Journal of Pathology and Translational Medicine

Original Articles

Mismatch repair deficiency and clinicopathological characteristics in endometrial carcinoma: a systematic review and meta-analysis: Alaa Salah Jumaah, Hawraa Sahib Al-Haddad, Mais Muhammed Salem, Katherine Ann McAllister, Akeel Abed Yasseen; J Pathol Transl Med. 2021;55(3):202-211. Published online April 14, 2021; DOI: https://doi.org/10.4132/jptm.2021.02.19

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Background
Loss of mismatch repair (MMR) occurs frequently in endometrial carcinoma (EC) and is an important prognostic marker. However, the frequency of MMR deficiency (D-MMR) in EC remains inconclusive. This systematic review and meta-analysis addressed this inconsistency and evaluated related clinicopathology.
Methods
Electronic databases were searched for articles: PubMed, Science Direct, Web of Science, EMBASE, and the Wiley Online Library. Data were extracted from 25 EC studies of D-MMR to generate a clinical dataset of 7,459 patients. A random-effects model produced pooled estimates of D-MMR EC frequency with 95% confidence interval (CI) for meta-analysis.
Results
The overall pooled proportion of D-MMR was 24.477% (95% CI, 21.022 to 28.106) in EC. The Lynch syndrome subgroup had 22.907% pooled D-MMR (95% CI, 14.852 to 32.116). D-MMR was highest in type I EC (25.810) (95% CI, 22.503 to 29.261) compared to type II (13.736) (95% CI, 8.392 to 20.144). Pooled D-MMR was highest at EC stage and grades I–II (79.430% and 65.718%, respectively) and lowest in stages III–IV and grade III (20.168% and 21.529%). The pooled odd ratios comparing D-MMR to proficient MMR favored low-stage EC disease (1.565; 0.894 to 2.740), lymphovascular invasion (1.765; 1.293 to 2.409), and myometrial invasion >50% (1.271; 0.871 to 1.853).
Conclusions
Almost one-quarter of EC patients present with D-MMR tumors. The majority has less aggressive endometrioid histology. D-MMR presents at lower tumor stages compared to MMR-proficient cases in EC. However other metastatic parameters are comparatively higher in the D-MMR disease setting.

Citations

Citations to this article as recorded by

miR-486-3p Controls the Apoptosis of Endometrial Carcinoma Cells
Donghua Wang, Xiaoli Liu, Lirong Cao, Shixiong Gong, Yi He, Xiangbin Jiang, Zhongxian Wang
Journal of Biomaterials and Tissue Engineering.2022; 12(5): 1002. CrossRef
The Role of Immunohistochemistry Markers in Endometrial Cancer with Mismatch Repair Deficiency: A Systematic Review
Amelia Favier, Justine Varinot, Catherine Uzan, Alex Duval, Isabelle Brocheriou, Geoffroy Canlorbe
Cancers.2022; 14(15): 3783. CrossRef

The frequency of POLE-mutation in endometrial carcinoma and prognostic implications: a systemic review and meta-analysis: Alaa Salah Jumaah, Mais Muhammed Salim, Hawraa Sahib Al-Haddad, Katherine Ann McAllister, Akeel Abed Yasseen; J Pathol Transl Med. 2020;54(6):471-479. Published online September 2, 2020; DOI: https://doi.org/10.4132/jptm.2020.07.23

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Abstract PDF Supplementary Material

Background
Endometrial carcinoma (EC) is classified into four distinct molecular subgroups including ultramutated DNA polymerase epsilon (POLE). POLE-mutated tumors have the best prognosis and are a promising target for immunotherapy. This meta-analysis consolidated the reported variation of POLE-mutant frequency and assessed prognostic value in EC.
Methods
Internet searches explored scientific data bases: EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials databases. Data was extracted from eligible studies including: sample size, number of positive POLE-mutant cases, sequencing information, clinicopathologic data, and survival data. Meta-analysis and a random-effects model produced pooled estimates of POLE frequency and prognostic parameters using 95% confidence intervals (CI), hazard ratios (HR), and odd ratios (OR).
Results
Six thousand three hundred and forty-six EC patient cases were pooled from 25 studies. The pooled proportion of POLE gene mutation in EC was 8.59% (95% CI, 7.01 to 10.32), of which 8.22% (95% CI, 6.27 to 10.42) were type I and 0.93% (95% CI, 0.34 to 1.81) type 2. Clinicopathologic data showed that POLE-mutated tumors are mostly endometrioid. They present at higher levels in earlier stages (I–II) of EC (89.51%; 95% CI, 81.11 to 95.66) at the highest grade III (51.53%; 95% CI, 36.08 to 66.84) with reduced myometrial invasion (OR, 1.48, 95% CI, 0.99 to 2.20). Survival analysis indicated favorable overall survival (HR, 0.90), disease-specific survival (HR, 0.41), and progression-free survival (HR, 0.23) for POLE mutant EC.
Conclusions
Almost one-tenth of EC patients have POLE-mutated tumors. Given their improved prognostic potential, identifying the POLE mutation status is key for the management of EC patients.

Citations

Citations to this article as recorded by

Fast and reliable Sanger POLE sequencing protocol in FFPE tissues of endometrial cancer
Izabela Laczmanska, Dagmara Michalowska, Marcin Jedryka, Dorota Blomka, Mariola Semeniuk, Ewelina Czykalko, Mariola Abrahamowska, Paulina Mlynarczykowska, Agnieszka Chrusciel, Ireneusz Pawlak, Adam Maciejczyk
Pathology - Research and Practice.2023; 242: 154315. CrossRef
Uterine Neoplasms, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology
Nadeem Abu-Rustum, Catheryn Yashar, Rebecca Arend, Emma Barber, Kristin Bradley, Rebecca Brooks, Susana M. Campos, Junzo Chino, Hye Sook Chon, Christina Chu, Marta Ann Crispens, Shari Damast, Christine M. Fisher, Peter Frederick, David K. Gaffney, Robert
Journal of the National Comprehensive Cancer Network.2023; 21(2): 181. CrossRef
The hereditary N363K POLE exonuclease mutant extends PPAP tumor spectrum to glioblastomas by causing DNA damage and aneuploidy in addition to increased mismatch mutagenicity
Guillaume Labrousse, Pierre Vande Perre, Genis Parra, Marion Jaffrelot, Laura Leroy, Frederic Chibon, Frederic Escudie, Janick Selves, Jean-Sebastien Hoffmann, Rosine Guimbaud, Malik Lutzmann
NAR Cancer.2023;[Epub] CrossRef
The clinicopathology and survival characteristics of patients with POLE proofreading mutations in endometrial carcinoma: A systematic review and meta-analysis
Alaa Salah Jumaah, Hawraa Sahib Al-Haddad, Katherine Ann McAllister, Akeel Abed Yasseen, Manish S. Patankar
PLOS ONE.2022; 17(2): e0263585. CrossRef
Enhanced polymerase activity permits efficient synthesis by cancer-associated DNA polymerase ϵ variants at low dNTP levels
Stephanie R Barbari, Annette K Beach, Joel G Markgren, Vimal Parkash, Elizabeth A Moore, Erik Johansson, Polina V Shcherbakova
Nucleic Acids Research.2022; 50(14): 8023. CrossRef
The Role of Immunohistochemistry Markers in Endometrial Cancer with Mismatch Repair Deficiency: A Systematic Review
Amelia Favier, Justine Varinot, Catherine Uzan, Alex Duval, Isabelle Brocheriou, Geoffroy Canlorbe
Cancers.2022; 14(15): 3783. CrossRef
The clinicopathological characteristics of POLE-mutated/ultramutated endometrial carcinoma and prognostic value of POLE status: a meta-analysis based on 49 articles incorporating 12,120 patients
Qing Wu, Nianhai Zhang, Xianhe Xie
BMC Cancer.2022;[Epub] CrossRef
Mismatch repair deficiency and clinicopathological characteristics in endometrial carcinoma: a systematic review and meta-analysis
Alaa Salah Jumaah, Hawraa Sahib Al-Haddad, Mais Muhammed Salem, Katherine Ann McAllister, Akeel Abed Yasseen
Journal of Pathology and Translational Medicine.2021; 55(3): 202. CrossRef
Evaluation of treatment effects in patients with endometrial cancer and POLE mutations: An individual patient data meta‐analysis
Jessica N. McAlpine, Derek S. Chiu, Remi A. Nout, David N. Church, Pascal Schmidt, Stephanie Lam, Samuel Leung, Stefania Bellone, Adele Wong, Sara Y. Brucker, Cheng Han Lee, Blaise A. Clarke, David G. Huntsman, Marcus Q. Bernardini, Joanne Ngeow, Alessand
Cancer.2021; 127(14): 2409. CrossRef
Endometrial cancer
Vicky Makker, Helen MacKay, Isabelle Ray-Coquard, Douglas A. Levine, Shannon N. Westin, Daisuke Aoki, Ana Oaknin
Nature Reviews Disease Primers.2021;[Epub] CrossRef

High Expression of Galectin-1, VEGF and Increased Microvessel Density Are Associated with MELF Pattern in Stage I-III Endometrioid Endometrial Adenocarcinoma: Dmitry Aleksandrovich Zinovkin, Sergey Leonidovich Achinovich, Mikhail Grigoryevich Zubritskiy, Jacqueline Linda Whatmore, Md Zahidul Islam Pranjol; J Pathol Transl Med. 2019;53(5):280-288. Published online June 27, 2019; DOI: https://doi.org/10.4132/jptm.2019.05.13

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Abstract PDF

Background
In this study, we investigate the expression of markers of angiogenesis and microvessel density (MVD) in cases of microcystic, elongated and fragmented (MELF) pattern, with its prognostic role in the survival of endometrioid endometrial adenocarcinomas (EA) patients.
Methods
In this study, 100 cases of EA, 49 cases with MELF pattern and 51 without, were immunohistochemically stained for galectin-1, vascular endothelial growth factor (VEGF), and MVD. Morphometry and statistical (univariate and multivariate) analyses were performed to assess overall survival (OS) and disease-free survival.
Results
The expression of VEGF (p<.001) and galectin-1 (p<.001), as well as MVD area (p<.001) and number of vessels/mm2 (p<.050), were significantly higher in the +MELF pattern group compared to the –MELF group. A low negative correlation between MELFpattern and the number of days of survival (p<.001, r=–0.47) was also found. A low positive correlation of MELF-pattern with galectin-1 expression (p<.001, r=0.39), area of vessels/mm2 (p<.001, r=0.36), outcome of EA (p<.001, r=0.42) and VEGF expression (p<.001, r=0.39) suggests potential pathological relevance of these factors in the prognosis of EA. A univariate survival analysis indicated a role for all parameters of survival. Multivariate Cox proportional hazard regression analysis revealed that only area of vessels/mm2 (hazard ratio [HR], 1.018; 95% confidence interval [CI], 1.002 to 1.033), galectin-1 (HR, 1.049; 95% CI, 1.025 to 1.074) and VEGF (HR, 1.049; 95% CI, 1.022 to 1.077) play key roles in OS.
Conclusions
This study reports an increase in MVD, VEGF and galectin-1 expression in EA with MELF pattern and suggests that MELF pattern, along with the angiogenic profile, may be a prognostic factor in EA.

Citations

Citations to this article as recorded by

Clinicopathologic association and prognostic impact of microcystic, elongated and fragmented pattern invasion, combined with tumor budding in endometrioid endometrial cancer
Xiqin Qi, Lun Zhu, Bei Zhang
Journal of Obstetrics and Gynaecology Research.2022; 48(9): 2431. CrossRef
Role of adipocytokines in endometrial cancer progression
Ran Li, Fang Dong, Ling Zhang, Xiuqin Ni, Guozhi Lin
Frontiers in Pharmacology.2022;[Epub] CrossRef
Advances in Anti-Cancer Immunotherapy: Car-T Cell, Checkpoint Inhibitors, Dendritic Cell Vaccines, and Oncolytic Viruses, and Emerging Cellular and Molecular Targets
Emilie Alard, Aura-Bianca Butnariu, Marta Grillo, Charlotte Kirkham, Dmitry Aleksandrovich Zinovkin, Louise Newnham, Jenna Macciochi, Md Zahidul Islam Pranjol
Cancers.2020; 12(7): 1826. CrossRef

A Study of Bcl-2 Oncoprotein Expression in Endometrial Carcinoma Correlated with Hormone Receptor Status.: Young Im Han, Hye Jin Lee, Ji Yeon Lee, Sun Kyung Lee; Korean J Pathol. 1996;30(5):408-416.

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Abstract PDF: Bcl-2 is a proto-oncogene initially described in follicular lymphoma, associated with chromosomal translocation(14;18). Recent studies have shown the presence of Bcl-2 in nonhematolymphoid tissue, especially in hormonally responsive tissue. The endometrium is an attractive model for studying the hormone dependent regulation of Bcl-2 expression. We have studied the immunoreactivity of Bcl-2 oncoprotein in relation to the immunoreactivity of estrogen receptors(ER) and progesterone receptors(PR) by immunohistochemistry in 52 human endometrial carcinomas, according to nuclear grade. The results obtained are summarized as followings, 1) Immunohistochemical grade of Bcl-2 showed a significant inverse correlation with nuclear grade. 2) Immunohistochemical grades of ER and PR also showed a significant inverse correlation with nuclear grade, and were well correlated with each other. 3) Immunohistochemical grades of Bcl-2 and hormone receptors showed a strongly significant correlation. On the basis of the above results, we suggest that Bcl-2 expression may be under hormone dependent control and that it can be used in prognosis and choice of hormonal therapy in the presence of hormone receptor.

Expression of p53 Protein in Endometrial Carcinoma.: Mi Jin Kim, Dong Suk Kim; Korean J Pathol. 1999;33(5):347-352.

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Abstract PDF: The mutation of p53, a tumor suppressor gene, has been considered to play an important role in tumorigenesis in a variety of human cancers and the abnormal expression of p53 are frequently associated with poor prognosis. In order to examine the association of p53 overexpression with known prognostic factors including estrogen receptors (ER) and progesterone receptors (PR), we studied the status of p53 protein expression by immunohistochemical staining of paraffin sections of 29 endometrial carcinoma (25 endometrioid carcinoma, 2 clear cell carcinoma, and 2 serous carcinoma), obtained from hysterectomy. The results were as follows: The expression of p53, ER, and PR was present in 9/29 (31%), 3/29 (16%), and 12/29 (48%), respectively. The expression of p53 in endometrioid adenocarcinoma was present in 6/25 (24%) and showed significant correlation with histologic grade, nuclear grade, and myometrial invasion. The status of PR showed significant inverse correlation with histologic grade, nuclear grade and myometrial invasion. There was no significant correlation between ER status and these histologic factors. The expression of p53 was inversely associated with the status of PR, but statistically not significant. Our results indicate that p53 may be useful in predicting prognosis in endometrial carcinoma and will be able to provide helpful information in predetermination of aggressive behavior of the tumor in evaluation of curettage specimen.

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