Central Nervous System: Brain, Spinal Cord, and Meninges
Richard J. Perrin
Sushama Patil
Arie Perry
I. INTRODUCTION. The task of evaluating a neuropathologic specimen often seems daunting, given the complexity of this organ system and its ever-enlarging list of diseases. However, when a methodical approach is applied using clinical, radiologic, histological and, increasingly, molecular information, the chances of error can be significantly reduced.
II. ANATOMY AND HISTOLOGY. The central nervous system (CNS) consists of cerebrum, cerebellum, brain stem, spinal cord, meninges, 12 paired cranial nerves, and the blood vessels supplying these structures. The brain and spinal cord are enclosed within the skeletal confines of the cranium and vertebral canal. The mature (adult) brain weighs around 1200 to 1400 g. The meninges covering the brain and spinal cord are of two principal types: (1) the dense fibrous dura mater and (2) the more delicate leptomeninges (pia and arachnoid mater). The cerebrum is divided into right and left hemispheres by a thick dural fold, the falx cerebri. A second dural fold between the cerebrum and the cerebellum (tentorium cerebelli) divides the brain into infra- and supratentorial compartments. Infratentorially, the midbrain, pons, and medulla oblongata (cranial to caudal) form the brain stem, which is connected to the cerebellum by means of three (superior, middle, and inferior) cerebellar peduncles. The supratentorial compartment contains cerebral cortex (frontal, temporal, parietal, and occipital lobes), white matter, and deep gray nuclei, such as basal ganglia, thalamus, and hypothalamus. The term “neuraxis” is sometimes used to refer to brain and spinal cord; thus, lesions that involve brain parenchyma are said to be “intra-axial” (e.g., astrocytoma, central neurocytoma, ependymoma), and those located outside of the parenchyma are referred to as “extra-axial” (e.g., meningioma, hemangiopericytoma [HPC], solitary fibrous tumor [SFT], and schwannoma of cranial nerve VIII). Similarly, in the spine, the terms “intramedullary” and “extramedullary” are used to denote lesions within or adjacent to the spinal cord parenchyma, respectively.
The CNS is composed of two tissue types, namely gray and white matter, that differ qualitatively on gross and microscopic examination. Neuronal cell bodies and dendrites reside mostly in the gray matter (cortex and deep gray nuclei), and axons create the framework of the white matter. Glial cells (astrocytes, oligodendroglial cells, and microglia) are present in different proportions in these tissues. Oligodendrocytes are more populous in the white matter; their processes form the sheaths of myelin that insulate CNS axons. The eosinophilic, finely granular to fibrillary material between cell bodies is often referred to as “neuropil”
and is formed by the processes of neurons (axons and dendrites) and glial cells. Neuronal morphology varies significantly, with cell body size ranging from <15 µm (e.g., small neocortical granular stellate neurons) to 100 µm (Betz cells of the primary motor cortex). For descriptive purposes, neocortical pyramidal neurons are often considered the morphologic prototype. These cells contain abundant amphophilic cytoplasm, clumpy basophilic Nissl substance, a large round central nucleus, a prominent nucleolus, coarse proximal cytoplasmic processes, and a prominent apical dendrite oriented perpendicular to the cortical surface. Ependymal glial cells form a ciliated cuboidal epithelium that lines the ventricles and central canal and focally transitions with epithelium of the choroid plexus. The choroid plexus, which produces cerebrospinal fluid (CSF) within the ventricles, is papillary; its branching fibrovascular cores are lined by a specialized epithelium with a hobnailed apical surface.
III. INTRAOPERATIVE EVALUATION, GROSS EXAMINATION, AND TISSUE SAMPLING. Evaluation of a surgical neuropathology specimen often begins with an intraoperative consultation, which may be requested by the surgeon (1) to confirm the presence of lesional tissue, (2) to provide a preliminary diagnosis that will guide surgical management (e.g., aggressive surgery for ependymoma, limited biopsy for lymphoma, culture sample to microbiology for abscess), and (3) to sample fresh or frozen tissue for ancillary studies (e.g., Western blot for Creutzfeldt-Jakob disease [CJD], molecular pathology, tumor banking, karyotyping). For optimal evaluation, specimens should ideally be submitted on Telfa nonstick gauze pads saturated with normal saline. Tissue that has been soaked in saline is certainly acceptable, but is more likely to fragment during transport and may demonstrate more severe freezing artifacts. Fresh brain tissue, especially small biopsy specimens, should never be placed on dry gauze or tissue paper, because subsequent tissue retrieval from these materials is almost impossible. Water content may be reduced through very gentle blotting on a clean dry plastic surface, but fresh brain tissue is very fragile, and improper handling can introduce cellular “touch” and “crush” artifacts.
For intraoperative diagnosis, small portions of the fresh specimen should be chosen for freezing, for cytologic “smear” or “touch” preparations, and for possible ultrastructural examination. Freezing or otherwise exhausting the entire specimen for intraoperative diagnosis should be avoided, for several reasons. First, the techniques available during intraoperative examination seldom yield sufficient information for a definitive final diagnosis; most diagnoses require the fine histologic detail afforded by paraffin sections and information from immunohistochemical stains and other ancillary molecular tests. Second, freezing introduces artifacts (e.g., ice crystals, clumping of nuclear chromatin). Third, on some occasions, surgical attempts to obtain additional diagnostic material from the patient cause bleeding or other complications that prevent further tissue acquisition.
The manner in which intraoperative specimens are processed for diagnosis is important. Before any tissue is frozen, a block of embedding compound (commonly referred to as “OCT”), formed within an empty tissue well within the cryostat, should be frozen fast to a cryostat “chuck.” After freezing, the chuck and OCT block are removed sharply and inverted; the tissue should be placed centrally on the flat surface of the frozen OCT block, immediately covered with a minimal amount of liquid OCT, and frozen from above by a flat, prechilled metallic weight (e-Fig. 41.1).* This process maximizes rate of freezing and minimizes (but does not eliminate) ice crystal formation. Cytologic evaluation by smear preparation is extremely helpful because it lacks freezing artifacts and preserves nuclear details. Smears can be prepared by gently compressing a very small amount of representative tissue between two glass slides, gently sliding them apart, and immediately fixing both smeared slides in 95% alcohol (e-Fig. 41.2). Lastly, a small tissue fragment (1 mm3) should also be fixed in glutaraldehyde and
processed for potential electron microscopic studies, particularly if the intraoperative diagnosis is unclear.
Gross examination and tissue sampling for permanent sections is less complicated. Most neuropathologic specimens are small and/or fragmented, limiting full appreciation of meaningful gross features. Even when large resection specimens are submitted intact, gross abnormalities are often absent or subtle. In fact, radiographs are commonly considered the “gross pathology” for CNS biopsies. In either case, specimens are usually entirely submitted for histologic analysis after adequate formalin fixation (a few hours for smaller specimens and overnight fixation for large specimens). Because most neuropathologic processes are heterogeneous, even when the diagnosis seems clear, if a resection specimen is too large for complete processing, it should still be extensively sampled. For similar reasons, Cavitronic UltraSound Aspirator (CUSA) material should not be dismissed as worthless; such material may be somewhat less preserved than resected tissue due to partial autolysis and other artifacts, but occasionally it provides essential clues to the final diagnosis.
A. CNS biopsy for special circumstances. Brain and sometimes meningeal biopsies for nonneoplastic indications are occasionally performed (e.g., nonresolving chronic meningitis, neurosarcoidosis). Similarly, a “blind” frontal lobe biopsy is sometimes obtained for neurodegenerative disorders that do not have a clearly defined etiology, particularly in younger patients. When a prion protein disease like CJD is suspected, the neuropathologist should be given advance notice and should be involved from the outset. One piece of cortex from the biopsy should be snap frozen for Western blot analysis by a reference laboratory such as the National Prion Disease Pathology Surveillance Center (NPDPSC) (special shipping containers must be used, and specific procedures must be followed; see http://www.cjdsurveillance.com/). The remaining tissue should be fixed in 10% neutral buffered formalin for 24 hours, followed by immersion in 88% to 98% formic acid (undiluted stock solution) for 1 hour, prior to routine processing. If initial histologic examination reveals pathologic features consistent with CJD or fails to suggest an alternative diagnosis to explain the clinical findings, paraffin-embedded material (blocks or unstained slides) must accompany the frozen specimen to the reference laboratory to allow immunohistochemistry to be performed. CJD pathology can be patchy within the brain (even when the abnormal protein is widespread), and rare cases of CJD are caused by a protease-sensitive prion requiring immunohistochemical rather than immunoblot analysis for definitive diagnosis (Ann Neurol. 2010;68:162). Lab equipment (gloves, instruments, etc.) are decontaminated with 1N sodium hydroxide solution for a minimum of 1 hour or, alternatively, in 10% or 20% bleach solution for 1 hour, followed by auto-claving. Many disinfection protocols that may be more or less appropriate for particular circumstances have been reported (Infect Control Hosp Epidemiol. 2010;31:107). Frozen tissue diagnosis should not be attempted on tissues suspected of prion protein diseases.
B. Ancillary studies
1. Electron microscopy (EM). The utilization of EM for diagnosis of CNS lesions is labor intensive, time-consuming, and expensive, and it is mainly used to evaluate nerve and muscle biopsies. However, ultrastructural evaluation remains invaluable for many other neuropathologic diagnoses, including CADASIL (see Section VIII.D), neuronal ceroid lipofuscinoses, and for distinguishing ambiguous brain tumor cases, particularly meningioma and ependymoma.
2. Immunohistochemistry is now routinely used in evaluation of complex surgical neuropathology cases, especially in the area of tumor neuropathology. Frequently utilized antibodies and their immunoreactivity for common tumor types are summarized in Table 41.1.
TABLE 41.1 Typical Immunoprofiles of Common CNS Neoplasms
Tumor
Positive (+)
Positive or negative (±)
Negative (-)
PA
GFAP
NF (few entrapped axons)
IDH-1, YKL-40
GBM (primary)
GFAP, YKL-40, NF (axons), S-100, CK
IDH-1, CAM 5.2
DA
S-100, GFAP, IDH-1a
CKb, LCA, SYN, HMB-45
Oligodendroglioma
S-100, GFAPc, IDH-1
SYN (dot-like)
CKb, LCA
Ependymoma
S-100, GFAP, D2-40, and CD99 (lumens)
EMA (luminal), CK
LCA, SYN, IDH-1
Choroid plexus tumors
S-100, CK, VIM, transthyretind
GFAP
EMA, CEA
Metastatic carcinoma
EMA and CK, CK7 (lung), CK20 (colon), TTF1 (lung), CAM 5.2
CEA, S-100, SYN
GFAP, LCA, HMB-45, IDH-1
Melanoma
S-100, HMB-45, Melan-A (MART-1)
GFAP, CK, LCA, IDH-1
Lymphoma
LCA, CD20 (L26), CD79a
EMAe
CK, GFAP, HMB-45, SYN, CD3
Meningioma
EMA, VIM, PRf, BAF47
S-100, CD34, CKg
GFAP, HMB-45
HPC
VIM, CD99, bcl-2, Factor XIIIah
CD34
EMA, CK, GFAP, S-100
Medulloblastoma
SYN, BAF47
S-100, GFAP
CK, LCA, EMA
AT/RT
VIM, EMA, CK, actin
SYN, GFAP, desmin, AFP
PLAP, β-hCG, LCA, BAF47i
GG
SYN, NF, CG, GFAP
Neu-N
CK, EMA, PLAP
Central neurocytoma
SYN, Neu-N
GFAP, S-100
NF, CG, CK, LCA
Schwannoma
GFAP, HMB-45k
EMA, NF, CK
Paraganglioma
SYN, CG, S-100l
NF
GFAP, CK, HMB-45
HB
S-100, NSE, inhibin
GFAP
CK, EMA
Germinoma
β-hCGn, CK
AFP, EMA, HMB-45, LCA
Yolk sac tumor
AFP, CK
PLAP, c-kitm
β-hCG, GFAP, OCT4, EMA
Choriocarcinoma
β-hCG, CK, EMA
PLAP
AFP, OCT4, GFAP, HMB-45
Embryonal carcinoma
CK, OCT4, PLAP, CD30
β-hCG, LCA, HMB-45
Teratoma
CK, EMA
AFP, PLAP
β-hCG, c-kit
a IDH-1 stains the majority of diffuse gliomas including secondary GBM, but not primary GBM.
b CAM 5.2 recommended, because CK (AE1/AE3) AE1/AE3 stains reactive astrocytes and frequently stains gliomas.
c Strongly positive in minigemistocytes and gliofibrillary oligodendrocytes.
d Not specific for choroid plexus.
e Positive in myeloma.
f Nuclear PR reactivity is strong in most WHO I meningiomas, weaker or absent in WHO grade II and III.
g Positive in secretory variant.
h Characteristic pattern of scattered, individual immunoreactive cells.
i Loss of BAF-47 immunoreactivity is observed in the vast majority of ATRT; reactivity is retained in most other pathologies.
j Diffuse, strong expression.
k Positive in melanotic schwannomas.
l Positive in sustentacular cells.
m Membranous pattern in germinoma, cytoplasmic in embryonal carcinoma/yolk sac tumor.
n Positive in syncytiotrophoblasts, present in a minority of the cases.
GFAP, glial fibrillary acid protein; NF, neurofilament; IDH-1, isocitrate dehydrogenase 1; YKL-40, chitinase-3-like 1; CK, cytokeratin; CAM5.2, cytokeratin negative in glial cells; TTF1, thyroid transcription factor 1; LCA, leukocyte common antigen; SYN, synaptophysin; D2-40, podoplanin; EMA, epithelial membrane antigen; VIM, vimentin; PR, progesterone receptor; CEA, carcinoembryonic antigen; PLAP, placental alkaline phosphatase; AFP, α-fetoprotein; β-hCG, β-human chorionic gonadotrophin; BAF47, also called SNF5 and INI1; CG, chromogranin; Coll IV, collagen type IV; and NSE, neuron-specific enolase.
a. Glial markers. The most commonly used glial marker in neuropathology practice is glial fibrillary acid protein (GFAP). This intermediate filament protein is fairly (but not completely) specific for glial lineage. However, it does not reliably distinguish astrocytic, oligodendroglial, and ependymal tumors from one another, and may also be encountered in other tumors with glial differentiation such as choroid plexus tumors, medulloblastomas and/or primitive neuroectodermal tumors (PNETs), gangliogliomas (GGs). GFAP can even be detected to some extent in nonglial neoplasms, such as nerve sheath and cartilaginous tumors.
b. Neuronal markers. The most commonly used neuronal markers include neurofilament (NF) protein, synaptophysin (SYN), chromogranin, and Neu-N.
SYN is one of the more sensitive markers of neuronal differentiation. It is typically found even in the most primitive neuronal tumors (medulloblastomas and PNETs) and is very useful for highlighting neoplastic ganglion cells, pituitary adenomas and carcinomas, carcinoid tumors, neurocytomas, and paragangliomas. One major disadvantage of SYN is that it fails to differentiate native (entrapped) neuropil from tumor neuropil. Additionally SYN stains a proportion of tumors (e.g., pilocytic astrocytomas [PAs]) that are generally not considered to have neuronal differentiation. In some cases, however, this feature is actually somewhat useful; classic oligodendrogliomas show dot-like paranuclear reactivity for SYN.
NF is a heteropolymer unique to neurons and axons. Mature neuronal tumors, such as GGs, often stain for NF; however, more primitive neuronal tumors such as medulloblastomas are often negative. Additionally, NF also stains normal axons, a property that is of great utility for demonstrating an infiltrative growth pattern by highlighting entrapped axons (e-Fig. 41.3).
Neu-N is a marker of advanced neuronal differentiation; it has the advantage of clearly marking neuronal nuclei and cell bodies rather than surrounding neuropil. As a result, it is particularly useful for identifying architectural abnormalities in cortical dysplasia, and for highlighting neuronal loss (e.g., in mesial temporal sclerosis) and neurons entrapped within invasive tumors. Surprisingly, most neoplastic ganglion cells in GGs are negative for Neu-N; this feature can be useful because entrapped cortical neurons are virtually always strongly positive.
c. Epithelial markers. The commonly used epithelial markers include cytokeratin (CK; AE1/AE3), epithelial membrane antigen (EMA), and CAM 5.2. CKs are used predominantly in the diagnosis of metastatic carcinomas, but are also used to identify craniopharyngiomas, chordomas, and choroid plexus tumors. Due to cross-reactivity with GFAP, gliomas (and reactive astrocytes) may show CK reactivity, a major pitfall in the differential between glioblastoma (GBM) and metastatic carcinoma. In such instances, CAM 5.2 is recommended, because gliomas (and reactive astrocytes) are virtually always negative. EMA is frequently used in the identification of meningiomas, which, unlike true epithelial tumors, usually display minimal to no CK expression (secretory meningioma is an exception). EMA is also useful in the diagnosis of ependymomas, along with CD99 and D2-40 antibody (podoplanin).
d. S-100 protein is a marker of neuroectodermal cells, including melanocytes, glia, Schwann cells, chondrocytes, and the sustentacular cells in tumors such as paraganglioma, pheochromocytoma, and olfactory neuroblastoma. In conjunction with collagen IV, which stains basement membranes, S-100 is particularly helpful for demonstrating
Schwann cell differentiation in benign and malignant peripheral nerve sheath tumors (MPNSTs).
e. Proliferation markers are used in conjunction with mitotic counts in brain tumors to guide determination of tumor grade and prognosis. The most widely used marker is Ki-67, which labels nuclei that are not in the G0 phase of the cell cycle.
f. “Molecular test” markers. Recently, several antibodies have been developed that can be used in lieu of more complicated molecular tests for diagnosis and prognosis of various neoplasms.
i. INI1/BAF47 deletions are detected in ˜70% of the atypical teratoid/rhabdoid tumors (AT/RTs); however, loss of the corresponding INI1 protein is even more common than the genetic alteration. Loss of INI1 nuclear immunoreactivity in tumor cells is used as a surrogate for genetic testing to demonstrate biallelic inactivation of the gene.
ii. Isocitrate dehydrogenase (IDH1/IDH2) mutations have been detected in the majority of diffuse gliomas, with the notable exception of primary (de novo) GBM, and appear to play a fundamental and early role in oncogenesis (N Eng J Med. 2009;360:765). The most common mutation is in the IDH1 gene (R132H), and is recognized by monoclonal antibody IDH-1. Diagnostically, this immunohistochemical stain shows greatest promise for its potential to distinguish low-grade diffuse glioma from gliosis (Am J Surg Pathol. 2010;34:1199; Acta Neuropathol. 2010;119:509). Prognostically, the presence of this mutation is favorable, as such tumors appear to show greater response to therapy.
3. Molecular diagnostics involves the measurement of diagnostically or prognostically relevant pathologic features at the DNA (epigenetic, genomic [nuclear or mitochondrial], mRNA, or protein levels.
The most common and practical approaches to detect changes in DNA (deletions of chromosomal regions, amplifications of oncogenes, or loss of specific tumor suppressor genes) include fluorescence in situ hybridization (FISH) and quantitative polymerase chain reaction (PCR) techniques. FISH has the advantages of simplicity, morphologic preservation, and minimal tissue and purity requirements. However, FISH is insensitive to very small deletions/amplifications, substitution mutations, or epigenetic modification (e.g., methylation).
The most notable use of FISH in surgical neuropathology is to detect losses of chromosomal arms 1p and 19q testing as a prognostic and/or management tool for adult patients with oligodendroglial tumors (Adv Anat Pathol. 2005;12:180). Other clinical applications of FISH include detection of EGFR amplification and/or 10q deletions to distinguish the small cell variant of GBM from anaplastic oligodendroglioma; 22q11.2 deletion (INI1 locus) to distinguish AT/RT from variants of medulloblastoma (Hum Pathol. 2001;32:156); isochromosome 17q (i17q) and NMYC or CMYC amplifications to diagnose and predict outcome for medulloblastomas, large cell/anaplastic medulloblastomas and other aggressive forms of CNS-PNET; meningioma-associated deletions (NF2, DAL1, 1p, 14q) to distinguish anaplastic meningiomas from other malignancies or benign meningiomas from foci of meningothelial hyperplasia; and (9p21) to provide prognostic information about higher-grade meningiomas.
A common use of PCR-based techniques is to detect O6-methylguanine-DNA methyltransferase (MGMT) gene methylation, which blocks MGMT transcription. As the MGMT gene product plays an important role in DNA repair, GBMs with this epigenetic modification show greater sensitivity to
alkylating agents (like temozolomide) and radiation therapy (N Eng J Med. 2005;352:987).
IV. BASIC ELEMENTS OF CNS PATHOLOGY. The cells and tissues of the CNS are capable of displaying diverse histologic abnormalities. A few of these are pathognomonic for a given disease, but most diseases require a constellation of findings to suggest a diagnosis.
A. Neurons.
1. Axonal injury. When an axon is damaged and the associated neuron survives, the axon itself may form a swelling, or axonal spheroid, at the site of injury. If the axon is severed, in most cases the distal portion will disintegrate in an active cellular process called Wallerian degeneration. In some cases, the axotomized neuron will undergo “chromatolysis,” in which the cell body appears mildly swollen and achromatic; this change reflects a loss of Nissl substance that occurs as the cell alters its metabolism to allow repair of its damaged axon.
2. Apoptosis. If neuronal injury is severe enough to cause cell death, neurons may undergo apoptosis (as occurs in the basis pontis and subiculum from hypoxic ischemic injury late in gestation, a pattern labeled with the misnomer pontosubicular necrosis). Alternatively, neurons may undergo necrosis.
3. Necrosis. The classic histologic appearance of acute neuronal necrosis includes (1) variably intense cytoplasmic eosinophilia (accounting for the name “red neurons”) and (2) shrunken pyknotic nuclei (e-Fig. 41.4). Red neurons require 12 to 24 hours to develop within a living brain; individuals who die within minutes or a few hours of an ischemic stroke do not show red neurons in affected region(s). Although red neurons are commonly caused by ischemia, many insults (e.g., hypoxia, hypoglycemia, epilepsy, herpes simplex virus [HSV] infection) can also cause neuronal necrosis. It is important to note that a common artifact caused by overmanipulation of fresh brain tissue can cause normal healthy neurons to (superficially) resemble red neurons. Neurons affected by this “dark cell change” usually show more basophilia than red neurons, a nucleus that is less distinct within the cell body, and an apical dendrite that resembles a spiral or corkscrew (e-Fig. 41.5).
4. Ferrugination. Occasionally, damaged neurons around the edge of a remote infarct or traumatic injury become encrusted with basophilic iron and calcium salts. This condition is often referred to as mineralization or ferrugination.
5. Binucleation of neurons, rare in normal brains, is infrequently noted in dysplastic/malformative processes (e.g., tuberous sclerosis, TS), in certain neoplasms (e.g., GG), and in Alzheimer disease (AD) (Neuropathol Appl Neurobiol. 2008;34:457) (e-Fig. 41.6).
6. Intraneuronal inclusion bodies form within neurons under many different circumstances. Some are pathognomonic, some are associated with one or more diseases, and others appear to have no pathologic significance.
a. Pick bodies are round, tau-positive intracytoplasmic neuronal inclusions. In Pick disease (a form of frontotemporal dementia), these are argyrophilic by Bielschowsky and Bodian (but not Gallyas) silver stains and are abundant in neurons of the cortex, hippocampus, and dentate gyrus. A similar (but less abundant, Gallyas positive) inclusion is seen in corticobasal degeneration.
b. Lewy bodies (LBs). Classic LBs, which occur within pigmented neurons of the brainstem, are spherical cytoplasmic inclusions with an eosinophilic core and a pale halo (e-Fig. 41.7). By contrast, cortical LBs appear as subtle spheres of homogeneous eosinophilia. Making detection even more
difficult, cortical LBs are not argyrophilic. Fortunately, LBs all show immunoreactivity for ubiquitin and α-synuclein (e-Fig. 41.8). These lesions (along with similar inclusions [Lewy neurites] that appear within cell processes) are seen in Lewy body disorders (e.g., Parkinson disease [PD], and dementia with Lewy bodies [DLBs]).
c. Marinesco bodies are small, eosinophilic, strongly ubiquitin-positive intranuclear inclusions located chiefly in pigmented brain stem neurons (e-Fig. 41.9). These have no known pathologic significance.
d. Neurofibrillary tangles (NFTs) (e-Fig. 41.10) are argyrophilic intracytoplasmic filamentous aggregates of hyperphosphorylated tau protein. Although characteristic of AD, they also appear in many other neurodegenerative disorders, and in rare GGs.
e. Hirano bodies are brightly eosinophilic rod-shaped or elliptical cytoplasmic inclusions that occur within the proximal dendrites of neurons, particularly in the hippocampus. Although not specific, they are particularly numerous in brains with AD pathology (e-Fig. 41.11).
f. Granulovacuolar degeneration (GVD) is common in hippocampal pyramidal neurons in AD, and less common in older brains without AD. GVD resembles many small bubbles, each with a small basophilic granule.
g. TDP-43 neuronal cytoplasmic inclusions (NCIs), as the name suggests, are immunoreactive for TDP-43. Although NCIs are characteristic of a subset of frontotemporal dementias, they are not specific, and may be seen in the temporal lobe in other neurodegenerative diseases (e.g., AD).
h. Bunina bodies are eosinophilic ubiquitin and TDP-43 immunoreactive intracytoplasmic inclusions that form in motor neurons in cases of familial and sporadic amyotrophic lateral sclerosis (ALS).
B. Astrocytes
1. Reactive astrocytosis. Normally, astrocytes are evenly dispersed (albeit with regional variation), mitotically silent, and GFAP positive. In most forms of brain injury, astrocytes become hypertrophic, increase their GFAP content, and may proliferate. Reactive astrocytes have prominent stellate processes and, often, abundant eccentrically distributed glassy cytoplasm that inspires the moniker “gemistocyte.” Nevertheless, reactive astrocytes generally maintain an even distribution, and do not exhibit nuclear atypia (radiation exposure is an exception). Grossly, tissues affected by chronic astrocytosis are usually firm; thus, the term “gliotic” is used to describe brain tissues that appear unusually firm or rubbery.
2. Bergmann gliosis refers to an accumulation of astrocytic nuclei (usually in association with neuron loss) within the Purkinje cell layer of the cerebellum.
3. Alzheimer type II astrocytes, with swollen pale nuclei and minimal visible cytoplasm, appear in hyperammonemic states (e.g., liver failure, Wilson disease). In the cortex and striatum, these nuclei are round with a prominent nucleolus (e-Fig. 41.12); in the pallidum, dentate nucleus, and brainstem, they are irregular and lobated.
4. Corpora amylacea are basophilic, round, concentrically lamellated aggregates of polyglucosan (polyglucosan bodies) that develop within astrocytic processes. Common in normal brains, particularly near ventricular and pial surfaces, these become more numerous with age. Similar structures (Lafora bodies) form in far greater numbers in astrocytes and neurons (and in eccrine sweat glands) in Lafora body disease.
5. Rosenthal fibers (RFs) are brightly eosinophilic, somewhat refractile, irregular/beaded structures that range from ˜10 to 40 µm in diameter. EM reveals them as swollen astrocytic processes filled with electron-dense amorphous granular material and glial filaments. RFs are commonly observed in PA, but
are also commonly seen in nonneoplastic tissues adjacent to slowly growing neoplasms (e.g., craniopharyngioma, ependymoma), cysts, and syrinx; such RF-abundant tissue reaction is called piloid gliosis (e-Fig. 41.13).
6. Eosinophilic granular bodies (EGBs), although not present in nonneoplastic astrocytes, are found in slowly growing astrocytic and glioneuronal tumors (PA, GG, and pleomorphic xanthoastrocytoma [PXA]). EGBs appear on H&E sections (or cytologic smear preparations) as refractile clusters of small, round hyaline droplets, and are PAS-positive (e-Fig. 41.14).
C. Microglia. Normal residents of the brain, microglial cells are of monocytic lineage (and are consequently immunoreactive for leukocyte common antigen [LCA/CD45] as well as CD68 and CD163). In response to various signals, these cells undergo activation, whereupon they change their morphology (appearing as irregular elongated “rod cells”), become motile, and intensify their communication with other cells via secreted factors (e.g., cytokines and interleukins). They may also participate in limited phagocytosis. Small clusters of activated microglial cells (microglial nodules) are characteristic of viral encephalitis and may be seen decorating dying neurons, in a process called neuronophagia. Capacity for phagocytosis increases in the setting of injury, infection, or demyelinating disease when microglia differentiates into macrophages. Monocytes and macrophages may also be recruited into the CNS from the systemic circulation. Occasionally, brisk mitotic activity among macrophages in these settings (particularly in tumefactive multiple sclerosis (MS), which radiographically resembles GBM) can cause diagnostic confusion with gliomas. Gliomas themselves often contain a large number of microglial cells, which appear to play a role in tumorigenesis (Cancer Res. 2008;68:10358).
D. Cerebral edema is an increase in brain volume due to increased water content. Depending on its pathogenesis, cerebral edema can be classified as vasogenic, cytotoxic, osmotic, or interstitial (resulting from obstructive hydrocephalus). However, combinations of different edema types often coexist. In vasogenic edema, the fluid collection is predominantly extracellular and results from breakdown of the blood-brain barrier. In cytotoxic edema, the fluid accumulation is intracellular, the result of impaired Na/K-ATPase function in glial cells caused by toxins, ischemia, or various other conditions. Osmotic edema results when osmolality of the brain interstitial fluid exceeds that of the plasma. Interstitial edema results from transependymal flow from the ventricles in the setting of obstructive hydrocephalus.
E. Hydrocephalus, an abnormal increase in the intracranial volume of CSF associated with dilatation of all or part of the ventricular system, may be classified as communicating, noncommunicating (obstructive), normal pressure, or ex vacuo.
1. Noncommunicating hydrocephalus results from physical blockage of CSF flow, usually by tumor compressing a narrow channel, such as the foramen of Monro or the cerebral aqueduct.
2. Communicating hydrocephalus results from impaired resorption of CSF at the arachnoid granulations, as may occur in the setting of subarachnoid hemorrhage or meningitis; less commonly, it may result from increased CSF production, for example, by a choroid plexus papilloma.
3. Normal pressure hydrocephalus (NPH), characterized classically by the clinical triad of dementia, ataxia, and incontinence, is poorly understood. NPH may represent a circumstance in which production and resorption of CSF reach a new equilibrium after a prolonged period of impaired resorption.
4. Hydrocephalus ex vacuo describes a state of ventricle expansion due to loss of adjacent parenchyma or generalized cerebral atrophy (as occurs in AD).
F. Intracranial pressure (ICP) and brain herniation. Normally, the cranial cavity contents (blood, brain, and CSF) are maintained in volumetric balance
within the rigid skull and dura. ICP increases when this balance is strained, as may result from diffuse brain edema, increased cerebral blood flow and blood volume, or development of space-occupying lesions (e.g., tumor, abscess, hematoma, or large edematous infarct). Elevated ICP, if not treated, can cause herniation; herniation syndromes include subfalcine (cingulate gyrus), transtentorial (uncal), and cerebellar tonsillar/brainstem herniations.
G. Duret (secondary brain stem) hemorrhage occurs when penetrating pontine arteries (which arise perpendicularly from the basilar artery) become kinked in association with brainstem herniation; the resulting acute hemorrhagic infarction of the pons is often fatal.
V. NEOPLASMS OF THE CNS. For most CNS tumors, incidence varies greatly with age and gender. Among adults, metastases, GBM, and meningioma are the most common CNS neoplasms; among children, PA, medulloblastoma, and ependymoma are far more common. Likewise, tumors often differ in their radiographic features and propensity for certain anatomic sites. For this reason, microscopic evaluation of a CNS biopsy specimen is incomplete without considering the neuroradiologic findings that describe the targeted lesion in situ. Indeed, neuroradiologic assessment can be considered to be the neuropathology surrogate for gross examination. Imaging studies are particularly helpful when evaluating small biopsy samples. The World Health Organization (WHO) currently lists more than 100 types of CNS tumors and their variants (Table 41.2). Table 41.3 organizes common CNS tumor diagnoses on the basis of location, patient age, and imaging characteristics.
Histologic features are also critical for diagnosis. Because a final diagnosis may not be obvious from an initial histomorphologic examination, it is worthwhile to begin with a broad differential based on a specimen’s general histopathologic pattern. Table 41.4 lists eight major histopathologic patterns that may be encountered, along with their most commonly associated diagnostic entities. Once a differential diagnosis has been formulated on the basis of these data, closer examination of microscopic details can refine the differential further and suggest what ancillary tests (if any) are required to arrive at a final diagnosis.
A. Gliomas
1. Diffuse (infiltrating) astrocytomas (DAs), WHO grade II. Diffuse gliomas are the most frequent primary CNS neoplasms. Because they are diffusely infiltrative, complete resection is nearly impossible. On MRI, DAs are nonenhancing, T1 hypointense, T2/FLAIR hyperintense, ill-defined intra-axial masses that can occur throughout the neuraxis, but commonly involve the cerebral hemispheres. Clinically, they present with new-onset seizures (the most common symptom), headaches, or functional neurologic deficits. Grossly, these lesions may appear gray-tan to gelatinous and obscure the native gray-white junction. Microscopically, tumor cells invade adjacent cortex along white matter tracts. They aggregate around neurons and blood vessels and beneath pial and ependymal surfaces to produce the so-called secondary structures of Scherer. The cytologic features of astrocytic tumor cells can vary widely from uniform and minimally atypical, to highly pleomorphic both in cytoplasmic and nuclear features (e-Fig. 41.15). Cells with elongate, irregular, hyperchromatic nuclei with minimal cytoplasm are seen in fibrillary astrocytomas, whereas cells with eccentrically located nuclei and abundant eosinophilic cytoplasm characterize the gemistocytic variant. Tumor cells are often, but not invariably, immunoreactive to GFAP. A recently identified immunohistochemical marker, antibody IDH-1, is proving invaluable for distinguishing the majority of DAs (but not primary GBMs) from gliosis. Mitotic activity is very low or nonexistent.
2. Anaplastic astrocytoma (AA), WHO grade III, is a diffusely infiltrating glioma with a mean age of presentation in the fifth decade. AA may appear de novo, or through progression of a preexisting DA. Like DA, AA preferentially involves the cerebral hemispheres. On MRI, AA is similar to DA, but may show faint focal enhancement. Histologically, AA is distinguished by increased cellularity, pleomorphism, and increased proliferative index. The defining feature that distinguishes AA from DA is mitotic activity, which should be evaluated in the context of sample size. In a limited (needle/core) biopsy, a single mitosis is sufficient to designate a glioma as anaplastic. However, in large resections there should be at least a few mitoses before the tumor is considered anaplastic. By definition, AAs do not have microvascular proliferation or necrosis.
TABLE 41.2 WHO Classification and Grading of CNS Tumors
I
II
III
IV
Tumors of neuroepithelial tissue
Astrocytic tumors
PA
*
PMA
*
SEGA
*
PXA
*
DA
*
Fibrillary astrocytoma
Gemistocytic astrocytoma
Protoplasmic astrocytoma
AA
*
GBM
*
Giant cell GBM
*
GS
*
Gliomatosis cerebri
*
Oligodendroglial tumors
Oligodendroglioma
*
Anaplastic oligodendroglioma
*
Oligoastrocytic tumors
Oligoastrocytoma
*
Anaplastic oligoastrocytoma
*
Ependymal tumors
Subependymoma
*
Myxopapillary ependymoma
*
Ependymoma
*
Cellular
*
Papillary
*
Clear cell
*
Tanycytic
*
Anaplastic ependymoma
*
Choroid plexus tumors
Choroid plexus papilloma
*
Atypical choroid plexus papilloma
*
Choroid plexus carcinoma
*
Other neuroepithelial tumors
AB
CGs of the third ventricle
*
AGs
*
Neuronal and mixed neuronal-glial tumors
Dysplastic gangliocytoma of cerebellum (Lhermitte-Duclos)
*
Desmoplastic infantile astrocytoma/GG
*
DNT
*
Gangliocytoma
*
GG
*
Anaplastic GG
*
Central neurocytoma
*
Extraventricular neurocytoma
*
Cerebellar liponeurocytoma
*
PGNT
*
RGNT of the fourth ventricle
*
Paraganglioma
*
Tumors of the pineal region
Pineocytoma
*
PPTID
*
*
Pineoblastoma
*
PTPR
*
*
Embryonal tumors
Medulloblastoma
*
Desmoplastic/nodular medulloblastoma
*
Medulloblastoma with extensive nodularity
*
Anaplastic medulloblastoma
*
Large cell medulloblastoma
*
CNS PNET
*
CNS neuroblastoma
*
CNS ganglioneuroblastoma
*
Medulloepithelioma
*
Ependymoblastoma
*
AT/RT
*
Tumors of cranial and paraspinal nerves
Schwannoma (neurilemoma, neurinomas)
*
Cellular
*
Plexiform
*
Melanotic
*
Neurofibroma
*
Plexiform
Perineurioma, NOS
*
*
*
Perineurioma (intraneural)
*
Malignant perineurioma
*
MPNSTs
*
*
Epithelioid MPNST
*
*
MPNST with mesenchymal differentiation
*
*
Melanotic MPNST
*
*
MPNST with glandular differentiation
*
*
Tumors of the meninges
Meningioma
Meningothelial
*
Fibrous (fibroblastic)
*
Transitional (mixed)
*
Psammomatous
*
Angiomatous
*
Microcystic
*
Secretory
*
Lymphoplasmacyte-rich
*
Metaplastic
*
Chordoid
*
Clear cell
*
Atypical
*
Papillary
*
Rhabdoid
*
Anaplastic (malignant)
*
Mesenchymal, nonmeningothelial tumors
Lipoma
Angiolipoma
Hibernoma
Liposarcoma
Fibromatosis
SFT
Inflammatory myofibroblastic tumor
Fibrosarcoma
Malignant fibrous histiocytoma
Leiomyoma
Leiomyosarcoma
Rhabdomyoma
Rhabdomyosarcoma
Chondroma
Chondrosarcoma
Osteoma
Osteosarcoma
Osteochondroma
Hemangioma
Epithelioid hemangioendothelioma
HPC
*
Anaplastic HPC
*
Angiosarcoma
Kaposi sarcoma
Ewing sarcoma-PNET
Primary melanocytic lesions
Diffuse melanocytosis
Melanocytoma
Malignant melanoma
Melanomatosis
Other neoplasms related to the meninges
HB
*
Tumors of the hematopoietic system
Malignant lymphomas/primary CNSLs
B-cell lymphoma
DLBCL
Low-grade B-cell lymphoma
Marginal zone B-cell lymphoma
Plasmacytoma
Intravascular B-cell lymphoma
T-cell lymphoma
Anaplastic large-cell lymphoma
NK/T-cell lymphoma
Hodgkin’s disease
Histiocytic tumors
LCH
Rosai-Dorfman disease
Erdheim-Chester disease
Haemophagocytic lymphohistiocytosis
JXG
Malignant histiocytic disorders (histiocytic sarcoma)
GCTs
Germinoma
Embryonal carcinoma
Yolk sac tumor
Choriocarcinoma
Teratoma
Mature
Immature
Teratoma with malignant transformation
Mixed GCT
Tumors of the sellar region
Craniopharyngioma
*
Adamantinomatous
*
Papillary
*
Granular cell tumor of the neurohypophysis
*
Pituicytoma
*
Spindle cell oncocytoma of the adenohypophysis
*
Modified from: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, eds. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC Press; 2007. Used with permission.
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