Publications by authors named "Xavier Matias-Guiu"

264 Publications

Mutant Allele Frequency (MAF) Influences Melanoma Clinicopathologic Characteristics.

Cancers (Basel) 2021 Oct 11;13(20). Epub 2021 Oct 11.

Department of Dermatology, Hospital Universitari Arnau de Vilanova de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), Universitat de Lleida, 25198 Lleida, Spain.

Background: Cutaneous melanoma shows high variability regarding clinicopathological presentation, evolution and prognosis.

Methods: Next generation sequencing was performed to analyze hotspot mutations in different areas of primary melanomas (MMp) and their paired metastases. Clinicopathological features were evaluated depending on the degree of variation of the mutant allele frequency (MAF) in MMp.

Results: In our cohort of 14 superficial spreading, 10 nodular melanomas and 52 metastases, 17/24 (71%) melanomas had a mutation and 5/24 (21%) had a mutation. We observed a high variation of MAF (H-) in 7/17 (41%) MMp. The H- MMp were all located on the trunk, had lower Breslow and mitotic indexes and predominantly, a first nodal metastasis. Regions with spindled tumor cells (Spin) and high lymphocytic infiltrate (HInf) were more frequent in the H- patients (4/7; 57%), whereas regions with epithelial tumor cells (Epit) and low lymphocytic infiltrate (LInf) were predominant (6/10; 60%) and exclusive in the low MAF variation tumors (L-). The H-/Spin/HInf MMp patients had better prognostic features and nodal first metastasis.

Conclusions: The H- MMp were located on the trunk, had better prognostic characteristics, such as lower Breslow and mitotic indexes as well as high lymphocytic infiltrate.
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http://dx.doi.org/10.3390/cancers13205073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533792PMC
October 2021

Differential Immunoexpression of BRAF/V600E, Senescence Markers, PTEN, and T-type Calcium Channels in Acquired Naevi According to their Histopathological and Dermoscopic Classification.

Acta Derm Venereol 2021 Nov 24;101(11):adv00597. Epub 2021 Nov 24.

Department of Dermatology, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLleida, Avda Alcalde Rovira Roure 80, ES-25198 Lleida, Spain.

BRAF/V600E mutation and other cell growth/growth-control mechanisms are involved in naevogenesis and melanomagenesis. Immunoexpression of BRAF/V600E and other molecules (p16, phosphatase and tensin homologue (PTEN), Ki67, hTERT and Cav3.1 and 3.2 calcium channels) were investigated in 80 histopatho-logically and dermoscopically classified acquired naevi. Regarding BRAF/V600E, dysplastic naevi showed lower immunostaining than common naevi, which was significant in comparison with intradermal naevi, which showed the highest BRAF/V600E histoscore. Junctional naevi showed the lowest BRAF/V600E levels. Globular/cobblestone and reticular dermoscopic patterns were consistently associated with high and low BRAF/V600E immunoexpression, respectively, but Zalaudek's peripheral globule pattern (CR/PG) showed the highest BRAF/V600E immunoexpression. Among global patterns, the previously not investigated multicomponent pattern showed the lowest BRAF/V600E immunoexpression. Regarding the remaining biomarkers, new immunohistochemical features were found, in particular p16 and PTEN low expression in multicomponent pattern; and Ki67, hTERT and Cav.3.1 high expression in CR/PG. In conclusion, histopathology and dermoscopy provide complementary information regarding the biology of melanocytic naevi.
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http://dx.doi.org/10.2340/actadv.v101.361DOI Listing
November 2021

Endometrial PTEN Deficiency Leads to SMAD2/3 Nuclear Translocation.

Cancers (Basel) 2021 Oct 5;13(19). Epub 2021 Oct 5.

Oncologic Pathology Group, Departament de Ciències Mèdiques Bàsiques, Institut de Recerca Biomèdica de Lleida, IRBLleida, Universitat de Lleida, Centro de Investigación Biomédica en Red Cáncer CIBERONC, 25198 Lleida, Spain.

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.
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http://dx.doi.org/10.3390/cancers13194990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507901PMC
October 2021

Sensitivity of cervical cytology in endometrial cancer detection in a tertiary hospital in Spain.

Cancer Med 2021 Oct 4;10(19):6762-6766. Epub 2021 Sep 4.

Cancer Epidemiology Research Programme, IDIBELL, Catalan Institute of Oncology, Barcelona, Spain.

Introduction: Cervical cytology is a well-stablished cervical cancer screening method. However, due to the anatomical continuity of the genital tract, it can also detect signs of endometrial disease. Our aim was to estimate the sensitivity of cervical cytology in endometrial cancer detection and prognosis in a large population over a 30-year period in a large academic tertiary hospital in Spain.

Methodology: We performed a search for women diagnosed with endometrial cancer from 1990 to 2020, who were surgically treated and had a previous cervical cytology result. Information Technologies Department databases from Bellvitge University Hospital and the Screenwide case-control study's database were used. Cervical cytology results were classified as abnormal when squamous lesions, glandular atypia or malignant cells were identified.

Results: Overall, we evaluated 371 women with endometrial cancer and a documented cervical cytology performed within 3 years previous to surgical treatment. Overall, the sensitivity of cervical cytology for endometrial cancer detection was 25.6%. Several clinico-pathological characteristics, such as non-endometrioid histology and a higher stage, were correlated with higher sensitivity.

Discussion: We observed a low sensitivity of cervical cytology to effectively diagnose endometrial cancer. However, recent technological advances using genomics and epigenomics may offer a promising perspective to detect endometrial cancer with high sensitivity in these cervical specimens.
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http://dx.doi.org/10.1002/cam4.4217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495290PMC
October 2021

Paired Somatic-Germline Testing of 15 Polyposis and Colorectal Cancer-Predisposing Genes Highlights the Role of APC Mosaicism in de Novo Familial Adenomatous Polyposis.

J Mol Diagn 2021 11 25;23(11):1452-1459. Epub 2021 Aug 25.

Hereditary Cancer Program, Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), Bellvitge Institute for Biomedical Research (IDIBELL), Catalan Institute of Oncology, l'Hospitalet del Llobregat, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. Electronic address:

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome responsible for 1% of colorectal cancers (CRCs). Up to 90% of classic FAPs are caused by inactivating mutations in APC, and mosaicism has been previously reported in 20% of de novo cases, usually linked to milder phenotypic manifestations. This study aimed to explore the prevalence of mosaicism in 11 unsolved cases of classic FAP and to evaluate the diagnostic yield of somatic testing. Paired samples of colorectal polyps, tumors, and/or mucosa were analyzed using a custom next-generation sequencing panel targeting 15 polyposis and CRC-predisposing genes. Whenever possible, the extension of mosaicism to blood or sperm was also examined. Of 11 patients with classic adenomatous polyposis, a mosaic pathogenic variant in APC was identified in 7 (64%). No other altered genes were identified. In two of seven patients (29%), mosaicism was found restricted to colonic tissues, whereas in five of seven patients (71%), it was extended to the blood. Germline affectation was confirmed in one patient. We report the first analysis at a somatic level of 15 genes associated with CRC susceptibility, which highlights the role of APC mosaicism in classic FAP etiology. The results further reinforce the importance of testing target tissues when blood test results are negative.
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http://dx.doi.org/10.1016/j.jmoldx.2021.07.024DOI Listing
November 2021

Diagnosis and management of an endometrial cancer patient with Cowden syndrome.

Gynecol Oncol 2021 Oct 23;163(1):14-21. Epub 2021 Aug 23.

Pathology and Medical Oncology Departments, Hospital Universitari Arnau de Vilanova, IRBLLEIDA, CIBERONC, University of Lleida, Lleida, Spain; Pathology Department, Hospital Universitaride Bellvitge, IDIBELL, University of Barcelona, Barcelona, Spain. Electronic address:

Somatic PTEN alterations are common in endometrial carcinoma (EC), but in rare cases PTEN mutations are associated with inherited syndromes. Here, we present a case of Cowden syndrome-associated EC. We discuss clinical, pathologic and molecular features of her tumor and PTEN-mutated EC, inherited syndromes predisposing to EC and PTEN-targeted therapies.
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http://dx.doi.org/10.1016/j.ygyno.2021.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515352PMC
October 2021

SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade.

Nat Commun 2021 07 14;12(1):4319. Epub 2021 Jul 14.

Cancer Genetics Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain.

Despite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading to the aberrant accumulation of H3K27me3. SMARCA4-mutant cells also show an impaired transactivation and significantly reduced levels of the histone demethylases KDM6A/UTX and KDM6B/JMJD3, and a strong dependency on these histone demethylases, so that its inhibition compromises cell viability. Administering the KDM6 inhibitor GSK-J4 to mice orthotopically implanted with SMARCA4-mutant lung cancer cells or primary small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), had strong anti-tumour effects. In this work we highlight the vulnerability of KDM6 inhibitors as a characteristic that could be exploited for treating SMARCA4-mutant cancer patients.
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http://dx.doi.org/10.1038/s41467-021-24618-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280185PMC
July 2021

[A four-year Action Plan for the Sociedad Española de Anatomía Patológica].

Rev Esp Patol 2021 Jul-Sep;54(3):145-146. Epub 2021 May 26.

Hospital Universitario 12 de Octubre. Presidente SEAP 2021-2023, Madrid, España.

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http://dx.doi.org/10.1016/j.patol.2021.03.001DOI Listing
May 2021

Characterizing the Invasive Tumor Front of Aggressive Uterine Adenocarcinoma and Leiomyosarcoma.

Front Cell Dev Biol 2021 3;9:670185. Epub 2021 Jun 3.

Cancer CIBER (CIBERONC), Madrid, Spain.

The invasive tumor front (the tumor-host interface) is vitally important in malignant cell progression and metastasis. Tumor cell interactions with resident and infiltrating host cells and with the surrounding extracellular matrix and secreted factors ultimately determine the fate of the tumor. Herein we focus on the invasive tumor front, making an in-depth characterization of reticular fiber scaffolding, infiltrating immune cells, gene expression, and epigenetic profiles of classified aggressive primary uterine adenocarcinomas (24 patients) and leiomyosarcomas (11 patients). Sections of formalin-fixed samples before and after microdissection were scanned and studied. Reticular fiber architecture and immune cell infiltration were analyzed by automatized algorithms in colocalized regions of interest. Despite morphometric resemblance between reticular fibers and high presence of macrophages, we found some variance in other immune cell populations and distinctive gene expression and cell adhesion-related methylation signatures. Although no evident overall differences in immune response were detected at the gene expression and methylation level, impaired antimicrobial humoral response might be involved in uterine leiomyosarcoma spread. Similarities found at the invasive tumor front of uterine adenocarcinomas and leiomyosarcomas could facilitate the use of common biomarkers and therapies. Furthermore, molecular and architectural characterization of the invasive front of uterine malignancies may provide additional prognostic information beyond established prognostic factors.
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http://dx.doi.org/10.3389/fcell.2021.670185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209546PMC
June 2021

Relevance of pathologic features in risk stratification for early-stage endometrial cancer.

J Gynecol Oncol 2021 07;32(4):e67

Department of Pathology, Hospital Universitari de Bellvitge, Institut d'Investigació Biomédica de Bellvitge (IDIBELL), University of Barcelona, Barcelona, Spain.

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http://dx.doi.org/10.3802/jgo.2021.32.e67DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192231PMC
July 2021

Characterization of the Endometrial MSC Marker Ectonucleoside Triphosphate Diphosphohydrolase-2 (NTPDase2/CD39L1) in Low- and High-Grade Endometrial Carcinomas: Loss of Stromal Expression in the Invasive Phenotypes.

J Pers Med 2021 Apr 22;11(5). Epub 2021 Apr 22.

Departament de Patologia i Terapèutica Experimental, Facultat de Medicina i Ciències de la Salut, Campus Bellvitge, Universitat de Barcelona, 08907 L'Hospitalet de Llobregat, Spain.

Ectonucleoside triphosphate diphosphohydrolase-2 (NTPDase2/CD39L1) has been described in human non-pathological endometrium in both epithelial and stromal components without changes along the cycle. It was identified as a stromal marker of basalis. In the present study, we aimed to evaluate NTPDase2 distribution, using immunolabeling and in situ enzyme activity approaches, in endometrial carcinoma (EC) at different tumor grades. NTPDase2 was present in tumor epithelial EC cells, as in the non-pathological endometria, but the expression underwent changes in subcellular distribution and also tended to decrease with the tumor grade. In stroma, NTPDase2 was identified exclusively at the tumor-myometrial junction but this expression was lost in tumors of invasive phenotype. We have also identified in EC samples the presence of the perivascular population of endometrial mesenchymal stem cells (eMSCs) positive for sushi domain containing 2 (SUSD2) and for NTPDase2, already described in non-tumoral endometrium. Our results point to NTPDase2 as a histopathological marker of tumor invasion in EC, with diagnostic relevance especially in cases of EC coexisting with other endometrial disorders, such as adenomyosis, which occasionally hampers the assessment of tumor invasion parameters.
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http://dx.doi.org/10.3390/jpm11050331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146812PMC
April 2021

Understanding the Molecular Mechanism of miR-877-3p Could Provide Potential Biomarkers and Therapeutic Targets in Squamous Cell Carcinoma of the Cervix.

Cancers (Basel) 2021 Apr 6;13(7). Epub 2021 Apr 6.

Molecular Pathology of Cancer Group, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain.

No therapeutic targets and molecular biomarkers are available in cervical cancer (CC) management. In other cancer types, micro-RNA-877-3p (miR-877-3p) has been associated with events relevant for CC development. Thus, we aimed to determine miR-877-3p role in CC. miR-877-3p levels were examined by quantitative-PCR in 117 cervical lesions and tumors. Effects on CC cell proliferation, migration, and invasion were evaluated upon anti-miR-877-3p transfection. miR-877-3p dependent molecular mechanism was comprehensively explored by proteomics, dual-luciferase reporter assay, western blot, and immunohistochemistry. Cervical tumors expressed higher miR-877-3p levels than benign lesions. miR-877-3p promoted CC cell migration and invasion, at least partly by modulating cytoskeletal protein folding through the chaperonin-containing T-complex protein 1 complex. Notably, miR-877-3p silencing synergized with paclitaxel. Interestingly, miR-877-3p downregulated the levels of an in silico-predicted target, ZNF177, whose expression and subcellular location significantly distinguished high-grade squamous intraepithelial lesions (HSILs) and squamous cell carcinomas of the cervix (SCCCs). Cytoplasmic ZNF177 was significantly associated with worse progression-free survival in SCCC. Our results suggest that: (i) miR-877-3p is a potential therapeutic target whose inhibition improves paclitaxel effects; (ii) the expression and location of its target ZNF177 could be diagnostic biomarkers between HSIL and SCCC; and (iii) cytoplasmic ZNF177 is a poor-prognosis biomarker in SCCC.
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http://dx.doi.org/10.3390/cancers13071739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038805PMC
April 2021

Response to: Are we confident treating pT1a G1 lymphovascular space invasion-negative patients (with myometrial invasion) with chemoradiotherapy on the basis of p53abn?

Int J Gynecol Cancer 2021 06 28;31(6):947. Epub 2021 Apr 28.

Department of Radiation Oncology, Leiden University Medical Center, Leiden, Netherlands.

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http://dx.doi.org/10.1136/ijgc-2021-002668DOI Listing
June 2021

M-TRAP: Safety and performance of metastatic tumor cell trap device in advanced ovarian cancer patients.

Gynecol Oncol 2021 Jun 29;161(3):681-686. Epub 2021 Mar 29.

Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela (IDIS), University Hospital of Santiago de Compostela (SERGAS), CIBERONC, Santiago de Compostela, Spain. Electronic address:

Objective: Despite radical surgery and chemotherapy, most patients with ovarian cancer die due to disease progression. M-Trap is an implantable medical device designed to capture peritoneal disseminated tumor cells with the aim to focalize the disease. This trial analyzed the safety and performance of the device.

Methods: This first-in-human prospective, multi-center, non-blinded, single-arm study enrolled 23 women with high-grade serous advanced ovarian cancer. After primary or interval debulking surgery, 3 M-Trap devices were placed in the peritoneum of the abdominal cavity. 18-months post-implantation or at disease progression, devices were initially removed by laparoscopy. The primary safety endpoint was freedom from device and procedure-related major adverse events (MAEs) through 6-months post-implantation compared to an historical control. The primary performance endpoint was histopathologic evidence of tumor cells capture.

Results: Only one major adverse event was attributable to the device. 18 women were free of device and procedure related MAEs (78.3%). However, the primary safety endpoint was not achieved (p = 0.131), primarily attributable to the greater surgical complexity of the M-Trap patient population. 62% of recurrent patients demonstrated tumor cell capture in at least one device with a minimal tumor cell infiltration. No other long-term device-related adverse events were reported. The secondary performance endpoint demonstrated a lack of disease focalization.

Conclusions: The M-Trap technology failed to meet its primary safety objective, although when adjusted for surgical complexity, the study approved it. Likewise, the devices did not demonstrate the anticipated benefits in terms of tumor cell capture and disease focalization in recurrent ovarian cancer.
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http://dx.doi.org/10.1016/j.ygyno.2021.03.022DOI Listing
June 2021

ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma.

Radiother Oncol 2021 01;154:327-353

Department of Radiation Oncology, Leiden University Medical Center, Leiden Netherlands.

A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide. ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined.
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http://dx.doi.org/10.1016/j.radonc.2020.11.018DOI Listing
January 2021

ESGO/ESTRO/ESP Guidelines for the management of patients with endometrial carcinoma.

Virchows Arch 2021 Feb;478(2):153-190

Department of Pathology, Hospital Universitari Arnau de Vilanova, University of Lleida, CIBERONC, Irblleida, Spain.

A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide. ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined.
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http://dx.doi.org/10.1007/s00428-020-03007-zDOI Listing
February 2021

The Role of Predictive Biomarkers in Endocervical Adenocarcinoma: Recommendations From the International Society of Gynecological Pathologists.

Int J Gynecol Pathol 2021 Mar;40(Suppl 1):S102-S110

To review the scientific evidence related to predictive biomarkers in cervical adenocarcinoma (ADC). The authors reviewed the literature regarding predictive biomarkers in cervical ADC. There were several limitations: (1) there is an overlap between predictive and prognostic biomarkers, as the vast majority of patients are treated with anticancer strategies; (2) in many studies and clinical trials, cervical ADC patients are included in a large series of patients predominantly composed of cervical squamous cell carcinomas; and (3) in most of the studies, and clinical trials, there is no distinction between human papillomavirus (HPV)-associated and HPV-independent cervical ADCs, or between various histologic subtypes. Results obtained from a small group of studies confirm that cervical ADCs exhibit distinct molecular features as compared with squamous carcinomas, and that there are different molecular features between different types of cervical ADCs. Promising areas of interest include ERBB2 (HER2) mutations and PD-L1 expression as predictive biomarkers for anti-HER2 treatment and immunotherapy, respectively. To date, no definitive data can be obtained from the literature regarding predictive biomarkers for cervical ADC. Clinical trials specifically designed for endocervical ADC patients are required to elucidate the predictive value of HER2 mutations and PD-L1 expression. The distinction between HPV-associated and HPV-independent cervical ADCs as well as early involvement of pathologists in the design of future clinical trials are needed to identify new predictive biomarkers in cervical ADC.
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http://dx.doi.org/10.1097/PGP.0000000000000755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969151PMC
March 2021

Reproducibility of scoring criteria for HER2 immunohistochemistry in endometrial serous carcinoma: a multi-institutional interobserver agreement study.

Mod Pathol 2021 06 3;34(6):1194-1202. Epub 2021 Feb 3.

Department of Pathology, Yale School of Medicine, New Haven, CT, USA.

Targeted anti-human epidermal growth factor receptor 2 (HER2) therapy has recently been proven to improve progression-free and overall survival of patients with advanced stage or recurrent endometrial serous carcinoma. To date, no specific pathology HER2 testing or scoring guidelines exist for endometrial cancer. However, based on evidence from the recent successful clinical trial and comprehensive pre-trial pathologic studies, a new set of HER2 scoring criteria have been proposed for endometrial serous carcinoma-distinct from the existing breast and gastric cancer-specific criteria. We present the first study assessing interobserver agreement of HER2 scores using the proposed serous endometrial cancer-specific scoring system. A digitally scanned set of 40 HER2-immunostained slides of endometrial serous carcinoma were sent to seven gynecologic pathologists, who independently assigned HER2 scores for each slide following a brief tutorial. Follow-up fluorescent in situ hybridization (FISH) for HER2 gene amplification was performed on cases with interobserver disagreement when a 2+ HER2 score was assigned by at least one observer. Complete agreement of HER2 scores among all 7 observers was achieved on 15 cases, and all but one case had an agreement by at least 4 observers. The overall agreement was 72.3% (kappa 0.60), 77.5% (kappa 0.65), and 83.3% (kappa 0.65), using four (0 to 3+ ), three (0/1+ , 2+ , 3+ ), or two (0/1+ , 2/3+ ) HER2 scoring categories, respectively. Based on the combination of HER2 immunostaining scores and FISH, the interobserver disagreement may have potentially resulted in a clinically significant difference in HER2 status only in three tumors. We conclude, that the proposed serous endometrial cancer-specific HER2 scoring criteria are reproducible among gynecologic pathologists with moderate to substantial interobserver agreement rates comparable to those of previously reported in breast and gastric carcinomas. Our findings significantly strengthen the foundation for establishing endometrial cancer-specific HER2 scoring guidelines in the future.
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http://dx.doi.org/10.1038/s41379-021-00746-5DOI Listing
June 2021

ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma.

Int J Gynecol Cancer 2021 01 18;31(1):12-39. Epub 2020 Dec 18.

Department of Radiation Oncology, Leiden University Medical Center, Leiden, Netherlands.

A European consensus conference on endometrial carcinoma was held in 2014 to produce multi-disciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.
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http://dx.doi.org/10.1136/ijgc-2020-002230DOI Listing
January 2021

Predicting the rising incidence and mortality of endometrial cancers among women aged 65-74 years in Catalonia.

Maturitas 2021 Feb 30;144:11-15. Epub 2020 Sep 30.

Bellvitge Biomedical Research Institute (IDIBELL), Av Gran Vía 199-203, L'Hospitalet de Llobregat, Barcelona, 08908, Spain; Cancer Plan, Catalan Institute of Oncology, Av Gran Vía 199-203, L'Hospitalet de Llobregat, Barcelona, 08908, Spain; Department of Clinical Sciences, Faculty of Medicine, University of Barcelona Feixa Llarga s/n, L'Hospitalet de Llobregat, Barcelona, 08907, Spain. Electronic address:

Endometrial cancer is currently one of the most common gynecological cancers. Reported incidence rates vary in Spain depending on the region. We estimated what the incidence and mortality of endometrial cancers in Catalonia will be by 2030 and compared the predictions with data from 2010. Bayesian autoregressive age-period-cohort models were employed to predict incidence and mortality rates for 2015-2030. The incidence of endometrial cancer for women younger than 65 years was predicted to be lower in 2030 than in 2010, whereas it was predicted to be higher for women aged 65-74 years. Moreover, mortality rates for women aged ≥65 in 2030 are likely to exceed the rates in 2010. Five-year relative survival for all ages was slightly higher in the period 2005-2009 (79.3 %, 95 %CI: 75.8 %-82.9 %) compared with those in 1995-1999 (76.0 %, 95 %CI: 72.1 %-80.2 %). This plausible new scenario might be useful to plan new clinical and preventive strategies in the near future.
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http://dx.doi.org/10.1016/j.maturitas.2020.09.006DOI Listing
February 2021

The cutoff for estrogen and progesterone receptor expression in endometrial cancer revisited: a European Network for Individualized Treatment of Endometrial Cancer collaboration study.

Hum Pathol 2021 03 15;109:80-91. Epub 2020 Dec 15.

Department of Oncology, KU Leuven, 3000, Leuven, Belgium; Center for Gynaecologic Oncology, Netherlands Cancer Institute and Amsterdam University Medical Center, 1066, CX, Amsterdam, the Netherlands.

There is no consensus on the cutoff for positivity of estrogen receptor (ER) and progesterone receptor (PR) in endometrial cancer (EC). Therefore, we determined the cutoff value for ER and PR expression with the strongest prognostic impact on the outcome. Immunohistochemical expression of ER and PR was scored as a percentage of positive EC cell nuclei. Cutoff values were related to disease-specific survival (DSS) and disease-free survival (DFS) using sensitivity, specificity, and multivariable regression analysis. The results were validated in an independent cohort. The study cohort (n = 527) included 82% of grade 1-2 and 18% of grade 3 EC. Specificity for DSS and DFS was highest for the cutoff values of 1-30%. Sensitivity was highest for the cutoff values of 80-90%. ER and PR expression were independent markers for DSS at cutoff values of 10% and 80%. Consequently, three subgroups with distinct clinical outcomes were identified: 0-10% of ER/PR expression with, unfavorable outcome (5-year DSS = 75.9-83.3%); 20-80% of ER/PR expression with, intermediate outcome (5-year DSS = 93.0-93.9%); and 90-100% of ER/PR expression with, favorable outcome (5-year DSS = 97.8-100%). The association between ER/PR subgroups and outcomes was confirmed in the validation cohort (n = 265). We propose classification of ER and PR expression based on a high-risk (0-10%), intermediate-risk (20-80%), and low-risk (90-100%) group.
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http://dx.doi.org/10.1016/j.humpath.2020.12.003DOI Listing
March 2021

Clonal relationship and directionality of progression of synchronous endometrial and ovarian carcinomas in patients with DNA mismatch repair-deficiency associated syndromes.

Mod Pathol 2021 05 16;34(5):994-1007. Epub 2020 Dec 16.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Sporadic synchronous endometrial (ECs) and ovarian cancers (OCs), although clinically considered to be independent primaries, have been shown to be clonally related and likely constitute metastases from each other. We sought to define whether synchronous ECs/OCs in patients with DNA mismatch repair (MMR)-deficiency syndromes would be clonally related. We subjected synchronous ECs/OCs from four patients (LS3-LS6) with clinically confirmed Lynch syndrome (LS) and one patient with constitutional mismatch repair-deficiency syndrome (CMMRD) to massively parallel sequencing targeting 468 cancer-related genes. Somatic mutations, copy number alterations (CNAs), clonal relatedness and clonal decomposition analyses were performed using previously described bioinformatics methods. All synchronous ECs/OCs analyzed were considered independent primaries based on clinicopathologic criteria. Sequencing analysis revealed that the ECs/OCs of three cases (LS2-CMMRD, L3, L4) harbored similar repertoires of somatic mutations and CNAs and were clonally related. In these three cases, a subset of subclonal mutations in the EC became clonal in the OC, suggesting that the EC was likely the substrate from which the OC developed. LS5's EC/OC had distinct mutational profiles but shared specific CNAs. In contrast, LS6's EC/OC harbored distinct somatic mutations and lacked CNAs, consistent with each tumor constituting an independent primary lesion. In LS5 and LS6, PTEN mutations and PTEN loss of protein expression were found to be restricted to the EC. Finally, re-analysis of sequencing data of sporadic synchronous ECs/OCs supported the observations made in the current study that the directionality of progression is likely from the endometrium to the ovary. In conclusion, contrary to sporadic synchronous ECs/OCs, which are almost invariably clonally related, ECs/OCs simultaneously involving the uterus and ovary in LS patients may represent distinct primary tumors. A subset of MMR-deficiency syndrome-related synchronous ECs/OCs, however, may originate from a single primary tumor at variance with their clinical diagnosis, with the endometrium being the likeliest site of origin.
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http://dx.doi.org/10.1038/s41379-020-00721-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076061PMC
May 2021

Assessing Effectiveness of Colonic and Gynecological Risk Reducing Surgery in Lynch Syndrome Individuals.

Cancers (Basel) 2020 Nov 18;12(11). Epub 2020 Nov 18.

Hereditary Cancer Program, Catalan Institute of Oncology-IDIBELL, ONCOBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain.

Background: Colorectal (CRC) and endometrial cancer (EC) are the most common types of cancer in Lynch syndrome (LS). Risk reducing surgeries (RRS) might impact cancer incidence and mortality. Our objectives were to evaluate cumulative incidences of CRC, gynecological cancer and all-cause mortality after RRS in LS individuals.

Methods: Retrospective analysis of 976 LS carriers from a single-institution registry. Primary endpoints were cumulative incidence at 75 years of cancer (metachronous CRC in 425 individuals; EC and ovarian cancer (OC) in 531 individuals) and all-cause mortality cumulative incidence, comparing extended (ES) vs. segmental surgery (SS) in the CRC cohort and risk reducing gynecological surgery (RRGS) vs. surveillance in the gynecological cohort.

Results: Cumulative incidence at 75 years of metachronous CRC was 12.5% vs. 44.7% ( = 0.04) and all-cause mortality cumulative incidence was 38.6% vs. 55.3% ( = 0.31), for ES and SS, respectively. Cumulative, incidence at 75 years was 11.2% vs. 46.3% for EC ( = 0.001) and 0% vs. 12.7% for OC ( N/A) and all-cause mortality cumulative incidence was 0% vs. 52.7% ( N/A), for RRGS vs. surveillance, respectively.

Conclusions: RRS in LS reduces the incidence of metachronous CRC and gynecological neoplasms, also indicating a reduction in all-cause mortality cumulative incidence in females undergoing RRGS.
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http://dx.doi.org/10.3390/cancers12113419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698735PMC
November 2020

Novel Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma.

Cancers (Basel) 2020 Nov 9;12(11). Epub 2020 Nov 9.

Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.

Over the past few years, next generation technologies have been applied to unravel the genetics of rare inherited diseases, facilitating the discovery of new susceptibility genes. We recently found germline gain-of-function variants in two patients with head and neck paragangliomas causing a characteristic hypermethylated DNA profile. Here, whole-exome sequencing identifies a novel germline variant (p.Gly332Arg) in a patient with bilateral carotid paragangliomas, papillary thyroid carcinoma and idiopathic intellectual disability. The variant, located in the Pro-Trp-Trp-Pro (PWWP) domain of the protein involved in chromatin targeting, affects a residue mutated in papillary thyroid tumors and located between the two residues found mutated in microcephalic dwarfism patients. Structural modelling of the variant in the DNMT3A PWWP domain predicts that the interaction with H3K36me3 will be altered. An increased methylation of target genes, compatible with a gain-of-function effect of the alteration, was observed in saliva DNA from the proband and in one independent acute myeloid leukemia sample carrying the same p.Gly332Arg variant. Although further studies are needed to support a causal role of variants in paraganglioma, the description of a new alteration in a patient with multiple clinical features suggests a heterogeneous phenotypic spectrum related to germline variants.
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http://dx.doi.org/10.3390/cancers12113304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697455PMC
November 2020

Multi-center real-world comparison of the fully automated Idylla™ microsatellite instability assay with routine molecular methods and immunohistochemistry on formalin-fixed paraffin-embedded tissue of colorectal cancer.

Virchows Arch 2021 May 10;478(5):851-863. Epub 2020 Nov 10.

Institute of Pathology, University Hospital Cologne, Cologne, Germany.

Microsatellite instability (MSI) is present in 15-20% of primary colorectal cancers. MSI status is assessed to detect Lynch syndrome, guide adjuvant chemotherapy, determine prognosis, and use as a companion test for checkpoint blockade inhibitors. Traditionally, MSI status is determined by immunohistochemistry or molecular methods. The Idylla™ MSI Assay is a fully automated molecular method (including automated result interpretation), using seven novel MSI biomarkers (ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A, SULF2) and not requiring matched normal tissue. In this real-world global study, 44 clinical centers performed Idylla™ testing on a total of 1301 archived colorectal cancer formalin-fixed, paraffin-embedded (FFPE) tissue sections and compared Idylla™ results against available results from routine diagnostic testing in those sites. MSI mutations detected with the Idylla™ MSI Assay were equally distributed over the seven biomarkers, and 84.48% of the MSI-high samples had ≥ 5 mutated biomarkers, while 98.25% of the microsatellite-stable samples had zero mutated biomarkers. The concordance level between the Idylla™ MSI Assay and immunohistochemistry was 96.39% (988/1025); 17/37 discordant samples were found to be concordant when a third method was used. Compared with routine molecular methods, the concordance level was 98.01% (789/805); third-method analysis found concordance for 8/16 discordant samples. The failure rate of the Idylla™ MSI Assay (0.23%; 3/1301) was lower than that of referenced immunohistochemistry (4.37%; 47/1075) or molecular assays (0.86%; 7/812). In conclusion, lower failure rates and high concordance levels were found between the Idylla™ MSI Assay and routine tests.
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http://dx.doi.org/10.1007/s00428-020-02962-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099763PMC
May 2021

WNT11-FZD7-DAAM1 signalling supports tumour initiating abilities and melanoma amoeboid invasion.

Nat Commun 2020 10 20;11(1):5315. Epub 2020 Oct 20.

Barts Cancer Institute, Queen Mary University of London, John Vane Science Building, Charterhouse Square, London, EC1M 6BQ, UK.

Melanoma is a highly aggressive tumour that can metastasize very early in disease progression. Notably, melanoma can disseminate using amoeboid invasive strategies. We show here that high Myosin II activity, high levels of ki-67 and high tumour-initiating abilities are characteristic of invasive amoeboid melanoma cells. Mechanistically, we find that WNT11-FZD7-DAAM1 activates Rho-ROCK1/2-Myosin II and plays a crucial role in regulating tumour-initiating potential, local invasion and distant metastasis formation. Importantly, amoeboid melanoma cells express both proliferative and invasive gene signatures. As such, invasive fronts of human and mouse melanomas are enriched in amoeboid cells that are also ki-67 positive. This pattern is further enhanced in metastatic lesions. We propose eradication of amoeboid melanoma cells after surgical removal as a therapeutic strategy.
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http://dx.doi.org/10.1038/s41467-020-18951-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575593PMC
October 2020

Complete Loss of EPCAM Immunoexpression Identifies Deletion Carriers in MSH2-Negative Colorectal Neoplasia.

Cancers (Basel) 2020 Sep 29;12(10). Epub 2020 Sep 29.

Department of Pathology, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Barcelona, Spain.

The use of epithelial cell adhesion molecule (EPCAM) immunohistochemistry (IHC) is not included in the colorectal cancer (CRC) screening algorithm to detect Lynch syndrome (LS) patients. The aim of the present study was to demonstrate that EPCAM IHC is a useful tool to guide the LS germ-line analysis when a loss of MSH2 expression was present. We retrospectively studied MSH2 and EPCAM IHC in a large series of 190 lesions composed of malignant neoplasms (102), precursor lesions of gastrointestinal (71) and extra-gastrointestinal origin (9), and benign neoplasms (8) from different organs of 71 patients suspicious of being LS due to alterations. LS was confirmed in 68 patients, 53 with mutations and 15 with 3'-end deletions. Tissue microarrays were constructed with human normal tissues and their malignant counterparts to assist in the evaluation of EPCAM staining. Among 154 MSH2-negative lesions, 17 were EPCAM-negative, including 10 CRC and 7 colorectal polyps, and 5 of them showed only isolated negative glands. All lesions showing a lack of EPCAM expression belonged to patients with 3'-end deletions. EPCAM IHC is a useful screening tool, with 100% specificity to identify LS patients due to 3'-end deletions in MSH2-negative CRC and MSH2-negative colorectal polyps.
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http://dx.doi.org/10.3390/cancers12102803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599495PMC
September 2020

An olaparib window-of-opportunity trial in patients with early-stage endometrial carcinoma: POLEN study.

Gynecol Oncol 2020 12 26;159(3):721-731. Epub 2020 Sep 26.

Instituto Valenciano de Oncología, Valencia, Spain; Initia Oncology, Hospital Quironsalud, Valencia, Spain.

Objective: Olaparib is a potent inhibitor of poly(ADP-ribose) polymerase (PARP)-1, 2, and 3 with potential activity in endometrial cancer (EC).

Methods: In this window-of-opportunity trial, women with operable type 1 EC received olaparib oral tablets (300mg) twice daily for 28days before surgery. The primary objective was to evaluate the effects of olaparib on EC in tissue samples taken at baseline and at treatment completion. Signal of activity was defined as significant changes in the expression of the cell cycle-related proteins cyclin D1, Ki67, and cleaved caspase-3.

Results: A total of 31 patients were included in the biomarker analysis. The median time of olaparib exposure was 24 days (1-39). Significant inhibition was found for cyclin D1 (p < 0.01), but not for Ki67 and active caspase 3 immunostaining. PARP-1 levels positively correlated with cyclin D1 levels (rho = 0.661, p = 0.0001). Both PARP-1 and cyclin D1 levels were significantly lower (p = 0.022 and p = 0.004, respectively) in patients with ARID1A[-] tumors than ARID1A[+] tumors. A significant relationship between plasma olaparib concentrations and decreased GLUT1 activity was observed (r = -0.5885; p < 0.05). Drug-related toxicity consisted mostly of gastrointestinal and grade 1 or 2 adverse events.

Conclusions: Olaparib reduced expression of cyclin D1, which positively correlated with PARP-1 levels. This effect was more evident in ARID1A-deficient tumors. Olaparib further induced inhibition of GLUT1 plasma activity. Our findings could have noteworthy implications in predicting which patients with EC would benefit from olaparib-based strategies.
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http://dx.doi.org/10.1016/j.ygyno.2020.09.013DOI Listing
December 2020

Small-Molecule Inhibitors (SMIs) as an Effective Therapeutic Strategy for Endometrial Cancer.

Cancers (Basel) 2020 Sep 24;12(10). Epub 2020 Sep 24.

Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Monforte de Lemos 3-5, 28029 Madrid, Spain.

Endometrial cancer (EC) is the sixth most common cancer in women. A continued number of low-risk EC patients at diagnosis, as well as patients diagnosed with advanced-stage disease, will experience an aggressive disease. Unfortunately, those patients will present recurrence or overt dissemination. Systemic cytotoxic chemotherapy treatment on advanced, recurrent, or metastatic EC patients has shown poor results, with median survival rates of less than one year, and median progression-free survival rates of four months. Therefore, the search for innovative and alternative drugs or the development of combinatorial therapies involving new targeted drugs and standard regimens is imperative. Over the last few decades, some small-molecule inhibitors have been introduced in the clinics for cancer treatment, but only a few have been approved by the Food and Drug Administration (FDA) for EC treatment. In the present review, we present the current state and future prospects of small-molecule inhibitors on EC treatment, both alone and in combination.
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http://dx.doi.org/10.3390/cancers12102751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598629PMC
September 2020
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