THE WHO 2000 TUMOR CLASSIFICATION James G. Smirniotopoulos, M.D. Uniformed Services University of the Health Sciences Bethesda, MD Visit us at:

The WHO 2000 Classification of Brain Tumors

DISCLAIMER: The opinions expressed herein are those of the author(s), and are not necessarily representative of the Uniformed Services University of the Health Sciences (USUHS), the Department of Defense (DOD); or the World Health Organization (WHO). Medicine is a constantly changing field, and medical information is subject to frequent correction and revision. Therefore the reader is entirely responsible for verifying the accuracy and relevance of the information contained herein. Portions copyright 1997 James G. Smirniotopoulos, M.D.

Traditional Tumor Grading l PATHOLOGIST –LOW GRADE –HIGH GRADE l RADIOLOGIST –NON-ENHANCING –ENHANCING l NEUROSURGEON –“SUCKABLE” –“NON-SUCKABLE”

Define the Problem: l Some Low Grade Enhance l Some Low Grade Do Not l Some Low Grade => GBM l Some Low Grade Do Not

WHO Classification l Defines Histologic Subtypes l Grades Biologic Potential l Allows International Cooperation

WHO Classification l Biological Potential l Ascending Scale of Aggression I - IV

WHO CORRELATION l Low Grade –Long-Term Survival –Stable History (No Progression)

WHO GRADING GRADE 1JPA SGCAGANG MENING GRADE 2PXA HPC GRADE 3PXA ANAPLASTIC HPC GRADE 4GBM

CNS NEOPLASM-GLIAL Prognostic Factors Location Age Histology Histology

Malignancy l HISTOLOGIC MALIGNANCY –microscopic l BIOLOGIC MALIGNANCY –macroscopic –labeling indices –molecular biology l CLINICAL MALIGNANCY

HISTOLOGIC MALIGNANCY l CELLULAR ATYPIA l MITOSES (Mitotic Index) l INFILTRATION (lack of margination or encapsulation) l NECROSIS (sign of uncontrolled growth) l VASCULAR CHANGES (tumor neovascularity)

Kernohan-Sayre (AFIP) Grading System: l GRADE I- “BENIGN” or “Low-Grade” l GRADE II - “ “ l GRADE III - ANAPLASTIC –cellular atypia, etc. l GRADE IV- MALIGNANT –NECROSIS !, Vascularity, Mitoses –GLIOBLASTOMA MULTIFORME l NOTE: Numerous modifications exist, most into three grades, e.g..: Low Grade (Benign), Anaplastic, and GBM (w/ NECROSIS).

HIGH-GRADE ASTROCYTOMAS MEDIAN SURVIVAL: l ANAPLASTIC (Grade 3/4) - 28Mos. l GBM (Grade 4/4, has NECROSIS) - 8 Mos.

ASTROCYTOMA Five Year Survival

BIOLOGIC MALIGNANCY: l RAPID GROWTH l HEMORRHAGE, NECROSIS l LOCAL EXTENSION l HEMATOGENOUS DISSEMINATION

“BENIGN” ASTROCYTOMA l Two types: –Low grade (“benign”) Diffuse (Adults) –Low grade “special” Circumscribed (Children)

ASTROCYTIC NEOPLASMS WHO Classification l Astrocytoma (Diffuse) (fibrillary, protoplasmic, or gemistocytic astrocytes) l Anaplastic Astrocytoma (AA) l Glioblastoma Multiforme (GBM) (Giant Cell GBM, Gliosarcoma) ______________________________ l Pilocytic Astrocytoma (Juvenile - JPA) l Subependymal Giant Cell Astrocytoma l Superficial Cerebral Astrocytoma l Pleomorphic Xanthoastrocytoma (PXA)

Grade vs. Type

Enhancement vs. Type

PATTERN ANALYSIS

ASTROCYTOMA: Circumscribed l “Special” astrocytomas, Astrocytoma of Young l Well circumscribed (yet, no capsule) l Various Locations l Do NOT change grade (except PXA) l Do NOT spread along WM l Constellation of findings correlates w/ Histology

PILOCYTIC ASTROCYTOMA Cystic Cerebellar Astrocytoma Juvenile Pilocytic Astrocytoma (“PA” or “JPA”)

PILOCYTIC ASTROCYTOMA l Synonyms: Polar Spongioblastoma, Cystic Cerebellar Astrocytoma l Cell of Origin: Astrocyte (bi-polar, hairlike) l Associations: in ON w/ NF-1 l Incidence: 3-6% of ALL Cranial, 32% of Child l Age: 5-15 (Zulch 3-7) Sex: Slight F (11/9) l Location: Cerebellum, Chiasm/Hypothal, Optic l Treatment: Surgery, patience l Prognosis: 77% at 5 yrs.

PILOCYTIC ASTROCYTOMA Radiology l Cerebellum, Diencephalon –rare in BS or Cerebrum l Majority have significant “cyst” –“Cyst and Mural Nodule” l part of lining does NOT enhance –Nodule may be heterogeneous –Exceptional purely solid l Nodule NOT hyperdense l Calcification in 5-25%

PATHOLOGY l Biphasic pattern –dense pilocytic glia –Rosenthal fibers –loose microcystic areas l No necrosis l Low grade l Abnormal capillaries –allow enhancement, fluid

Grading Gliomas 51 Pilocytic (WHO Gr. 1) KERNOHAN MAYO-ST.ANNE 1 26% 1 2% 2 69%2 55% 3 6%3 35% 4 0%4 8%

ASTROCYTOMA Five Year Survival

PILOCYTIC ASTROCYTOMA: Locations l CEREBELLUM l Chiasm And Optic Nerve l Hypothalmus/thalamus l Cerebral Hemisphere l Spinal Cord (Intramedullary)

Pilocytic Astrocytoma Hemangioblastoma Enhance Enhance Cyst w/ NoduleSolid Cystic Hypodense noduleHyperdense Calcification Never Ca++ NOT vascular Hypervascular, Flow Voids Nodule varies Nodule is “Subpial”

PILOCYTIC ASTROCYTOMA (Juvenile Pilocytic) l Childhood, Young Adults l Benign, no mitosis/necrosis l Circumscribed - Enhancing l Cyst Formation, Mural Nodule l Cerebellum and Diencephalon (Optic tracts, Hypothalmus) (Optic tracts, Hypothalmus)

WHO GRADE I l Circumscribed Astrocytoma –JPA (Pilocytic) –SGCA (Subependymal) l Ganglioglioma l Meningioma

CIRCUMSCRIBED vs DIFFUSE

ASTROCYTOMAS l “SPECIAL” ASTROCYTOMAS –Circumscribed Growth: l Pilocytic l Subependymal Giant Cell l Pleomorphic Xantho-Astrocytoma

PLEOMORPHIC XANTHOASTROCYTOMA l Recently Described, Rare Variant of Astrocytoma l Arises from Subpial Astrocytes l Affects Superficial Cerebral Cortex and Meninges l Temporal > Frontal > Parietal

PLEOMORPHIC XANTHOASTROCYTOMA l IMAGING: –CT APPEARANCE: l Well-Circumscribed Hypodense or Cystic Mass l Often Isodense Solid Nodule That Intensely Enhances l May Mimic Juvenile Pilocytic Astrocytoma l Calcifications Rare

PLEOMORPHIC XANTHOASTROCYTOMA l MR APPEARANCE: –Well-Circumscribed Mass of Variable Size –Superficial Cortical Location –T1: Low/Mixed Signal, –T2: High/Mixed Signal –Often with Cystic Component –Solid Portion Intensely Enhances –Adjacent Meninges May Enhance (Tail) –Little or No Mass Effect

ASTROCYTOMAS l “ORDINARY” ASTROCYTOMA Diffuse Infiltration of WM: l Fibrillary l Protoplasmic l Gemistocytic l WHO 2,3,4 (NOT 1) l KS & Mayo Grades 1-4

PATTERN ANALYSIS Neoplasm

KERNOHAN (KS) ANAPLASIA 0 Min >1/2 Marked CELLULARITY MildMild Inc Marked MITOSIS 0 0 Plus Marked ENDOTHELIAL0 Min Min Marked NECROSIS Marked TRANSITION TRANSITION

ST. ANNE-MAYO (1-3) 1 Point for Each ATYPIAMITOSISENDOTHELIALNECROSIS Grade = TOTAL POINTS Grade 1 = 0-1, Grade 2 = 2 points Grade 3 = 3,4 points

ASTROCYTOMA: DIFFUSE (Fibrillary, protoplasmic, etc.) “Adult type” or “Hemispheric” Astrocytoma Diffusely infiltrate brain, along WM tracts Continuum, from low-grade to high-grade Genetic Alterations 17 => 9 => 10 Many Progress in Histology over time, changing from WHO Gr. 2 => Gr. 3 => Gr. 4 (GBM) Imaging tends to correlate with histology

ASTROCYTOMA Radiologic Grading l TYPE 1 - (Benign, WHO 2 KS Grade 1-2) –Homogeneous –No Enhancement, No Edema l TYPE 2 - (Anaplastic - Grade 3) –Variable Enhancement, Edema l TYPE 3 - (Glioblastoma - Grade 4) –Heterogeneous (Necrosis, Blood) –Ring Enhancement, Edema

“BENIGN” ASTROCYTOMA: WHO 2, KS 1-2, Mayo 1 l YOUNGER PATIENT –CHILDHOOD –Young Adults (20’s - 40’s) l NL VESSELS (NO NEOVASCULARITY) –BBB INTACT –NO EDEMA –NO ENHANCEMENT –NO TUMOR VESSELS

Benign - Diffuse l HOMOGENEOUS –NO NECROSIS –NO HEMORRHAGE –INCREASED WATER DARK Poorly Demarcated on CT Sharp and Dark on T1W Sharp and Dark on T1W Sharp and BRIGHT on T2W Sharp and BRIGHT on T2W –MICROCYST >>> MACROCYST (macrocysts occur in JPA, etc.)

MODES OF SPREAD 1. Natural passages 2. Along surfaces 3. Along tracts 4. Across the meninges

SPREAD ALONG TRACTS: l CORONA RADIATA l PEDUNCLES l CORPUS CALLOSUM l ANTERIOR COMMISURE l ARCUATE FIBRES

“MALIGNANT” ASTROCYTOMA: l Older patient –40’s and up –exceptions (PNET) –~ 1/2 arise from previous low grade (2-3) l Abnl. Vessels (neovascularity) -- BBB abnormality –vasogenic edema –contrast enhancement –irregular vessels, shunting, etc. l HETEROGENEOUS –hemorrhage (old/new) –tumor necrosis –tumor itself

GBM l LOW DENSITY CENTER –variegated necrosis l ENHANCING RIM –hypercellular, fleshy neoplasm –greatest neovascularity l CORONA OF HYPODENSITY –“edematous” white matter –areas of neoplastic infiltration

GLIOBLASTOMA MULTIFORME (Malignant Astrocytoma) l Adults over 40 yrs. l Malignant with mitoses, neovascularity l Discrete ring-enhancing lesion l Central necrosis, vasogenic edema l Cerebral hemispheres (cross the corpus callosum)

GLIAL TUMORS MR Grading* Low Grade (KS 1-2) High Grade (KS 3-4) HomogeneousHeterogeneous Well definedPoorly defined Min. MassMore Mass Min. Edema Vasogenic edema No blood Hemosiderin *Radiology (1990) 174:

GRADING SYSTEMS Sem Rad Onc (1991); 1: 2-9 KernohanBergerWHO 1 Pilocytic,SEGA Benign (1)Astrocytoma 2 Astrocytoma Benign (2) Anaplastic3 Anaplastic Anaplastic (3) Glioblastoma4 Glioblastoma Malignant (4)

NEUROEPITHELIAL TUMORS WHO Classification l Astrocytic l Oligodendroglial l Ependymal l Choroid Plexus Tumors l Neuronal l Neuronal Mixed w/ Glial l Pineal l Embryonal (PNET)

NEOPLASMS OF THE MENINGES WHO Classification 1. MENINGIOMA: a. Meningioma (typical) b. Atypical Meningioma c. Anaplastic (Malignant) Meningioma 2. MESENCHYMAL (non-meningothelial) 3. Primary MELANOCYTIC Lesions 4. UNCERTAIN Origin a. Hemangiopericytoma b. Hemangioblastoma

MENINGEAL TUMORS WHO Grades TYPEGRADE MENINGIOMA I ATYPICAL MENINGIOMA II PAPILLARY MENINGIOMAII-III HEMANGIOPERICYTOMAII-III ANAPLASTIC MENINGIOMA III

MENINGIOMA “Malignant Meningioma” l Hemangio-Peri-Cytoma (HPC) l Malignant Fibrous Histiocytoma (MFH) l Papillary Meningioma l “Benign” Metastasizing Meningioma

HEMANGIOPERICYTOMA (HPC) l Narrow dural base (“Mushrooming”) l No Hyperostosis, No Calcification l Lobulated (not hemispheric) l Internal Signal Voids (on MRI) l Hypervascular on Angio

DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR (DNT) l IMAGING: –MR APPEARANCE l Focal cortical mass, usually temporal lobe l Hypointense on T1 l Hyperintense on T2 l Multinodular –Microcystic –Megagyric - may cause bony erosion l Occasional Enhancement

DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR (DNT) l IMAGING: –CT APPEARANCE l Hypodense Mass l No Edema l Rare Calcification l Calvarial Erosion l CT Normal in 10%

THE NEW WHO l Biological Potential l Ascending Scale of Aggression I - IV

CORRELATION l Low Grade l Long-Term Survival l Stable Histology

WHO GRADE I l Circumscribed Astrocytoma –JPA (Pilocytic) –SGCA (Subependymal) l Ganglioglioma l Meningioma

Define the Problem: l Some Low Grade Enhance l Some Low Grade Do Not l Some Low Grade => GBM l Some Low Grade Do Not

Enhancement vs. Type