AIMS: Embryonal tumours with PLAGL1 or PLAGL2 amplification (ET, PLAGL) show substantial heterogeneity regarding their clinical characteristics and have been treated inconsistently, resulting in diverse outcomes. In this study, we aimed to evaluate the clinical behaviour of ET, PLAGL and elucidate their response pattern across the different applied treatment regimens. METHODS: We conducted an in-depth retrospective analysis of clinical and serial imaging data of 18 patients with ET, PLAGL (nine each of PLAGL1 and PLAGL2 amplified). RESULTS: Patients with PLAGL1-amplified tumours (ET, PLAGL1) had fewer relapses (3/9), while PLAGL2-amplified tumours (ET, PLAGL2) were prone to early relapse or progression (8/9) and to distant, leptomeningeal and intraventricular relapses. Progression-free survival differed significantly between the subtypes (log-rank test, p = 0.0055). Postoperative treatment included chemotherapy (n = 17, various protocols), alone (n = 8) or combined with radiotherapy (n = 9). Responses to chemotherapy were observed in both subtypes, and incomplete resection was not associated with inferior survival. All three survivors with ET, PLAGL2 were treated with induction and high-dose chemotherapy with (n = 1-low-dose CSI and boost) or without (n = 2) radiotherapy, whereas five patients with less intensive chemotherapy relapsed. All six survivors with ET, PLAGL1 were treated with conventional chemotherapy regimens, with (n = 4-local radiotherapy n = 3; CSI and boost n = 1) or without (n = 2) radiotherapy. Two patients with ET, PLAGL1 relapsed after 8 years. CONCLUSIONS: Adjuvant therapy should be considered for all ET, PLAGL patients: Patients with ET, PLAGL2 might benefit from intensified chemotherapy regimens. In contrast, patients with ET, PLAGL1 showed superior outcomes without high-dose chemotherapy or craniospinal irradiation.

Aix Marseille University APHM CNRS INP Institute De Neurophysiopathologie CHU Timone Service d'Anatomie Pathologique et de Neuropathologie Marseille France

Children's Cancer Centre The Royal Children's Hospital Parkville Victoria Australia

Crown Princess Victoria Children's Hospital Linköping University Hospital Linköping Sweden

Department of Biomedical and Clinical Sciences Linköping University Linköping Sweden

Department of Clinical Pathology Kuopio University Hospital and Unit of Pathology Institute of Clinical Medicine University of Eastern Finland Kuopio Finland

Department of Clinical Radiology Kuopio University Hospital Kuopio Finland

Department of Diagnostic and Interventional Neuroradiology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Neuro Oncology Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands

Department of Neuroradiology University Hospital Augsburg Augsburg Germany

Department of Paediatric and Adolescent Medicine Aarhus University Hospital Aarhus Denmark

Department of Paediatrics The University of Melbourne Parkville Victoria Australia

Department of Pathology Amsterdam University Medical Centers Location VUmc and Brain Tumor Center Amsterdam Amsterdam the Netherlands

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Pediatric Haematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Pediatric Hematology and Oncology Alder Hey Children's NHS Foundation Trust Liverpool UK

Department of Pediatric Hematology Oncology Valley Children's Hospital Madera California USA

Department of Pediatric Oncology and Hematology Charité Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin Humboldt Universität zu Berlin and Berlin Institute of Health Berlin Germany

Department of Pediatric Oncology and Hematology Skåne University Hospital Lund University Lund Sweden

Department of Pediatric Oncology Hematology Immunology Olgahospital Klinikum Stuttgart Stuttgart Germany

Department of Pediatrics and Adolescent Medicine Comprehensive Cancer Center and Comprehensive Center for Pediatrics Medical University of Vienna Vienna Austria

Department of Pediatrics and Adolescent Medicine Turku University Hospital and University of Turku Turku Finland

Department of Pediatrics Pediatric Hematology and Oncology Ward Kuopio University Hospital and Institute of Clinical Medicine University of Eastern Finland Kuopio Finland

Department of Radiology Alder Hey Children's NHS Foundation Trust Liverpool UK

Department of Radiology Olgahospital Klinikum Stuttgart Stuttgart Germany

Division of Imaging and Oncology Department of Radiology UMC Utrecht the Netherlands

Division of Neuropathology and Neurochemistry Department of Neurology Medical University of Vienna Vienna Austria

Division of Pediatric Glioma Research Hopp Children's Cancer Center Heidelberg Heidelberg Germany

Division of Pediatric Hemato Oncology Department of Pediatrics and Adolescent Medicine Medical University of Graz Graz Austria

Division of Pediatric Hematology and Oncology University Medical Center Göttingen Göttingen Germany

German Cancer Research Center Heidelberg Germany

Institut d'Hemato oncologie Pediatrique Lyon France

Institut de Pathologie Est Hospices Civils de Lyon Université Claude Bernard Lyon 1 INSERM 1052 CNRS 5286 Centre de Recherche en Cancérologie de Lyon Lyon France

Institute of Clinical Medicine University of Eastern Finland Kuopio Finland

Institute of Neuropathology University Medical Center Hamburg Eppendorf Hamburg Germany

Institute of Neuroradiology Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin Berlin Germany

Mildred Scheel Cancer Career Center HaTriCS4 University Medical Center Hamburg Eppendorf Hamburg Germany

Murdoch Children's Research Institute The Royal Children's Hospital Parkville Victoria Australia

National Center for Tumor Diseases NCT Heidelberg A Partnership Between DKFZ and Heidelberg University Hospital Heidelberg Germany

Prague Brain Tumor Research Group 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands

Rare Cancers Genomics Team Genomic Epidemiology Branch International Agency for Research on Cancer World Health Organization Lyon France

Service de Neurochirurgie B CHU de Bordeaux Bordeaux France

Styrian Children's Cancer Research Research Unit for Cancer and Inborn Errors of the Blood and Immunity in Children Medical University of Graz Graz Austria

Université de Bordeaux Bordeaux INP CNRS IMB UMR 5251 Talence France

See more in PubMed

Capper D., Jones D. T. W., Sill M., et al., “DNA Methylation‐Based Classification of Central Nervous System Tumours,” Nature 555, no. 7697 (2018): 469–474, 10.1038/nature26000. PubMed DOI PMC

Jones C. and Baker S. J., “Unique Genetic and Epigenetic Mechanisms Driving Paediatric Diffuse High‐Grade Glioma,” Nature Reviews. Cancer 14, no. 10 (2014): 651–661, 10.1038/nrc3811. PubMed DOI PMC

Jones C., Karajannis M. A., Jones D. T. W., et al., “Pediatric High‐Grade Glioma: Biologically and Clinically in Need of New Thinking,” Neuro‐Oncology 19, no. 2 (2017): 153–161, 10.1093/neuonc/now101. PubMed DOI PMC

Louis D. N., Perry A., Wesseling P., et al., “The 2021 WHO Classification of Tumors of the Central Nervous System: A Summary,” Neuro‐Oncology 23, no. 8 (2021): 1231–1251, 10.1093/neuonc/noab106. PubMed DOI PMC

Pfister S. M., Reyes‐Mugica M., Chan J. K. C., et al., “A Summary of the Inaugural WHO Classification of Pediatric Tumors: Transitioning From the Optical Into the Molecular Era,” Cancer Discovery 12, no. 2 (2022): 331–355, 10.1158/2159-8290.CD-21-1094. PubMed DOI PMC

Schwartzentruber J., Korshunov A., Liu X. Y., et al., “Driver Mutations in Histone H3.3 and Chromatin Remodelling Genes in Paediatric Glioblastoma,” Nature 482, no. 7384 (2012): 226–231, 10.1038/nature10833. PubMed DOI

Wu G., Broniscer A., McEachron T. A., et al., “Somatic Histone H3 Alterations in Pediatric Diffuse Intrinsic Pontine Gliomas and Non‐Brainstem Glioblastomas,” Nature Genetics 44, no. 3 (2012): 251–253, 10.1038/ng.1102. PubMed DOI PMC

Sturm D., Capper D., Andreiuolo F., et al., “Multiomic Neuropathology Improves Diagnostic Accuracy in Pediatric Neuro‐Oncology,” Nature Medicine 29, no. 4 (2023): 917–926, 10.1038/s41591-023-02255-1. PubMed DOI PMC

Alhalabi K. T., Stichel D., Sievers P., et al., “PATZ1 Fusions Define a Novel Molecularly Distinct Neuroepithelial Tumor Entity With a Broad Histological Spectrum,” Acta Neuropathologica 142, no. 5 (2021): 841–857, 10.1007/s00401-021-02354-8. PubMed DOI PMC

Keck M. K., Sill M., Wittmann A., et al., “Amplification of the PLAG‐Family Genes‐PLAGL1 and PLAGL2‐Is a Key Feature of the Novel Tumor Type CNS Embryonal Tumor With PLAGL Amplification,” Acta Neuropathologica 145, no. 1 (2023): 49–69, 10.1007/s00401-022-02516-2. PubMed DOI PMC

Sievers P., Henneken S. C., Blume C., et al., “Recurrent Fusions in PLAGL1 Define a Distinct Subset of Pediatric‐Type Supratentorial Neuroepithelial Tumors,” Acta Neuropathologica 142, no. 5 (2021): 827–839, 10.1007/s00401-021-02356-6. PubMed DOI PMC

Koelsche C., Schrimpf D., Stichel D., et al., “Sarcoma Classification by DNA Methylation Profiling,” Nature Communications 12, no. 1 (2021): 498, 10.1038/s41467-020-20603-4. PubMed DOI PMC

R Core Team , R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, 2019).

Tietze A., Mankad K., Lequin M. H., et al., “Imaging Characteristics of CNS Neuroblastoma‐FOXR2: A Retrospective and Multi‐Institutional Description of 25 Cases,” AJNR. American Journal of Neuroradiology 43, no. 10 (2022): 1476–1480, 10.3174/ajnr.A7644. PubMed DOI PMC

Tietze A., Bison B., Engelhardt J., et al., “CNS Embryonal Tumor With PLAGL Amplification, a New Tumor Type in Children and Adolescents: Insights From a Comprehensive MRI Analysis,” American Journal of Neuroradiology 46, no. 3 (2024): 536–543, 10.3174/ajnr.A8496. PubMed DOI PMC

Morana G., Shaw D., MacDonald S. M., et al., “Imaging Response Assessment for CNS Germ Cell Tumours: Consensus Recommendations From the European Society for Paediatric Oncology Brain Tumour Group and North American Children's Oncology Group,” Lancet Oncology 23, no. 5 (2022): e218–e228, 10.1016/S1470-2045(22)00063-8. PubMed DOI

Sturm D., Orr B. A., Toprak U. H., et al., “New Brain Tumor Entities Emerge from Molecular Classification of CNS‐PNETs,” Cell 164, no. 5 (2016): 1060–1072, 10.1016/j.cell.2016.01.015. PubMed DOI PMC

World Medical Association , “World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects,” Journal of the American Medical Association 310, no. 20 (2013): 2191–2194, 10.1001/jama.2013.281053. PubMed DOI

Tauziède‐Espariat A., Siegfried A., Nicaise Y., et al., “PLAG1 Fusions Extend the Spectrum of PLAG(L)‐Altered CNS Tumors,” Acta Neuropathologica 146, no. 6 (2023): 841–844, 10.1007/s00401-023-02643-4. PubMed DOI PMC

Maldonado F., Geraldo A. F., Guarnizo A., Fernández‐Ponce N., Baroni L., and Rugilo C., “Central Nervous System Embryonal Tumor With PLAGL1 Amplification: A Case Report of a Novel Entity Focusing on Imaging Findings,” Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery 40, no. 8 (2024): 2603–2607, 10.1007/s00381-024-06422-8. PubMed DOI

Chang C. H., Housepian E. M., and C. Herbert, Jr. , “An Operative Staging System and a Megavoltage Radiotherapeutic Technic for Cerebellar Medulloblastomas,” Radiology 93, no. 6 (1969): 1351–1359, 10.1148/93.6.1351. PubMed DOI

Coltin H., Pequeno P., Liu N., et al., “The Burden of Surviving Childhood Medulloblastoma: A Population‐Based, Matched Cohort Study in Ontario, Canada,” Journal of Clinical Oncology 41, no. 13 (2023): 2372–2381, 10.1200/JCO.22.02466. PubMed DOI PMC

Taylor M. D., Northcott P. A., Korshunov A., et al., “Molecular Subgroups of Medulloblastoma: The Current Consensus,” Acta Neuropathologica 123, no. 4 (2012): 465–472, 10.1007/s00401-011-0922-z. PubMed DOI PMC

Johann P. D., Erkek S., Zapatka M., et al., “Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups With Distinct Enhancer Landscapes,” Cancer Cell 29, no. 3 (2016): 379–393, 10.1016/j.ccell.2016.02.001. PubMed DOI

Torchia J., Picard D., Lafay‐Cousin L., et al., “Molecular Subgroups of Atypical Teratoid Rhabdoid Tumours in Children: An Integrated Genomic and Clinicopathological Analysis,” Lancet Oncology 16, no. 5 (2015): 569–582, 10.1016/S1470-2045(15)70114-2. PubMed DOI

von Hoff K., Haberler C., Schmitt‐Hoffner F., et al., “Therapeutic Implications of Improved Molecular Diagnostics for Rare CNS Embryonal Tumor Entities: Results of an International, Retrospective Study,” Neuro‐Oncology 23, no. 9 (2021): 1597–1611, 10.1093/neuonc/noab136. PubMed DOI PMC

Gojo J., Kjærsgaard M., Zezschwitz B. V., et al., “Rare Embryonal and Sarcomatous Central Nervous System Tumours: State‐of‐the Art and Future Directions,” European Journal of Medical Genetics 66, no. 1 (2022): 104660, 10.1016/j.ejmg.2022.104660. PubMed DOI