for endometrial cancer at a specialist centre. Clinical diagnosis of hypothyroidism was based on clinical and biochemical assessment, verified by general practitioner (GP) records. Pre-treatment serum samples were tested for thyrotropin (TSH), thyroid hormones (free T4 and total T3), and thyroid peroxidase antibodies. Kaplan–Meier survival estimates and log-rank tests were used to compare survival between groups, while Cox regression was used for multivariable analysis, adjusting for known confounders and effect modifications. In total, 333 women with median age and body mass index (BMI) of 66 years (interquartile range (IQR) 56, 73) and 33 kg/m2 (IQR 27, 41) respectively were included. A total of 51 (15.3%) women had a diagnosis of hypothyroidism, 39 (11.9%) had biochemical evidence of overt or subclinical hypothyroidism. Median follow-up was 35 months (IQR 21, 45) with 38 (11.7%) relapses and 50 (15.0%) deaths. Women with a diagnosis of hypothyroidism had improved overall survival (adjusted HR = 0.22, 95%CI 0.06–0.74, p = 0.02), cancer-specific survival (adjusted HR = 0.21, 95%CI 0.05–0.98, p = 0.04) and fewer recurrences (adjusted HR = 0.17, 95%CI 0.04–0.77, p = 0.02) than those who did not. Confirmatory studies should explore underlying mechanisms and the potential for therapeutic exploitation. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
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11 pages, 504 KiB  
Article
Mismatch Repair Deficiency as a Predictive and Prognostic Biomarker in Molecularly Classified Endometrial Carcinoma
by Mikko Loukovaara, Annukka Pasanen and Ralf Bützow
Cancers 2021, 13(13), 3124; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13133124 - 22 Jun 2021
Cited by 7 | Viewed by 2074
Abstract
The aggressiveness of mismatch repair (MMR) deficient endometrial carcinomas was examined in a single institution retrospective study. Outcomes were similar for MMR proficient (n = 508) and deficient (n = 287) carcinomas, identified by immunohistochemistry. In accordance with molecular classification based [...] Read more.
The aggressiveness of mismatch repair (MMR) deficient endometrial carcinomas was examined in a single institution retrospective study. Outcomes were similar for MMR proficient (n = 508) and deficient (n = 287) carcinomas, identified by immunohistochemistry. In accordance with molecular classification based on The Cancer Genome Atlas (TCGA), tumors with abnormal p53 staining or polymerase-ϵ exonuclease domain mutation were excluded from the MMR proficient subgroup, termed as “no specific molecular profile” (NSMP). Compared with NSMP (n = 218), MMR deficiency (n = 191) was associated with poor disease-specific survival (p = 0.001). MMR deficiency was associated with an increased risk of cancer-related death when controlling for confounders (hazard ratio 2.0). In the absence of established clinicopathologic risk factors, MMR deficiency was invariably associated with an increased risk of cancer-related death in univariable analyses (hazard ratios ≥ 2.0). In contrast, outcomes for MMR deficient and NSMP subgroups did not differ when risk factors were present. Lymphatic dissemination was more common (p = 0.008) and the proportion of pelvic relapses was higher (p = 0.029) in the MMR deficient subgroup. Our findings emphasize the need for improved triage to adjuvant therapy and new therapeutic approaches in MMR deficient endometrial carcinomas. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
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21 pages, 6157 KiB  
Article
ARID1A and CTNNB1/β-Catenin Molecular Status Affects the Clinicopathologic Features and Prognosis of Endometrial Carcinoma: Implications for an Improved Surrogate Molecular Classification
by Antonio De Leo, Dario de Biase, Jacopo Lenzi, Giovanna Barbero, Daniela Turchetti, Marco Grillini, Gloria Ravegnini, Sabrina Angelini, Claudio Zamagni, Sara Coluccelli, Giulia Dondi, Pierandrea De Iaco, Anna Myriam Perrone, Giovanni Tallini, Donatella Santini and Claudio Ceccarelli
Cancers 2021, 13(5), 950; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13050950 - 25 Feb 2021
Cited by 33 | Viewed by 3927
Abstract
The collaborative Cancer Genome Atlas (TCGA) project identified four distinct prognostic groups of endometrial carcinoma (EC) based on molecular alterations: (i) the ultramutated subtype that encompasses POLE mutated (POLE) cases; (ii) the hypermutated subtype, characterized by MisMatch Repair deficiency (MMRd); (iii) [...] Read more.
The collaborative Cancer Genome Atlas (TCGA) project identified four distinct prognostic groups of endometrial carcinoma (EC) based on molecular alterations: (i) the ultramutated subtype that encompasses POLE mutated (POLE) cases; (ii) the hypermutated subtype, characterized by MisMatch Repair deficiency (MMRd); (iii) the copy-number high subtype, with p53 abnormal/mutated features (p53abn); (iv) the copy-number low subtype, known as No Specific Molecular Profile (NSMP). Although the prognostic value of TCGA molecular classification, NSMP carcinomas present a wide variability in molecular alterations and biological aggressiveness. This study aims to investigate the impact of ARID1A and CTNNB1/β-catenin alterations by targeted Next-generation sequencing (NGS) and immunohistochemistry (IHC) in a consecutive series of 125 molecularly classified ECs. NGS and IHC were used to assign surrogate TCGA groups and to identify molecular alterations of multiple target genes including POLE, PTEN, ARID1A, CTNNB1, TP53. Associations with clinicopathologic parameters, molecular subtypes, and outcomes identified NSMP category as the most heterogeneous group in terms of clinicopathologic features and outcome. Integration of surrogate TCGA molecular classification with ARID1A and β-catenin analysis showed NSMP cases with ARID1A mutation characterized by the worst outcome with early recurrence, while NSMP tumors with ARID1A wild-type and β-catenin alteration had indolent clinicopathologic features and no recurrence. This study indicates how the identification of ARID1A and β-catenin alterations in EC represents a simple and effective way to characterize NSMP tumor aggressiveness and metastatic potential. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
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Review

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11 pages, 276 KiB  
Review
Do Not Forget about Hormonal Therapy for Recurrent Endometrial Cancer: A Review of Options, Updates, and New Combinations
by Vincent M. Wagner and Floor J. Backes
Cancers 2023, 15(6), 1799; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15061799 - 16 Mar 2023
Cited by 3 | Viewed by 2312
Abstract
Hormonal therapy has long been a treatment modality for recurrent endometrial cancer. It is appealing for patients with low-grade, slow-growing tumors or in patients for which other treatment types may be too toxic. Hormonal therapy is well tolerated and has response rates ranging [...] Read more.
Hormonal therapy has long been a treatment modality for recurrent endometrial cancer. It is appealing for patients with low-grade, slow-growing tumors or in patients for which other treatment types may be too toxic. Hormonal therapy is well tolerated and has response rates ranging from 9 to 33%. Hormonal treatment options take advantage of the estrogen-dependent molecular pathways in endometrial cancers. Current options for hormonal therapies include progesterone therapy (medroxyprogesterone acetate and megestrol acetate) as a single agent or in combination and agents that target the estrogen pathway. Aromatase inhibitors have had modest single-agent activity, but synergistic effects have been found when used in combination with targeted therapy including mTOR inhibitors and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Molecular profiling of endometrial cancers has begun to help individualize treatments. This review will report on existing data and ongoing trials investigating novel hormonal therapy agents. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
19 pages, 702 KiB  
Review
Ion Channels in Endometrial Cancer
by Bruna Pasqualotto Costa, Fernanda Bordignon Nunes, Francini Corrêa Noal and Gisele Branchini
Cancers 2022, 14(19), 4733; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194733 - 28 Sep 2022
Cited by 2 | Viewed by 1731
Abstract
Uterine or endometrial cancer (EC) is the sixth most common neoplasia among women worldwide. Cancer can originate from a myriad of causes, and increasing evidence suggests that ion channels (IC) play an important role in the process of carcinogenesis, taking part in many [...] Read more.
Uterine or endometrial cancer (EC) is the sixth most common neoplasia among women worldwide. Cancer can originate from a myriad of causes, and increasing evidence suggests that ion channels (IC) play an important role in the process of carcinogenesis, taking part in many pathways such as self-sufficiency in growth signals, proliferation, evasion of programmed cell death (apoptosis), angiogenesis, cell differentiation, migration, adhesion, and metastasis. Hormones and growth factors are well-known to be involved in the development and/or progression of many cancers and can also regulate some ion channels and pumps. Since the endometrium is responsive and regulated by these factors, the ICs could make an important contribution to the development and progression of endometrial cancer. In this review, we explore what is beyond (ion) flow regulation by investigating the role of the main families of ICs in EC, including as possible targets for EC treatment. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
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19 pages, 768 KiB  
Review
Therapeutic Benefit of Systematic Lymphadenectomy in Node-Negative Uterine-Confined Endometrioid Endometrial Carcinoma: Omission of Adjuvant Therapy
by Isao Otsuka
Cancers 2022, 14(18), 4516; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14184516 - 17 Sep 2022
Cited by 1 | Viewed by 3111
Abstract
Endometrial cancer is the most common gynecological tract malignancy in developed countries, and its incidence has been increasing globally with rising obesity rates and longer life expectancy. In endometrial cancer, extrauterine disease, in particular lymph node metastasis, is an important prognostic factor. Nevertheless, [...] Read more.
Endometrial cancer is the most common gynecological tract malignancy in developed countries, and its incidence has been increasing globally with rising obesity rates and longer life expectancy. In endometrial cancer, extrauterine disease, in particular lymph node metastasis, is an important prognostic factor. Nevertheless, pelvic lymphadenectomy is not considered to have a therapeutic benefit, as it did not improve survival in randomized studies. However, lymphadenectomy may have a therapeutic benefit if adjuvant therapy can be omitted without decreasing oncological outcomes, as the long-term quality of life is maintained by avoiding morbidities associated with adjuvant therapy. In intermediate- and high-risk endometrioid endometrial carcinomas, adjuvant therapy may be safely omitted without decreasing long-term survival by open surgery including systematic pelvic and para-aortic lymphadenectomy when patients are node-negative. Systematic lymphadenectomy may remove undetectable low-volume lymph node metastasis in both pelvic and para-aortic regions, and open surgery may reduce vaginal recurrence even without vaginal brachytherapy. However, lymphadenectomy may not improve survival in elderly patients and patients with p53-mutant tumors. In this review, I discuss the characteristics of lymph node metastasis, the methods of lymph node assessment, and the therapeutic benefits of systematic lymphadenectomy in patients with intermediate- and high-risk endometrioid endometrial carcinoma. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
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20 pages, 357 KiB  
Review
Current Approaches to the Management of Patients with Endometrial Cancer
by Emmanouil Kalampokas, Georgios Giannis, Theodoros Kalampokas, Angeliki-Astero Papathanasiou, Dimitra Mitsopoulou, Evangelia Tsironi, Olga Triantafyllidou, Mahalakshmi Gurumurthy, David E. Parkin, Mary Cairns and Nikolaos F. Vlahos
Cancers 2022, 14(18), 4500; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14184500 - 16 Sep 2022
Cited by 20 | Viewed by 2799
Abstract
The incidence of endometrial cancer (EC) is rising and healthcare professionals need to be informed about the latest data on the constant developments in the field of its management. With particular interest in the classification and management of EC, we surveyed current literature, [...] Read more.
The incidence of endometrial cancer (EC) is rising and healthcare professionals need to be informed about the latest data on the constant developments in the field of its management. With particular interest in the classification and management of EC, we surveyed current literature, national and international data, and guidelines, as well as the latest studies to present the most recent data regarding the management of EC. It became evident that despite the consensus on low-risk EC, there are still controversies surrounding the management of high-risk EC, especially regarding the role of sentinel lymph node biopsy (SLNB). Our aim is to present the old and new perspectives in the management of EC, the different available surgical routes, the possible desire for fertility preservation, the role of adjuvant therapies and the focus on the advantages and the limitations of the implementation of SLNB in therapeutic strategies. It became evident throughout our search and based on literature data that minimally invasive surgery (MIS) leads to satisfying outcomes, thus becoming gradually the preferred route of surgery, while SLNB could provide essential information and guidance about the overall management needed in cases of both low-risk and high-risk EC. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
18 pages, 1168 KiB  
Review
The Perspectives of Fertility Preservation in Women with Endometrial Cancer
by Jure Knez, Leyla Al Mahdawi, Iztok Takač and Monika Sobočan
Cancers 2021, 13(4), 602; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040602 - 03 Feb 2021
Cited by 18 | Viewed by 3074
Abstract
Endometrial cancer is the most common gynecological cancer in developed countries. The disease is diagnosed with increasing frequency in younger women, commonly also in their reproductive age. The standard treatment of endometrial cancer is surgical in the form of hysterectomy and bilateral salpingo-oophorectomy, [...] Read more.
Endometrial cancer is the most common gynecological cancer in developed countries. The disease is diagnosed with increasing frequency in younger women, commonly also in their reproductive age. The standard treatment of endometrial cancer is surgical in the form of hysterectomy and bilateral salpingo-oophorectomy, and this precludes future fertility in younger women. The current challenge is to identify the group of women with endometrial cancer and low-risk features that would benefit from more conservative treatment options. More focus in management needs to be aimed towards the preservation of quality of life, without jeopardizing oncological outcomes. In this review, we analyze the current approaches to identification of women for conservative management and evaluate the success of different medical options for treatment and surgical techniques that are fertility sparing. We also elaborate on the future perspectives, focusing on the incorporation of molecular characterization of endometrial cancer to fertility preservation algorithms. Future studies should focus specifically on identifying reliable clinical and molecular predictive markers in this group of young women. With improved knowledge and better risk assessment, the precision medicine is the path towards improved understanding of the disease and possibly widening the group of women that could benefit from treatment methods preserving their fertility. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
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Other

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17 pages, 689 KiB  
Systematic Review
Uterine Preservation Treatments in Sarcomas: Oncological Problems and Reproductive Results: A Systematic Review
by Giulia Dondi, Eleonora Porcu, Alessandra De Palma, Giuseppe Damiano, Eugenia De Crescenzo, Linda Cipriani, Maria Dirodi, Gloria Ravegnini, Antonio De Leo, Margherita Nannini, Martina Ferioli, Alessio G. Morganti, Maria Abbondanza Pantaleo, Pierandrea De Iaco and Anna Myriam Perrone
Cancers 2021, 13(22), 5808; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225808 - 19 Nov 2021
Cited by 6 | Viewed by 2056
Abstract
Uterine sarcomas are rare cancers, sometimes diagnosed in women of childbearing age. Hysterectomy is the standard treatment in early stages. The option of lesion removal to save fertility is described in the literature, but it is still considered experimental. The objective of this [...] Read more.
Uterine sarcomas are rare cancers, sometimes diagnosed in women of childbearing age. Hysterectomy is the standard treatment in early stages. The option of lesion removal to save fertility is described in the literature, but it is still considered experimental. The objective of this systematic review is to report on the available evidence on the reproductive and oncological outcomes of fertility-sparing treatment in women with uterine sarcomas. PubMed, Scopus and Cochrane Central Register of Controlled Trials were searched between 1 January 2011 and 21 June 2021 for publications in English about women with uterine sarcoma treated with a fertility-sparing intervention. Thirty-seven studies were included for a total of 210 patients: 63 low-grade endometrial stromal sarcomas, 35 embryonal rhabdomyosarcomas of the cervix, 19 adenosarcomas, 7 leiomyosarcomas and 2 uterine tumors resembling an ovarian sex cord. Conservative treatment ensured pregnancy in 32% of cases. In terms of oncological outcomes, relapse was related to histology and the worst prognosis was reported for leiomyosarcoma, followed by low-grade endometrial stromal sarcoma, which relapsed in 71% and 54% of cases, respectively. The highest death rate was associated with leiomyosarcoma (57.1%). This study demonstrated that fertility-sparing treatments may be employed in selected cases of early stage uterine sarcoma. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
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