Rare embryonic tumor of the central nervous system – neuroblastoma with FOXR2-activation

Introduction. The development of technologies for molecular genetic typing of tumors of the central nervous system (CNS) has significantly increased the specificity of traditional histological and immunohistochemical research methods. As a result, completely new variants of tumors have appeared, as well as improved results of treatment of tumors with a long-term favorable prognosis. Thanks to new biomarkers, among morphologically similar small-cell embryonic CNS tumors, extremely rare tumors have been identified: ETMR (embryonic tumor with multiple rosettes C19MC), CNS NB-FOXR2 (CNS neuroblastoma (NB) with FOXR2-activation), CNS EFT-CIC (tumor of the CNS sarcoma family of sarcoma alteration), CNS HGNET-MN1 (neuroepithelial tumor of the CNS of high grade with MN1 alteration), CNS HGNET-BCOR (neuroepithelial tumor of the CNS of high grade with BCOR alteration).
The aim of the study was to assess the historical prerequisites for the emergence of a new rare nosological form “CNS NB with FOXR2- activation”, as well as presentation of own results of diagnostics and treatment of children with this tumor.
Materials and methods. The results of diagnosis and treatment of 7 patients with CNS NB with FOXR2-activation were studied. Tumor identification was carried out using a new DNA methylation technique for CNS tumor profiles using the Heidelberg (Germany) brain tumor classifier (www.molecularneuropathology.org), which has recently become available in Russia.
Results and discussion. Based on a review of international experience, the evolution of the appearance in the classification of CNS tumors, as well as the clinical and molecular features of CNS neuroblastoma with FOXR2-activation are presented. The authors present their own results of diagnostics and treatment of 7 patients with a rare tumor CNS neuroblastoma with FOXR2-activation.
Conclusion. Biomarkers have been proposed for the differential diagnosis of small-cell PNET-like tumors of the CNS in children. Due to the molecular identification of this tumor in children, it became clear that such patients, provided that the treatment protocol is adequately followed, have quite satisfactory long-term survival results.

1. Ostrom Q.T., Gittleman H., Truitt G., Boscia A., Kruchko C., Barnholtz-Sloan J.S. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2011–2015. Neuro Oncol. 2018;20(suppl_4):iv1–iv86. doi: 10.1093/neuonc/noy131.

2. Louis D.N., Ohgaki H., Wiestler O.D., Cavenee W.K. (eds.). WHO classifi cation of tumours of the central nervous system. 4th ed. Lyon: IARC Press, 2016. 408 p.

3. Korshunov A., Okonechnikov K., Schmitt-Hoff ner F., Ryzhova M., Sahm F., Stichel D., Schrimpf D., Reuss D.E., Sievers P., Suwala A.K., Kumirova E., Zheludkova O., Golanov A., Jones D.T.W., Pfi ster S.M., Kool M., von Deimling A. Molecular analysis of pediatric CNS-PNET revealed nosologic heterogeneity and potent diagnostic markers for CNS neuroblastoma with FOXR2-activation. Acta Neuropathol Commun. 2021;9(1):20. doi: 10.1186/s40478-021-01118-5.

4. Bhimani A.D., Ryoo J.S., Reddy A.K., Denyer S., McGuire L.S., Alonso M., Mehta A.I. Diff erentiation of outcomes by treatment regimen and histology in central nervous system primary embryonal tumors. World Neurosurg. 2020;141:e289–e306. doi: 10.1016/j.wneu.2020.05.103.

5. Bianchi F., Tamburrini G., Gessi M., Frassanito P., Massimi L., Caldarelli M. Central nervous system (CNS) neuroblastoma. Childs Nerv Syst. 2018;34(5):817–23. doi: 10.1007/s00381-018-3764-3.

6. Rorke L.B., Trojanowski J.Q., Lee V.M., Zimmerman R.A., Sutton L.N., Biegel J.A., Goldwein J.W., Packer R.J. Primitive neuroectodermal tumors of the central nervous system. Brain Pathol. 1997;7(2):765–84. doi: 10.1111/j.1750-3639.1997.tb01063.x.

7. Louis D.N., Ohgaki H., Wiestler O.D., Cavenee W.K., Burger P.C., Jouvet A., Scheithauer B.W., Kleihues P. The 2007 WHO classifi cation of tumours of the central nervous system. Acta Neuropathol. 2007;114(2):97–109. doi: 10.1007/s00401-007-0243-4.

8. Sturm D., Orr B.A., Toprak U.H., Hovestadt V., Jones D.T.W., Capper D. New brain tumor entities emerge from molecular classifi cation of CNS-PNETs. Cell. 2016;164(5):1060–72. doi: 10.1016/j.cell.2016.01.015.

9. Hoff K.V.H., Hansford J.R., Robinson G., Hwang E., Leary S., Pizer B. PNR-33. Molecular re-evaluation of institutionally diagnosed CNSPNETs: clinical consequences of confi ned diagnostic groups. Neuro Oncol. 2016;18(suppl 3):iii13.2–iii13. doi: 10.1093/neuonc/now067.28.

10. Hoff K.V.H., Haberler C., Robinson G., Sumerauer D., Cho J., Mynarek M. EMBR-15. Diagnostic re-evaluation and pooled clinical data analysis of patients with previous diagnosis of CNS-PNET. Neuro Oncol. 2018;20(suppl_2):i72–i72. doi: 10.1093/neuonc/noy059.199.

11. Louis D.N., Wesseling P., Aldape K., Brat D.J., Capper D., Cree I.A. cIMPACT-NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT-Utrecht meeting on future CNS tumor classifi cation and grading. Brain Pathol. 2020;30(4):844–56. doi: 10.1111/bpa.12832.

12. Louis D.N., Wesseling P., Paulus W., Giannini C., Batchelor T.T., Cairncross J.G. cIMPACT-NOW update 1: Not Otherwise Specifi ed (NOS) and Not Elsewhere Classifi ed (NEC). Acta Neuropathol. 2018;135(3):481–4. doi: 10.1007/s00401-018-1808-0.

13. Miettinen M., McCue P.A., Sarlomo-Rikala M., Biernat W., Czapiewski P., Kopczynski J. Sox10 – a marker for not only schwannian and melanocytic neoplasms but also myoepithelial cell tumors of soft tissue: a systematic analysis of 5134 tumors. Am J Surg Pathol. 2015;39(6):826–35. doi: 10.1097/PAS.0000000000000398.

14. Bannykh S.I., Stolt C.C., Kim J., Perry A., Wegner M. Oligodendroglial-specifi c transcriptional factor SOX10 is ubiquitously expressed in human gliomas. J Neurooncol. 2006;76(2):115–27. doi: 10.1007/s11060-005-5533-x.

15. Kleinschmidt-DeMasters B.K., Donson A.M., Richmond A.M., Pekmezci M., Tihan T., Foreman N.K. SOX10 distinguishes pilocytic and pilomyxoid astrocytomas from ependymomas but shows no diff erences in expression level in ependymomas from infants versus older children or among molecular subgroups. J Neuropathol Exp Neurol. 2016;75(4):295–8. doi: 10.1093/jnen/nlw010.

16. Kordes U., Hagel C. Expression of SOX9 and SOX10 in central neuroepithelial tumor. J Neurooncol. 2006;80(2):151–5. doi: 10.1007/s11060-006-9180-7.

17. James T., Lindén M., Morikawa H., Fernandes S.J., Ruhrmann S., Huss M. Impact of genetic risk loci for multiple sclerosis on expression of proximal genes in patients. Hum Mol Genet. 2018;27(5):912–28. doi: 10.1093/hmg/ddy001.

18. Rushing E.J. WHO classifi cation of tumors of the nervous system: preview of the upcoming 5th edition. Memo, 2021. doi: 10.1007/s12254-021-00680-x.

19. Capper D., Jones D.T.W., Sill M., Hovestadt V., Schrimpf D., Sturm D. DNA methylation-based classifi cation of central nervous system tumours. Nature. 2018;555(7697):469–74. doi: 10.1038/nature26000.

20. Capper D., Stichel D., Sahm F., Jones D.T.W., Schrimpf D., Sill M. Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience. Acta Neuropathol. 2018;136(2):181–210. doi: 10.1007/s00401-018-1879-y.

21. Łastowska M., Trubicka J., Sobocińska A., Wojtas B., Niemira M., Szałkowska A. Molecular identifi cation of CNS NB-FOXR2, CNS EFT-CIC, CNS HGNET-MN1 and CNS HGNET-BCOR pediatric brain tumors using tumor-specifi c signature genes. Acta Neuropathol Commun. 2020;8(1):105. doi: 10.1186/s40478-020-00984-9.

22. Рыжова М.В., Телышева Е.Н., Шайхаев Е.Г., Старовойтов Д.В., Котельникова А.О., Галстян С.А., Оконечников К.В. Современные диагностические возможности молекулярного исследования опухолей мозга в Центре нейрохирургии им. акад. Н.Н. Бурденко. Вопросы нейрохирургии имени Н.Н. Бурденко. 2021;85(6):92–5. doi: 10.17116/neiro20218506192. [Ryzhova M.V., Telysheva E.N., Shaikhaev E.G., Starovoitov D.V., Kotelnikova A.O., Galstyan S.A., Okonechnikov K.V. Current diagnostic methods in molecular classifi cation of brain tumors at the Burdenko Neurosurgical Center. Zhurnal Voprosy Neirokhirurgii Imeni N.N. Burdenko = Burdenko’ Journal of Neurosurgery. 2021;85(6):98–101. (In Russ.)].