Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: results of an international, retrospective study

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 tumor with multi-layered 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 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.

Imaging Characteristics of CNS Neuroblastoma-FOXR2: A Retrospective and Multi-Institutional Description of 25 Cases

“…Of these tumors, CNS NB-FOXR2 is the only type that, to the best of our knowledge, has exclusively presented in a supratentorial location, whereas the other tumor types can develop infratentorially with varying frequencies. 4,10,11,[13][14][15][16][17][18][19] In addition, patient age may help with differentiation because the median age at diagnosis for patients with CNS NB-FOXR2 is 5 years (range, 1-20 years), while patients rarely present within the first 2 years of life. 4 In contrast, patients with ATRT are typically younger than 2 years of age, with 33% younger than 1 year of age at diagnosis.…”

“…4,10,11,[13][14][15][16][17][18][19] In addition, patient age may help with differentiation because the median age at diagnosis for patients with CNS NB-FOXR2 is 5 years (range, 1-20 years), while patients rarely present within the first 2 years of life. 4 In contrast, patients with ATRT are typically younger than 2 years of age, with 33% younger than 1 year of age at diagnosis. 20 ETMR usually presents in the first 4 years of life, 4,21,22 and the median age for presentation with CNS BCOR-ITD is 4 years (range, 0.6-22 years).…”

“…4 In contrast, patients with ATRT are typically younger than 2 years of age, with 33% younger than 1 year of age at diagnosis. 20 ETMR usually presents in the first 4 years of life, 4,21,22 and the median age for presentation with CNS BCOR-ITD is 4 years (range, 0.6-22 years). The presentation age for supratentorial ependymomas is highly dependent on the molecular subtype.…”

“…The cohort is based on a previously published cohort of pathology samples with the original diagnosis of CNS-PNET, which was subsequently molecularly reclassified as CNS NB-FOXR2. 4 This study was evaluated and approved by the ethics board of the coordinating institutions. Molecular diagnosis was confirmed by DNA methylation classification (Version 11b4 or higher; www.…”

“…Available clinical data so far suggest that favorable rates of overall survival can be achieved for patients with CNS NB-FOXR2 when treated with surgical resection, craniospinal irradiation, and chemotherapy. 4,5 Imaging characteristics suggesting the diagnosis are currently based on the description of single patients, 6,7 and to the best of our knowledge, larger series are not yet available. The reason is undoubtedly the increasingly detailed tumor classification, which results in a low incidence of confirmed cases in single centers and makes international collaboration essential to pool imaging data.…”