Specialty Guide · Path-iQ Global Pathology Review
Neuropathology is the subspecialty of pathology concerned with diseases of the nervous system — brain, spinal cord, peripheral nerves, and muscle. It is among the most rapidly evolving fields in diagnostic pathology: the WHO CNS5 Classification (2021) fundamentally restructured brain tumour taxonomy around molecular markers rather than morphology alone, and the molecular neuropathology of neurodegenerative diseases is transforming both research and clinical practice.
The WHO Classification of Tumours of the Central Nervous System (5th edition, 2021) introduced the concept of "integrated diagnosis" — the final diagnosis requires integration of histological features with molecular parameters. A tumour that looks like a glioblastoma on H&E but carries IDH mutation is now classified differently from IDH-wildtype GBM, because these entities have completely different prognoses and treatment implications.
| WHO CNS5 Entity | Key Molecular Features | Grade | Prognosis |
|---|---|---|---|
| Astrocytoma, IDH-mutant | IDH1/2 mut; ATRX loss; no 1p/19q codeletion; CDKN2A/B del = grade 4 | 2, 3, or 4 | Grade 2 median OS ~10yr; grade 4 ~3–5yr |
| Oligodendroglioma, IDH-mutant, 1p/19q-codeleted | IDH1/2 mut + 1p/19q codeletion; TERT promoter mut; CIC/FUBP1 mut | 2 or 3 | Grade 2 median OS ~12–15yr; best prognosis of diffuse gliomas |
| Glioblastoma, IDH-wildtype | IDH wildtype + any of: EGFR amp, TERT promoter mut, +7/−10; WHO grade 4 by definition | 4 | Median OS ~15 months with temozolomide + radiotherapy (Stupp protocol) |
| Diffuse midline glioma, H3 K27-altered | H3.3 K27M (HIST1H3B, H3F3A) or H3.1 K27M; predominantly children; thalamus, brainstem, spinal cord | 4 | Median OS ~9–15 months; DIPG prototype |
| Diffuse hemispheric glioma, H3 G34-mutant | H3.3 G34R/V mutation; young adults; cerebral hemisphere | 4 | Intermediate; better than GBM IDH-wildtype |
| Ependymoma (ZFTA fusion-positive) | ZFTA-RELA fusion; supratentorial; children; previously "RELA-fusion" | 2 or 3 | Grade 3: higher recurrence risk; CNS irradiation important |
| Medulloblastoma, WNT-activated | CTNNB1 mutation; monosomy 6; best prognosis of MB subtypes | 4 | 5-yr OS >90%; de-escalation trials ongoing |
| Medulloblastoma, SHH-activated, TP53-mutant | TP53 mutation + SHH pathway activation; poor prognosis | 4 | 5-yr OS ~40%; worst prognosis among MB subtypes |
| Marker | Method | Clinical Significance |
|---|---|---|
| IDH1 R132H | IHC (clone H09); confirmed by sequencing if negative in young patient | Distinguishes IDH-mutant glioma (better prognosis) from IDH-wildtype GBM; present in ~70% of grade 2–3 gliomas |
| IDH1/2 sequencing (non-R132H) | Sanger or NGS; needed if IHC negative but IDH mutation suspected (age <55) | IDH2 mutations (R172) and non-canonical IDH1 mutations missed by IHC alone |
| 1p/19q codeletion | FISH; or SNP array; or NGS copy number | Diagnostic of oligodendroglioma (with IDH mutation); associated with alkylating chemotherapy sensitivity |
| TERT promoter mutation | Sanger or NGS (C228T, C250T hotspots) | IDH-wildtype GBM signature (with EGFR amp / +7/−10); also in oligodendroglioma |
| ATRX loss (IHC) | IHC (nuclear loss in tumour cells) | Supports IDH-mutant astrocytoma (ATRX loss ± IDH mut + no codeletion = astrocytoma lineage) |
| EGFR amplification | FISH; or NGS copy number | GBM IDH-wildtype molecular criterion per WHO CNS5; EGFRvIII variant therapeutic target |
| CDKN2A/B homozygous deletion | FISH or NGS; required to upgrade IDH-mutant astrocytoma to grade 4 | IDH-mutant grade 4 astrocytoma carries similar prognosis to IDH-wildtype GBM |
| MGMT promoter methylation | Pyrosequencing; methylation-specific PCR | Predicts benefit from temozolomide; methylated MGMT = improved OS in GBM treated with Stupp protocol |
| H3 K27M (IHC + sequencing) | IHC (clone D1B2); confirmed by NGS | Diagnostic of diffuse midline glioma; identifies DIPG regardless of grade on H&E |
| DNA methylation profiling (MethylationArray) | Illumina 850K EPIC array; classifier (Heidelberg) | Classifies CNS tumours into >90 methylation classes; resolves diagnostically ambiguous cases; increasingly standard at tertiary centres |
Neuropathology intraoperative consultation uses the smear (squash) preparation as the primary technique, not frozen section — brain tissue smears easily and the fibrillary processes of glioma cells are best appreciated in smear preparations stained with H&E or toluidine blue. Frozen sections are used for solid, less-cellular tumours (meningioma, lymphoma, metastasis).
Post-mortem brain examination remains the gold standard for definitive neurodegenerative disease diagnosis. Neuropathological staging systems quantify protein aggregate burden across brain regions to assess disease severity and support clinicopathological correlation.
| Disease | Hallmark Pathology | Staging / Grading System | Key IHC |
|---|---|---|---|
| Alzheimer's disease | Amyloid plaques (Aβ) + neurofibrillary tangles (tau) | ABC-D: A=Thal Aβ phase (0–5); B=Braak NFT stage (I–VI); C=CERAD neuritic plaque score; D=ADNC | Anti-Aβ (6E10); anti-tau (AT8); anti-phospho-tau (AT100) |
| Parkinson's disease / DLB | Lewy bodies (α-synuclein aggregates) in neurons | Braak PD staging (stages 1–6); McKeith criteria for DLB (limbic vs neocortical) | Anti-α-synuclein (LB509, EP1646Y) |
| Multiple system atrophy (MSA) | Glial cytoplasmic inclusions (GCIs) of α-synuclein in oligodendrocytes | MSA-P (striatonigral) vs MSA-C (olivopontocerebellar); glial vs neuronal inclusion pattern | Anti-α-synuclein; p62 |
| Progressive supranuclear palsy (PSP) | 4R tau astrocytic tufts + neurofibrillary tangles in basal ganglia / brainstem | NINDS-NINDNA criteria; NBA staging | Anti-tau (4R isoform-specific: RD4) |
| Frontotemporal dementia (FTD / FTLD) | TDP-43 (FTLD-TDP), FUS (FTLD-FUS), or tau (FTLD-tau) inclusions by subtype | TDP-43 subtype A–E; FUS subtypes; tau (CBD, PSP, Pick's) subtypes | Anti-TDP-43 (pS409/410); anti-FUS; 3R/4R tau |
| CJD / prion disease | Spongiform change; prion protein (PrPSc) plaques; astrocytic gliosis; neuronal loss | PrP IHC pattern (synaptic, perivacuolar, plaque-like); codon 129 polymorphism (MM/MV/VV) | Anti-PrP (3F4, 12F10); RT-QuIC (CSF) |
| ALS / MND | TDP-43 inclusions in motor cortex + anterior horn cells; Bunina bodies | Neuropathological staging (Brettschneider); SOD1, FUS, TDP-43, C9orf72 subtyping | Anti-TDP-43; anti-ubiquitin; p62 |
Neuromuscular pathology encompasses muscle biopsy interpretation for myopathies and dystrophies, and nerve biopsy interpretation for peripheral neuropathies. The biopsy protocol requires fresh-frozen tissue (for enzyme histochemistry and immunofluorescence) as well as formalin-fixed paraffin-embedded (FFPE) tissue and glutaraldehyde-fixed tissue for electron microscopy.
Lead editor of the WHO Classification of Tumours of the CNS (5th edition, 2021). Defined the integrated diagnosis framework for brain tumours. Authority on IDH mutation biology and molecular neuropathology of gliomas.
Led development of the Heidelberg DNA methylation classifier — the most significant advance in CNS tumour diagnostics of the past decade. Authority on paediatric high-grade glioma molecular subtyping and DIPG biology.
Editor of Brain Pathology, the leading neuropathology journal. Expert on meningioma grading, ependymoma molecular classification, and adult diffuse glioma pathology.
Pioneered IDH mutation sequencing in clinical neuropathology and was central to establishing 1p/19q codeletion as a diagnostic criterion for oligodendroglioma.
Director of the Harvard Alzheimer's Disease Research Center. Authority on synaptic pathology in AD, tau propagation, and the development of the ABC-D neuropathological criteria.
Expert in prion disease neuropathology, the Western blot characterisation of PrPSc strains, and the German CJD surveillance programme contributing to European prion disease epidemiology.