GLIOMA UPDATE: CNS WHO 2021 AND BEYOND

Gliomas are the common primary central nervous system CNS (brain tumor) and require proper classification and grading. The classification of gliomas for the past century has been based largely on histogenesis and microscopic similarities. There has been a paradigm shift with the emergence of next generation sequencing (NGS) technique clarifying the genetic bases of tumor genesis and paving a way forward for classification of gliomas from a genetic standpoint. The 2016 World Health Organization classification of tumors of central nervous system encouraged “integrated diagnosis” and facilitated precise diagnoses of genetically defined entities. This also unraveled many tumors that did not fit into classification .The international society of neuropathology sponsored an initiative cIMPACT-NOW to propose changes in between two WHOs .The changes, entities thus recognized, along with many other modifications have been incorporated in the 2021 CNS WHO. The discovery of isocitrate dehdrogenase (IDH) mutations in gliomas lead to refinement in clinically relevant diagnostic schema of diffuse gliomas. The latter could be precisely classified into astrocytic or oligodendroglial tumors by using IDH, TP53, ATRXand 1p/19q codeletion studies.

Table 3. Grading within types

Table 4: Layered / structured reporting

Specific Changes: Gliomas, Glioneuronal Tumors and Neuronal Tumors have been divided into  6 different families and fourteen newly recognized types have been added to the classification. Division of diffuse gliomas that primarily occur in adults (termed “adult type”) and those occur primarily in children (termed “pediatric type”).

Figure 1: Schematic framework of pediatric- and adult-types difuse gliomas

(The orange triangles represent high-grade tumors, while the blue one represents low-grade tumors)

{Komori, T. The molecular framework of pediatric-type diffuse gliomas: shifting toward the revision of the WHO classification of tumors of the central nervous system. Brain Tumor Pathol 38, 1–3 (2021)}

Adult type, diffuse astrocytic gliomas

In 2021 CNS WHO there has been an attempt for simplification of the classification of common, adult type, diffuse gliomas into only 3 types: Astrocytoma, IDH-mutant, Oligodendroglioma, IDH-mutant and 1p/19q codeleted; and Glioblastoma, IDH-wildtype.

All IDH mutant, diffuse astrocytic tumors are considered a single type (Astrocytoma, IDH-mutant) and are then graded as CNS WHO grade 2, 3, 4. Moreover, grading is no longer entirely histological, since the presence of CDKN2A/B homozygous deletion with or without necrosis or microvascular proliferation results in a CNS WHO grade of 4.

For IDH –wildtype(wt) diffuse astrocytic tumors in adults, presence of 1 or more of 3 genetic parameters (TERT promoter mutation, EGFR gene amplification, combined gain of entire chromosome 7 and loss of entire chromosome 10 [+7/-10] is sufficient to assign the highest WHO grade i.e Glioblastoma,IDH wt  .

Figure 2: Diagnostic algorithm for classification of diffuse gliomas in adults

{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 18, 170–186 (2021). https://doi.org/10.1038/s41571-020-00447}

Pediatric-type diffuse gliomas

Majority of pediatric gliomas are low grade, slow growing lesions (Grade I or II ) and account for 25%-30% of pediatric CNS tumors. The low-grade group includes 4 entities that feature diffuse growth in the brain but with sometimes overlapping and less specific histological features. A significant fraction of pediatric gliomas progress rapidly (WHO Grade III) and are designated pediatric high-grade gliomas (pHGGs) and comprise 8%-12% of all pediatric gliomas. The low-grade group includes 4 entities that feature diffuse growth in the brain but with sometimes overlapping and less specific histological features.

Figure: 3 Major histology and genetic alterations in pediatric-type diffuse gliomas

{Komori, T. The molecular framework of pediatric-type diffuse gliomas: shifting toward the revision of the WHO classification of tumors of the central nervous system. Brain Tumor Pathol 38, 1–3 (2021).}

Figure 4:  Molecular testing decision tree for pediatric low grade gliomas

{Mahajan S, Sharma M C, Sarkar C, Suri V. Approach to integrating molecular markers for assessment of pediatric gliomas. Int J Neurooncol 2021; 4, Suppl S1:166-74}

Molecular landscape of pediatric high-grade gliomas

pHGGs are predominantly de novo and can occur throughout the CNS. Approximately one-half of pHGGs occur in the midline location. The key discovery that best illustrates the unique biology of pHGG’s was the identification of somatic histone mutations. Specific and mutually exclusive mutation in the genes encoding the histone H3.3 (H3F3A) and H3.1 (HIST1H3B, HIST1H3C) variants along with BRAF V600E mark distinct subgroups of disease in children and young adults.

Figure 5: Molecular testing decision tree for pediatric high grade gliomas

{Mahajan S, Sharma M C, Sarkar C, Suri V. Approach to integrating molecular markers for assessment of pediatric gliomas. Int J Neurooncol 2021; 4, Suppl S1:166-74}

Diffuse midline glioma (DMG), H3-K27M-altered

Diffuse midline gliomas, H3-K27M mutant was recognized as a new diagnostic entity in the updated 2016 WHO classification of CNS tumors unifying DIPGs and gliomas from the thalamus and spinal cord harboring a histone H3-K27M mutation.

Recently, studies identified a few  cases of midline glial tumors that lacked H3-K27M mutation, has showed H3K27me3 loss along with wither enhancer of zest homologus inhibitory protein{EZHIP) overexpression or epidermal growth factor receptor (EGFR) mutation, thus extending the spectrum of DMG’s beyond H3-K27M mutation.

Diffuse hemispheric glioma, H3G34-mutant

Mutations on H3F3A that substitutes glycine to arginine or valine at position 34 (G34R/V) have been identified in approximately 20% of the pHGG located in the cerebral hemispheres.

They occur predominantly within the age range of 11-30years. Patients harboring tumor with this mutation tend to have longer OS (median survival of 20 months) than DMG.

“Glioblastoma” is no longer used in the setting of a pediatric-type neoplasm.

Conclusion

Precise classification of gliomas,requires molecular characterization and the integration of histopathological and molecular information, in a tiered diagnostic format. Needless to say, careful morphologic analysis of gliomas, judicious use of immunohistochemical stains, FISH and Sanger sequencing technologies can be used to obtain genetically rich and useful data essential for patient stratification in future clinical trials and to develop new efficient targeted therapies for gliomas.

References:

1. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, Soffietti R, von Deimling A, Ellison DW. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021 Aug 2;23 (8):1231-1251. doi: 10.1093/neuonc/noab106. PMID: 34185076; PMCID: PMC8328013.
2. Ryall, S., Tabori, U. & Hawkins, C. Pediatric low-grade glioma in the era of molecular diagnostics. acta neuropathol commun8, 30 (2020). https://doi.org/10.1186/s40478-020-00902.

Author, Dr. Anila Sharma,
Sr. Consultant, Department of Laboratory Medicine,
RGCIRC, New Delhi