Newer Entities in the WHO CNS Tumor Classification, 5th Edition (2021)

1. Adult-Type Diffuse Gliomas - Restructured

• Astrocytoma, IDH-mutant Grade 4 is a new designation - previously called IDH-mutant GBM, it is now separated from IDH-wildtype GBM because it carries a better prognosis.
• Glioblastoma is now exclusively IDH-wildtype. Any diffuse glioma with IDH mutation is no longer called GBM.
• CDKN2A/B homozygous deletion in IDH-mutant astrocytoma now upgrades it to Grade 4 regardless of histology.
• Adams & Victor's Principles of Neurology, 12th Ed.

2. Pediatric-Type Diffuse Gliomas - Two Entirely New Families

A. Pediatric-Type Diffuse LOW-Grade Gliomas (4 new/reorganized types)

1. Diffuse astrocytoma, MYB- or MYBL1-altered - Predominantly in children; slow-growing; driven by MYB/MYBL1 fusions or mutations.
2. Angiocentric glioma - MYBL1-rearranged; cortical, associated with epilepsy in young patients; biphasic pattern with angiocentric growth.
3. Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) - New entity; associated with BRAF fusion or FGFR alterations; epilepsy-associated cortical tumor in children and young adults; oligodendroglioma-like calcified lesion but molecularly distinct.
4. Diffuse low-grade glioma, MAPK pathway-altered - Driven by BRAF, FGFR1, or other MAPK pathway alterations; a catch-all for low-grade pediatric diffuse gliomas not fitting other categories.

B. Pediatric-Type Diffuse HIGH-Grade Gliomas (all new or newly defined)

1. Diffuse midline glioma, H3 K27-altered - Previously introduced in 2016; now expanded to include not just H3 K27M but also EZHIP overexpression (without H3 mutation). Arises in thalamus, brainstem, spinal cord. WHO Grade 4.
2. Diffuse hemispheric glioma, H3 G34-mutant - New in 2021. Harbors H3.3 G34R/V mutations with co-occurring ATRX and TP53 mutations. Arises in cerebral hemispheres in adolescents/young adults. Highly aggressive, Grade 4.
3. Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype - New in 2021. A molecularly heterogeneous category defined by absence of H3 and IDH mutations; EGFR amplification and MYCN amplification are common drivers. Affects young children.
4. Infant-type hemispheric glioma - New in 2021. Occurs in infants under 1 year; driven by RTK fusions (ALK, NTRK, ROS1, MET). May respond to targeted therapy. Classified separately due to unique biology and clinical behavior.

• Harrison's Principles of Internal Medicine, 22nd Ed., Table 95-3; Adams & Victor's, 12th Ed.

3. Circumscribed Astrocytic Gliomas - New Entities

1. High-grade astrocytoma with piloid features - New in 2021. Defined by DNA methylation profile; occurs in adults; features BRAF, NF1, or ATRX alterations with aggressive behavior despite resemblance to pilocytic astrocytoma histologically. Grade 4.
2. Astroblastoma, MN1-altered - Previously provisional; now formally recognized as a distinct entity defined by MN1 gene fusions. Predominantly in young females; perivascular pseudorosettes; frequently supratentorial.

4. Ependymal Tumors - Molecular Restructuring

• Robbins & Kumar Basic Pathology; Harrison's 22nd Ed.; Adams & Victor's 12th Ed.

5. Glioneuronal and Neuronal Tumors - New Entities

1. Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC) - New provisional entity defined by DNA methylation; predominantly pediatric; located in posterior fossa; oligodendroglioma-like histology but lacks 1p/19q codeletion.
2. Myxoid glioneuronal tumor - New entity; PDGFRA p.K385 mutation; septum pellucidum/lateral ventricles; low-grade.
3. Multinodular and vacuolating neuronal tumor (MVNT) - Now formally recognized as a distinct entity (was a variant before).

6. Embryonal Tumors - New Entities

1. CNS neuroblastoma, FOXR2-activated - New in 2021. Previously grouped under "CNS primitive neuroectodermal tumors" (CNS PNETs), which as a category has been abolished. Defined by FOXR2 activation.
2. CNS tumor with BCOR internal tandem duplication (ITD) - New in 2021. Shares histologic features with Ewing sarcoma-like tumors; predominantly in the brain but not definitively neuroectodermal; BCOR exon 15 ITD is the defining feature.
3. Medulloblastoma, non-WNT/non-SHH - Further molecularly subdivided into 8 subgroups (Groups 3 and 4 are now split). SHH-activated medulloblastoma now has 4 subgroups based on TP53 status and age.
4. AT/RT molecular subgroups - Three subtypes recognized: ATRT-TYR, ATRT-SHH, and ATRT-MYC based on DNA methylation.
5. ETMR with DICER1 alteration - A new subtype of embryonal tumor with multilayered rosettes beyond the classic C19MC-amplified form.

7. Pineal Region Tumors - New Entity

1. Desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant - New in 2021. Rare; characterized by SMARCB1 loss (like AT/RT); locally aggressive.

8. Mesenchymal Tumors - New Entities and Retirements

1. Intracranial mesenchymal tumor, FET-CREB fusion-positive - New provisional entity; low-grade; meningeal-based.
2. CIC-rearranged sarcoma - Now included as a CNS entity; aggressive; CIC gene rearrangement.
3. Primary intracranial sarcoma, DICER1-mutant - New entity; associated with DICER1 syndrome; young patients.
4. Hemangiopericytoma - Retired. Now called Solitary fibrous tumor (SFT) to align with soft tissue nomenclature; retains a 3-tiered grading scheme.

9. Sellar Region Tumors - Major Changes

1. Pituitary neuroendocrine tumor (PitNET) - New preferred term alongside "pituitary adenoma." Reflects neuroendocrine nature and aligns with the WHO classification of neuroendocrine neoplasms elsewhere. The term "adenoma" remains acceptable but PitNET is now encouraged.
2. Pituitary blastoma - New entity. Extremely rare; occurs in infants; associated with germline DICER1 mutations; highly aggressive; resembles embryonal pituitary tissue.
3. Adamantinomatous craniopharyngioma and Papillary craniopharyngioma - Now recognized as two separate tumor types (not subtypes) due to distinct molecular drivers: CTNNB1 (beta-catenin) mutations in adamantinomatous type vs. BRAF V600E mutation in papillary type.
4. Tumors of the neurohypophysis - Consolidated into one group (pituicytoma, granular cell tumor, spindle cell oncocytoma) as they likely represent morphologic variants of the same neoplasm.

10. Nerve and Paraganglioma Changes

• Cauda equina neuroendocrine tumor - Paragangliomas of the cauda equina are now renamed to reflect their autonomic nervous system origin and moved to the nerve tumor chapter.
• Malignant melanotic nerve sheath tumor - Replaces the old "melanotic schwannoma" to better reflect its malignant potential and distinct biology (PRKAR1A mutations, Carney complex association).
• Hybrid nerve sheath tumor - Formally recognized.

Key Conceptual Changes (Not Just New Entities)

Summary Table: Brand New Entities in WHO CNS5