title: Primitive neuroectodermal tumors of the brainstem in children treated according to the HIT trials: clinical findings of a rare disease.
abstract: OBJECTIVE
  Primitive neuroectodermal tumors of the central nervous system (CNS-PNET) arising in the brainstem are extremely rare, and knowledge about them is limited. The few existing case series report fatal outcomes. The purpose of this study was to analyze clinical characteristics of and outcome for brainstem CNS-PNET patients treated according to the consecutive, population-based HIT studies covering a 19-year time period.
  
  
  METHODS
  Between September 1992 and November 2011, 6 eligible children with histologically proven brainstem CNS-PNET not otherwise specified and 2 children with brainstem ependymoblastomas (3, partial resection; 3, subtotal resection; 2, biopsy), median age 3.3 years (range 1.2-10.6 years), were treated according to consecutive multimodal HIT protocols for CNS-PNET/medulloblastoma. Postoperative treatment was according to maintenance chemotherapy protocols (3, craniospinal irradiation [CSI] followed by maintenance chemotherapy), sandwich chemotherapy protocols (2, neoadjuvant chemotherapy, CSI, maintenance chemotherapy), or a therapy protocol for children younger than 4 years (3, postoperative chemotherapy followed by CSI).
  
  
  RESULTS
  The median duration of prediagnostic symptoms, predominantly cranial nerve deficits (n = 7), pyramidal tract signs (n = 5), or ataxia (n = 5), was 5 weeks (range 1-13 weeks). The tumors were all located in the pons. Most involved more than half of the pontine axial diameter and were sharply marginated. All patients had postoperative residual disease, including metastasis in 1 case. With 1 exception all tumors progressed early during treatment within 3.9 months (range 2.5-10.4 months), leading to a 1-year event-free survival rate (± standard error) of 13% ± 12%. After progression, patients succumbed early to their disease resulting in a 1-year overall survival rate of 25% ± 15%. The only surviving patient had a partially resected CNS-PNET, received a sandwich chemotherapy protocol, and is without disease progression 14 months after diagnosis.
  
  
  CONCLUSIONS
  CNS-PNET is a rare but important differential diagnosis in childhood brainstem tumors. So far, efficient therapies are lacking. The sampling of tumor material for improved biological understanding and identification of new therapeutic targets is important.
authors.affiliation: Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg;
authors.forename: Carsten
authors.initials: C
authors.lastname: Friedrich
authors.forename: Monika
authors.initials: M
authors.lastname: Warmuth-Metz
authors.forename: André O
authors.initials: AO
authors.lastname: von Bueren
authors.forename: Johannes
authors.initials: J
authors.lastname: Nowak
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bison
authors.forename: Katja
authors.initials: K
authors.lastname: von Hoff
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.forename: Rolf D
authors.initials: RD
authors.lastname: Kortmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Rutkowski
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D020295:Brain Stem Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000601:surgery / Q000628:therapy*; D017024:Chemotherapy, Adjuvant; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007223:Infant; D060046:Maintenance Chemotherapy; D008297:Male; D020360:Neoadjuvant Therapy / Q000379:methods*; D018365:Neoplasm, Residual; D018242:Neuroectodermal Tumors, Primitive / Q000188:drug therapy / Q000532:radiotherapy / Q000601:surgery / Q000628:therapy*; D011149:Pons / Q000473:pathology*; D035583:Rare Diseases
keywords: ADC = apparent diffusion coefficient; CN = cranial nerve; CNS-PNET = central nervous system primitive neuroectodermal tumor; CSI = craniospinal irradiation; DPIG = diffuse intrinsic pontine glioma; EFS = event-free survival; GPOH = Gesellschaft für Pädiatrische Onkologie und Hämatologie (German Society for Pediatric Oncology and Hematology); OS = overall survival; PFS = progression-free survival; brain tumors; brainstem; chemotherapy; children; oncology; primitive neuroectodermal tumor; radiotherapy