Katja von Hoff1, Christine Haberler2, Felix Schmitt-Hoffner3,4,5, Elizabeth Schepke6, Teresa de Rojas7, Sandra Jacobs8, Michal Zapotocky9, David Sumerauer9, Marta Perek-Polnik10, Christelle Dufour11,12, Dannis van Vuurden13, Irene Slavc14, Johannes Gojo14, Jessica C Pickles15,16, Nicolas U Gerber17, Maura Massimino18, Maria Joao Gil-da-Costa19, Miklos Garami20, Ella Kumirova21, Astrid Sehested22, David Scheie23, Ofelia Cruz24, Lucas Moreno25, Jaeho Cho26, Bernward Zeller27, Niels Bovenschen28, Michael Grotzer17, Daniel Alderete29, Matija Snuderl30, Olga Zheludkova31, Andrey Golanov32, Konstantin Okonechnikov3,4, Martin Mynarek33, Björn Ole Juhnke33, Stefan Rutkowski33, Ulrich Schüller33,34,35, Barry Pizer36, Barbara von Zezschwitz1, Robert Kwiecien37, Maximilian Wechsung38, Frank Konietschke38, Eugene I Hwang39, Dominik Sturm40,41, Stefan M Pfister3,4,41, Andreas von Deimling42,43, Elisabeth J Rushing44, Marina Ryzhova45, Peter Hauser20, Maria Łastowska46, Pieter Wesseling13,47, Felice Giangaspero48,49, Cynthia Hawkins50, Dominique Figarella-Branger51, Charles Eberhart52, Peter Burger52, Marco Gessi53, Andrey Korshunov42,43, Tom S Jacques16, David Capper54,55, Torsten Pietsch56, Marcel Kool3,4,13. 1. Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. 2. Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria. 3. Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany. 4. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany. 5. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. 6. The Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden. 7. Pediatric OncoGenomics Unit, Children's University Hospital Niño Jesús, Madrid, Spain. 8. Department of Pediatrics, KU Leuven and University Hospitals Leuven, Leuven, Belgium. 9. Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic. 10. Department of Oncology, The Children's Memorial Health Institute, University of Warsaw, Warsaw, Poland. 11. Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Villejuif, France. 12. INSERM, Molecular Predictors and New Targets in Oncology, Paris-Saclay University, Villejuif, France. 13. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands. 14. Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria. 15. Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK. 16. Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. 17. Department of Oncology, University Children's Hospital, Zurich, Switzerland. 18. Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 19. Pediatric Oncology Department, University Hospital São João, Porto, Portugal. 20. 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary. 21. Department of Neuro-Oncology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia. 22. Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen,Denmark. 23. Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 24. Pediatric Oncology Department, Hospital Sant Joan de Déu, Barcelona, Spain. 25. Paediatric Haematology and Oncology Division, Hospital Universitari Vall d'Hebron, Barcelona, Spain. 26. Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea. 27. Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway. 28. Department of Pathology, University Medical Centre Utrecht, Utrecht, the Netherlands. 29. Service of Hematology/Oncology, Hospital JP Garrahan, Buenos Aires, Argentina. 30. Department of Pathology, NYU Langone Health and School of Medicine, New York, New York, USA. 31. Department of Neurooncology, Russian Scientific Center of Radiology, Moscow, Russia. 32. Department of Neuroradiology, Burdenko Neurosurgical Institute, Moscow, Russia. 33. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 34. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 35. Research Institute Children's Cancer Center Hamburg, Hamburg, Germany. 36. Institute of Translational Research, University of Liverpool, Liverpool, UK. 37. Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany. 38. Institute of Biometry and Clinical Epidemiology, Charité University Medicine and Berlin Institute of Health, Berlin, Germany. 39. Department of Pediatric Hematology-Oncology, Center for Cancer and Immunology Research and Neuroscience Research, Children's National Medical Center, Washington DC, USA. 40. Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany. 41. Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany. 42. Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany. 43. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 44. Institute of Neuropathology, University Medical Center Zurich, Zurich, Switzerland. 45. Department of Neuropathology, Burdenko Neurosurgical Institute, Moscow, Russia. 46. Department of Pathomorphology, Children's Memorial Health Institute, Warsaw, Poland. 47. Department of Pathology, Amsterdam University Medical Center/VUmc, Amsterdam, the Netherlands. 48. Department of Radiological, Oncological and Anatomopathological Sciences, Sapienza University of Rome, Rome, Italy. 49. IRCCS Neuromed, Pozzilli (IS), Italy. 50. Division of Pathology, The Hospital for Sick Children, Toronto, Canada. 51. Inst Neurophysiopathol, CHU Timone, Service d'Anatomie Pathologique et de Neuropathologie, Aix-Marseille Univ, APHM, CNRS, INP, Marseille, France. 52. Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA. 53. Neuropathology Unit, Division of Pathology, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy. 54. Department of Neuropathology, Charité University Medicine and Berlin Institute of Health, Berlin, Germany. 55. German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany. 56. Department of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn, DZNE German Center for Neurodegenerative Diseases, Bonn, Germany.
Abstract
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.
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.
Authors: Paul A Northcott; Andrey Korshunov; Vijay Ramaswamy; Hallie Coltin; Lakshmikirupa Sundaresan; Kyle S Smith; Patryk Skowron; Luca Massimi; Charles G Eberhart; Karisa C Schreck; Nalin Gupta; William A Weiss; Daniela Tirapelli; Carlos Carlotti; Kay K W Li; Marina Ryzhova; Andrey Golanov; Olga Zheludkova; Oksana Absalyamova; Konstantin Okonechnikov; Damian Stichel; Andreas von Deimling; Caterina Giannini; Scott Raskin; Erwin G Van Meir; Jennifer A Chan; Daniel Fults; Lola B Chambless; Seung-Ki Kim; Alexandre Vasiljevic; Cecile Faure-Conter; Rajeev Vibhakar; Shin Jung; Sarah Leary; Jaume Mora; Roger E McLendon; Ian F Pollack; Peter Hauser; Wieslawa A Grajkowska; Joshua B Rubin; Marie-Lise C van Veelen; Pim J French; Johan M Kros; Linda M Liau; Stefan M Pfister; Marcel Kool; Noriyuki Kijima; Michael D Taylor; Roger J Packer Journal: Acta Neuropathol Date: 2021-08-18 Impact factor: 15.887
Authors: A Tietze; K Mankad; M H Lequin; L Ivarsson; D Mirsky; A Jaju; M Kool; K V Hoff; B Bison; U Löbel Journal: AJNR Am J Neuroradiol Date: 2022-09-22 Impact factor: 4.966