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Neuropathology Patterns and Introduction


CNS Tumor Classification Schemes and Additional “Neuropathology Patterns”

The first comprehensive classification of nervous system tumors, formulated by Percival Bailey and Harvey Cushing in 1926, was founded on presumed parallels between embryologic and neoplastic cells. In large part, this histogenetic “cell of origin” model still forms the basis for today's nomenclature, although much of the terminology has changed considerably. Renewed interest in the role of developmental pathways in tumorigenesis has led to more recent studies focusing on cancer stem cells and progenitor cells, as well as in disease-defining driver mutations. In 1949, as a means of enhancing the clinical utility of tumor classification, Kernohan contributed a tumor grading system focusing on correlations with patient prognosis. As progress was made over time, Russell and Rubinstein continued to modify and update the Bailey and Cushing system from the 1960s through the 1980s. Nonetheless, considerable variability in diagnostic practice existed on both sides of the Atlantic Ocean. In order to enhance consistency, an experts' consensus scheme known as the World Health Organization (WHO) classification scheme was first completed in 1979 and then revised in 1993, 2000, 2007, and 2016. This latter scheme is now the most widely utilized by neuropathologists for tumor typing and grading.

The 2016 WHO “blue book” currently lists over 100 types of nervous system tumors and their variants. It also departs from prior editions in being the first to integrate molecular criteria into the definitions of many adult and pediatric tumor types. This level of complexity can be daunting; therefore, an organized approach or algorithm is required. As a first step, consideration of clinical and radiologic characteristics is a critical way to narrow the differential diagnosis, often to a few fairly common entities. In fact, the combination of patient age and neuroimaging features (including tumor location) provides some of the most powerful diagnostic clues before any tissue is even sampled or examined under the microscope. For example, the differential varies considerably for supratentorial versus infratentorial, pediatric versus adult, and enhancing versus nonenhancing tumors. The most common diagnostic considerations are therefore summarized by age, location, and imaging features in Table 1.1 , with each specific entity discussed in greater detail in subsequent chapters. Also, for a much more detailed background on the use of neuroimaging, the reader is referred to Chapter 4 , while the more recent approach of using classic molecular patterns/profiles as a diagnostic aid is summarized in a completely new Chapter 5 . Radiology is a particularly critical topic in surgical neuropathology, since brain and spinal cord biopsies are often small and the neuroimaging essentially provides the “gross pathology.” At the opposite end of the pathology spectrum (i.e., submicroscopic), molecular alterations are increasingly providing diagnostic, prognostic, and/or predictive data that are essential for the daily care of brain tumor patients. Therefore, the reader must be aware of their burgeoning roles in routine neuropathology and practical ways to integrate these new genetic and genomic algorithms.

Table 1.1
Common CNS Tumor Diagnoses by Location, Age, and Imaging Characteristics
Location Child/Young Adult Older Adult
Cerebral/Supratentorial Ganglioglioma (TL, cyst-MEN, E)
DNT (TL, intracortical nodules)
PXA (TL, cyst-MEN, E)
CNS embryonal neoplasms (solid, E)
Ependymoma (solid, E)
AT/RT (infant, E)		 WHO grades II–III diffuse glioma (NE, focal E)
GBM (E or rim E, butterfly mass)
Metastases (grey-white junctions, E or rim E)
Lymphoma (periventricular, E)
Cerebellar/Infratentorial/Fourth ventricle PA (cyst-MEN)
Medulloblastoma (vermis, E)
Ependymoma (4th v., E)
Choroid plexus papilloma (4th v., E)
AT/RT (infant, E)		 Metastases (multiple, E or rim E)
Hemangioblastoma (cyst-MEN)
Choroid plexus papilloma (4th v., E)
Brainstem PA (dorsal, exophytic, cyst-MEN)
DMG, H3 K27M mutant (pons, ±E)		 Diffuse glioma/Gliomatosis cerebri (multifocal, ±E)
Metastases (multiple, E or rim E)
Spinal cord (intramedullary) Ependymoma (E, ±syrinx)
PA (cystic, E)
DMG, H3 K27M mutant (expansile, ±E)
Drop metastases (cauda equine, E)
MPE (filum terminale, E)		 Ependymoma (E, ±syrinx)
DMG, H3 K27M-mutant (expansile, ±E)
MPE (filum terminale, E)
Paraganglioma (filum terminale, E)
Spinal cord (intradural, extramedullary) Clear cell meningioma (±dural tail, E)
Schwannoma (NF2, nerve origin, dumbbell shape, E)
Drop metastases (leptomeningeal, E)
Melanocytoma/melanoma (E, meningeal based)		 Schwannoma (nerve origin, dumbbell shape, E)
Meningioma (±dural tail, E)
Melanocytoma/melanoma (E, meningeal based)
MPNST (±NF1, E, necrotic)
Spinal cord (extradural) Bone tumor spread (EWS, usually E)
Meningioma (±dural tail, E)
Abscess (E)
Vascular malformations (dilated vessels on imaging, ±E)		 Herniated disc (T1-spin echo, NE)
Postoperative scar (E)
Secondary lymphoma (E)
Metastases (E)
Abscess (E)
Extra-axial/Dural/Leptomeningeal Secondary lymphoma/leukemia (E)
Meningeal rhabdomyosarcoma (E)
EWS (E, ± dural tail)
DLGNT (diffuse meningeal E, ±intraventricular masses)
Meningeal gliomatosis
CSF dissemination of medulloblastoma or CNS embryonal tumor (drop mets or diffuse meningeal E)		 Meningioma (E with dural tail)
SFT/HPC (E with dural tail)
Metastases (E)
Secondary lymphoma/Leukemia (E)
Marginal zone lymphoma (E)
Rosai-Dorfman disease (E)
IgG4 disease and collagen vascular disorders (E)
Meningeal carcinomatosis, melanomatosis, sarcomatosis, lymphomatosis, or hemangioblastomatosis (diffuse meningeal E)
Intrasellar Pituitary adenoma (solid, E)
Craniopharyngioma (cystic, E)
Rathke cleft cyst (cystic, ±E)
Pituicytoma/SCO/GCT (solid, E)		 Pituitary adenoma (solid, E)
Craniopharyngioma (cystic, E)
Rathke cleft cyst (cystic, ±E)
Pituicytoma/SCO/GCT (solid, E)
Suprasellar/Hypothalamic/Optic pathway/Third ventricle Germinoma/MGCT (E)
Craniopharyngioma (cystic, E, Ca + )
PA (cyst-MEN)
Pilomyxoid astrocytoma (infant, solid, E)
Langerhans cell histiocytosis (E)		 Colloid cyst (3rd v., ±E)
Craniopharyngioma (cystic, E, Ca + )
Chordoid glioma (anterior 3rd v., E)
Pineal Germinoma/MGCT (solid, E)
Pineocytoma (solid, E)
PPTID (solid, E)
Pineoblastoma (solid, E)
Pineal cyst (cystic, NE)		 Pineocytoma (solid, E)
PPTID (sold, E)
Pineal cyst (cystic, NE)
Thalamus PA (cyst-MEN)
DMG, H3 K27M-mutant (E, NE)		 DMG, H3 K27M-mutant (E, NE) GBM (rim E)
Lymphoma (E, ±multifocality)
Cerebellopontine angle Vestibular schwannoma (NF2, E, involves internal auditory meatus)
Choroid plexus tumor (E, component in 4th v.)
AT/RT (infant, E)		 Vestibular schwannoma (E, involves internal auditory meatus)
Meningioma (E with dural tail)
Lateral ventricle Central neurocytoma (E)
SEGA (tuberous sclerosis, E)
Choroid plexus papilloma (E)
Choroid plexus carcinoma (infant, E, large, invasive)		 Central neurocytoma (E)
SEGA (tuberous sclerosis, E)
Choroid plexus papilloma (E)
Subependymoma (±E)
Meningioma (E with dural tail)
Nerve root/Paraspinal Neurofibroma (NF1, E)
MPNST (NF1, E, necrotic)
Melanotic schwannoma/malignant melanotic schwannian tumor (E, ±Carney complex)		 Schwannoma (E, dumbbell shape)
Meningioma (E with dural tail)
Secondary lymphoma (E)
Neurofibroma (NF1, E)
MPNST (E, necrotic)
Melanotic schwannoma/Malignant melanotic schwannian tumor (E, ±Carney complex)
AT/RT, Atypical teratoid/rhabdoid tumor; Ca + , calcified; DMG, H3 K27M-mutant, diffuse midline glioma with histone 3 K27M mutation; DLGNT, diffuse leptomeningeal glioneuronal tumor; DNT, dysembryoplastic neuroepithelial tumor; E, enhancing; GCT, granular cell tumor; EWS, Ewing sarcoma; GBM, glioblastoma; MEN, mural-enhancing nodule; MGCT, mixed germ cell tumor; MPE, myxopapillary ependymoma; MPNST, malignant peripheral nerve sheath tumor; NE, nonenhancing; PA, pilocytic astrocytoma; PPTID, pineal parenchymal tumor of intermediate differentiation; PXA, pleomorphic xanthoastrocytoma; SCO, spindle cell oncocytoma; SEGA, subependymal giant cell astrocytoma; SFT/HPC, solitary fibrous tumor/hemangiopericytoma; TL, temporal lobe.

The next set of clues is naturally provided by classic histopathology. The 8 major patterns provided at the beginning of this textbook narrow the differential diagnosis considerably based purely on the overall low magnification appearance, and the subheadings of additional findings provide a useful diagnostic algorithm. When presented with a challenging biopsy, the pathologist can start with either the clinical- or morphology-based approach, but is encouraged to incorporate all available data before making a final diagnosis. In the vast majority of cases, the clinical, radiologic, and pathologic features are all consistent with one another; if not, the pathologist should very carefully reexamine the biopsy to ensure that all appropriate differentials have been considered and, if necessary, excluded or proven with ancillary studies. The use of common ancillary diagnostic techniques is briefly summarized in this chapter, with many more specific examples provided in the subsequent chapters on specific topics. As useful secondary algorithms, the major differential diagnosis based on an additional 24 minor histologic patterns is presented in Table 1.2 , with helpful clinicopathologic features summarized for 21 common differential diagnoses in Table 1.3 .

Table 1.2
Minor Histopathologic Patterns of Nervous System Tumors

“Fried Egg” or Clear Cells Lobulated, Nested, or Nodular

  • Oligodendroglioma

  • Glioblastoma, small cell variant

  • Dysembryoplastic neuroepithelial tumor

  • Clear cell ependymoma

  • Central/extraventricular neurocytoma

  • Pineocytoma

  • Pilocytic astrocytoma

  • Poorly preserved diffuse astrocytomas

  • Autolyzed non-neoplastic brain

  • Demyelinating disease (macrophages)

  • Cerebral infarct (macrophages)

  • Rosette-forming glioneuronal tumor

  • Paraganglioma

  • Clear cell meningioma

  • Germinoma

  • Pituitary adenoma

  • Hemangioblastoma (more often foamy)

  • Histiocytic disorders

  • Metastatic carcinoma (e.g., renal)

  • DLGNT

  • Desmoplastic/nodular medulloblastoma

  • Extensively nodular medulloblastoma

  • Dysembryoplastic neuroepithelial tumor

  • Oligodendrogliomas, mostly high grade

  • Subependymoma

  • Ganglioglioma

  • Paraganglioma

  • Metastatic carcinoma

  • Pineal parenchymal tumors, mostly of intermediate differentiation

  • Plexiform neurofibroma or schwannoma

  • Epithelioid MPNST

  • Meningiomas: mostly meningothelial, chordoid, and atypical

  • Melanocytoma and melanoma

  • Germinoma

  • Pituitary adenoma

Fascicles/Storiform Bundles of Spindled Cells Sheets of Epithelioid Cells

  • Fibrous, transitional, or anaplastic meningiomas

  • Schwannoma

  • SFT/HPC

  • MPNST or other spindle cell sarcomas

  • Spindled glioblastomas/astrocytomas

  • Metastatic carcinoma

  • Meningioma

  • Melanoma

  • Atypical teratoid/rhabdoid tumor

  • Pituitary adenoma

  • Gliosarcoma

  • Pleomorphic xanthoastrocytoma

  • DIG/DIA

  • Tanycytic ependymoma

  • Atypical teratoid/rhabdoid tumor

  • Melanocytoma or melanoma

  • Pituicytoma

  • Spindle cell oncocytoma of pituitary

  • Histiocytic disorders

  • Fibrous or granulomatous reactions

  • Anaplastic oligodendroglioma

  • Ependymoma

  • Choroid plexus tumors

  • Astroblastoma

  • Chordoid glioma

  • Germ cell tumors

  • Paraganglioma

  • Epithelioid glioblastoma

  • Epithelioid nerve sheath tumors

  • Craniopharyngioma

  • Anaplastic large cell lymphoma

  • Plasmacytoma

  • Cellular hemangioblastoma

Monomorphic Cytology Biphasic Pattern (Loose and Compact Areas)

  • Central/extraventricular neurocytomas

  • Pineocytoma

  • Oligodendroglioma

  • Pituitary adenoma

  • Pilomyxoid astrocytoma

  • Angiocentric glioma

  • Lymphomas

  • Glioblastoma, small cell variant

  • DLGNT

  • Pilocytic astrocytoma

  • Pleomorphic xanthoastrocytoma

  • Ganglioglioma

  • Schwannoma

  • SFT/HPC

  • MPNST

Microcystic Myxoid/Mucin Rich

  • Diffuse gliomas, mostly low grade

  • Pilocytic/pilomyxoid astrocytomas

  • Pleomorphic xanthoastrocytoma

  • Dysembryoplastic neuroepithelial tumor

  • Myxopapillary ependymoma

  • Chordoid glioma of the third ventricle

  • Subependymoma

  • Ganglioglioma

  • Schwannoma

  • Microcystic meningioma

  • Hemangioblastoma

  • Yolk sac tumor

  • Teratoma

  • Craniopharyngioma

  • Cerebral infarcts or prior trauma (cystic encephalomalacia)

  • Chordoid meningioma

  • Chordoma

  • Metaplastic chondromyxoid meningioma

  • Pilocytic/pilomyxoid astrocytomas

  • Diffuse gliomas, mostly low grade

  • Rosette-forming glioneuronal tumor

  • Atypical teratoid/rhabdoid tumor

  • Nerve sheath tumors

  • Yolk sac tumor

  • Teratoma

  • Metastatic adenocarcinoma

Rosette Forming and/or Neuropil Rich Perivascular Pseudorosettes

  • Ependymoma (true ependymal)

  • Medulloblastoma (Homer Wright)

  • CNS embryonal neoplasms (Homer Wright, true rosettes)

  • Neurocytomas (neurocytic)

  • Pineocytoma (pineocytic)

  • Pineoblastoma (Homer Wright, Flexner-Wintersteiner)

  • Embryonal tumor with multilayered rosettes (true)

  • CNS (ganglio)neuroblastoma (neuropil)

  • Pituitary adenoma (rosette-like pattern)

  • Metastatic adenocarcinomas and neuroendocrine neoplasms (rosette-like pattern)

  • Rosette-forming glioneuronal tumor (neurocytic)

  • Diffuse glioma with neuropil islands (neuropil)

  • GBM with primitive neuronal component (Homer Wright)

  • Ependymoma

  • Astroblastoma

  • Angiocentric glioma

  • Papillary glioneuronal tumor

  • Central/extraventricular neurocytomas

  • Pineocytoma

  • CNS embryonal neoplasms (occasionally)

  • Medulloblastomas (occasionally)

  • Glioblastoma (occasionally)

  • Papillary meningioma

  • Pituitary adenoma

  • Paraganglioma

  • Subependymal giant cell astrocytoma

  • Metastases (e.g., neuroendocrine)

Palisading Cells Papillary/Pseudopapillary

  • Glioblastoma (palisading necrosis)

  • Schwannoma (Verocay bodies)

  • Pilocytic astrocytoma (spongioblastic)

  • Choroid plexus tumors

  • Papillary ependymoma

  • Myxopapillary ependymoma

  • Oligodendroglioma (spongioblastic)

  • Ependymoma (spongioblastic)

  • Medulloblastoma (spongioblastic)

  • Angiocentric glioma (subpial palisades)

  • Anaplastic PXA, PA, or GG (palisading necrosis)

  • Astroblastoma

  • Metastatic papillary carcinomas

  • Papillary meningioma

  • SFT/HPC

  • Papillary glioneuronal tumor

  • Atypical teratoid/rhabdoid tumor

  • Papillary craniopharyngioma

  • Germ cell tumors (e.g., yolk sac tumor)

  • Papillary tumor of the pineal region

  • Pituitary adenoma

“Small Blue Cells” (i.e., Primitive) Multinucleated Giant Cells

  • Medulloblastoma

  • CNS embryonal neoplasms

  • Pineoblastoma

  • Atypical teratoid/rhabdoid tumor

  • Metastatic small cell carcinoma

  • Lymphoma/leukemia

  • GBM with primitive neuronal component

  • Choroid plexus carcinoma (rarely)

  • Ewing sarcoma

  • SFT/HPC

  • MPNST (occasionally)

  • Melanoma (occasionally)

  • Embryonal rhabdomyosarcoma

  • Giant cell glioblastoma

  • Pleomorphic xanthoastrocytoma

  • Subependymal giant cell astrocytoma

  • Melanoma

  • Choriocarcinoma

  • Giant cell ependymoma

  • “Ancient changes” in schwannoma, neurofibroma, or meningioma

  • Pilocytic astrocytoma (occasionally)

  • Ganglioglioma (occasionally)

  • Pleomorphic sarcomas

  • Any poorly differentiated primary or metastatic malignancy

  • Granulomatous/histiocytic disorders

  • CNS vasculitis

  • Krabbe disease (globoid cell leukodystrophy)

Extensive Calcification Desmoplasia or Sclerosis

  • Ganglioglioma

  • Central/extraventricular neurocytomas

  • Oligodendroglioma

  • Astroblastoma

  • Desmoplastic/nodular medulloblastoma

  • Desmoplastic infantile ganglioglioma or astrocytoma (DIG/DIA)

  • Psammomatous meningioma

  • Meningioangiomatosis

  • Calcifying pseudoneoplasm of the neuroaxis

  • Craniopharyngioma

  • Tuber/focal cortical dysplasia

  • Vascular malformation

  • Subependymoma (occasionally)

  • Ependymoma (occasionally)

  • Astroblastoma (occasionally)

  • Choroid plexus papilloma

  • Lactotroph adenoma (rare)

  • Meningioma, especially clear cell variant

  • SFT/HPC

  • Sarcomas

  • Neurofibroma

  • Pleomorphic xanthoastrocytoma

  • Gliosarcoma

  • Ganglioglioma

  • Ependymoma (occasionally)

  • Abscess

  • Granulomas

  • Meningeal inflammation or neoplasm

  • IgG4 and collagen vascular disorders

Hypervascular Inflammation Rich

  • Hemangioblastoma

  • Hemangiomas/vascular malformations

  • Metastases (e.g., renal cell carcinoma)

  • Vascular neoplasms (e.g., angiosarcoma)

  • SFT/HPC

  • Angiomatous meningioma

  • Glioblastomas/high-grade gliomas

  • Pilocytic astrocytoma (occasionally)

  • Paraganglioma

  • Ganglioglioma

  • Pleomorphic xanthoastrocytoma

  • Gemistocytic/giant cell astrocytomas

  • Germinoma

  • Chordoid glioma

  • Lymphoplasmacyte-rich meningioma

  • Inflammatory myofibroblastic tumor

  • Lymphomas and histiocytic disorders

  • Demyelinating diseases

  • Infections, granulomas, collagen vascular disorders

  • Autoimmune encephalitides

  • CNS vasculitis

Rosenthal Fibers/Eosinophilic Granular Bodies Discohesive

  • Pilocytic astrocytoma

  • Ganglioglioma

  • Pleomorphic xanthoastrocytoma

  • Atypical teratoid/rhabdoid tumor

  • Papillary and/or rhabdoid meningiomas

  • Lymphomas/leukemias

  • Dysembryoplastic neuroepithelial tumor (occasionally)

  • Histiocytic disorders (occasionally)

  • Piloid gliosis next to craniopharyngioma, hemangioblastoma, ependymoma, pineal cyst, or any slowly progressive process

  • Alexander disease

  • Histiocytic disorders

  • Poorly differentiated malignancies

Whorls Psammoma Bodies

  • Meningioma

  • Schwannoma (occasionally)

  • Perineurioma

  • Metastatic tumors (rare)

  • Paraganglioma (rare)

  • Meningioma

  • CAPNON

  • PMS

  • Metastatic carcinoma (rare)

  • Lactotroph pituitary adenoma

Clear Vacuoles Granular/Oncocytic Features

  • Ependymoma

  • Choroid plexus tumors

  • Chordoid glioma of third ventricle

  • Metastatic neoplasms

  • Hemangioblastoma

  • Glioblastoma (occasionally)

  • Pleomorphic xanthoastrocytoma

  • Ganglioglioma

  • Histiocytic disorders

  • Infections

  • Granular cell astrocytoma/GBM

  • Metastatic carcinoma (e.g., RCC)

  • Oncocytic pituitary adenoma

  • Granular cell tumor of pituitary

  • Spindle cell oncocytoma of pituitary

  • Histiocyte-rich processes

  • Granular cell tumor of PNS

  • Choroid plexus tumors (rare)

  • Oncocytic meningioma (rare)

  • Oligodendroglioma (rare)

  • Ependymoma (rare)

CAPNON, Calcifying pseudoneoplasm of the neural axis; DIG/DIA, desmoplastic infantile ganglioglioma or astrocytoma; DLGNT, diffuse leptomeningeal glioneuronal tumor; GBM, glioblastoma; GG, ganglioglioma; MPNST, malignant peripheral nerve sheath tumor; PA, pilocytic astrocytoma; PMS, psammomatous melanotic schwannoma or malignant melanotic schwannian tumor; PNS, peripheral nervous system; PXA, pleomorphic xanthoastrocytoma; RCC, renal cell carcinoma; SFT/HPC, solitary fibrous tumor/hemangiopericytoma.

Table 1.3
Helpful Features in Common Differential Diagnoses of Surgical Neuropathology
Atypical Gliosis vs. Diffuse Glioma (WHO Grade II)

  • Evenly spaced astrocytes

  • Abundant eosinophilic cytoplasm

  • Radially oriented GFAP+ processes

  • Other reactive changes such as inflammatory infiltrates, macrophages, hemosiderin deposits, etc.

  • Clustered cells

  • “Naked nuclei”

  • Large, hyperchromatic, irregular nuclei

  • IDH1 R132H positive

  • Loss of ATRX expression (astrocytoma)

  • Ki-67 labels suspicious nuclei

  • Nuclei are strongly OLIG2, SOX10, and/or p53 positive

  • MAP2 positive glial cells

  • Demonstrable chromosomal alterations

Diffuse Astrocytoma vs. Pilocytic Astrocytoma

  • MRI: ill defined, nonenhancing

  • Predominantly infiltrative

  • Clustered cells

  • “Naked nuclei”

  • Large, hyperchromatic, irregular nuclei

  • IDH1 R132H positive

  • Loss of ATRX expression

  • Nuclei are strongly p53 positive (not helpful if negative)

  • Numerous intratumoral NFP+ axons

  • MRI: demarcated, cystic, enhancing

  • Predominantly solid with focal invasion

  • Biphasic loose and compact areas

  • Long, thin, “hair-like” processes

  • Rosenthal fibers and EGBs

  • Multinucleate “pennies on a plate” cells

  • Hyalinized blood vessels

  • Strong, diffuse GFAP positivity

  • Few intratumoral NFP+ axons

  • Low Ki-67 LI, except in blood vessels

  • KIAA1549-BRAF fusion

Pleomorphic Xanthoastrocytoma vs. Giant Cell Glioblastoma

  • MRI: demarcated, cystic, enhancing, often temporal lobe, minimal edema

  • Rare mitoses, despite pleomorphism

  • Spindled mesenchymal-like element

  • Foamy tumor cells (only in ~30%)

  • Eosinophilic granular bodies

  • CD34+ cells

  • BRAF V600E mutation or IHC+

  • MRI: ring-enhancing, marked edema and mass effects

  • “Frankly anaplastic” cytology

  • Numerous mitoses

  • Atypical mitoses

  • Palisading necrosis

  • Extensive p53 positivity

Diffuse Glioma/Glioblastoma vs. CNS Lymphoma

  • Secondary structures, such as perineuronal satellitosis

  • “Naked nuclei” or fibrillary processes

  • Eosinophilic cytoplasm

  • Nuclear hyperchromasia/pleomorphism

  • Microvascular proliferation

  • Palisading necrosis

  • GFAP and/or S-100 positive

  • OLIG2- and/or SOX10-positive nuclei

  • IDH1 R132H positive

  • Angiocentric growth pattern

  • Discohesive on intraoperative smear

  • Open chromatin, large nucleoli

  • Rounded cells with scant blue cytoplasm

  • Prominent apoptosis

  • LCA, CD20, or PAX-5 positive

  • Intermixed reactive CD3-positive T lymphocytes

High-Grade Glioma or Lymphoma vs. Demyelinating Disease

  • Frankly anaplastic cells

  • Ill-defined lesional borders

  • Perineuronal satellitosis (gliomas)

  • Necrosis (gliomas or immunodeficiency-associated lymphomas)

  • Microvascular proliferation (gliomas)

  • GFAP+ or CD20+ atypical cells

  • EBV+ cells (immunodeficiency-associated lymphomas)

  • Relatively sharp demarcation

  • Fairly restricted to white matter

  • Myelin pallor with hypercellular infiltrate

  • Sheets of CD68+ histiocytes (better recognized on smear than frozen section)

  • Creutzfeldt cells

  • LFB-PAS shows marked myelin loss

  • NFP shows relative axonal preservation

  • CD20+ cells are all small and mature

  • GFAP+ cells are evenly spaced

Glioblastoma vs. Abscess

  • Palisading necrosis

  • Microvascular proliferation

  • Infiltrative component

  • Secondary structure formation

  • GFAP+ atypical cells

  • Strong p53 positivity

  • OLIG2- and/or SOX10-positive atypical nuclei

  • MAP2-positive glial cells

  • Abundant neutrophils in necrotic foci

  • “Tissue culture” fibroblasts with variable nuclear atypia

  • Inflammatory rim

  • Brisk gliosis at edge of lesion

  • Trichrome reveals collagen deposition

  • Presence of infectious organisms

Glioblastoma vs. Metastasis

  • Infiltrative growth pattern

  • Secondary structure formation

  • Palisading necrosis

  • Microvascular proliferation

  • GFAP and/or OLIG2 positive

  • NFP+ intratumoral axons

  • Cytokeratin CAM 5.2 (do not use cocktails such as AE1/AE3, which often cross react with GFAP)

  • Sharp demarcation from brain

  • Glands or cytoplasmic mucin (adenocarcinoma)

  • Azzopardi effect (small cell ca)

  • Pigment (melanoma)

  • CK7+, TTF1+, and/or Napsin A+ (lung ca)

  • CK20+, CDX2+ (colon ca)

  • CK7+, GATA3+, mammaglobin+ (breast ca)

  • PAX8+, CD10+ (renal cell ca)

  • HMB45+, Melan-A+, S-100+, SOX10+ (melanoma)

  • CK5/6+, p40+, p63+ (squamous cell ca)

Recurrence/Progression of Glioma vs. Radiation Necrosis/Radiation Effects

  • Palisading necrosis

  • Microvascular proliferation

  • Viable tumor with mitotic activity

  • Cells with high N/C ratio

  • High Ki-67 labeling index

  • IDH1 R132H positive cells

  • Coagulative and fibrinoid parenchymal and vascular necrosis

  • Vascular hyalinization

  • Vascular telangiectasias

  • Rarefied hypocellular parenchyma

  • Dystrophic calcification

  • Radiation-induced atypia (bizarre bubbly nuclei and abundant pink cytoplasm)

Anaplastic Oligodendroglioma vs. Small Cell Glioblastoma

  • Round uniform nuclei

  • Enlarged epithelioid cells with open chromatin and large nucleoli

  • Mucin-rich microcystic spaces

  • GFAP+ minigemistocytes and gliofibrillary oligodendrocytes

  • IDH1 R132H positive

  • Chromosome 1p/19q codeletions

  • Oval uniform nuclei

  • Frequent mitoses despite “low-grade” cytology (delicate chromatin)

  • Palisading necrosis

  • GFAP+ thin cytoplasmic processes

  • IDH1 R132H negative

  • EGFRvIII expression (~50%)

  • EGFR amplification (~70%)

  • Chromosome 10q deletions (>95%)

Oligodendroglioma vs. Diffuse Astrocytoma

  • Round uniform nuclei with crisp nuclear membranes and small nucleoli

  • Clear haloes, no cytoplasm, or small eccentric belly of pink cytoplasm (minigemistocytes or microgemistocytes)

  • “Chicken wire” capillaries

  • Hypercellular nodules

  • Epithelioid/plasmacytoid cells with large nucleoli (anaplastic)

  • GFAP− or GFAP+ minigemistocytes and gliofibrillary oligodendrocytes

  • Mostly p53 negative and ATRX retained

  • Chromosome 1p/19q codeletion

  • Variably elongate, irregular, hyperchromatic nuclei

  • “Naked nuclei,” elongate processes, or large eccentric belly of pink cytoplasm (gemistocytes)

  • Variably GFAP+ cytoplasm in most, although fibrillary and small cell variants may be negative due to minimal cytoplasm; high GFAP background makes interpretation difficult in others

  • Strongly p53+ and/or loss of ATRX expression in IDH-mutant examples

Oligodendroglioma vs. Dysembryoplastic Neuroepithelial Tumor

  • MRI: cerebral nonenhancing tumor with significant mass effect

  • Extensive white matter component

  • Perineuronal satellitosis prominent

  • IDH1 R132H positive

  • MAP2+ glial cells

  • Chromosome 1p/19q codeletion

  • MRI: gyriform, intracortical lesion, often mesial temporal lobe, with minimal mass effect; focal enhancement in a subset

  • Mucin-rich, patterned intracortical nodules

  • “Floating neurons”

  • Component resembling pilocytic astrocytoma in complex form

  • Adjacent cortical dysplasia

  • Rosenthal fibers/EGBs (occasionally)

  • CD34+ cells in subset of cases

Oligodendroglioma vs. Central/Extraventricular Neurocytoma

  • Ill-defined margins

  • Perineuronal satellitosis

  • GFAP+ minigemistocytes and gliofibrillary oligodendrocytes

  • Entrapped NFP+ axons

  • IDH1 R132H positive

  • Chromosome 1p/19q codeletion

  • Solid tumor with discrete borders

  • Neurocytic rosettes/neuropil formation

  • Diffuse synaptophysin positivity, including center of neurocytic rosettes

  • Neuronal features on EM

Oligodendroglioma vs. Clear Cell Ependymoma

  • Ill-defined margins

  • Perineuronal satellitosis

  • GFAP+ minigemistocytes and gliofibrillary oligodendrocytes

  • Entrapped NFP+ axons

  • IDH1 R132H positive

  • Chromosome 1p/19q codeletion

  • Sharp demarcation

  • Vague perivascular pseudorosettes, highlighted on GFAP stain

  • Nuclear grooves/folds

  • Dot-like cytoplasmic EMA, CD99, and/or D2-40 positivity

  • NFP+ axons pushed to periphery of tumor

  • Ependymal features on EM

Ependymoma vs. Diffuse Astrocytoma

  • Sharp demarcation

  • Perivascular pseudorosettes, highlighted on GFAP stain

  • Dot-like EMA, CD99, and/or D2-40 positivity

  • NFP+ axons pushed to periphery of tumor

  • Ependymal features on EM

  • Infiltrative growth pattern

  • Secondary structures

  • “Naked nuclei”

  • Numerous intratumoral NFP+ axons

  • IDH1 R132H positive

  • Loss of ATRX expression

  • Extensive OLIG2 and/or SOX10 positivity

Cellular Ependymoma vs. Medulloblastoma/Embryonal Neoplasm

  • Solid growth pattern

  • Low mitotic/proliferative

  • Perivascular pseudorosettes with fibrillar processes, highlighted with GFAP

  • Dot-like EMA, CD99, and/or D2-40 positivity

  • NFP+ axons pushed to the periphery

  • Ependymal features on EM

  • Solid and infiltrative growth patterns

  • High mitotic/proliferative index

  • Homer Wright rosettes and occasional pseudorosettes with delicate neuropil

  • Synaptophysin positive

  • Ki-67 high

  • Unique genetic alterations

Medulloblastoma vs. Atypical Teratoid/Rhabdoid Tumor

  • Mostly children/young adults

  • Solid and infiltrative growth patterns

  • Homer Wright rosettes

  • Retained INI1 expression

  • Synaptophysin+, GFAP focal+, most other markers negative

  • WNT- or SHH-activated in ~40%

  • Genetics often shows i17q and/or MYC/MYCN amplifications in non-WNT, non-SHH groups

  • Mostly infants (age < 3 years)

  • Mostly solid growth pattern

  • Variable small blue cell, carcinoma-like, and sarcoma-like foci

  • Rhabdoid cells present, but may be rare

  • Loss of INI1 or BRG1 expression

  • Polyphenotypic profile (vimentin, EMA, SMA, cytokeratin, etc.)

  • Genetics: SMARCB1 or SMARCA4 gene mutations (may be germline), chromosome 22q losses

Medulloblastoma/Embryonal Neoplasm vs. Glioblastoma

  • Mostly children/young adults

  • Solid and infiltrative growth patterns

  • Small blue cells with high mitotic and pyknotic indices

  • Homer Wright rosettes

  • Synaptophysin+

  • Unique genetic alterations

  • Mostly adults

  • Infiltrative growth pattern

  • Secondary structure formation

  • Palisading necrosis

  • Microvascular proliferation

  • GFAP+

  • IDH mutant and ATRX lost in ~10%

  • H3 K27M+ in diffuse midline glioma

  • Genetics often shows EGFR amplification and/or PTEN/chromosome 10q loss

Meningioma vs. Schwannoma

  • Dural attachment

  • Whorls

  • Epithelioid cells

  • Psammoma bodies

  • Nuclear holes and pseudoinclusions

  • EMA+, S-100 patchy+

  • Diffuse SSTR2a positivity

  • Encapsulated with parent nerve at periphery

  • Biphasic (Antoni A and B)

  • Verocay bodies

  • Wavy cells, wavy nuclei

  • Diffusely S-100+, collagen IV+

  • SOX10+

Meningioma vs. SFT/HPC

  • Whorls

  • Storiform pattern

  • Epithelioid cells

  • Psammoma bodies

  • Nuclear holes and pseudoinclusions

  • EMA+ (~80%)

  • PR+ (more so in benign forms)

  • Diffuse SSTR2a positivity

  • “Staghorn” vasculature

  • Marked hypercellularity with scattered pale islands (HPC)

  • Lace-like intercellular collagen (SFT)

  • Nuclear STAT6 expression

  • Reticulin rich

  • CD99+, BCL2+

  • Diffuse CD34+ (SFT)

Hemangioblastoma vs. Metastatic Renal Cell Carcinoma

  • Foamy clear cells

  • Delicate chromatin or degenerative nuclear atypia

  • Adjacent piloid gliosis

  • Low mitotic/proliferative indices

  • Inhibin+, D2-40+, S-100+, NSE+

  • PR+

  • Focally GFAP+ (occasionally)

  • Solid sheets of uniformly clear cells

  • Epithelioid cells with pink cytoplasm

  • Vesicular nuclei with prominent nucleoli

  • High mitotic/proliferative indices

  • Cytokeratin+, EMA+, PAX8 +, CD10+

  • RCC+ in a subset

Hemangioblastoma vs. Angiomatous Meningioma

  • Parenchymal +/− leptomeningeal (almost exclusively infratentorial)

  • Inhibin+, NSE+

  • Extramedullary hematopoiesis (~10%)

  • Dural-based mass

  • Foci of other meningioma subtypes

  • Psammoma bodies

  • EMA+

  • Diffuse SSTR2a positivity

ca, Carcinoma; DLGNT, diffuse leptomeningeal glioneuronal tumor; EBV, Epstein-Barr virus; EGFR, epidermal growth factor receptor; EMA, epithelial membrane antigen; GFAP, glial fibrillary acidic protein; IDH1, isocitrate dehydrogenase 1; LCA, leukocyte common antigen; LFB-PAS, Luxol fast blue and periodic acid–Schiff; MAP2, microtubule-associated protein 2; MPNST, malignant peripheral nerve sheath tumor; NFP, neurofilament protein; NSE, neuron specific enolase; PR, progesterone receptor; RCC, renal cell carcinoma; SMA, smooth muscle actin; SFT/HPC, solitary fibrous tumor/hemangiopericytoma; SSTR2a, somatostatin receptor 2a; TTF1, thyroid transcription factor 1.

Electron Microscopy

Although electron microscopy (EM) has historically been vital in defining a number of diagnostic entities, its everyday use in surgical neuropathology is generally labor intensive, time consuming, and expensive, with interpretation typically delayed by one to several weeks. For these reasons, EM has largely been supplanted by immunohistochemistry (IHC) and molecular pathology in most medical centers. Nevertheless, EM remains extremely valuable in specific scenarios; for instance, it is still the gold standard for proving ependymal differentiation in diagnostically challenging examples. As with lineage-specific immunostains, ultrastructural pathology primarily provides insight into various forms of cellular differentiation by visualizing organelles, other cytoplasmic constituents, and cell membrane structures (intermediate filaments, neurosecretory granules, synapses, pinocytotic vesicles, intercellular junctions, cilia, microvilli, basement membrane, etc.). Further examples of EM use in surgical neuropathology are provided in subsequent disease-specific chapters.

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