BACKGROUND: Only few data are available on treatment-associated behavior of distinct rare CNS embryonal tumor entities previously treated as "CNS-primitive neuroectodermal tumors" (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumors with multilayered rosettes (ETMR) are needed for development of differentiated treatment strategies. METHODS: Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n = 307). Additional cases (n = 66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n = 292) were descriptively analyzed. RESULTS: DNA methylation profiling of "CNS-PNET" classified 58 (19%) cases as ETMR, 57 (19%) as high-grade glioma (HGG), 36 (12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63% ± 7%, OS: 85% ± 5%, n = 63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18% ± 6% and 22% ± 7%, and 5-year OS of 24% ± 6% and 25% ± 7%, respectively. CONCLUSION: The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk CSI-based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments.

2nd Department of Pediatrics Semmelweis University Budapest Hungary

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

Clinical Cooperation Unit Neuropathology German Cancer Research Center Heidelberg Germany

Department of Histopathology Great Ormond Street Hospital for Children NHS Foundation Trust London UK

Department of Neuro Oncology Dmitry Rogachev National Medical Research Center of Pediatric Hematology Oncology and Immunology Moscow Russia

Department of Neurooncology Russian Scientific Center of Radiology Moscow Russia

Department of Neuropathology Burdenko Neurosurgical Institute Moscow Russia

Department of Neuropathology Charité University Medicine and Berlin Institute of Health Berlin Germany

Department of Neuropathology DGNN Brain Tumor Reference Center University of Bonn DZNE German Center for Neurodegenerative Diseases Bonn Germany

Department of Neuropathology Heidelberg University Hospital Heidelberg Germany

Department of Neuroradiology Burdenko Neurosurgical Institute Moscow Russia

Department of Oncology The Children's Memorial Health Institute University of Warsaw Warsaw Poland

Department of Oncology University Children's Hospital Zurich Switzerland

Department of Pathology Amsterdam University Medical Center VUmc Amsterdam the Netherlands

Department of Pathology Johns Hopkins University Baltimore Maryland USA

Department of Pathology NYU Langone Health and School of Medicine New York New York USA

Department of Pathology Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department of Pathology University Medical Centre Utrecht Utrecht the Netherlands

Department of Pathomorphology Children's Memorial Health Institute Warsaw Poland

Department of Pediatric and Adolescent Oncology Gustave Roussy Cancer Center Villejuif France

Department of Pediatric Hematology and Oncology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Pediatric Hematology Oncology Center for Cancer and Immunology Research and Neuroscience Research Children's National Medical Center Washington DC USA

Department of Pediatric Oncology and Hematology Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin Berlin Germany

Department of Pediatric Oncology Hematology and Immunology Heidelberg University Hospital Heidelberg Germany

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

Department of Pediatrics and Adolescent Medicine Rigshospitalet Copenhagen Denmark

Department of Pediatrics KU Leuven and University Hospitals Leuven Leuven Belgium

Department of Radiation Oncology Yonsei Cancer Center Yonsei University College of Medicine Seoul South Korea

Department of Radiological Oncological and Anatomopathological Sciences Sapienza University of Rome Rome Italy

Developmental Biology and Cancer Research and Teaching Department UCL Great Ormond Street Institute of Child Health London UK

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

Division of Pathology The Hospital for Sick Children Toronto Canada

Division of Pediatric and Adolescent Medicine Oslo University Hospital Oslo Norway

Division of Pediatric Neurooncology German Cancer Research Center Heidelberg Germany

Faculty of Biosciences Heidelberg University Heidelberg Germany

German Cancer Consortium Heidelberg Germany

Hopp Children's Cancer Center Heidelberg Germany

INSERM Molecular Predictors and New Targets in Oncology Paris Saclay University Villejuif France

Inst Neurophysiopathol CHU Timone Service d'Anatomie Pathologique et de Neuropathologie Aix Marseille Univ APHM CNRS INP Marseille France

Institute of Biometry and Clinical Epidemiology Charité University Medicine and Berlin Institute of Health Berlin Germany

Institute of Biostatistics and Clinical Research University of Muenster Muenster Germany

Institute of Neuropathology University Medical Center Hamburg Eppendorf Hamburg Germany

Institute of Neuropathology University Medical Center Zurich Zurich Switzerland

Institute of Translational Research University of Liverpool Liverpool UK

IRCCS Neuromed Pozzilli Italy

Neuropathology Unit Division of Pathology Fondazione Policlinico Universitario A Gemelli IRCCS Università Cattolica del Sacro Cuore Rome Italy

Paediatric Haematology and Oncology Division Hospital Universitari Vall d'Hebron Barcelona Spain

Pediatric Glioma Research German Cancer Research Center Heidelberg Germany

Pediatric OncoGenomics Unit Children's University Hospital Niño Jesús Madrid Spain

Pediatric Oncology Department Hospital Sant Joan de Déu Barcelona Spain

Pediatric Oncology Department University Hospital São João Porto Portugal

Pediatric Unit Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands

Research Institute Children's Cancer Center Hamburg Hamburg Germany

Service of Hematology Oncology Hospital JP Garrahan Buenos Aires Argentina

The Queen Silvia Children's Hospital Sahlgrenska University Hospital Gothenburg Sweden

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