CNS Tumors – clinical and radiological aspects

Czech version

Authors: Renata Emmerová ¹; Jana Engelová ^2,3; Stěpan Vinakurau ^3,4; Barbora Ondrová ^3,4
Authors‘ workplace: Odděleni klinické a radiační onkologie, Krajská nemocnice Liberec, a. s. ¹; Radiodiagnostické oddělení Nemocnice Jablonec nad Nisou ²; Centrum protonové léčby v Praze ³; Onkologická klinika 2. LF UK a FN Motol Praha ⁴
Published in: Čes.-slov. Patol., 58, 2022, No. 3, p. 150-160
Category: Reviews Article

Overview

Tumors of the central nervous system (CNS) include primary tumors - itraaxial, growing from brain and spinal cord cells (neuroepithelial tumors) or extraaxial, growing from surrounding structures (brain and spinal cord, nerve sheaths, vascular structures, lymphatic tissue, germ cells, malformations, pituitary glands). Much more often they are located in the intracranial space a solitary or multiple metastatic spread of malignancy originating from another organ (eg lung, breast, malignant melanoma, Grawitz’s tumor). The occurrence of metastases of solid tumors is then in the intraaxial or extraaxial region, leptomeningeal or dural. Even morphologically benign tumors with their occurrence in a closed CNS compartment can have malignant behaviour and cause severe slowly developing to acute neurological symptoms, including intracranial hypertension. Primary tumors of the central nervous system present 1-2% of all cancers, with a higher incidence in adults after the age of 60, with a slight predominance in men, with higher mortality in men than in women. About 5% of CNS tumors are hereditary (e.g., Li-Fraumeni syndrome, neurofibromatosis type I, II). The causes of most brain and spinal cord tumors are unclear, the effect of radiation has been definitely demonstrated, there is an increased risk in transplant patients and AIDS (Acquired Immune Deficiency Syndrome) patients, and the potentiating effects of some chemicals and viruses on the development of CNS neoplasms are uncertain.

The effectiveness of treatment of brain and spinal cord tumors is influenced by the existence of the so-called hematoencephalic barrier, which protects the brain from the penetration of toxic substances, but at the same time prevents the penetration of most cytostatics to the tumor target. Another obstacle may be the localization of the tumor in areas difficult to access for histological verification (brain stem, optical chiasma) due to the high risk of complications even after stereotactic biopsy. In some cases, in an effort not to cause an irreversible neurological deficit by inconsiderate tissue collection, the sample of histological material can then become inconclusive to tumor cells, i.e., tumor cells are not captured. Last but not least, the radiosensitivity of some brain structures is also limiting, which makes it impossible to apply a higher dose of ionizing radiation to a tumor affecting sensitive tissues or located near of these sensitive tissues.

The rapid development of immunohistochemical (IHC) and molecular genetic analysis methods has significantly refined diagnostics and thus theoretically facilitates the choice of the optimal treatment procedure for the individual patient. While advances in modern conformal photon and particle (currently the most frequently proton) radiotherapy, stereotactic radiosurgery has enabled accurately targeted irradiation of the CNS tumor site and at the same time spare the high-risk brain structures, thereby significantly reduce the risk of acute and late neurotoxicity, pharmacotherapy options are still limited. Just molecular-genetic knowledge already provides us with predictive and prognostic information. They should increasingly stratify patients for targeted therapy.

Keywords:

Tumors of the central nervous system – diagnosis and treatment of CNS tumors – immunohistochemical methods – molecular analysis

Sources

1. Hegi ME, Stupp R. Withholding TMZ in glioblastoma patients with unmethylated MGMT promoter-still a dilemma? Neuro Oncol 2015; 17: 1425-1427.

2. Weller M, Pfister SM, Wick W, et al. Molecular neuro-oncology in clinical practice : a new horizont. Lancet Oncol 2013; 14: 370-379.

3. Dubbink HJ, Atmodimedjo PN, Kros JM, et al. Molecular classification of anaplastic oligodendroglioma using next-generation sequencing: a report of the prospective randomized EORTC Brain Tumor Group 26951 phase III trial. Neuro Oncol 2016; 18: 388-400.

4. Brat DJ, Verhaak RG, et al. Cancer Genome Atlas Research N. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. N Engl J Med 2015; 372: 2481-2498.

5. Capper D, Jones DTW, Sill M, et al. DNA methylation based classification of central nervous system tumours. Nature 2018; 555: 469-474.

6. Wen PY, Packer RJ. The 2021 WHO Classification of Tumors of the Central Nervous System: clinical implications, Neuro-Oncology 2021; 23(8): 1215-1217.

7. Gonzalez Castro LN, Wesseling P. The cIMPACT- NOW updates and their significance to current neuro-oncology practice. Neurooncol Pract 2020; 29(1): 4-10.

8. Louis DN, Aldape K, Brat DJ, et al. Announcing cIMPACT-NOW: the Consortium to inform molecular and practical approaches to CNS tumor taxonomy. Acta Neuropathol 2017; 133(1): 1-3.

9. Louis DN, Wesseling P, Paulus W, et al. cIMPACT- NOW update 1: not otherwise specified (NOS) and not elsewhere classified (NEC). Acta Neuropathol 2018; 135(3): 481-484.

10. Louis DN, Giannini C, Capper D, et al. cIMPACT- NOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant. Acta Neuropathol 2018; 135(4): 639–642.

11. Brat DJ, Aldape K, Colman H, et al. cIMPACT- NOW update 3: recom mended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV.”Acta Neuropathol 2018; 136(5): 805–810.

12. Ellison DW, Hawkins C, Jones DTW, et al. cIMPACT-NOW update 4: diffuse gliomas characterized by MYB, MYBL1, or FGFR1 alterations or BRAFV600E mutation. Acta Neuropathol 2019; 137(4):683–687.9.

13. Louis DN, Ellison DW, Brat DJ, et al. cIMPACT- NOW: a practical summary of diagnostic points from Round 1 updates. Brain Pathol 2019; 29(4): 469–472.

14. Yeaney GA, Brat DJ. What every neuropathologist needs to know: update on cIMPACT- NOW. J Neuropathol Exp Neurol 2019; 78(4): 294–296.

15. Louis DN, Wesseling P, Aldape K, et al. cIMPACT- NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT Utrecht meeting on future CNS tumor classification and grading. Brain Pathol 2020; 30(4): 844–856.

16. Kristensen BW, Priesterbach-Ackley LP, Petersen JK, et al. Molecular pathology of tumors of the central nervous system. Ann Oncol 2019; 30(8): 1265-1278.

17. Hartmann C, Meyer J, Balss J, et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial defferentiation and age:a study of 1,010 diffuse gliomas. Acta Neuropathol 2009; 118: 469-474.

18. Horbinsky C. What do we know about IDH1/2 mutation so far, and how do we use it? Acta Neuropathol 2013; 125: 621-636.

19. Houillier C, Wang X, Kaloshi G, et al. IDH1 or IDH2 mutations predict longer survival and response to TMZ in low-grade gliomas. Neurology 2010; 75: 1560-1566.

20. Berzero G, Di Stefano AL, Ronchi S, et al. IDH-wildtype lower-grade diffuse gliomas: the importance of histological grade and molecular assessment for prognostic stratification. Neuro Oncol 2021; 23(6): 955-966.

21. Shirahata M, Ono T, Stichel D, et al. Novel, impoved grading system(s) for IDH mutant astrocytic gliomas. Acta Neuropathol 2018; 136: 153-166.

22. Reis GF, Pekmezci M, Hansen HM, et al. CDKN2A loss is associated with shortened overall survival in lower-grade (World Health Organization Grades II-III) astrocytomas. J Neuropathol Exp Neurol 2015; 74: 442-452.

23. Yang RR, Shi ZF, Zhang ZY, et al. IDH mutant lower grade (WHO grades II/III) astrocytomas can be stratified for risk by CDKN2A, CDK4 and PDGFRA copy number alterations. Brain Pathol 2020; 30: 541-553.

24. Caincross G, Wang M, Shaw E, et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: Long-term results of RTOG 9402. J Clin Oncol 2013; 31: 344-350.

25. Arita H, Matsushita Y, Machida R, et al. TERT promoter mutation confers favorable prognosis regardless of 1p/19q status in adult diffuse gliomas with IDH1/2 mutations. Acta Neuropathol Commun 2020; 8: 201.

26. Killela PJ, Reitman ZJ, Jiao Y, et al. TERT promotor mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci USA 2013; 110: 6021-6026.

27. Eckel-Passow JE, Lachance DH, Molinaro AM, et al. Glioma groups based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. N Engl J Med 2015; 372: 2499-2508.

28. Schwartzentruber J, Korshunov A, Liu XY, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 2012; 482: 226-231.

29. BT, Zhang L, Daniels DJ. Treatment Strategies in Diffuse Midline Gliomas With the H3K27M Mutation: The Role of Convection- Enhanced Delivery in Overcoming Anatomic Challenges. Front Oncol 2019; 9: 31.

30. Meyronet D, Esteban-Mader M, Bonnet C, et al. Characteristics of H3 K27M-mutant gliomas in adult. Neuro Oncol 2017; 19: 1127- 1134.

31. Yoshimoto K, Hatae R, Sangatsuda Y, et al. Prevalence and clinicopathological features od H3.3 G34-mutant high-grade gliomas: A retrospective study of 411 consecutive glioma cases in a single institution. Brain Tumor Pathol 2017; 34: 103-112.

32. Korshunov A, Capper D, Reuss D, et al. Histological distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single nosologic entity. Acta Neuropathol 2016; 131: 137-146.

33. Wick W, Platten M, Meisner C, et al. TMZ chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol 2012; 13: 707-715.

34. Weller M, van den Bent M, Preusser M, et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021; 18(3): 170-186.

35. Balana C. Vaz MA, Sepúlveda JM, et al. A phase II randomized, multicenter, open-label trial of continuing adjuvant temozolomide beyond six cycles in patients with glioblastoma (GEINO 14-01). Neuro Oncol 2020; 22(12): 1851-1861.

36. Natsumeda M, Chang M, Gabdulkhaev R, et al. Predicting BRAF V600E mutation in glioblastoma: utility of radiographic features. Brain Tumor Pathol 2021; 38(3): 228-233.

37. Bender K, Perez E, Chirica M, et al. High grade astrocytoma with piloid features (HGAP): the Charité experience wit a new central nervous system tumor entity. J Neurooncol 2021; 153(1): 109-120.

38. Rudà R, Reifenberger G, Frappaz D, et al. EANO guidelines for the diagnosis and treatment of ependymal tumors. Neuro Oncol 2018; 20(4): 445-456.

39. Delgado-López PD, Corrales-García EM, Alonso-García E, et al. Central nervous system ependymoma: clinical implications of the new molecular classification, treatment guidelines and controversial issues. Clin Transl Oncol 2019; 21(11): 1450-1463.

40. Pajtler KW, Mack SC, Ramaswamy V, et al. The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol 2017; 133: 5-12.

41. Pajtler KW, Witt H, Sill M, et al. Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell 2015; 27: 728-743.

42. Fukuoka K, Kanemura Y, Shofuda T, et al. on behalf of the Japan Pediatric Molecular Neuro-Oncology Group (JPMNG). Significance of molecular classification of ependymomas: C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors. Acta Neuropathol Commun 2018; 6: 134; 2018.

43. Kool M, Korshunov A, Remke M, et al. Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol 2012; 123: 473-484.

44. Kock L, Sabbaghian N, Druker H, et al. Germ-line and somatic DICER1 mutations in pinealoblastoma. Acta Neuropathol 2014; 128(4): 583-595.

45. Lee JC, Villanueva-Meyer JE, Ferris SP, et al. Primary intracranial sarcomas with DICER1 mutation often contain prominent eosinophilic cytoplasmic globules and can occur in the setting of neurofibromatosis type 1. Acta Neuropathol 2019; 137(3): 521-525.

46. Fritchie KJ, Jin L, Rubin BP, et al. NAB2- STAT6 Gene Fusion in Meningeal Hemangiopericytoma and Solitary Fibrous Tumor. J Neuropathol Exp Neurol 2016; 75(3): 263-271.

47. Huisman TW, Tanghe HJ, Koper JW, et al. Progesterone, oestradiol, somatostatin and epidermal growth factor receptors on human meningiomas and their CT characteristics. E J Cancer Clin Oncol 1991; 27: 1453-1457.

48. Sioka C, Kyritsis AP. Chemotherapy, hormonal therapy, and immunotherapy for recurrent meningiomas. J Neurooncol 2009; 92: 1-6.

49. Sadetzki S, Flint-Richter P, Ben-Tal T, et al. Radiation-induced meningioma: a descriptive study of 253 cases. J Neurosurg 2002; 97: 1078-1082.

50. Phillips LE, Frankenfeld CL, Drangsholt M, et al. Intracranial meningioma and ionizing radiation in medical and occupational settings. Neurology 2005; 64: 350-352.

51. Suppiah S, Nassiri F, Bi WL, et al. Molecular and translational advances in meningiomas. Neuro Oncol 2019; 21: i4-17.

52. Ostrom QT, Gittleman H, Truitt G, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2011-2015. Neuro Oncol 2018; 20: 1-86.

53. Preusser M, Brastianos PK, Mawrin C. Advances in meningioma genetics: novel therapeutic opportunities. Nat Rev Neurol 2018; 14: 106-115.

54. Simpson D. The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiatry 1957; 20: 22-39.

55. Gousias K, Schramm J, Simon M. The Simpson grading revisited: aggressive surgery and its place in modern meningioma management. J Neurosurg 2016; 125: 551-560.

56. Weber RG, Boström J, Wolter M, et al. Analysis of genomic alterations in benign, atypical, and anaplastic meningiomas: toward a genetic model of meningioma progression. Proc Natl Acad Sci U S A 1997; 94: 14719-14724.

57. Aizer AA, Abedalthagafi M, Bi WL, et al. A prognostic cytogenetic scoring system to guide the adjuvant management of patients with atypical meningioma. Neuro Oncol 2016; 18: 269-274.

58. Zankl H, Zang KD. Cytological and cytogenetical studies on brain tumors. 4. Identification of the missing G chromosome in human meningiomas as no. 22 by fluorescence technique. Humangenetik 1972; 14: 167-169.

59. Seizinger BR, de la Monte S, Atkins L, et al. Molecular genetic approach to human meningioma: loss of genes on chromosome 22. Proc Natl Acad Sci U S A 1987; 84: 5419-5423.

60. Lamszus K. Meningioma pathology, genetics, and biology. J Neuropathol Exp Neurol 2004; 63: 275-286.

61. Tetreault MP, Yang Y, Katz JP. Kruppel-like factors in cancer. Nat Rev Cancer 2013; 13: 701-713.

62. Brastianos PK, Horowitz PM, Santagata S, et al. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet 2013; 45: 285-289.

63. Carpten JD, Faber AL, Horn C, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 2007; 448: 439-444.

64. Loo E, Khalili P, Beuhler K, Vasef MA. BRAF V600E mutation across multiple tumor types: correlation between DNA-based sequencing and mutation-specific immunohistochemistry. Appl Immunohistochem Mol Morphol 2018; 26: 709-713.

65. Spiegl-Kreinecker S, Lötsch D, Neumayer K, et al. TERT promoter mutations are associated with poor prognosis and cell immortalization in meningioma. Neuro Oncol 2018; 20(12): 1584-1593.

66. Kerr K, Qualmann K, Esquenazi Y, Hagan J, et al. Familial syndromes involving meningiomas provide mechanistic insight Into sporadic disease. Neurosurgery 2018; 83: 1107-1118.

67. Smith MJ, Beetz C, Williams SG, et al. Germline mutations in SUFU cause Gorlin syndrome- associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. J Clin Oncol 2014; 32: 4155- 4161.

68. Ng JM, Curran T. The Hedgehog‘s tale: developing strategies for targeting cancer. Nat Rev Cancer 2011; 11: 493-501.

69. Haugh AM, Njauw CN, Bubley JA, et al. Genotypic and phenotypic features of BAP1 cancer syndrome: a report of 8 new families and review of cases in the literature. JAMA Dermatol 2017; 153: 99-1006.

70. Olar A, Wani KM, Wilson CD, et al. Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma. Acta Neuropathol 2017; 133: 431-444.