cIMPACT recommendations for the classification of diffuse gliomas 2020

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cIMPACT (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) is a forum under the auspices of the International Society of Neuropathology that recommends proposed changes to future central nervous system tumor classification systems, primarily the WHO classification system.

Current (2016) classification

WHO classification of CNS tumors

Proposed (2020) changes to diffuse glioma classification

Several recommendations have been proposed by the cIMPACT group in order to further increase the standing of molecular phenotype in the classification of diffuse gliomas.

The changes proposed may be (over)simply summarized as:

  • a move away from IDHmt glioblastoma, thus all glioblastoma will be IDHwt
  • a move away from IDHwt astrocytoma, thus all diffuse astrocytoma will be IDHmt, and graded based on histological and molecular phenotype to grades 2 through 4
IDHmt diffuse gliomas

Previously, glioblastoma was defined as a glial tumor with necrosis or microvascular proliferation. IDH status predicted survival, and thus glioblastoma IDHwt and glioblastoma IDHmt subtypes were defined.

Given that IDHmt tumors comprised <10% of total glioblastomas, predicted significantly better survival and were thought to result from de-differentiation of lower-grade astrocytoma, there has been a move to reclassify these tumors to make 'glioblastoma' a more homogenous group.

Thus, the new recommendations to the classification system involve the removal of IDHmt glioblastoma and the institution of IDHmt astrocytoma grading up to WHO grade 4.

In the proposed grading system, IDHmt astrocytoma will be graded based on histology and the presence or absence of a novel genetic parameter, CDKN2A/B homozygous deletion (note the use of Arabic numerals, another proposed change):

  • astrocytoma, IDH-mutant, WHO grade 2
    • a diffusely infiltrative astrocytic glioma with an IDH1 or IDH2 mutation that is well-differentiated and lacks histologic features of anaplasia. Mitotic activity is not detected or low. Microvascular proliferation, necrosis and CDKN2A/B homozygous deletions are absent
  • astrocytoma, IDH-mutant, WHO grade 3
    • a diffusely infiltrative astrocytic glioma with an IDH1 or IDH2 mutation that exhibits focal or dispersed anaplasia and displays significant mitotic activity. Microvascular proliferation, necrosis and CDKN2A/B homozygous deletions are absent
  • astrocytoma, IDH-mutant, WHO grade 4
    • a diffusely infiltrative astrocytic glioma with an IDH1 or IDH2 mutation that exhibits microvascular proliferation or necrosis or CDKN2A/B homozygous deletion or any combination of these features

Thus, all (2016) IDHmt glioblastoma (defined by microvascular proliferation or necrosis) will become (2020) IDHmt astrocytoma WHO grade 4. Previous (2016) diffuse or anaplastic astrocytoma that harbor a CDKN2A/B mutation will become (2020) IDHmt Astrocytoma WHO grade 4.

IDHwt diffuse gliomas

The presence of IDHwt in diffuse glioma is a poor prognostic feature. Though this is not true for non-diffuse glioma (and indeed normal brain) which are inherently IDHwt. Many IDHwt astrocytomas, although histologically lower grade, due to the absence of mitoses, microvascular proliferation or necrosis, behave in an aggressive manner and parallel the dismal course of glioblastoma (IDHwt). Thus, there is a move to remove the entity that is IDHwt astrocytoma as many can be reclassified with further investigations into either more aggressive (i.e. IDHwt glioblastoma) or low grade (non-diffuse glioma or reactive normal brain) entities.

As a result, the diagnostic criteria for IDHwt glioblastoma (now the only type of glioblastoma), has been expanded to include molecular phenotypes that portend a poor prognosis: Glioblastoma, IDH-wildtype therefore are

  • an IDH-wildtype diffuse astrocytic glioma with any of:
    • microvascular proliferation
    • necrosis
    • one or more of the following molecular features:
      • TERT promoter mutation
      • EGFR gene amplification
      • whole chromosome 7 gain AND whole chromosome 10 loss (+7/-10)

Proposals

Further proposals by the cIMPACT group include molecular classification of pediatric diffuse glioma, new tumor entities (e.g. polymorphous low-grade neuroepithelial tumor of the young (PLNTY))

The updated (5th) edition of the WHO blue book is expected in late 2020.