Events in CNS Tumor Pathology Post-2016 WHO CNS: cIMPACT-NOW Updates and Other Advancements: A Comprehensive Review Plus a Summary of the Salient Features of 2021 WHO CNS 5

Figures & data

Table 1 Categories of CNS Tumors Recommended by Update 6 with Examples of Each

S. No	Category Type	Tumor Entities
1	Category 1: Examples of newly recognized tumor types and subtypes, new diagnostic criteria for some tumors or new family of tumors	- Specific genetic features sufficient for diagnosis of “Glioblastoma, IDH-wildtype” - Astrocytoma, IDH-mutant grades 2 to 4 - Pediatric type glial/glioneuronal tumors including Diffuse glioneuronal tumors with oligodendroglial features and nuclear clusters (DGONC) - Diffuse glioma, H3.3 G34 mutant - Astroblastoma, MN1-altered - Spinal ependymoma, MYCN amplified - Posterior fossa ependymoma, pediatric type/PFA, and adult-type/PFB - Supratentorial ependymoma YAP1 - MAMLD1 fusion-positive.
2	Category 2: Examples of tumor types with nomenclature modification	For chordoid glioma, the location (“of the third ventricle”) was deleted. For myxoid glioneuronal tumor, the location (“of the septum pellucidum and lateral ventricle”) was deleted. For extraventricular neurocytoma and ependymoma, the location was included in the nomenclature. Ependymoma to have combined histopathologic and molecular designations based on unique epigenetic and genetic signatures at different anatomic sites.
3	Category 3: Examples of existing tumor types that will not undergo any changes.	Pilocytic astrocytoma (PA) Extraventricular neurocytoma Pleomorphic xanthoastrocytoma (PXA) Papillary glioneuronal tumor Pineal parenchymal tumor of intermediate differentiation Diffuse leptomeningeal glioneuronal tumor.
4	Category 4: Examples of tumor types that remained sub judice (there was insufficient evidence, and no recommendation could be made)	PA with anaplastic features PXA with anaplastic features Infantile hemispheric glioma with NTRK fusion-positive or MET fusion-positive or ALK or ROS1 fusion-positive Myxopapillary ependymoma with anaplastic features Diffuse glioma, FGFR-TACC fusion-positive.

Table 2 Examples of Mix Match Approach Recommended by Update 6 for the Classification of Tumors

1	Diffuse Glioma, genetically defined	Diffuse glioma, MYB-altered Diffuse glioma, MYBL1-altered Diffuse glioma, FGFR1 TKD-duplicated Diffuse glioma, FGFR1-altered Diffuse glioma, BRAF V600E mutant Diffuse glioma, other MAPK pathway alteration
2	Diffuse glioma, histologically defined	Diffuse astrocytoma Oligodendroglioma

Table 3 Ependymoma Classification Recommended by Update 7

S. No	Ependymoma Type	Tumor Grade
1	Supratentorial ependymoma, C11 or f-95-RELA fusion-positive	No grade assigned*
2	Supratentorial ependymoma, YAP1 fusion-positive	No grade assigned*
3	Supratentorial ependymoma	Grade 2 or 3
4	Posterior fossa ependymoma, PFA	No grade assigned*
5	Posterior fossa ependymoma, PFB	No grade assigned*
6	Posterior fossa ependymoma	Grade 2 or 3
7	Spinal ependymoma, MYCN amplified	No grade assigned*
8	Myxopapillary ependymoma	Grade 2
9	Subependymoma (across all three anatomic compartments)	Grade 1

Note: *Sufficient data currently not available for WHO grades to be assigned to molecularly defined ependymomas.

Table 4 Some Examples of the Application of Molecular Diagnostics in More Common Adult and Pediatric CNS Tumors

S. No	Tumor Entity	Molecular Characteristics
1	Glioblastomas, IDH wild type	- Negative for IDH1 R132H - Retain ATRX on molecular IHC - Demonstrate combined whole chromosome gain of 7 and loss of 10 and/or EGFR amplification - Show TERT-p mutations - Alterations of p53 and/or RB pathways
2	Astrocytomas, IDH-mutant grades 2 to 4	- Positive for IDH1 R132H in 90% of cases - Show loss of ATRX on molecular IHC
3	Astrocytomas, IDH mutant grade 4	- Demonstrate H3 loss of CDKN2A/B - Show IDH1 p.R132 or IDH2 p.R172 - Alterations of ATRX and TP53
4	Oligodendrogliomas, IDH mutant and 1p 19q co-deleted	- Positive for IDH1 R132H in 90% cases - Retain ATRX on molecular IHC - Demonstrate whole arm 1p19q co-deletion - Show IDH1 p.R132 or IDH2 p.R172 and TERT-p mutations
5	Pilocytic astrocytomas	- Demonstrate tandem duplication of 7q34 causing a BRAF fusion in 70% of cases - show KIAA1549-BRAF fusion in 70% and BRAF p.V600E alterations in 5 to 10%
6	Ependymomas, RELA-fusion	- Express positivity for L1CAM on molecular IHC; 11q and C11 or f95-RELA fusion
7	Ependymomas, YAP1-fusion	- Show segmental CNVs of 11q(YAP1); and YAP1-MAMLD1 fusion
8	PFA ependymomas	- Reveal loss of H3 K27me3 on molecular IHC - Balanced genome in the majority of cases.
9	PFB ependymomas	- Reveal retention of H3 K27M on molecular IHC - Demonstrate multiple CNVs.
10	Medulloblastomas, WNT-activated	- Express nuclear β-catenin - Positive for YAP1 and negative for GAB1 on molecular IHC - Demonstrate monosomy 6 - Show CTNNB1 (most common) or APC mutations
11	Medulloblastomas, SHH activated	- Express YAP1 and GAB1 on molecular IHC - Loss of 9q and 10q and TP53-mutation - Show NF2 mutations
12	Medulloblastomas, Group 3	- Negative for GAB1 and YAP1 on molecular IHC - Show i (17q) and MYC amplification in 60% and 20% of cases respectively - Alterations in PTCH1, SMO, SUFU, TP53, etc
13	Medulloblastomas, Group 4	- Negative for GAB1 and YAP1 on molecular IHC - Demonstrate i(17q) in 80% cases.
14	AT/RTs	- Show INI-1 (or BRG1) loss on molecular IHC - SMARCB1 (or SMARCA4) - SMARCB1 (or SMARC A4) alterations
15	-Pleomorphic Xanthoastrocytomas	- Express BRAF V600E in 60 to 80% of cases - H3 loss of CDKN2A/B in 50 to 70% - BRAF p.V600E fusion in 60 to 80% cases