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.
