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Cancers
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Immunohistochemical Markers in Endometrial Cancer
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Immunohistochemical Markers in Endometrial Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Methods and Technologies Development".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 29908

Special Issue Editors

Prof. Dr. Valerio Mais

E-Mail Website
Guest Editor
Department of Surgical Sciences, University of Cagliari Medical School, 09124 Cagliari, Italy
Interests: gynecological oncology; endometrial cancer; intraoperative sentinel lymph node mapping
Dr. Michele Peiretti

E-Mail Website
Guest Editor
Division of Gynecology and Obstetrics, Department of Surgical Sciences, University of Cagliari, Cagliari ,Italy
Interests: gynecological oncology; conservative treatment for well-differentiated endometrial cancer; cytoreductive surgery; nerve-sparing radical hysterectomy

Special Issue Information

Dear Colleagues,

In the early 1980s, researchers proposed to classify endometrial cancer using two broad categories: type I (predominantly endometrioid, typical of perimenopause, with positive estrogen and progesterone receptors and usually a favorable prognosis) and type II (predominantly serous, typical of advanced post menopause, with negative estrogen and progesterone receptors and with a poorer prognosis). However, this classification did not allow for a clear location of grade III endometrioid carcinoma and clear cell carcinoma. For this reason, the current morphological classification of endometrial cancer is based on the use of numerous immunohistochemical markers to try to solve doubtful cases.

Less than ten years ago, a Cancer Genome Atlas (TCGA) study revealed that endometrial cancer is a complex pathology attributable to four molecular subtypes with prognostic significance. Unfortunately, this molecular classification cannot be obtained based on biopsy tissue before the definitive hysterectomy. For this reason, various immunohistochemical markers are now being studied as indicative of the belonging of a given tumor to a specific molecular subtype. This Special Issue aims to provide an overview of the current state of the art in the use of immunohistochemical markers to reclassify endometrial cancer into homogeneous groups characterized by specific prognoses and therapeutic possibilities.

Prof. Dr. Valerio Mais
Dr. Michele Peiretti
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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
  • immunohistochemistry
  • immunohistochemical markers
  • classification
  • prognosis

Published Papers (9 papers)

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Editorial

Jump to: Research, Review, Other

4 pages, 191 KiB  
Editorial
Immunohistochemical Markers in Endometrial Cancer: Latest Updates
by Valerio Mais and Michele Peiretti
Cancers 2023, 15(17), 4202; https://doi.org/10.3390/cancers15174202 - 22 Aug 2023
Viewed by 1107
Abstract
Ten years ago, The Cancer Genome Atlas (TGCA) Research Network classified endometrial cancer into four molecular categories with prognostic significance, suggesting sensitivity to postsurgical treatments [...] Full article
(This article belongs to the Special Issue Immunohistochemical Markers in Endometrial Cancer)
3 pages, 182 KiB  
Editorial
Immunohistochemical Markers in Endometrial Cancer
by Valerio Mais and Michele Peiretti
Cancers 2021, 13(3), 505; https://doi.org/10.3390/cancers13030505 - 29 Jan 2021
Cited by 2 | Viewed by 1686
Abstract
In 2018, 382,069 new cases of uterine cancer were registered worldwide and 89,929 deaths from this cancer were reported [...] Full article
(This article belongs to the Special Issue Immunohistochemical Markers in Endometrial Cancer)

Research

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11 pages, 1262 KiB  
Article
Testing for Lynch Syndrome in Endometrial Carcinoma: From Universal to Age-Selective MLH1 Methylation Analysis
by Annukka Pasanen, Mikko Loukovaara, Elina Kaikkonen, Alisa Olkinuora, Kirsi Pylvänäinen, Pia Alhopuro, Päivi Peltomäki, Jukka-Pekka Mecklin and Ralf Bützow
Cancers 2022, 14(5), 1348; https://doi.org/10.3390/cancers14051348 - 6 Mar 2022
Cited by 3 | Viewed by 3359
Abstract
International guidelines recommend universal screening of endometrial carcinoma (EC) patients for Lynch syndrome (LS). This screening is generally based on mismatch repair (MMR) protein immunohistochemistry followed by MLH1 methylation analysis of MLH1-negative cases to exclude the likely sporadic cases from germline testing. As [...] Read more.
International guidelines recommend universal screening of endometrial carcinoma (EC) patients for Lynch syndrome (LS). This screening is generally based on mismatch repair (MMR) protein immunohistochemistry followed by MLH1 methylation analysis of MLH1-negative cases to exclude the likely sporadic cases from germline testing. As LS-associated EC is uncommon in the elderly, age-selective methylation testing could improve cost-efficiency. We performed MMR immunohistochemistry on 821 unselected ECs (clinic-based cohort) followed by a MLH1 promoter methylation test of all MLH1/PMS2-negative tumors. Non-methylated MLH1-deficient cases underwent NGS and MLPA-based germline analyses to identify MLH1 mutation carriers. A reduction in the test burden and corresponding false negative rates for LS screening were investigated for various age cut-offs. In addition, the age distribution of 132 MLH1 mutation carriers diagnosed with EC (registry-based cohort) was examined. A germline MLH1 mutation was found in 2/14 patients with non-methylated MLH1-deficient EC. When compared to a universal methylation analysis, selective testing with a cut-off age of 65 years, would have reduced the testing effort by 70.7% with a false negative rate for LS detection of 0% and 3% in the clinic and registry-based cohorts, respectively. The use of age-selective methylation analysis is a feasible way of reducing the costs and laboratory burden in LS screening for EC patients. Full article
(This article belongs to the Special Issue Immunohistochemical Markers in Endometrial Cancer)
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12 pages, 34427 KiB  
Article
Molecular Profiling of Endometrial Cancer: An Exploratory Study in Aotearoa, New Zealand
by Claire E. Henry, Khoi Phan, Elena J. Orsman, Diane Kenwright, Michelle C. Thunders and Sara K. Filoche
Cancers 2021, 13(22), 5641; https://doi.org/10.3390/cancers13225641 - 11 Nov 2021
Cited by 6 | Viewed by 2717
Abstract
Background: Aotearoa, New Zealand, has one of the fastest-rising rates of endometrial cancer (EC) worldwide, increasing particularly in younger Māori and Pasifika women. There is a move towards using molecular profiling to direct treatment for each EC subtype. Aim: This study aimed to [...] Read more.
Background: Aotearoa, New Zealand, has one of the fastest-rising rates of endometrial cancer (EC) worldwide, increasing particularly in younger Māori and Pasifika women. There is a move towards using molecular profiling to direct treatment for each EC subtype. Aim: This study aimed to explore the molecular profiling of primary EC tissue in Aotearoa. Methods: We used the PORTEC guidelines for the molecular subtyping of 90 patients’ samples into four categories: POLE-mutated, p53 abnormal, mismatch repair deficient (MMRd) and no specific molecular profile (NSMP). The CTNNB1 mutation and L1CAM expression were also included in the analysis. POLE and CTNNB1 mutations were analysed using targeted next-generation sequencing (NGS). Novel mutations were assessed using VarSome. MMRd, L1CAM and p53 abnormalities were analysed using immunohistochemistry. Results: In total, 15 samples were MMRd, 9 were p53 abnormal, 8 were POLE-mutated and the rest (56) were NSMP. Eleven samples had exon 3 CTNNB1 mutations and eleven novel POLE mutations were described. Conclusion: Surrogate markers for POLE mutations should be investigated. The validation of POLE variants and CTNNB1 mutations as part of an Aotearoa-based molecular panel is warranted. Full article
(This article belongs to the Special Issue Immunohistochemical Markers in Endometrial Cancer)
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20 pages, 4984 KiB  
Article
Endometrial PTEN Deficiency Leads to SMAD2/3 Nuclear Translocation
by Núria Eritja, Raúl Navaridas, Anna Ruiz-Mitjana, Maria Vidal-Sabanés, Joaquim Egea, Mario Encinas, Xavier Matias-Guiu and Xavier Dolcet
Cancers 2021, 13(19), 4990; https://doi.org/10.3390/cancers13194990 - 5 Oct 2021
Cited by 11 | Viewed by 3289
Abstract
TGF-β has a dichotomous function, acting as tumor suppressor in premalignant cells but as a tumor promoter for cancerous cells. These contradictory functions of TGF-β are caused by different cellular contexts, including both intracellular and environmental determinants. The TGF-β/SMAD and the PI3K/PTEN/AKT signal [...] Read more.
TGF-β has a dichotomous function, acting as tumor suppressor in premalignant cells but as a tumor promoter for cancerous cells. These contradictory functions of TGF-β are caused by different cellular contexts, including both intracellular and environmental determinants. The TGF-β/SMAD and the PI3K/PTEN/AKT signal transduction pathways have an important role in the regulation of epithelial cell homeostasis and perturbations in either of these two pathways’ contributions to endometrial carcinogenesis. We have previously demonstrated that both PTEN and SMAD2/3 display tumor-suppressive functions in the endometrium, and genetic ablation of either gene results in sustained activation of PI3K/AKT signaling that suppresses TGF-β-induced apoptosis and enhances cell proliferation of mouse endometrial cells. However, the molecular and cellular effects of PTEN deficiency on TGF-β/SMAD2/3 signaling remain controversial. Here, using an in vitro and in vivo model of endometrial carcinogenesis, we have demonstrated that loss of PTEN leads to a constitutive SMAD2/3 nuclear translocation. To ascertain the function of nuclear SMAD2/3 downstream of PTEN deficiency, we analyzed the effects of double deletion PTEN and SMAD2/3 in mouse endometrial organoids. Double PTEN/SMAD2/3 ablation results in a further increase of cell proliferation and enlarged endometrial organoids compared to those harboring single PTEN, suggesting that nuclear translocation of SMAD2/3 constrains tumorigenesis induced by PTEN deficiency. Full article
(This article belongs to the Special Issue Immunohistochemical Markers in Endometrial Cancer)
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14 pages, 4286 KiB  
Article
AKR1B1 and AKR1B10 as Prognostic Biomarkers of Endometrioid Endometrial Carcinomas
by Marko Hojnik, Snježana Frković Grazio, Ivan Verdenik and Tea Lanišnik Rižner
Cancers 2021, 13(14), 3398; https://doi.org/10.3390/cancers13143398 - 7 Jul 2021
Cited by 9 | Viewed by 2739
Abstract
The roles of aldo-keto reductase family 1 member B1 (AKR1B1) and B10 (AKR1B10) in the pathogenesis of many cancers have been widely reported but only briefly studied in endometrial cancer. To clarify the potential of AKR1B1 and AKR1B10 as tissue biomarkers of endometrial [...] Read more.
The roles of aldo-keto reductase family 1 member B1 (AKR1B1) and B10 (AKR1B10) in the pathogenesis of many cancers have been widely reported but only briefly studied in endometrial cancer. To clarify the potential of AKR1B1 and AKR1B10 as tissue biomarkers of endometrial cancer, we evaluated the immunohistochemical levels of AKR1B1 and AKR1B10 in tissue paraffin sections from 101 well-characterized patients with endometrioid endometrial cancer and 12 patients with serous endometrial cancer and compared them with the clinicopathological data. Significantly higher immunohistochemical levels of AKR1B1 and AKR1B10 were found in adjacent non-neoplastic endometrial tissue compared to endometrioid endometrial cancer. A trend for better survival was observed in patients with higher immunohistochemical AKR1B1 and AKR1B10 levels. However, no statistically significant differences in overall survival or disease-free survival were observed when AKR1B1 or AKR1B10 were examined individually in endometrioid endometrial cancer. However, analysis of AKR1B1 and AKR1B10 together revealed significantly better overall and disease-free survival in patients with both AKR1B1 and AKR1B10 staining above the median values compared to all other patients. Multivariant Cox analysis identified strong AKR1B1 and AKR1B10 staining as a statistically important survival prediction factor. Conversely, no significant differences were found in serous endometrial cancer. Our results suggest that AKR1B1 and AKR1B10 play protective roles in endometrioid endometrial cancer and show potential as prognostic biomarkers. Full article
(This article belongs to the Special Issue Immunohistochemical Markers in Endometrial Cancer)
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Graphical abstract

Review

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15 pages, 6414 KiB  
Review
Dedifferentiated Endometrial Carcinoma: A Rare Aggressive Neoplasm-Clinical, Morphological and Immunohistochemical Features
by Giovanna Giordano, Elena Ferioli, Debora Guareschi and Alessandro Tafuni
Cancers 2023, 15(21), 5155; https://doi.org/10.3390/cancers15215155 - 26 Oct 2023
Cited by 1 | Viewed by 2554
Abstract
Dedifferentiated endometrioid adenocarcinoma is characterised by the coexistence of an undifferentiated carcinoma and a low-grade endometrioid adenocarcinoma. The low-grade component in this subtype of endometrial carcinoma is Grade 1 or 2 according to the Federation of Gynaecology and Obstetrics (FIGO) grading system. The [...] Read more.
Dedifferentiated endometrioid adenocarcinoma is characterised by the coexistence of an undifferentiated carcinoma and a low-grade endometrioid adenocarcinoma. The low-grade component in this subtype of endometrial carcinoma is Grade 1 or 2 according to the Federation of Gynaecology and Obstetrics (FIGO) grading system. The coexistence of low-grade endometrial carcinoma and solid undifferentiated carcinoma can cause diagnostic problems on histological examination. In fact, this combination can often be mistaken for a more common Grade 2 or Grade 3 endometrial carcinoma. Therefore, this subtype of uterine carcinoma can often go under-recognised. An accurate diagnosis of dedifferentiated endometrial carcinoma is mandatory because of its poorer prognosis compared to Grade 3 endometrial carcinoma, with a solid undifferentiated component that can amount to as much as 20% of the entire tumour. The aim of this review is to provide clinical, immunohistochemical, and molecular data to aid with making an accurate histological diagnosis and to establish whether there are any findings which could have an impact on the prognosis or therapeutic implications of this rare and aggressive uterine neoplasm. Full article
(This article belongs to the Special Issue Immunohistochemical Markers in Endometrial Cancer)
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20 pages, 1666 KiB  
Review
New Pathological and Clinical Insights in Endometrial Cancer in View of the Updated ESGO/ESTRO/ESP Guidelines
by Angela Santoro, Giuseppe Angelico, Antonio Travaglino, Frediano Inzani, Damiano Arciuolo, Michele Valente, Nicoletta D’Alessandris, Giulia Scaglione, Vincenzo Fiorentino, Antonio Raffone and Gian Franco Zannoni
Cancers 2021, 13(11), 2623; https://doi.org/10.3390/cancers13112623 - 26 May 2021
Cited by 86 | Viewed by 6830
Abstract
Endometrial carcinoma represents the most common gynecological cancer in Europe and the USA. Histopathological classification based on tumor morphology and tumor grade has played a crucial role in the management of endometrial carcinoma, allowing a prognostic stratification into distinct risk categories, and guiding [...] Read more.
Endometrial carcinoma represents the most common gynecological cancer in Europe and the USA. Histopathological classification based on tumor morphology and tumor grade has played a crucial role in the management of endometrial carcinoma, allowing a prognostic stratification into distinct risk categories, and guiding surgical and adjuvant therapy. In 2013, The Cancer Genome Atlas (TCGA) Research Network reported a large scale molecular analysis of 373 endometrial carcinomas which demonstrated four categories with distinct clinical, pathologic, and molecular features: POLE/ultramutated (7% of cases) microsatellite instability (MSI)/hypermutated (28%), copy-number low/endometrioid (39%), and copy-number high/serous-like (26%). In the present article, we report a detailed histological and molecular review of all endometrial carcinoma histotypes in light of the current ESGO/ESTRO/ESP guidelines. In particular, we focus on the distribution and prognostic value of the TCGA groups in each histotype. Full article
(This article belongs to the Special Issue Immunohistochemical Markers in Endometrial Cancer)
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Other

22 pages, 739 KiB  
Systematic Review
The Role of Immunohistochemistry Markers in Endometrial Cancer with Mismatch Repair Deficiency: A Systematic Review
by Amelia Favier, Justine Varinot, Catherine Uzan, Alex Duval, Isabelle Brocheriou and Geoffroy Canlorbe
Cancers 2022, 14(15), 3783; https://doi.org/10.3390/cancers14153783 - 3 Aug 2022
Cited by 11 | Viewed by 4231
Abstract
The objective of this systematic review was to summarize our current knowledge of the role of immunohistochemistry (IHC) markers for identifying mismatch repair-deficient (MMRd) tumors in endometrial cancer (EC). Identification of MMRd tumors, which occur in 13% to 30% of all ECs, has [...] Read more.
The objective of this systematic review was to summarize our current knowledge of the role of immunohistochemistry (IHC) markers for identifying mismatch repair-deficient (MMRd) tumors in endometrial cancer (EC). Identification of MMRd tumors, which occur in 13% to 30% of all ECs, has become critical for patients with colorectal and endometrial cancer for therapeutic management, clinical decision making, and prognosis. This review was conducted by two authors applying the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using the following terms: “immunohistochemistry and microsatellite instability endometrial cancer” or “immunohistochemistry and mismatch repair endometrial cancer” or “immunohistochemistry and mismatch repair deficient endometrial cancer”. Among 596 retrieved studies, 161 fulfilled the inclusion criteria. Articles were classified and presented according to their interest for the diagnosis, prognosis, and theragnostics for patients with MMRd EC. We identified 10, 18, and 96 articles using IHC expression of two, three, or four proteins of the MMR system (MLH1, MSH2, MHS6, and PMS2), respectively. MLH1 promoter methylation was analyzed in 57 articles. Thirty-four articles classified MMRd tumors with IHC markers according to their prognosis in terms of recurrence-free survival (RFS), overall survival (OS), stage, grade, and lymph node invasion. Theragnostics were studied in eight articles underlying the important concentration of PD-L1 in MMRd EC. Even though the role of IHC has been challenged, it represents the most common, robust, and cheapest method for diagnosing MMRd tumors in EC and is a valuable tool for exploring novel biotherapies and treatment modalities. Full article
(This article belongs to the Special Issue Immunohistochemical Markers in Endometrial Cancer)
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