Second series by the Italian Association of Pediatric Hematology and Oncology of children and adolescents with intracranial ependymoma: an integrated molecular and clinical characterization with a long-term follow-up

Maura Massimino; Francesco Barretta; Piergiorgio Modena; Hendrik Witt; Simone Minasi; Stefan M Pfister; Kristian W Pajtler; Manila Antonelli; Lorenza Gandola; Maria Luisa Garrè; Daniele Bertin; Angela Mastronuzzi; Maurizio Mascarin; Lucia Quaglietta; Elisabetta Viscardi; Iacopo Sardi; Antonio Ruggiero; Bianca Pollo; Annamaria Buccoliero; Luna Boschetti; Elisabetta Schiavello; Luisa Chiapparini; Alessandra Erbetta; Isabella Morra; Marco Gessi; Vittoria Donofrio; Carlo Patriarca; Felice Giangaspero; Pascal Johann; Francesca Romana Buttarelli

doi:10.1093/neuonc/noaa257

Second series by the Italian Association of Pediatric Hematology and Oncology of children and adolescents with intracranial ependymoma: an integrated molecular and clinical characterization with a long-term follow-up

Neuro Oncol. 2021 May 5;23(5):848-857. doi: 10.1093/neuonc/noaa257.

Authors

Maura Massimino¹, Francesco Barretta², Piergiorgio Modena³, Hendrik Witt⁴, Simone Minasi⁵, Stefan M Pfister⁴, Kristian W Pajtler⁴, Manila Antonelli⁶, Lorenza Gandola⁷, Maria Luisa Garrè⁸, Daniele Bertin⁹, Angela Mastronuzzi¹⁰, Maurizio Mascarin¹¹, Lucia Quaglietta¹², Elisabetta Viscardi¹³, Iacopo Sardi¹⁴, Antonio Ruggiero¹⁵, Bianca Pollo¹⁶, Annamaria Buccoliero¹⁷, Luna Boschetti¹¹, Elisabetta Schiavello¹¹, Luisa Chiapparini¹⁸, Alessandra Erbetta¹⁸, Isabella Morra¹⁹, Marco Gessi²⁰, Vittoria Donofrio²¹, Carlo Patriarca²², Felice Giangaspero²³, Pascal Johann⁴, Francesca Romana Buttarelli⁵

Affiliations

¹ Pediatric Radiotherapy, Oncology Referral Center, Aviano, Italy.
² Medical Statistics, Biometry and Bioinformatics, IRCCS Fondazione Istituto Nazionale dei Tumori, Milan, Italy.
³ Laboratory of Genetics, Sant'Anna General Hospital, Como, Italy.
⁴ Hopp-Children's Cancer Center Heidelberg, German Cancer Research Center, German Cancer Consortium , Heidelberg, Germany.
⁵ Departments of Neurology and Psychiatric, La Sapienza University, Rome, Italy.
⁶ Radiological, Oncological and Anatomo-Pathological Sciences, La Sapienza University, Rome, Italy.
⁷ Pediatric Radiotherapy, IRCCS Fondazione Istituto Nazionale dei Tumori, Milan, Italy.
⁸ Neuroncology and Neurosurgery Unit, Giannina Gaslini Institute, Genova, Italy.
⁹ Pediatric Onco-Hematology, Units, Regina Margherita Children's Hospital, Torino, Italy.
¹⁰ Pediatric Hematology and Oncology Department, Bambino Gesù Pediatric Hospital, Rome, Italy.
¹¹ Departments of Pediatric, IRCCS Fondazione Istituto Nazionale dei Tumori, Milan, Italy.
¹² Departments of Pediatric Oncology, Santobono-Pausillipon Hospital, Naples, Italy.
¹³ Pediatric Oncology, Padova University, Italy.
¹⁴ Neuroncology, Units, Meyer Pediatric Hospital, Firenze, Italy.
¹⁵ Pediatric Oncology, Units, A. Gemelli Polyclinic, Rome, Italy.
¹⁶ Pathology, Pozzilli, Italy.
¹⁷ Pathology, Units, Meyer Pediatric Hospital, Firenze, Italy.
¹⁸ Radiology, Pozzilli, Italy.
¹⁹ Pathology, Units, Regina Margherita Children's Hospital, Torino, Italy.
²⁰ Pathology, Units, Carlo Besta Neurological Institute, Milan, Italy.
²¹ Pathology, Santobono-Pausillipon Hospital, Naples, Italy.
²² Pathology Unit, Sant'Anna General Hospital, Como, Italy.
²³ IRCCS Neuromed, Pozzilli, Italy.

Abstract

Background: A prospective 2002-2014 study stratified 160 patients by resection extent and histological grade, reporting results in 2016. We re-analyzed the series after a median of 119 months, adding retrospectively patients' molecular features.

Methods: Follow-up of all patients was updated. DNA copy number analysis and gene-fusion detection could be completed for 94/160 patients, methylation classification for 68.

Results: Progression-free survival (PFS) and overall survival (OS) at 5/10 years were 66/58%, and 80/73%. Ten patients had late relapses (range 66-126 mo), surviving after relapse no longer than those relapsing earlier (0-5 y). On multivariable analysis a better PFS was associated with grade II tumor and complete surgery at diagnosis and/or at radiotherapy; female sex and complete resection showed a positive association with OS. Posterior fossa (PF) tumors scoring ≥0.80 on DNA methylation analysis were classified as PFA (n = 41) and PFB (n = 9). PFB patients had better PFS and OS. Eighteen/32 supratentorial tumors were classified as RELA, and 3 as other molecular entities (anaplastic PXA, LGG MYB, HGNET). RELA had no prognostic impact. Patients with 1q gain or cyclin-dependent kinase inhibitor 2A (CDKN2A) loss had worse outcomes, included significantly more patients >3 years old (P = 0.050) and cases of dissemination at relapse (P = 0.007).

Conclusions: Previously described prognostic factors were confirmed at 10-year follow-up. Late relapses occurred in 6.2% of patients. Specific molecular features may affect outcome: PFB patients had a very good prognosis; 1q gain and CDKN2A loss were associated with dissemination. To draw reliable conclusions, modern ependymoma trials need to combine diagnostics with molecular risk stratification and long-term follow-up.

Keywords: children; follow-up; intracranial ependymoma; molecular events; prognosis.

MeSH terms

Adolescent
Brain Neoplasms* / genetics
Brain Neoplasms* / therapy
Child
Child, Preschool
Ependymoma* / genetics
Ependymoma* / therapy
Female
Follow-Up Studies
Hematology*
Humans
Italy
Male
Prognosis
Prospective Studies
Retrospective Studies