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Radner M, Burmeister S, Jóźwiak K, Schaumann N, Gronewold M, Raap M, Bartels S, Christgen H, Kandt LD, Hillmann P, Lehmann U, Gluz O, Graeser M, Kümmel S, Eulenburg CZ, Harbeck N, Kreipe H, Christgen M. Clinicopathological Characteristics of a Distinct Tumor Phenotype: Invasive Lobular Carcinoma With Tubular Elements in the West German Study Group ADAPTcycle Trial. J Transl Med 2025; 105:104125. [PMID: 40049332 DOI: 10.1016/j.labinv.2025.104125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 01/15/2025] [Accepted: 02/23/2025] [Indexed: 04/01/2025] Open
Abstract
Invasive lobular carcinoma with tubular elements (ILC-TE) is a recently identified variant of invasive lobular breast carcinoma (ILC). The histology of ILC-TE is defined by noncohesive carcinoma cells mixed with cohesive tubular elements and complete loss of epithelial (E)-cadherin. Cell-cell adhesion is partially restored by switching from an E-cadherin-deficient to a placental (P)-cadherin-proficient status (EPS). The prevalence of ILC-TE remains unknown. Here, we report data from the central pathology review of >4500 hormone receptor-positive/HER2-negative breast cancer (BC) cases recruited to the West German Study Group (WSG) ADAPTcycle trial (NCT04055493). The central pathology review included prospective assessment of BC types, variants, and E-cadherin expression. Cases classified as ILC-TE were analyzed for their molecular features and clinicopathological characteristics. Pure ILC with complete loss of E-cadherin accounted for 630 of 4619 (13.6%) BC cases. ILC-TE accounted for 47 of 630 (7.5%) lobular carcinomas, making it more than twice as prevalent as mixed BC (NST/ILC). ILC-TE harbored deleterious CDH1/E-cadherin mutations in 27 of 35 (77%) cases tested. EPS was detected in 43 of 47 (91%) ILC-TE cases. EPS was significantly more common in ILC-TE than in classic ILC or other ILC variants (P < .001). Clinically, ILC-TE was associated with cT1 stage (P = .023), cN0 status (P = .024), lower histologic grade (P = .004), and lower Ki67 (P = .012). In contrast, solid ILC was associated with higher Ki67 (P = .006). Following preoperative endocrine therapy, higher post-preoperative endocrine therapy Ki67 levels were observed in trabecular ILC, solid-papillary ILC, and pleomorphic ILC (P < .001, P = .006, and P = .021, respectively). In summary, ILC-TE is a quite common ILC variant that is associated with EPS, less-aggressive clinical features, and slow growth.
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Affiliation(s)
- Martin Radner
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Sandy Burmeister
- Institute of Biostatistics and Registry Research, Brandenburg Medical School Theodor Fontane, Neuruppin, Germany
| | - Katarzyna Jóźwiak
- Institute of Biostatistics and Registry Research, Brandenburg Medical School Theodor Fontane, Neuruppin, Germany
| | - Nora Schaumann
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Malte Gronewold
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Mieke Raap
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Stephan Bartels
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | | | - Leonie D Kandt
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Pia Hillmann
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Ulrich Lehmann
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Oleg Gluz
- West German Study Group, Moenchengladbach, Germany; Ev. Hospital Bethesda, Breast Center Niederrhein, Moenchengladbach, Germany
| | - Monika Graeser
- West German Study Group, Moenchengladbach, Germany; Ev. Hospital Bethesda, Breast Center Niederrhein, Moenchengladbach, Germany
| | - Sherko Kümmel
- West German Study Group, Moenchengladbach, Germany; Breast Unit, Kliniken Essen-Mitte, Essen, Germany; Charité - Universitätsmedizin Berlin, Department of Gynecology with Breast Center, Berlin, Germany
| | | | - Nadia Harbeck
- West German Study Group, Moenchengladbach, Germany; Department of Gynecology and Obstetrics, Breast Center, University of Munich (LMU) and CCCLMU, Munich, Germany
| | - Hans Kreipe
- Institute of Pathology, Hannover Medical School, Hannover, Germany
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2
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Tran SK, Lichtenberg JY, Leonard CE, Williamson JR, Sterling HR, Panek GK, Pearson AH, Lopez S, Lemmon CA, Conway DE, Hwang PY. P-cadherin-dependent adhesions are required for single lumen formation and HGF-mediated cell protrusions during epithelial morphogenesis. iScience 2025; 28:111844. [PMID: 39981519 PMCID: PMC11840494 DOI: 10.1016/j.isci.2025.111844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 11/09/2024] [Accepted: 01/16/2025] [Indexed: 02/22/2025] Open
Abstract
During epithelial morphogenesis, in vivo, epithelial cells form cysts enclosing a single, hollow lumen and extend protrusions as a precursor for tubulogenesis. Cell-cell adhesions (e.g., cadherins) contribute to successful execution of these processes; while there are many different cadherins, one less studied cadherin in epithelial morphogenesis is P-cadherin (CDH3). Here, we investigated the role of CDH3 on successful lumen formation and cell protrusions, using three-dimensional cultures of Madin-Darby canine kidney (MDCK) and CDH3 knockout cell lines. We show that depletion of CDH3 leads to perturbations of hollow lumen formation associated with defects in cell protrusions and tubulogenesis, mediated by Rho/ROCK pathway. CDH3 knockout cells exert lower forces on the surrounding environment compared to wild-type cells, suggesting CDH3 acts as a mechanosensor for stable cell protrusion establishment. Together, our data suggest that CDH3 has an essential function during epithelial morphogenesis by contributing to lumen formation and cell protrusions.
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Affiliation(s)
- Sydnie K. Tran
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23220, USA
| | - Jessanne Y. Lichtenberg
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23220, USA
| | - Corinne E. Leonard
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23220, USA
| | - Jessica R. Williamson
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23220, USA
| | - Hazel R. Sterling
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23220, USA
| | - Grace K. Panek
- Department of Mechanical Engineering, Iowa State University, Ames, IA 50011, USA
| | - Amanda H. Pearson
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23220, USA
| | - Santiago Lopez
- Department of Biomedical Engineering, Rice University, Houston, TX 77251, USA
| | - Christopher A. Lemmon
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23220, USA
| | - Daniel E. Conway
- Department of Biomedical Engineering, The Ohio State University, Columbus, OH 43210, USA
| | - Priscilla Y. Hwang
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23220, USA
- Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
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Taha SR, Boulos F. E-cadherin staining in the diagnosis of lobular versus ductal neoplasms of the breast: the emperor has no clothes. Histopathology 2025; 86:327-340. [PMID: 39138705 PMCID: PMC11707503 DOI: 10.1111/his.15295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/15/2024]
Abstract
Categorizing breast neoplasia as ductal or lobular is a daily exercise that relies on a combination of histologic and immunohistochemical tools. The historically robust link between loss of the E-cadherin molecule and lobular neoplasia has rendered staining for E-cadherin by immunohistochemistry a staple of this diagnostic process. Unfortunately, discordances between E-cadherin expression and histomorphology, and variations in E-cadherin staining patterns and intensities abound in clinical practice, but are often neglected in favour of a binary interpretation of the E-cadherin result. In this article, we highlight the complexities of E-cadherin expression through a review of the E-cadherin protein and its associated gene (CDH1), the mechanisms leading to aberrant/absent E-cadherin expression, and the implications of these factors on the reliability of the E-cadherin immunohistochemical stain in the classification of ductal versus lobular mammary neoplasia.
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MESH Headings
- Female
- Humans
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/metabolism
- Breast Neoplasms/diagnosis
- Breast Neoplasms/pathology
- Breast Neoplasms/metabolism
- Cadherins/metabolism
- Cadherins/analysis
- Carcinoma, Ductal, Breast/diagnosis
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Ductal, Breast/metabolism
- Carcinoma, Lobular/diagnosis
- Carcinoma, Lobular/metabolism
- Carcinoma, Lobular/pathology
- Immunohistochemistry
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Affiliation(s)
- Seyed R Taha
- Department of Pathology and ImmunologyWashington University School of MedicineSt. LouisMOUSA
| | - Fouad Boulos
- Department of Pathology and ImmunologyWashington University School of MedicineSt. LouisMOUSA
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4
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Zhang H, Peng Y. Unique Molecular Alteration of Lobular Breast Cancer: Association with Pathological Classification, Tumor Biology and Behavior, and Clinical Management. Cancers (Basel) 2025; 17:417. [PMID: 39941785 PMCID: PMC11816017 DOI: 10.3390/cancers17030417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 01/23/2025] [Accepted: 01/26/2025] [Indexed: 02/16/2025] Open
Abstract
Invasive lobular carcinoma (ILC), accounting for up to 15% of diagnosed breast cancers, has garnered significant attention due to the loss of the epithelial cell-cell adhesion molecule E-cadherin. This loss contributes to its distinct biological, morphological, and clinical characteristics compared to non-lobular breast cancers. The use of immunohistochemistry (IHC) for E-cadherin and/or the associated cadherin-catenin complex, such as p120-catenin and beta-catenin, in morphologically equivocal cases, has been increasingly adopted in pathology practice. This approach has substantially improved diagnostic accuracy, interobserver reproducibility, and the identification of new morphologic variants of ILC. ILCs exhibit unique tumor biology, which presents considerable challenges in clinical management, especially in preoperative imaging evaluation, surgical management, and neoadjuvant treatment. Recent advances in translational and clinical research have enhanced our understanding of ILC and have spurred the development of new clinical trials specifically targeting these cancers. This review highlights recent progress in various aspects of ILC, including its unique molecular alteration, pathological classification and diagnostic approach, tumor biology and behavior, key clinical management challenges, and ongoing clinical trials, as well as the role of artificial intelligence in diagnosing ILC radiologically and pathologically. The goal of this review is to provide an updated understanding of the tumor biology, clinical manifestations, and molecular landscape of ILC and to help refine current tumor classification and diagnosis, subsequently improving management strategies and overall outcomes for lobular carcinoma patients.
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Affiliation(s)
- Huina Zhang
- Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Yan Peng
- Department of Pathology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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Pareja F, Bhargava R, Borges VF, Brogi E, Canas Marques R, Cardoso F, Desmedt C, Harigopal M, Lakhani SR, Lee A, Leone JP, Linden H, Lord CJ, Marchio C, Merajver SD, Rakha E, Reis-Filho JS, Richardson A, Sawyer E, Schedin P, Schwartz CJ, Tutt A, Ueno NT, Vincent-Salomon A, Weigelt B, Wen YH, Schnitt SJ, Oesterreich S. Unraveling complexity and leveraging opportunities in uncommon breast cancer subtypes. NPJ Breast Cancer 2025; 11:6. [PMID: 39856067 PMCID: PMC11760369 DOI: 10.1038/s41523-025-00719-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 01/09/2025] [Indexed: 01/27/2025] Open
Abstract
Special histologic subtypes of breast cancer (BC) exhibit unique phenotypes and molecular profiles with diagnostic and therapeutic implications, often differing in behavior and clinical trajectory from common BC forms. Novel methodologies, such as artificial intelligence may improve classification. Genetic predisposition plays roles in a subset of cases. Uncommon BC presentations like male, inflammatory and pregnancy-related BC pose challenges. Emerging therapeutic strategies targeting genetic alterations or immune microenvironment are being explored.
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Affiliation(s)
- Fresia Pareja
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Rohit Bhargava
- Department of Pathology, University of Pittsburgh School of Medicine, UPMC Magee-Womens Hospital, Pittsburgh, PA, USA
| | - Virginia F Borges
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Edi Brogi
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Fatima Cardoso
- Breast Unit, Champalimaud Clinical Centre/Champalimaud Foundation, Lisbon, Portugal
| | - Christine Desmedt
- Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Malini Harigopal
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sunil R Lakhani
- UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, and Pathology Queensland, Brisbane, QLD, Australia
| | - Adrian Lee
- Women's Cancer Research Center, Magee-Womens Research Institute, UPMC Hillmann Cancer Center, Pittsburgh, PA, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jose Pablo Leone
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Hannah Linden
- Division of Hematology and Oncology, Fred Hutchinson Cancer Center/University of Washington, Seattle, WA, USA
| | - Christopher J Lord
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Caterina Marchio
- Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Turin, Italy
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Sofia D Merajver
- Breast and Ovarian Cancer Risk Evaluation Program, Department of Internal Medicine, Michigan Medicine, Ann Arbor, MI, USA
| | - Emad Rakha
- Department of Pathology, School of Medicine, University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Jorge S Reis-Filho
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- AstraZeneca, Cambridge, UK
| | | | - Elinor Sawyer
- School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy's Cancer Centre, King's College London, London, UK
| | - Pepper Schedin
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Christopher J Schwartz
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Andrew Tutt
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Naoto T Ueno
- Breast Medical Oncology, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Anne Vincent-Salomon
- Department of Pathology, Curie Institute, Paris Sciences Lettres University, Paris, France
| | - Britta Weigelt
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Y Hannah Wen
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Stuart J Schnitt
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
| | - Steffi Oesterreich
- Women's Cancer Research Center, Magee-Womens Research Institute, UPMC Hillmann Cancer Center, Pittsburgh, PA, USA.
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
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6
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Sung YN, Jeon T, Lee JY, Oh J, An J, Kim A. Comprehensive characterization of invasive mammary carcinoma with lobular features: integrating morphology and E-cadherin immunohistochemistry patterns. Breast Cancer 2025; 32:186-196. [PMID: 39549221 DOI: 10.1007/s12282-024-01649-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 11/07/2024] [Indexed: 11/18/2024]
Abstract
BACKGROUND Breast cancer treatment prioritizes molecular subtypes over histologic types. However, considering the unique biological behavior of invasive lobular carcinoma (ILC), its diagnosis is crucial for patient management. Therefore, this study aimed to review breast cancer cases, focusing on the E-cadherin patterns and lobular morphology of cases misclassified in the original reports. METHODS A comprehensive review was conducted on 481 breast cancer biopsy cases diagnosed as invasive breast carcinoma of no special type (IBC-NST) or ILC with E-cadherin staining. These cases were categorized into six groups based on tumor morphology (ductal/lobular) and E-cadherin expression pattern (membranous/loss/aberrant): (1) ductal/membranous, (2) lobular/loss, (3) lobular/aberrant, (4) mixed, (5) ductal/loss or aberrant, and (6) lobular/membranous. RESULTS In 211 cases (43.8%), an E-cadherin pattern indicating ILC (loss and aberrant) was observed alongside lobular morphology, representing 5.52% of all breast cancer biopsies during the relevant period. Moreover, 181 cases (37.6%) showed a membranous pattern with ductal morphology, 4 (0.8%) were mixed IBC-NST and ILC, and 85 (17.7%) exhibited discordance between morphology and E-cadherin expression. Notably, only 25.9% (15/58) of cases in group 3, characterized by aberrant E-cadherin patterns, were initially diagnosed as ILC, highlighting a significant diagnostic discrepancy. In group 6, where membranous E-cadherin pattern was present with lobular morphology, only 3.4% (2/58) were diagnosed as ILC in the original reports, indicating diagnostic challenges in morphology and immunohistochemistry discordance. Similarly, in group 5, which had ductal morphology with loss or aberrant E-cadherin expression, the initial diagnosis rate of IBC-NST was 33.3% (9/27), reflecting the complexities in interpreting discordant cases. CONCLUSIONS In real-world practice, diagnosing ILC often heavily depends on E-cadherin results. This study emphasizes the need for diagnostic clarification in cases with discordance between morphology and E-cadherin patterns.
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Affiliation(s)
- You-Na Sung
- Department of Pathology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Taesung Jeon
- Department of Pathology, Korea University Guro Hospital, Korea University College of Medicine, 148 Gurodong-Ro, Guro-Gu, Seoul, 08308, Republic of Korea
| | - Ji-Yun Lee
- Department of Pathology, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jaewon Oh
- Department of Pathology, Korea University Guro Hospital, Korea University College of Medicine, 148 Gurodong-Ro, Guro-Gu, Seoul, 08308, Republic of Korea
| | - Jungsuk An
- Department of Pathology, Ewha Womans University Mokdong Hospital, Ewha Womans College of Medicine, Seoul, Republic of Korea
| | - Aeree Kim
- Department of Pathology, Korea University Guro Hospital, Korea University College of Medicine, 148 Gurodong-Ro, Guro-Gu, Seoul, 08308, Republic of Korea.
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7
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Cserni G. Invasive lobular carcinoma of the breast: we diagnose it, but do we know what it is? Pathologica 2024; 116:273-284. [PMID: 39748709 DOI: 10.32074/1591-951x-1043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 07/05/2024] [Indexed: 01/04/2025] Open
Abstract
Invasive lobular carcinoma of the breast is the most common special type breast cancer. It has been defined using morphological features, has a characteristic immunophenotype associated with the loss of E-cadherin mediated intercellular adhesion, and the background of this immunohistochemistry and morphology is generally a biallelic genetic alteration of the CDH-1 gene coding E-cadherin. However, the morphology may often deviate from the classical, and immunohistochemistry may also deviate from the typical, and then the diagnosis of invasive lobular carcinoma becomes less straight forward. Eventually, the definitions of this histological type, although similar, are not identical and this may also give ground to occasional different interpretations. This review summarizes different approaches to invasive lobular carcinomas and the deviations from what is considered normal.
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Affiliation(s)
- Gábor Cserni
- Department of Pathology, Bács-Kiskun County Teaching Hospital, Kecskemét, Hungary
- Department of Pathology, Albert Szent-Györgyi Faculty of Medicine, University of Szeged, Szeged, Hungary
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8
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De Schepper M, Koorman T, Richard F, Christgen M, Vincent-Salomon A, Schnitt SJ, van Diest PJ, Zels G, Mertens F, Maetens M, Vanden Bempt I, Harbeck N, Nitz U, Gräser M, Kümmel S, Gluz O, Weynand B, Floris G, Derksen PWB, Desmedt C. Integration of Pathological Criteria and Immunohistochemical Evaluation for Invasive Lobular Carcinoma Diagnosis: Recommendations From the European Lobular Breast Cancer Consortium. Mod Pathol 2024; 37:100497. [PMID: 38641322 DOI: 10.1016/j.modpat.2024.100497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 04/11/2024] [Accepted: 04/11/2024] [Indexed: 04/21/2024]
Abstract
Invasive lobular carcinoma (ILC) is the second most frequent type of breast cancer (BC) and its peculiar morphology is mainly driven by inactivation of CDH1, the gene coding for E-cadherin cell adhesion protein. ILC-specific therapeutic and disease-monitoring approaches are gaining momentum in the clinic, increasing the importance of accurate ILC diagnosis. Several essential and desirable morphologic diagnostic criteria are currently defined by the World Health Organization, the routine use of immunohistochemistry (IHC) for E-cadherin is not recommended. Disagreement in the diagnosis of ILC has been repeatedly reported, but interpathologist agreement increases with the use of E-cadherin IHC. In this study, we aimed to harmonize the pathological diagnosis of ILC by comparing 5 commonly used E-cadherin antibody clones (NCH-38, EP700Y, Clone 36, NCL-L-E-cad [Clone 36B5], and ECH-6). We determined their biochemical specificity for the E-cadherin protein and IHC staining performance according to type and location of mutation on the CDH1 gene. Western blot analysis on mouse cell lines with conditional E-cadherin expression revealed a reduced specificity of EP700Y and NCL-L-E-cad for E-cadherin, with cross-reactivity of Clone 36 to P-cadherin. The use of IHC improved interpathologist agreement for ILC, lobular carcinoma in situ, and atypical lobular hyperplasia. The E-cadherin IHC staining pattern was associated with variant allele frequency and likelihood of nonsense-mediated RNA decay but not with the type or position of CDH1 mutations. Based on these results, we recommend the indication for E-cadherin staining, choice of antibodies, and their interpretation to standardize ILC diagnosis in current pathology practice.
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Affiliation(s)
- Maxim De Schepper
- Department of Oncology, Laboratory for Translational Breast Cancer Research, KU Leuven, Leuven, Belgium; Department of Pathology, University Hospitals Leuven, UH Leuven, Leuven, Belgium
| | - Thijs Koorman
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - François Richard
- Department of Oncology, Laboratory for Translational Breast Cancer Research, KU Leuven, Leuven, Belgium
| | | | - Anne Vincent-Salomon
- Department of Pathology-Genetics_Immunology, Institut Curie, PSL Research University, Diagnostic and Theranostic Medicine Division, Paris, France
| | - Stuart J Schnitt
- Department of Pathology, Brigham and Women's Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Paul J van Diest
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Gitte Zels
- Department of Oncology, Laboratory for Translational Breast Cancer Research, KU Leuven, Leuven, Belgium; Department of Pathology, University Hospitals Leuven, UH Leuven, Leuven, Belgium
| | - Freya Mertens
- Department of Pathology, University Hospitals Leuven, UH Leuven, Leuven, Belgium
| | - Marion Maetens
- Department of Oncology, Laboratory for Translational Breast Cancer Research, KU Leuven, Leuven, Belgium
| | | | - Nadia Harbeck
- West German Study Group, Mönchengladbach, Germany; Department of Gynecology and Obstetrics, Breast Center, University of Munich (LMU) and CCCLMU, Munich, Germany
| | - Ulrike Nitz
- West German Study Group, Mönchengladbach, Germany; Ev. Hospital Bethesda, Breast Center Niederrhein, Mönchengladbach, Germany
| | - Monika Gräser
- West German Study Group, Mönchengladbach, Germany; Ev. Hospital Bethesda, Breast Center Niederrhein, Mönchengladbach, Germany; Department of Gynecology, University Medical Center Hamburg, Germany
| | - Sherko Kümmel
- West German Study Group, Mönchengladbach, Germany; Charité - Universitätsmedizin Berlin, Department of Gynecology with Breast Center, Berlin, Germany; Clinics Essen-Mitte, Breast Unit, Essen, Germany
| | - Oleg Gluz
- West German Study Group, Mönchengladbach, Germany; Ev. Hospital Bethesda, Breast Center Niederrhein, Mönchengladbach, Germany; University Clinics Cologne, Women's Clinic and Breast Center, Cologne, Germany
| | - Birgit Weynand
- Department of Pathology, University Hospitals Leuven, UH Leuven, Leuven, Belgium
| | - Giuseppe Floris
- Department of Pathology, University Hospitals Leuven, UH Leuven, Leuven, Belgium.
| | - Patrick W B Derksen
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
| | - Christine Desmedt
- Department of Oncology, Laboratory for Translational Breast Cancer Research, KU Leuven, Leuven, Belgium.
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Cserni G, Bori R, Ambrózay É, Serfőző O. Histological Patterns and Mammographic Presentation of Invasive Lobular Carcinoma Show No Obvious Associations. Cancers (Basel) 2024; 16:1640. [PMID: 38730592 PMCID: PMC11083920 DOI: 10.3390/cancers16091640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 04/21/2024] [Accepted: 04/22/2024] [Indexed: 05/13/2024] Open
Abstract
Invasive lobular carcinoma of the breast has different mammographic appearances, including spiculated or lobulated masses, architectural distortion, increased breast density, and the possibility of also being occult. Histologically, the morphology is also variable, as several patterns have been described beside the classical one, including the solid, the alveolar, the trabecular, the one with tubular elements, and others. Of 146 ILC cases, 141 were reviewed for mammographic appearance and 136 for histological patterns by two radiologist and two pathologists, respectively; 132 common cases were analyzed for possible associations between mammographic presentation and the histological patterns. Interobserver agreement on the presence or absence of a given mammographic morphology ranged from 45% (increased density) to 95% (occult lesion); the most common radiomorphology was that of a spiculated mass. Interobserver agreement on the presence or absence of a given histological pattern ranged between 79% (solid) and 99% (classical) but was worse when semi-quantification was also included. The mammography-pathology correlation was less than optimal. Multifocality was more commonly detected by histology. The identification of a mammographic mass lesion often coincided with a mass-like lesion on the histological slides and vice versa, but nearly half of the mammographically occult lesions were felt to have masses on histological slides assessed grossly. Histological patterns showed no obvious associations with one or the other mammographic appearance.
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Affiliation(s)
- Gábor Cserni
- Department of Pathology, Bács-Kiskun County Teaching Hospital, Nyíri út 38., 6000 Kecskemét, Hungary;
- Department of Pathology, Albert Szent-Györgyi Faculty of Medicine, University of Szeged, Állomás u. 1., 6725 Szeged, Hungary
| | - Rita Bori
- Department of Pathology, Bács-Kiskun County Teaching Hospital, Nyíri út 38., 6000 Kecskemét, Hungary;
| | - Éva Ambrózay
- Breast Diagnostic Department of MaMMa Zrt at Kecskemét, Bács-Kiskun County Teaching Hospital, Nyíri út 38., 6000 Kecskemét, Hungary; (É.A.); (O.S.)
- MaMMa Egészségügyi Zrt. Center, Kapás u. 22., 1027 Budapest, Hungary
| | - Orsolya Serfőző
- Breast Diagnostic Department of MaMMa Zrt at Kecskemét, Bács-Kiskun County Teaching Hospital, Nyíri út 38., 6000 Kecskemét, Hungary; (É.A.); (O.S.)
- MaMMa Egészségügyi Zrt. Center, Kapás u. 22., 1027 Budapest, Hungary
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10
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Gronewold M, Grote I, Bartels S, Christgen H, Kandt LD, Brito MJ, Cserni G, Daemmrich ME, Fogt F, Helmke BM, ter Hoeve N, Lang‐Schwarz C, Vieth M, Wellmann A, Kuehnle E, Kulik U, Riedel G, Reineke‐Plaass T, Lehmann U, Koorman T, Derksen PWB, Kreipe H, Christgen M. Microenvironment-induced restoration of cohesive growth associated with focal activation of P-cadherin expression in lobular breast carcinoma metastatic to the colon. J Pathol Clin Res 2024; 10:e12361. [PMID: 38618992 PMCID: PMC10796744 DOI: 10.1002/2056-4538.12361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 11/30/2023] [Accepted: 12/21/2023] [Indexed: 04/16/2024]
Abstract
Invasive lobular carcinoma (ILC) is a special breast cancer type characterized by noncohesive growth and E-cadherin loss. Focal activation of P-cadherin expression in tumor cells that are deficient for E-cadherin occurs in a subset of ILCs. Switching from an E-cadherin deficient to P-cadherin proficient status (EPS) partially restores cell-cell adhesion leading to the formation of cohesive tubular elements. It is unknown what conditions control EPS. Here, we report on EPS in ILC metastases in the large bowel. We reviewed endoscopic colon biopsies and colectomy specimens from a 52-year-old female (index patient) and of 18 additional patients (reference series) diagnosed with metastatic ILC in the colon. EPS was assessed by immunohistochemistry for E-cadherin and P-cadherin. CDH1/E-cadherin mutations were determined by next-generation sequencing. The index patient's colectomy showed transmural metastatic ILC harboring a CDH1/E-cadherin p.Q610* mutation. ILC cells displayed different growth patterns in different anatomic layers of the colon wall. In the tunica muscularis propria and the tela submucosa, ILC cells featured noncohesive growth and were E-cadherin-negative and P-cadherin-negative. However, ILC cells invading the mucosa formed cohesive tubular elements in the intercryptal stroma of the lamina propria mucosae. Inter-cryptal ILC cells switched to a P-cadherin-positive phenotype in this microenvironmental niche. In the reference series, colon mucosa infiltration was evident in 13 of 18 patients, one of which showed intercryptal EPS and conversion to cohesive growth as described in the index patient. The large bowel is a common metastatic site in ILC. In endoscopic colon biopsies, the typical noncohesive growth of ILC may be concealed by microenvironment-induced EPS and conversion to cohesive growth.
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Affiliation(s)
- Malte Gronewold
- Institute of PathologyHannover Medical SchoolHannoverGermany
| | - Isabel Grote
- Institute of PathologyHannover Medical SchoolHannoverGermany
| | - Stephan Bartels
- Institute of PathologyHannover Medical SchoolHannoverGermany
| | | | - Leonie D Kandt
- Institute of PathologyHannover Medical SchoolHannoverGermany
| | | | - Gàbor Cserni
- Department of PathologyUniversity of SzegedSzegedHungary
| | | | - Franz Fogt
- Pennsylvania Hospital – Penn Pathology and Laboratory MedicinePhiladelphiaPAUSA
| | | | - Natalie ter Hoeve
- Department of PathologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | | | - Michael Vieth
- Klinikum Bayreuth – Institut für PathologieBayreuthGermany
| | | | - Elna Kuehnle
- Clinic for Obstetrics and Gynecology the NeonatologyHannover Medical SchoolHannoverGermany
| | - Ulf Kulik
- Department of General, Visceral, and Transplant SurgeryHannover Medical SchoolHannoverGermany
| | - Gesa Riedel
- Department of Immunology and RheumatologyHannover Medical SchoolHannoverGermany
| | | | - Ulrich Lehmann
- Institute of PathologyHannover Medical SchoolHannoverGermany
| | - Thijs Koorman
- Department of PathologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Patrick WB Derksen
- Department of PathologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Hans Kreipe
- Institute of PathologyHannover Medical SchoolHannoverGermany
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11
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Schaumann N, Bartels S, Kuehnle E, Kreipe H, Christgen M. Malignant phyllodes tumor and invasive lobular breast carcinoma: Morpho-molecular characterization of an uncommon collision tumor and review of the literature. Pathol Res Pract 2024; 254:155100. [PMID: 38277744 DOI: 10.1016/j.prp.2024.155100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 01/03/2024] [Accepted: 01/04/2024] [Indexed: 01/28/2024]
Abstract
Phyllodes tumor (PT) of the breast is a biphasic neoplasia composed of mesenchymal and epithelial cells. PTs are graded as benign, borderline or malignant according to histological criteria. Invasive lobular carcinoma (ILC) is a special breast cancer subtype defined by non-cohesive growth and loss of E-cadherin. PT is treated by resection. ILC is treated by resection and adjuvant endocrine therapy with or without chemotherapy. Collision tumors composed of PT and concurrent ILC are rare. Due to their dissociated growth, ILC cells may escape histologic detection when admixed with PTs. Here we report the case of a 71-years-old female diagnosed with a PT/ILC collision tumor. The patient presented with a tumor in the right breast. A core needle biopsy showed mesenchymal spindle cell proliferates suspicious for a PT. The resection specimen confirmed a malignant PT with stromal overgrowth. Unexpectedly, the resection specimen also revealed sparse infiltrates of ILC admixed with the PT. Immunohistochemistry of mesenchymal PT cells and ILC cells was consistent with the histomorphological diagnosis. Molecular analyses demonstrated a IDH1 variant of unknown significance and GNAS gene mutation in microdissected PT tissue. ILC tissue showed wild-type IDH1 and GNAS, but harbored CDH1/E-cadherin and TP53 gene mutations, arguing against clonal relatedness of the two lesions. Review of the literature identified six reported PT/ILC collision tumors, involving three benign, two borderline and one malignant PT. In summary, this is the second report on a malignant PT/ILC collision tumor. Correct histologic diagnosis of PT/ILC collision tumors is clinically relevant, because adjuvant endocrine therapy is mandatory for ILC.
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Affiliation(s)
- Nora Schaumann
- Institute of Pathology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany,.
| | - Stephan Bartels
- Institute of Pathology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany,.
| | - Elna Kuehnle
- Department for Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
| | - Hans Kreipe
- Institute of Pathology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany,.
| | - Matthias Christgen
- Institute of Pathology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany,.
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12
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Cserni G, Kálmán E, Udvarhelyi N, Papp E, Grote I, Bartels S, Christgen M, Kreipe H, Kulka J. Evaluation of the routine use of E-cadherin immunohistochemistry in the typing of breast carcinomas: results of a randomized diagnostic study. Histopathology 2023; 83:810-821. [PMID: 37609779 DOI: 10.1111/his.15026] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 07/03/2023] [Accepted: 07/30/2023] [Indexed: 08/24/2023]
Abstract
AIMS Invasive lobular carcinoma (ILC) has distinct morphology and association with loss of E-cadherin function. It has special clinical and imaging features, and its proper recognition is important. Following a recent proposal, we tested the value of the routine use of E-cadherin immunohistochemistry (IHC) in recognizing ILC. METHODS AND RESULTS Five pathologists with experience in breast pathology from four Hungarian institutions histotyped 1001 breast cancers from diagnostic core biopsies or excision specimens randomly assigned to haematoxylin and eosin (HE) diagnosis first, followed by E-cadherin IHC; or to immediate HE and E-cadherin-based diagnosis. Of 524 cases with HE diagnosis, 73(14%) were deemed uncertain. E-cadherin made the initial histological type change in 14/524 cases (2.7%), including three with confident HE-based type allocation. Use of E-cadherin immunostaining was considered useful in 88/477 cases (18%) with immediate dual assessment, and typing uncertainty went down to 5% (25/477 cases), but was not zero. Collective assessment of 171 uncertain, difficult, nonclassical cases resulted in consensus diagnosis in most cases, but 15 cases were still doubtful as concerns their proper histological type. CDH1 gene sequencing was attempted and successful in 13; pathogenic genetic alterations were identified in seven cases. CONCLUSIONS The routine use of E-cadherin IHC decreases the uncertainty in typing and improves the typing accuracy at the cost of potentially redundant additional immunostains. Furthermore, this procedure does not exclude uncertainty due to E-cadherin-positive ILCs, which are occasionally difficult to confidently label as ILC, especially when the growth pattern is not classic.
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Affiliation(s)
- Gábor Cserni
- Department of Pathology, Bács-Kiskun County Teaching Hospital, Kecskemét, Hungary
- Department of Pathology, Albert Szent-Györgyi Medical Centre, University of Szeged, Szeged, Hungary
| | - Endre Kálmán
- Institute of Pathology, University of Pécs, Pécs, Hungary
| | - Nóra Udvarhelyi
- Department of Surgical and Molecular Pathology, Centre of Tumour Pathology, National Institute of Oncology, Budapest, Hungary
| | - Eszter Papp
- Department of Surgical and Molecular Pathology, Centre of Tumour Pathology, National Institute of Oncology, Budapest, Hungary
| | - Isabel Grote
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Stephan Bartels
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | | | - Hans Kreipe
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Janina Kulka
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Budapest, Hungary
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13
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São José C, Garcia-Pelaez J, Ferreira M, Arrieta O, André A, Martins N, Solís S, Martínez-Benítez B, Ordóñez-Sánchez ML, Rodríguez-Torres M, Sommer AK, Te Paske IBAW, Caldas C, Tischkowitz M, Tusié MT, Hoogerbrugge N, Demidov G, de Voer RM, Laurie S, Oliveira C. Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer. Gastric Cancer 2023; 26:653-666. [PMID: 37249750 PMCID: PMC10361908 DOI: 10.1007/s10120-023-01395-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 04/30/2023] [Indexed: 05/31/2023]
Abstract
BACKGROUND Germline CDH1 pathogenic or likely pathogenic variants cause hereditary diffuse gastric cancer (HDGC). Once a genetic cause is identified, stomachs' and breasts' surveillance and/or prophylactic surgery is offered to asymptomatic CDH1 carriers, which is life-saving. Herein, we characterized an inherited mechanism responsible for extremely early-onset gastric cancer and atypical HDGC high penetrance. METHODS Whole-exome sequencing (WES) re-analysis was performed in an unsolved HDGC family. Accessible chromatin and CDH1 promoter interactors were evaluated in normal stomach by ATAC-seq and 4C-seq, and functional analysis was performed using CRISPR-Cas9, RNA-seq and pathway analysis. RESULTS We identified a germline heterozygous 23 Kb CDH1-TANGO6 deletion in a family with eight diffuse gastric cancers, six before age 30. Atypical HDGC high penetrance and young cancer-onset argued towards a role for the deleted region downstream of CDH1, which we proved to present accessible chromatin, and CDH1 promoter interactors in normal stomach. CRISPR-Cas9 edited cells mimicking the CDH1-TANGO6 deletion display the strongest CDH1 mRNA downregulation, more impacted adhesion-associated, type-I interferon immune-associated and oncogenic signalling pathways, compared to wild-type or CDH1-deleted cells. This finding solved an 18-year family odyssey and engaged carrier family members in a cancer prevention pathway of care. CONCLUSION In this work, we demonstrated that regulatory elements lying down-stream of CDH1 are part of a chromatin network that control CDH1 expression and influence cell transcriptome and associated signalling pathways, likely explaining high disease penetrance and very young cancer-onset. This study highlights the importance of incorporating scientific-technological updates and clinical guidelines in routine diagnosis, given their impact in timely genetic diagnosis and disease prevention.
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Affiliation(s)
- Celina São José
- i3S-Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- Doctoral Programme in Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
| | - José Garcia-Pelaez
- i3S-Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- Doctoral Programme in Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Marta Ferreira
- i3S-Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- Department Computer Science Faculty of Science, University of Porto, Porto, Portugal
| | - Oscar Arrieta
- Thoracic Oncology Unit, Department of Thoracic Oncology, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Ana André
- i3S-Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
| | - Nelson Martins
- i3S-Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- Master Programme in Molecular Medicine and Oncology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Samantha Solís
- INCMNSZ/Instituto de Investigaciones Biomédicas, Unidad de Biología Molecular y Medicina Genómica Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, UNAM Mexico City, Mexico
| | - Braulio Martínez-Benítez
- Pathology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, INCMNSZ Mexico City, Mexico
| | - María Luisa Ordóñez-Sánchez
- INCMNSZ/Instituto de Investigaciones Biomédicas, Unidad de Biología Molecular y Medicina Genómica Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, UNAM Mexico City, Mexico
| | - Maribel Rodríguez-Torres
- INCMNSZ/Instituto de Investigaciones Biomédicas, Unidad de Biología Molecular y Medicina Genómica Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, UNAM Mexico City, Mexico
| | - Anna K Sommer
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany
| | - Iris B A W Te Paske
- Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Carlos Caldas
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK
- Department of Oncology, University of Cambridge, Cambridge, UK
- Cambridge Experimental Cancer Medicine Centre (ECMC), CRUK Cambridge Centre, NIHR Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Marc Tischkowitz
- Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
| | - Maria Teresa Tusié
- INCMNSZ/Instituto de Investigaciones Biomédicas, Unidad de Biología Molecular y Medicina Genómica Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, UNAM Mexico City, Mexico
| | - Nicoline Hoogerbrugge
- Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - German Demidov
- Institute of Medical Genetics and Applied Genomics, Tübingen, Germany
| | - Richarda M de Voer
- Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Steve Laurie
- The Barcelona Institute of Science and Technology, CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona, Spain
| | - Carla Oliveira
- i3S-Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal.
- FMUP-Faculty of Medicine of the University of Porto, Porto, Portugal.
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14
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Tapadar P, Pal A, Ghosal N, Kumar B, Paul T, Biswas N, Pal R. CDH1 overexpression sensitizes TRAIL resistant breast cancer cells towards rhTRAIL induced apoptosis. Mol Biol Rep 2023; 50:7283-7294. [PMID: 37422537 DOI: 10.1007/s11033-023-08657-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 06/29/2023] [Indexed: 07/10/2023]
Abstract
PURPOSE Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is well known for its unique ability to induce apoptosis in cancer cells but not normal cells. However, a subpopulation of cancer cells exist that does not respond to toxic doses of TRAIL. In this study, we aimed to identify key factors regulating TRAIL resistance in breast cancer. METHODS rhTRAIL (recombinant human TRAIL) resistant cells (TR) isolated from TRAIL sensitive MDA-MB-231 parental cells (TS) were confirmed using trypan blue assay, cell viability assay and AO/EtBr (acridine orange/ethidium bromide) staining. Microarray was performed followed by analysis using DAVID and Cytoscape bioinformatics software to identify the candidate hub gene. Gene expression of the candidate gene was confirmed using real-time PCR and western blot. Candidate gene was overexpressed via transient transfection to identify its significance in the context of rhTRAIL. Breast cancer patient data was obtained from The Cancer Genome Atlas (TCGA) database. RESULTS Whole transcriptome analysis identified 4907 differentially expressed genes (DEGs) between TS and TR cells. CDH1 was identified as the candidate hub gene, with 18-degree centrality. We further observed CDH1 protein to be downregulated, overexpression of which increased apoptosis in TR cells after rhTRAIL treatment. TCGA patient data analysis also showed CDH1 mRNA to be low in TRAIL resistant patient group compared to TRAIL sensitive group. CONCLUSION CDH1 overexpression sensitizes TR cells towards rhTRAIL induced apoptosis. Therefore, we can hypothesize that CDH1 expression should be taken into account while performing TRAIL therapy in breast cancer.
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Affiliation(s)
- Poulami Tapadar
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, West Bengal, 700073, India
| | - Ambika Pal
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, West Bengal, 700073, India
| | - Nirajan Ghosal
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, West Bengal, 700073, India
| | - Bhupender Kumar
- Department of Biochemistry, Institute of Home Economics, University of Delhi, New Delhi, 110016, India
| | - Tamalika Paul
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, West Bengal, 700073, India
| | - Nabendu Biswas
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, West Bengal, 700073, India
| | - Ranjana Pal
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, West Bengal, 700073, India.
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15
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Pontecorvi P, Ceccarelli S, Cece F, Camero S, Lotti LV, Niccolai E, Nannini G, Gerini G, Anastasiadou E, Scialis ES, Romano E, Venneri MA, Amedei A, Angeloni A, Megiorni F, Marchese C. Assessing the Impact of Polyethylene Nano/Microplastic Exposure on Human Vaginal Keratinocytes. Int J Mol Sci 2023; 24:11379. [PMID: 37511139 PMCID: PMC10380279 DOI: 10.3390/ijms241411379] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/24/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
The global rise of single-use throw-away plastic products has elicited a massive increase in the nano/microplastics (N/MPLs) exposure burden in humans. Recently, it has been demonstrated that disposable period products may release N/MPLs with usage, which represents a potential threat to women's health which has not been scientifically addressed yet. By using polyethyl ene (PE) particles (200 nm to 9 μm), we showed that acute exposure to a high concentration of N/MPLs induced cell toxicity in vaginal keratinocytes after effective cellular uptake, as viability and apoptosis data suggest, along with transmission electron microscopy (TEM) observations. The internalised N/MPLs altered the expression of junctional and adherence proteins and the organisation of the actin cortex, influencing the level of genes involved in oxidative stress signalling pathways and that of miRNAs related to epithelial barrier function. When the exposure to PE N/MPLs was discontinued or became chronic, cells were able to recover from the negative effects on viability and differentiation/proliferation gene expression in a few days. However, in all cases, PE N/MPL exposure prompted a sustained alteration of DNA methyltransferase and DNA demethylase expression, which might impact epigenetic regulation processes, leading to accelerated cell ageing and inflammation, or the occurrence of malignant transformation.
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Affiliation(s)
- Paola Pontecorvi
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (P.P.); (S.C.); (F.C.); (S.C.); (L.V.L.); (G.G.); (M.A.V.); (A.A.); (F.M.)
| | - Simona Ceccarelli
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (P.P.); (S.C.); (F.C.); (S.C.); (L.V.L.); (G.G.); (M.A.V.); (A.A.); (F.M.)
| | - Fabrizio Cece
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (P.P.); (S.C.); (F.C.); (S.C.); (L.V.L.); (G.G.); (M.A.V.); (A.A.); (F.M.)
| | - Simona Camero
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (P.P.); (S.C.); (F.C.); (S.C.); (L.V.L.); (G.G.); (M.A.V.); (A.A.); (F.M.)
| | - Lavinia Vittoria Lotti
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (P.P.); (S.C.); (F.C.); (S.C.); (L.V.L.); (G.G.); (M.A.V.); (A.A.); (F.M.)
| | - Elena Niccolai
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy; (E.N.); (G.N.); (A.A.)
| | - Giulia Nannini
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy; (E.N.); (G.N.); (A.A.)
| | - Giulia Gerini
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (P.P.); (S.C.); (F.C.); (S.C.); (L.V.L.); (G.G.); (M.A.V.); (A.A.); (F.M.)
| | - Eleni Anastasiadou
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Via di Grottarossa 1035, 00189 Rome, Italy;
| | - Elena Sofia Scialis
- Department of Innovative Technologies in Medicine and Dentistry, University “G. D’Annunzio” Chieti—Pescara, Via dei Vestini 31, 66100 Chieti, Italy;
| | - Enrico Romano
- Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy;
| | - Mary Anna Venneri
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (P.P.); (S.C.); (F.C.); (S.C.); (L.V.L.); (G.G.); (M.A.V.); (A.A.); (F.M.)
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy; (E.N.); (G.N.); (A.A.)
| | - Antonio Angeloni
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (P.P.); (S.C.); (F.C.); (S.C.); (L.V.L.); (G.G.); (M.A.V.); (A.A.); (F.M.)
| | - Francesca Megiorni
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (P.P.); (S.C.); (F.C.); (S.C.); (L.V.L.); (G.G.); (M.A.V.); (A.A.); (F.M.)
| | - Cinzia Marchese
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (P.P.); (S.C.); (F.C.); (S.C.); (L.V.L.); (G.G.); (M.A.V.); (A.A.); (F.M.)
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16
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Sflomos G, Schaumann N, Christgen M, Christgen H, Bartels S, Kreipe H, Battista L, Brisken C. Optimized Modeling of Metastatic Triple-Negative Invasive Lobular Breast Carcinoma. Cancers (Basel) 2023; 15:3299. [PMID: 37444409 DOI: 10.3390/cancers15133299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/07/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Invasive lobular carcinoma (ILC) is a common breast cancer subtype that is often diagnosed at advanced stages and causes significant morbidity. Late-onset secondary tumor recurrence affects up to 30% of ILC patients, posing a therapeutic challenge if resistance to systemic therapy develops. Nonetheless, there is a lack of preclinical models for ILC, and the current models do not accurately reproduce the complete range of the disease. We created clinically relevant metastatic xenografts to address this gap by grafting the triple-negative IPH-926 cell line into mouse milk ducts. The resulting intraductal xenografts accurately recapitulate lobular carcinoma in situ (LCIS), invasive lobular carcinoma, and metastatic ILC in relevant organs. Using a panel of 15 clinical markers, we characterized the intratumoral heterogeneity of primary and metastatic lesions. Interestingly, intraductal IPH-926 xenografts express low but actionable HER2 and are not dependent on supplementation with the ovarian hormone estradiol for their growth. This model provides a valuable tool to test the efficiency of potential new ILC therapeutics, and it may help detect vulnerabilities within ILC that can be exploited for therapeutic targeting.
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Affiliation(s)
- George Sflomos
- ISREC-Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
| | - Nora Schaumann
- Institute of Pathology, Hannover Medical School, Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Matthias Christgen
- Institute of Pathology, Hannover Medical School, Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Henriette Christgen
- Institute of Pathology, Hannover Medical School, Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Stephan Bartels
- Institute of Pathology, Hannover Medical School, Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Hans Kreipe
- Institute of Pathology, Hannover Medical School, Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Laura Battista
- ISREC-Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
| | - Cathrin Brisken
- ISREC-Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
- Institute of Pathology, Hannover Medical School, Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK
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17
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São José C, Pereira C, Ferreira M, André A, Osório H, Gullo I, Carneiro F, Oliveira C. 3D Chromatin Architecture Re-Wiring at the CDH3/CDH1 Loci Contributes to E-Cadherin to P-Cadherin Expression Switch in Gastric Cancer. BIOLOGY 2023; 12:803. [PMID: 37372088 DOI: 10.3390/biology12060803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/25/2023] [Accepted: 05/29/2023] [Indexed: 06/29/2023]
Abstract
Cadherins are cell-cell adhesion molecules, fundamental for cell architecture and polarity. E-cadherin to P-cadherin switch can rescue adherens junctions in epithelial tumours. Herein, we disclose a mechanism for E-cadherin to P-cadherin switch in gastric cancers. CDH1 and CDH3 mRNA expression was obtained from 42 gastric tumours' RNA-seq data. CRISPR-Cas9 was used to knock out CDH1 and a putative regulatory element. CDH1-depleted and parental cells were submitted to proteomics and enrichment GO terms analysis; ATAC-seq/4C-seq with a CDH1 promoter viewpoint to assess chromatin accessibility and conformation; and RT-PCR/flow cytometry to assess CDH1/E-cadherin and CDH3/P-cadherin expression. In 42% of gastric tumours analysed, CDH1 to CDH3 switch was observed. CDH1 knockout triggered CDH1/E-cadherin complete loss and CDH3/P-cadherin expression increase at plasma membrane. This switch, likely rescuing adherens junctions, increased cell migration/proliferation, commonly observed in aggressive tumours. E- to P-cadherin switch accompanied increased CDH1 promoter interactions with CDH3-eQTL, absent in normal stomach and parental cells. CDH3-eQTL deletion promotes CDH3/CDH1 reduced expression. These data provide evidence that loss of CDH1/E-cadherin expression alters the CDH3 locus chromatin conformation, allowing a CDH1 promoter interaction with a CDH3-eQTL, and promoting CDH3/P-cadherin expression. These data highlight a novel mechanism triggering E- to P-cadherin switch in gastric cancer.
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Affiliation(s)
- Celina São José
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Doctoral Programme in Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Carla Pereira
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
| | - Marta Ferreira
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Doctoral Program in Computer Sciences, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
| | - Ana André
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
| | - Hugo Osório
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Irene Gullo
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- Department of Pathology, Centro Hospitalar Universitário São João, 4200-319 Porto, Portugal
| | - Fátima Carneiro
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- Department of Pathology, Centro Hospitalar Universitário São João, 4200-319 Porto, Portugal
| | - Carla Oliveira
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
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18
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Christgen M, Kreipe H. Correspondence on: "Standardization in the diagnosis of invasive lobular carcinoma of the breast". Mod Pathol 2023; 36:100163. [PMID: 36965702 DOI: 10.1016/j.modpat.2023.100163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 03/19/2023] [Indexed: 03/27/2023]
Affiliation(s)
| | - Hans Kreipe
- Institute of Pathology, Hannover Medical School, Hannover, Germany.
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19
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Hwang PY, Mathur J, Cao Y, Almeida J, Ye J, Morikis V, Cornish D, Clarke M, Stewart SA, Pathak A, Longmore GD. A Cdh3-β-catenin-laminin signaling axis in a subset of breast tumor leader cells control leader cell polarization and directional collective migration. Dev Cell 2023; 58:34-50.e9. [PMID: 36626870 PMCID: PMC10010282 DOI: 10.1016/j.devcel.2022.12.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 08/10/2022] [Accepted: 12/07/2022] [Indexed: 01/11/2023]
Abstract
Carcinoma dissemination can occur when heterogeneous tumor and tumor-stromal cell clusters migrate together via collective migration. Cells at the front lead and direct collective migration, yet how these leader cells form and direct migration are not fully appreciated. From live videos of primary mouse and human breast tumor organoids in a 3D microfluidic system mimicking native breast tumor microenvironment, we developed 3D computational models, which hypothesize that leader cells need to generate high protrusive forces and overcome extracellular matrix (ECM) resistance at the leading edge. From single-cell sequencing analyses, we find that leader cells are heterogeneous and identify and isolate a keratin 14- and cadherin-3-positive subpopulation sufficient to lead collective migration. Cdh3 controls leader cell protrusion dynamics through local production of laminin, which is required for integrin/focal adhesion function. Our findings highlight how a subset of leader cells interact with the microenvironment to direct collective migration.
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Affiliation(s)
- Priscilla Y Hwang
- Departments of Medicine (Oncology), Washington University in St. Louis, St Louis, MO 63110, USA; ICCE Institute, Washington University in St. Louis, St Louis, MO 63110, USA; Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - Jairaj Mathur
- Departments of Mechanical Engineering and Materials Science, Washington University in St. Louis, St Louis, MO 63110, USA
| | - Yanyang Cao
- Departments of Medicine (Oncology), Washington University in St. Louis, St Louis, MO 63110, USA; ICCE Institute, Washington University in St. Louis, St Louis, MO 63110, USA
| | - Jose Almeida
- Departments of Biomedical Engineering, Washington University in St. Louis, St Louis, MO 63110, USA
| | - Jiayu Ye
- Departments of Cell Biology and Physiology, Washington University in St. Louis, St Louis, MO 63110, USA; ICCE Institute, Washington University in St. Louis, St Louis, MO 63110, USA
| | - Vasilios Morikis
- Departments of Medicine (Oncology), Washington University in St. Louis, St Louis, MO 63110, USA; ICCE Institute, Washington University in St. Louis, St Louis, MO 63110, USA
| | - Daphne Cornish
- Departments of Medicine (Oncology), Washington University in St. Louis, St Louis, MO 63110, USA; ICCE Institute, Washington University in St. Louis, St Louis, MO 63110, USA
| | - Maria Clarke
- Departments of Medicine (Oncology), Washington University in St. Louis, St Louis, MO 63110, USA; ICCE Institute, Washington University in St. Louis, St Louis, MO 63110, USA
| | - Sheila A Stewart
- Departments of Cell Biology and Physiology, Washington University in St. Louis, St Louis, MO 63110, USA; ICCE Institute, Washington University in St. Louis, St Louis, MO 63110, USA
| | - Amit Pathak
- Departments of Mechanical Engineering and Materials Science, Washington University in St. Louis, St Louis, MO 63110, USA; Departments of Biomedical Engineering, Washington University in St. Louis, St Louis, MO 63110, USA
| | - Gregory D Longmore
- Departments of Medicine (Oncology), Washington University in St. Louis, St Louis, MO 63110, USA; Departments of Cell Biology and Physiology, Washington University in St. Louis, St Louis, MO 63110, USA; ICCE Institute, Washington University in St. Louis, St Louis, MO 63110, USA; Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA.
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20
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Kuba MG, Brogi E. Update on lobular lesions of the breast. Histopathology 2023; 82:36-52. [PMID: 36482279 PMCID: PMC9752180 DOI: 10.1111/his.14829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 10/09/2022] [Accepted: 10/12/2022] [Indexed: 12/13/2022]
Abstract
The current histological classification of in-situ and invasive lobular carcinomas (ILCs) includes different morphological variants, some of which have been recently described. In this review, we will focus upon: (i) the diagnostic criteria of non-invasive lobular neoplasia and treatment implications across different countries; (ii) utility and limitations of immunohistochemistry; (iii) recently described variants of ILC; and (iv) the significance of lobular differentiation in invasive carcinoma for clinical management.
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Affiliation(s)
- Maria Gabriela Kuba
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Edi Brogi
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
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21
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Niu ZS, Wang WH, Niu XJ. Recent progress in molecular mechanisms of postoperative recurrence and metastasis of hepatocellular carcinoma. World J Gastroenterol 2022; 28:6433-6477. [PMID: 36569275 PMCID: PMC9782839 DOI: 10.3748/wjg.v28.i46.6433] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 10/31/2022] [Accepted: 11/21/2022] [Indexed: 12/08/2022] Open
Abstract
Hepatectomy is currently considered the most effective option for treating patients with early and intermediate hepatocellular carcinoma (HCC). Unfortunately, the postoperative prognosis of patients with HCC remains unsatisfactory, predominantly because of high postoperative metastasis and recurrence rates. Therefore, research on the molecular mechanisms of postoperative HCC metastasis and recurrence will help develop effective intervention measures to prevent or delay HCC metastasis and recurrence and to improve the long-term survival of HCC patients. Herein, we review the latest research progress on the molecular mechanisms underlying postoperative HCC metastasis and recurrence to lay a foundation for improving the understanding of HCC metastasis and recurrence and for developing more precise prevention and intervention strategies.
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Affiliation(s)
- Zhao-Shan Niu
- Laboratory of Micromorphology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Wen-Hong Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Xiao-Jun Niu
- Department of Internal Medicine, Qingdao Shibei District People's Hospital, Qingdao 266033, Shandong Province, China
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22
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Davey MG, Keelan S, Lowery AJ, Kerin MJ. The Impact of Chemotherapy Prescription on Long-Term Survival Outcomes in Early-Stage Invasive Lobular Carcinoma - A Systematic Review and Meta-Analysis. Clin Breast Cancer 2022; 22:e843-e849. [PMID: 36229335 DOI: 10.1016/j.clbc.2022.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 09/06/2022] [Accepted: 09/14/2022] [Indexed: 01/25/2023]
Abstract
INTRODUCTION Invasive lobular carcinoma (ILCs) are typically endocrine responsive breast cancers which respond poorly to chemotherapy. The long-term survival advantage of prescribing chemotherapy in such cases remains unclear. To perform a systematic review and meta-analysis assessing, the impact of prescribing chemotherapy in such patients on long-term disease-free (DFS) and overall (OS) survival outcomes. METHODS A systematic review and meta-analysis was performed in accordance with the PRISMA guidelines. Ten-year DFS and OS were pooled as odds ratios (ORs) with 95% confidence intervals (CI) using the Mantel-Haenszel method. Time-to-effect modelling was performed using the generic inverse variance method. RESULTS Overall, 9 studies including 28,218 patients were included. The mean follow-up was 74 months (range: 0-150 months) and mean age was 60 years (range: 22-90 years). Of these, 34.7% received chemotherapy (9,797/28,218) and 66.3% did not receive chemotherapy (18,421/28,218). Chemotherapy prescription failed to improve 10-year DFS (OR: 0.89, 95% CI: 0.65-1.23) and OS (OR: 0.92, 95% CI: 0.72-1.18). When using time-to-effect modelling, chemotherapy prescription failed to improve DFS (hazard ratio (HR): 1.01, 95% CI: 0.78-1.31) and OS (HR: 1.07, 95% CI: 0.89-1.27, I2= 67%). CONCLUSION This meta-analysis illustrates no long-term survival advantage associated with chemotherapy prescription in the setting of early-stage ILC. In the absence of well-designed, prospective clinical trials evaluating the impact of chemotherapy on long-term outcomes in ILC, these results should be considered by the multidisciplinary team when deciding on the value of systemic chemotherapy prescription in ILC.
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Affiliation(s)
- Matthew G Davey
- Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Republic of Ireland.
| | - Stephen Keelan
- Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Republic of Ireland
| | - Aoife J Lowery
- Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Republic of Ireland
| | - Michael J Kerin
- Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Republic of Ireland
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23
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Koufopoulos N, Pateras IS, Gouloumis AR, Ieronimaki AI, Zacharatou A, Spathis A, Leventakou D, Economopoulou P, Psyrri A, Arkadopoulos N, Panayiotides IG. Diagnostically Challenging Subtypes of Invasive Lobular Carcinomas: How to Avoid Potential Diagnostic Pitfalls. Diagnostics (Basel) 2022; 12:diagnostics12112658. [PMID: 36359501 PMCID: PMC9689338 DOI: 10.3390/diagnostics12112658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/11/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022] Open
Abstract
Invasive lobular carcinoma is the most common special breast carcinoma subtype, with unique morphological (discohesive cells, single-cell files, targetoid pattern) and immunohistochemical (loss of E-cadherin and β-catenin staining) features. Moreover, ILC displays a poor response to neoadjuvant therapy, a different metastatic pattern compared to invasive breast carcinoma of no special type, as well as unique molecular characteristics. In addition to the classic variant of invasive lobular carcinoma, several other well-recognized variants exist, including classic, alveolar, tubulolobular, solid, pleomorphic, signet-ring, and mixed. Furthermore, three novel variants of invasive lobular carcinoma, i.e., with extracellular mucin production, papillary features, and tubular elements, have been described during the last decade. We herewith focus on the unique morphological and immunohistochemical characteristics of these novel varieties of invasive lobular carcinoma, as well as differential diagnostic considerations and potential diagnostic pitfalls, especially when dealing with biopsy specimens.
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Affiliation(s)
- Nektarios Koufopoulos
- Second Department of Pathology, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Chaidari, 12462 Athens, Greece
- Correspondence: ; Tel.: +30-697-203-0941
| | - Ioannis S. Pateras
- Second Department of Pathology, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Chaidari, 12462 Athens, Greece
| | - Alina Roxana Gouloumis
- Second Department of Pathology, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Chaidari, 12462 Athens, Greece
| | - Argyro Ioanna Ieronimaki
- Second Department of Pathology, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Chaidari, 12462 Athens, Greece
| | - Andriani Zacharatou
- Second Department of Pathology, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Chaidari, 12462 Athens, Greece
| | - Aris Spathis
- Second Department of Pathology, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Chaidari, 12462 Athens, Greece
| | - Danai Leventakou
- Second Department of Pathology, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Chaidari, 12462 Athens, Greece
| | - Panagiota Economopoulou
- Medical Oncology Unit, 2nd Department of Internal Medicine-Propaedeutic, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Chaidari, 12462 Athens, Greece
| | - Amanda Psyrri
- Medical Oncology Unit, 2nd Department of Internal Medicine-Propaedeutic, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Chaidari, 12462 Athens, Greece
| | - Nikolaos Arkadopoulos
- 4th Department of Surgery, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Chaidari, 12462 Athens, Greece
| | - Ioannis G. Panayiotides
- Second Department of Pathology, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Chaidari, 12462 Athens, Greece
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24
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Kreipe HH. [Second opinions and reference pathology in breast cancer]. PATHOLOGIE (HEIDELBERG, GERMANY) 2022; 43:74-80. [PMID: 36269419 DOI: 10.1007/s00292-022-01144-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 09/21/2022] [Indexed: 06/16/2023]
Abstract
Second opinion in pathology recruits expert knowledge for the diagnosis in difficult cases and has a tradition in Germany with generation of a network between primarily diagnostic and academic institutes of pathology, active in research. The term reference pathology does mean a label for a class of institutes for pathology but rather specifies a function within prospective clinical trials with defined endpoints and a central pathology, which will derive expert knowledge from this function. On either way generated collection of samples and expertise will enable diagnostic support in difficult cases. Furthermore, research based on this tissue material might lead to the establishment of novel biomarkers and methods, which when transferred to decentral application will enhance diagnostic validity of pathological tissue analysis as a whole. Thus, for all institutes participating in the network, pathology as a diagnostic discipline and patients, second opinion and reference pathology provide considerable benefit with regard to quality of histopathological diagnoses.
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Affiliation(s)
- Hans H Kreipe
- Institut für Pathologie, Medizinische Hochschule Hannover, Carl-Neubergstraße 1, 30925, Hannover, Deutschland.
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25
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Burrai GP, Baldassarre V, Brunetti B, Iussich S, Maniscalco L, Mariotti F, Sfacteria A, Cocumelli C, Grieco V, Millanta F, Paciello O, Papparella S, Rasotto R, Romanucci M, Zappulli V. Canine and feline in situ mammary carcinoma: A comparative review. Vet Pathol 2022; 59:894-902. [PMID: 35735255 DOI: 10.1177/03009858221105060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Carcinoma in situ of the breast is a well-known entity in humans. In veterinary medicine, particularly in canine and feline mammary literature, there is no agreement whether the term in situ should be used to indicate a specific carcinoma histotype or the noninvasive status of a carcinoma of any histotype. Moreover, in the most recent histologic classification of mammary tumors published by the Davis-Thompson Foundation, it is suggested to abandon the term carcinoma in situ given the lack of standardized criteria defining this entity, replacing it with epitheliosis or ductal/lobular hyperplasia with severe atypia. This publication presents a critical review of the term in situ in human and veterinary medicine considering the evolution of the term over the years and its heterogeneous use by different authors, including variations in immunohistochemical markers for classification. This review aims to point out the lack of uniformity in the nomenclature and classification issues in veterinary medicine regarding the use of the term in situ, laying the ground for a process of standardization in future publications.
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Affiliation(s)
| | | | | | | | - Lorella Maniscalco
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, Turin, Italy
| | | | | | - Cristiano Cocumelli
- Istituto Zooprofilattico Sperimentale del Lazio e della Toscana M. Aleandri, Rome, Italy
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26
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Christgen M, Kandt LD, Antonopoulos W, Bartels S, Van Bockstal MR, Bredt M, Brito MJ, Christgen H, Colpaert C, Cserni B, Cserni G, Daemmrich ME, Danebrock R, Dedeurwaerdere F, van Deurzen CH, Erber R, Fathke C, Feist H, Fiche M, Gonzalez CA, Ter Hoeve ND, Kooreman L, Krech T, Kristiansen G, Kulka J, Laenger F, Lafos M, Lehmann U, Martin-Martinez MD, Mueller S, Pelz E, Raap M, Ravarino A, Reineke-Plaass T, Schaumann N, Schelfhout AM, De Schepper M, Schlue J, Van de Vijver K, Waelput W, Wellmann A, Graeser M, Gluz O, Kuemmel S, Nitz U, Harbeck N, Desmedt C, Floris G, Derksen PW, van Diest PJ, Vincent-Salomon A, Kreipe H. Inter-observer agreement for the histological diagnosis of invasive lobular breast carcinoma. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2022; 8:191-205. [PMID: 34889530 PMCID: PMC8822373 DOI: 10.1002/cjp2.253] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 11/17/2021] [Accepted: 11/24/2021] [Indexed: 12/20/2022]
Abstract
Invasive lobular breast carcinoma (ILC) is the second most common breast carcinoma (BC) subtype and is mainly driven by loss of E‐cadherin expression. Correct classification of BC as ILC is important for patient treatment. This study assessed the degree of agreement among pathologists for the diagnosis of ILC. Two sets of hormone receptor (HR)‐positive/HER2‐negative BCs were independently reviewed by participating pathologists. In set A (61 cases), participants were provided with hematoxylin/eosin (HE)‐stained sections. In set B (62 cases), participants were provided with HE‐stained sections and E‐cadherin immunohistochemistry (IHC). Tumor characteristics were balanced. Participants classified specimens as non‐lobular BC versus mixed BC versus ILC. Pairwise inter‐observer agreement and agreement with a pre‐defined reference diagnosis were determined with Cohen's kappa statistics. Subtype calls were correlated with molecular features, including CDH1/E‐cadherin mutation status. Thirty‐five pathologists completed both sets, providing 4,305 subtype calls. Pairwise inter‐observer agreement was moderate in set A (median κ = 0.58, interquartile range [IQR]: 0.48–0.66) and substantial in set B (median κ = 0.75, IQR: 0.56–0.86, p < 0.001). Agreement with the reference diagnosis was substantial in set A (median κ = 0.67, IQR: 0.57–0.75) and almost perfect in set B (median κ = 0.86, IQR: 0.73–0.93, p < 0.001). The median frequency of CDH1/E‐cadherin mutations in specimens classified as ILC was 65% in set A (IQR: 56–72%) and 73% in set B (IQR: 65–75%, p < 0.001). Cases with variable subtype calls included E‐cadherin‐positive ILCs harboring CDH1 missense mutations, and E‐cadherin‐negative ILCs with tubular elements and focal P‐cadherin expression. ILCs with trabecular growth pattern were often misclassified as non‐lobular BC in set A but not in set B. In conclusion, subtyping of BC as ILC achieves almost perfect agreement with a pre‐defined reference standard, if assessment is supported by E‐cadherin IHC. CDH1 missense mutations associated with preserved E‐cadherin protein expression, E‐ to P‐cadherin switching in ILC with tubular elements, and trabecular ILC were identified as potential sources of discordant classification.
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Affiliation(s)
| | | | | | - Stephan Bartels
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | | | - Martin Bredt
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Maria Jose Brito
- Pathology and Breast Unit, Champalimaud Foundation, Lisbon, Portugal
| | | | - Cecile Colpaert
- Department of Pathology, Universitair Ziekenhuis Leuven, Leuven, Belgium
| | | | - Gábor Cserni
- Department of Pathology, University of Szeged, Szeged, Hungary
| | | | | | | | | | - Ramona Erber
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), and Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
| | - Christine Fathke
- Institute of Pathology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Henning Feist
- Institute of Pathology, Diakonissenkrankenhaus Flensburg, Flensburg, Germany
| | - Maryse Fiche
- Institute of Pathology Aurigen, Aurigen SA, Lausanne, Switzerland
| | - Claudia Aura Gonzalez
- Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Natalie D Ter Hoeve
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Loes Kooreman
- Institute of Pathology and GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Till Krech
- Institute of Pathology, University Clinics Hamburg-Eppendorf, Hamburg, Germany.,Germany and Pathocom Network for Pathology, Osnabrück, Germany
| | | | - Janina Kulka
- 2nd Department of Pathology, Semmelweis University Budapest, Budapest, Hungary
| | - Florian Laenger
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Marcel Lafos
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Ulrich Lehmann
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | | | - Sophie Mueller
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Enrico Pelz
- Institute of Pathology Viersen, Viersen, Germany
| | - Mieke Raap
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | | | | | - Nora Schaumann
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | | | - Maxim De Schepper
- Department of Pathology, University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium.,Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Jerome Schlue
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Koen Van de Vijver
- Cancer Research Institute Ghent, Ghent University Hospital, Ghent, Belgium
| | - Wim Waelput
- Department of Pathology, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | | | - Monika Graeser
- West German Study Group, Moenchengladbach, Germany.,Ev. Hospital Bethesda, Breast Center Niederrhein, Moenchengladbach, Germany.,Gynecologic University Clinic Hamburg-Eppendorf (UKE), Hamburg, Germany
| | - Oleg Gluz
- West German Study Group, Moenchengladbach, Germany.,Ev. Hospital Bethesda, Breast Center Niederrhein, Moenchengladbach, Germany
| | - Sherko Kuemmel
- West German Study Group, Moenchengladbach, Germany.,Breast Unit, Kliniken Essen-Mitte, Essen, Germany, and Charité - Universitätsmedizin Berlin, Department of Gynecology with Breast Center, Berlin, Germany
| | - Ulrike Nitz
- West German Study Group, Moenchengladbach, Germany.,Ev. Hospital Bethesda, Breast Center Niederrhein, Moenchengladbach, Germany
| | - Nadia Harbeck
- West German Study Group, Moenchengladbach, Germany.,Department of Gynecology and Obstetrics, Breast Center, University of Munich (LMU) and CCCLMU, Munich, Germany
| | - Christine Desmedt
- Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Giuseppe Floris
- Department of Pathology, University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium.,Department of Imaging and Radiology, Laboratory for Cell and Tissue Translational Research, KU-Leuven/UZ Leuven, Leuven, Belgium
| | - Patrick Wb Derksen
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Paul J van Diest
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Anne Vincent-Salomon
- Pathology-Genetics-Immunology Department, Institut Curie, PSL Research University, Paris, France
| | - Hans Kreipe
- Institute of Pathology, Hannover Medical School, Hannover, Germany
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27
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De Schepper M, Vincent-Salomon A, Christgen M, Van Baelen K, Richard F, Tsuda H, Kurozumi S, Brito MJ, Cserni G, Schnitt S, Larsimont D, Kulka J, Fernandez PL, Rodríguez-Martínez P, Olivar AA, Melendez C, Van Bockstal M, Kovacs A, Varga Z, Wesseling J, Bhargava R, Boström P, Franchet C, Zambuko B, Matute G, Mueller S, Berghian A, Rakha E, van Diest PJ, Oesterreich S, Derksen PWB, Floris G, Desmedt C. Results of a worldwide survey on the currently used histopathological diagnostic criteria for invasive lobular breast cancer. Mod Pathol 2022; 35:1812-1820. [PMID: 35922548 PMCID: PMC9708574 DOI: 10.1038/s41379-022-01135-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 12/24/2022]
Abstract
Invasive lobular carcinoma (ILC) represents the second most common subtype of breast cancer (BC), accounting for up to 15% of all invasive BC. Loss of cell adhesion due to functional inactivation of E-cadherin is the hallmark of ILC. Although the current world health organization (WHO) classification for diagnosing ILC requires the recognition of the dispersed or linear non-cohesive growth pattern, it is not mandatory to demonstrate E-cadherin loss by immunohistochemistry (IHC). Recent results of central pathology review of two large randomized clinical trials have demonstrated relative overdiagnosis of ILC, as only ~60% of the locally diagnosed ILCs were confirmed by central pathology. To understand the possible underlying reasons of this discrepancy, we undertook a worldwide survey on the current practice of diagnosing BC as ILC. A survey was drafted by a panel of pathologists and researchers from the European lobular breast cancer consortium (ELBCC) using the online tool SurveyMonkey®. Various parameters such as indications for IHC staining, IHC clones, and IHC staining procedures were questioned. Finally, systematic reporting of non-classical ILC variants were also interrogated. This survey was sent out to pathologists worldwide and circulated from December 14, 2020 until July, 1 2021. The results demonstrate that approximately half of the institutions use E-cadherin expression loss by IHC as an ancillary test to diagnose ILC and that there is a great variability in immunostaining protocols. This might cause different staining results and discordant interpretations. As ILC-specific therapeutic and diagnostic avenues are currently explored in the context of clinical trials, it is of importance to improve standardization of histopathologic diagnosis of ILC diagnosis.
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Affiliation(s)
- Maxim De Schepper
- grid.5596.f0000 0001 0668 7884Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Anne Vincent-Salomon
- grid.440907.e0000 0004 1784 3645Diagnostic and Theranostic Medicine Division, Institut Curie, PSL Research University, Paris, France
| | - Matthias Christgen
- grid.10423.340000 0000 9529 9877Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Karen Van Baelen
- grid.5596.f0000 0001 0668 7884Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium
| | - François Richard
- grid.5596.f0000 0001 0668 7884Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Hitoshi Tsuda
- grid.416620.7Department of Basic Pathology, National Defense Medical College Hospital, Tokorozawa, Saitama Japan
| | - Sasagu Kurozumi
- grid.411731.10000 0004 0531 3030Department of Breast Surgery, International University of Health and Welfare, Narita, Chiba Japan
| | - Maria Jose Brito
- grid.421010.60000 0004 0453 9636Breast Unit, Champalimaud Clinical Center, Champalimaud Foundation, Lisbon, Portugal
| | - Gabor Cserni
- grid.9008.10000 0001 1016 9625Department of Pathology, Bács-Kiskun County Teaching Hospital, Kecskemét, Hungary & Department of Pathology, Albert Szent-Györgyi Medical Center, University of Szeged, Szeged, Hungary
| | - Stuart Schnitt
- grid.38142.3c000000041936754XBrigham and Women’s Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Denis Larsimont
- grid.418119.40000 0001 0684 291XDepartment of Pathology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Janina Kulka
- grid.11804.3c0000 0001 0942 9821Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Budapest, Pest Hungary
| | - Pedro Luis Fernandez
- grid.7080.f0000 0001 2296 0625Hospital German Trias i Pujol, Universidad Autonoma de Barcelona, Barcelona, Spain
| | - Paula Rodríguez-Martínez
- grid.7080.f0000 0001 2296 0625Hospital German Trias i Pujol, Universidad Autonoma de Barcelona, Barcelona, Spain
| | - Ana Aula Olivar
- grid.411295.a0000 0001 1837 4818University Hospital Doctor Josep Trueta, Girona, Spain
| | - Cristina Melendez
- grid.411295.a0000 0001 1837 4818University Hospital Doctor Josep Trueta, Girona, Spain
| | - Mieke Van Bockstal
- grid.48769.340000 0004 0461 6320Department of Pathology, Cliniques universitaires Saint-Luc Bruxelles, Woluwé-Saint-Lambert, Brussels, Belgium
| | - Aniko Kovacs
- grid.1649.a000000009445082XDepartment of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Zsuzsanna Varga
- grid.412004.30000 0004 0478 9977Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Jelle Wesseling
- grid.430814.a0000 0001 0674 1393Divisions of Molecular Pathology and Diagnostic Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Rohit Bhargava
- grid.411487.f0000 0004 0455 1723Department of Pathology, UPMC Magee-Womens Hospital, Pittsburgh, PA USA
| | - Pia Boström
- grid.410552.70000 0004 0628 215XDepartment of Pathology, Turku University Hospital and University of Turku, Turku, Finland
| | - Camille Franchet
- grid.488470.7Institut Claudius Regaud, Institut Universitaire du Cancer Toulouse - Oncopole, Toulouse, France
| | - Blessing Zambuko
- grid.7621.20000 0004 0635 5486Department of Pathology, Sir Ketumile Masire Teaching Hospital, University of Botswana, Gaborone, Botswana
| | - Gustavo Matute
- grid.412249.80000 0004 0487 2295Clínica Universitaria Bolivariana, Universidad Pontificia Bolivariana, Medellín, Colombia
| | - Sophie Mueller
- grid.10423.340000 0000 9529 9877Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Anca Berghian
- grid.418189.d0000 0001 2175 1768Department of Biopathology, Centre Henri Becquerel, Rouen, France
| | - Emad Rakha
- grid.240404.60000 0001 0440 1889Department of Histopathology, Nottingham University Hospital NHS Trust, City Hospital Campus Hucknall Road, Nottingham, UK
| | - Paul J. van Diest
- grid.7692.a0000000090126352Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Steffi Oesterreich
- grid.460217.60000 0004 0387 4432Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee-Womens Research Institute, Pittsburgh, PA USA
| | - Patrick W. B. Derksen
- grid.7692.a0000000090126352Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Giuseppe Floris
- Department of Pathology, University Hospitals Leuven, UZ Leuven, Leuven, Belgium.
| | - Christine Desmedt
- Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium.
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28
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Lobular Breast Cancer: Histomorphology and Different Concepts of a Special Spectrum of Tumors. Cancers (Basel) 2021; 13:cancers13153695. [PMID: 34359596 PMCID: PMC8345067 DOI: 10.3390/cancers13153695] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/15/2021] [Accepted: 07/18/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Invasive lobular breast cancer (ILC) is a special type of breast cancer (BC) that was first described in 1941. The diagnosis of ILC is made by microscopy of tumor specimens, which reveals a distinct morphology. This review recapitulates the developments in the microscopic assessment of ILC from 1941 until today. We discuss different concepts of ILC, provide an overview on ILC variants, and highlight advances which have contributed to a better understanding of ILC as a special histologic spectrum of tumors. Abstract Invasive lobular breast cancer (ILC) is the most common special histological type of breast cancer (BC). This review recapitulates developments in the histomorphologic assessment of ILC from its beginnings with the seminal work of Foote and Stewart, which was published in 1941, until today. We discuss different concepts of ILC and their implications. These concepts include (i) BC arising from mammary lobules, (ii) BC growing in dissociated cells and single files, and (iii) BC defined as a morpho-molecular spectrum of tumors with distinct histological and molecular characteristics related to impaired cell adhesion. This review also provides a comprehensive overview of ILC variants, their histomorphology, and differential diagnosis. Furthermore, this review highlights recent advances which have contributed to a better understanding of the histomorphology of ILC, such as the role of the basal lamina component laminin, the molecular specificities of triple-negative ILC, and E-cadherin to P-cadherin expression switching as the molecular determinant of tubular elements in CDH1-deficient ILC. Last but not least, we provide a detailed account of the tumor microenvironment in ILC, including tumor infiltrating lymphocyte (TIL) levels, which are comparatively low in ILC compared to other BCs, but correlate with clinical outcome. The distinct histomorphology of ILC clearly reflects a special tumor biology. In the clinic, special treatment strategies have been established for triple-negative, HER2-positive, and ER-positive BC. Treatment specialization for patients diagnosed with ILC is just in its beginnings. Accordingly, ILC deserves greater attention as a special tumor entity in BC diagnostics, patient care, and cancer research.
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29
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Trapani D, Gandini S, Corti C, Crimini E, Bellerba F, Minchella I, Criscitiello C, Tarantino P, Curigliano G. Benefit of adjuvant chemotherapy in patients with lobular breast cancer: A systematic review of the literature and metanalysis. Cancer Treat Rev 2021; 97:102205. [PMID: 33878560 DOI: 10.1016/j.ctrv.2021.102205] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 04/05/2021] [Indexed: 12/12/2022]
Abstract
The role of adjuvant chemotherapy (aCT) for patients with localized lobular breast cancer (ILC) is still controversial. It is unclear what is the magnitude of benefit of the CT in this setting. In this systematic review of the literature and metanalysis, we aimed to estimate the benefit of aCT in addition to the standard treatments in the early ILC setting. We identified the records by searching Medline, CENTRAL, Web of Science, SCOPUS, and Google Scholar, and the meeting proceeding of the principal oncology meetings of the last 10 years, with no language or time restriction. A research strategy was developed with mapped and MeSH terms. Studies on the clinical use of aCT reporting survival outcomes in the ILC setting were double-screened and tabulated. PRISMA methodology was used for data extraction and synthesis. We extracted information on the study design and setting, eligible population and population size, histology variants, menopausal status, treatment regimens, follow-up duration. Hazard ratios (HR) and 95% confidence interval (CI) were extracted and transformed into logHR and corresponding standard error to obtain the Summary HR (SHR). Heterogeneity (I2 statistics) and publication bias (Macaskill test) were tested; a random effect models provided by SAS Proc Mixed was used for data analysis. Sensitivity analysis was conducted to examine the impact of inclusion criteria on the summary results. Disease-free (DFS), overall (OS) and cancer-specific survival (BCSS) were the primary endpoints of the investigation. The systematic review and metanalysis included 38,387 patients across 8 clinical studies. aCT was not associated with an improvement of OS (SHR 0.99; 95%CI 0.86-1.14), with low heterogeneity (I2 = 28%) and no publication bias (p = 0.43). Sensitivity analysis resulted in unchanged conclusions. We did not perform a metanalysis of the DFS estimates, as only reported in 3 studies. The value of aCT in improving DFS was unconfirmed, consistently with the OS results. Our research did not confirm a certain role of aCT for patients with ILC. Research gaps were identified, warranting the development of prospective, controlled ad hoc investigations.
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Affiliation(s)
- D Trapani
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy
| | - S Gandini
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCSS, Milan, Italy
| | - C Corti
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy; Departement of Hematology and Oncology (DIPO), University of Milan, Milan, Italy
| | - E Crimini
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy; Departement of Hematology and Oncology (DIPO), University of Milan, Milan, Italy
| | - F Bellerba
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCSS, Milan, Italy
| | - I Minchella
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy
| | - C Criscitiello
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy; Departement of Hematology and Oncology (DIPO), University of Milan, Milan, Italy
| | - P Tarantino
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy; Departement of Hematology and Oncology (DIPO), University of Milan, Milan, Italy
| | - G Curigliano
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy; Departement of Hematology and Oncology (DIPO), University of Milan, Milan, Italy.
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30
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McCart Reed AE, Kalinowski L, Simpson PT, Lakhani SR. Invasive lobular carcinoma of the breast: the increasing importance of this special subtype. Breast Cancer Res 2021; 23:6. [PMID: 33413533 PMCID: PMC7792208 DOI: 10.1186/s13058-020-01384-6] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 12/15/2020] [Indexed: 12/15/2022] Open
Abstract
Invasive lobular carcinoma (ILC) is the most common of the breast cancer special types, accounting for up to 15% of all breast cancer cases. ILCs are noted for their lack of E-cadherin function, which underpins their characteristic discohesive growth pattern, with cells arranged in single file and dispersed throughout the stroma. Typically, tumours are luminal in molecular subtype, being oestrogen and progesterone receptor positive, and HER2 negative. Since last reviewing the lobular literature (McCart Reed et al., Breast Cancer Res 17:12, 2015), there has been a considerable increase in research output focused on this tumour type, including studies into the pathology and management of disease, a high-resolution definition of the genomic landscape of tumours as well as the evolution of several potential therapeutic avenues. There abounds a huge amount of new data, which we will review herein.
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Affiliation(s)
- Amy E McCart Reed
- UQ Centre for Clinical Research, The University of Queensland, Herston, Brisbane, Australia.
- QIMR Berghofer Medical Research Institute, Herston, Brisbane, Australia.
| | - Lauren Kalinowski
- UQ Centre for Clinical Research, The University of Queensland, Herston, Brisbane, Australia
- Department of Histopathology, Sullivan Nicolaides Pathology, Bowen Hills, Brisbane, Australia
| | - Peter T Simpson
- UQ Centre for Clinical Research, The University of Queensland, Herston, Brisbane, Australia
- QIMR Berghofer Medical Research Institute, Herston, Brisbane, Australia
| | - Sunil R Lakhani
- UQ Centre for Clinical Research, The University of Queensland, Herston, Brisbane, Australia
- Pathology Queensland, Royal Brisbane and Women's Hospital, Herston, Brisbane, Australia
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