Normal Brain Histopathology
2 
Normal Brain Histopathology
Introduction 19
Cell Types  19
Tissue Organization  26
Features of Infancy and Childhood  34
Features of the Aging Nervous System  36
Introduction
The practice of surgical neuropathology can be challenging for the
generalist and specialist alike. Much of the difficulty results from the
intrinsic complexity of the human central nervous system (CNS), an
organ that is unrivaled in regional variation and specialized organiza-
tion. Nevertheless, a basic understanding of the types of cells and their
regional organization in the normal brain is necessary for the practice
of surgical neuropathology, because recognition of the abnormal
rests upon a firm knowledge of the normal. Even in the current
age of advanced neuroimaging and image-guided biopsies, many
neurosurgically sampled specimens contain normal or only slightly
abnormal tissue that needs to be recognized as nondiagnostic. Indeed,
much of the anxiety that arises at the time of frozen section seems
to be due to a discomfort with distinguishing normal from abnormal
rather than from correctly categorizing an abnormal biopsy. The “sea
of pink” noted under the microscope from a brain biopsy of normal
brain tissue has been known to cause even the most experienced
surgical pathologist a great degree of uncertainty. The changes of “reactive
gliosis” only exacerbate the problem. Much like the pattern recognition
approach used in this textbook for classifying diseases of the CNS,
so too can the normal histology of the brain be approached based
on recognition of tissue pattern. Like other forms of pattern recogni-
tion, this takes practice. For the neuropathologist, repeated exposure
to normal CNS structure in surgical specimens is supplemented by
the regular review of autopsy brains. For generalists that practice
surgical neuropathology, review of autopsy brain sections can similarly
add confidence. This chapter introduces the cell types and normal
histology of the human CNS at a depth necessary for routine diagnostic
Daniel J. Brat, MD, PhD
practice. Most of its content describes the normal adult brain, but certain
aspects of age-related phenomena and developmental considerations
that are routinely encountered in diagnostic neuropathology are also
considered.
Cell Types
Given the high degree of functional complexity, it may be surprising
that the brain and spinal parenchyma consist predominantly of only
two cell types, neurons and glia, while their coverings mostly feature
meningothelial and mesenchymal cell types. The normal anatomy and
histology of the pineal gland, pituitary gland, and peripheral nervous
system are also covered to some extent in their respective tumor chapters.
Both neurons and glia are large families with many members that have
highly specialized functions, yet the underlying structure and cell biology
of each retain some central features. Most imposing for the practicing
surgical pathologist is the great degree of morphologic and geographic
diversity of normal, reactive, and degenerative states of these two cell
families.
Neurons
Neurons are the sensing, integrating, transmitting, and effecting cells
of the nervous system, communicating by chemical and electrical
means. The spectrum of their morphology, connectivity, and function
is enormous. As a rule, neurons have a cell body (i.e., perikaryon),
branching processes called dendrites for integrating incoming signals, and
a longer cell process—the axon—with a terminal synapse for chemically
transmitting an electrical signal over a short space from one neuron
to the next (or to a muscle cell through a neuromuscular junction).
Cell body shape and size, as well as the number and arrangement of
branching processes, vary considerably. For practicing pathologists,
recognizing the major forms of neurons within their anatomic setting
is requisite, because individual populations show differential vulner-
ability to injury and variable pathologic reactions in specific disease
processes.
The pyramidal neurons of the cerebral cortex and subfields of the
hippocampus represent a morphologic prototype (Fig. 2.1A and B).
They are characterized by large, triangular cell bodies, a prominent
apical dendrite extending toward the brain’s surface, and numerous
finer branching basal dendrites. Measuring approximately 10 to 50
19
 Normal Brain Histopathology

Abstract
Surgical neuropathology can be challenging due to the intrinsic complex-
ity of the human brain, yet a basic understanding of cell types and
their organization is necessary. Much like pattern recognition is used
for classifying diseases, so too can normal histology be approached
based on tissue pattern recognition. Normal cells of the brain include
neurons, glia, and microglia, as well as endothelial and perivascular cells,
leptomeningeal cells, melanocytes, and choroid plexus. The morphologies,
organization, and function of these cell types vary dramatically based on
2
brain region, which is evident by the contrasting histologic features of
the cerebral cortex and white matter, basal ganglia, thalamus, brainstem,
cerebellum, and spinal cord, as well as specialized structures such as
the pineal and pituitary glands and the hippocampus. The practice of
surgical neuropathology also requires a familiarity with the features
of the developing brain as well as those features associated with aging.

Keywords
brain
spinal cord
cerebellum
histology
neurons
glia

19.e1
 Practical Surgical Neuropathology

A B

C D

E F G
Fig. 2.1  Neurons. (A) Pyramidal neurons (arrow) of the cerebral cortex. (B) Pyramidal neurons of the hippocampus. (C) Betz cells (upper motor neurons) of the motor cortex (arrow).
(D) Granular neurons of the dentate fascia of the hippocampal formation. (E) Purkinje cells (arrow) and granular cells (arrowhead) of the cerebellar cortex. (F) Anterior horn cells
(lower motor neurons) of the spinal cord. (G) Dopaminergic neurons of the substantia nigra are deeply pigmented due to accumulation of neuromelanin.

20

microns in greatest dimension, their cell bodies contain abundant
cytoplasm, variable hematoxyphilic Nissl substance (rough endoplasmic
reticulum) near the entry zone of cell processes, and a large nucleus
with open chromatin and a prominent nucleolus. Open chromatin and
prominent nucleoli are typical of neurons that are almost constantly
transcriptionally and translationally active and distinguish them from
the more quiescent glia.
Cortical granular (stellate) neurons are the smaller counterparts of
pyramidal neurons in the cortex, typically measuring 15 microns or
less in diameter. Being interneurons, they have numerous shorter
processes that remain within the confines of the cortex.
Betz cells are the largest neurons of the cerebral cortex (70 to 100
microns) and are found in the primary motor cortex where they dwarf
their neighboring cortical pyramidal cells (Fig. 2.1C). Not only the cell
size and amount of cytoplasm, but also the amount of Nissl substance
and the number of visible processes far exceed normal pyramidal cells.
Betz cells are upper motor neurons.
Small, tightly packed granular neurons form the stratum granulosum
of the dentate gyrus in the medial temporal lobe, intimately connected
to the hippocampus proper (Fig. 2.1D). These neurons are nearly as
small as the cerebellar granular cells (see discussion to come) and have
an extensive dendritic arbor that forms the adjacent molecular layer
of the dentate gyrus.
Purkinje cells are large (50 to 80 microns), histologically distinctive
neurons of the cerebellum with cell bodies that sit at the interface of
the molecular and internal granular cell layers (Fig. 2.1E). Each neuron
has a prominent pink cell body and an expansive dendritic tree with
thick processes that extend into the molecular layer, as well as a large
axon that travels centrally out of the cerebellar cortex.
Granular neurons of the cerebellar granular cell layer are tiny
and densely packed, often displaying a linear arrangement or loose
rosettes around delicate neuropil (Fig. 2.1E). Perinuclear cytoplasm
is sparse, giving the appearance of only nuclei on hematoxylin-eosin
(H & E) stains. This population can cause confusion on frozen section
or cytologic preparations, because they resemble “small round blue
cell tumors.”
Anterior horn cells are large, lower motor neurons (alpha motor
neurons) that populate all levels of the spinal cord in the anterior horns
and send long axonal processes via the anterior roots for their eventual
termination on peripheral skeletal muscle endplates (Fig. 2.1F).
A B
Fig. 2.2  Normal glia. (A) Normal white matter shows oligodendrocytes (arrow), which have round dark nuclei often with a slight perinuclear halo, and astrocytes, with oblong
nuclei (arrowheads). Glial cytoplasm blends with the neuropil and cannot typically be noted in the resting state. (B) Cytologic preparation of normal cortex demonstrates normal
oligodendrocytes (short arrow), astrocytes (arrowhead), neurons (long arrow), and capillaries (asterisk).
Normal Brain Histopathology
The CNS also contains a small number of highly specialized nuclei that
contain neurons that produce specific bioaminergic neurotransmitters
and project diffusely throughout the brain to affect global or regional
2
tone. Rarely seen in biopsied material, these include the substantia
nigra, locus ceruleus, raphe nuclei, and nucleus basalis of Meynert.
The dopaminergic cells of the substantia nigra pars reticulata (and
the ventral tegmental area) are large, heavily pigmented neurons with
“neuromelanin” (not to be confused with melanin of melanocytes),
which accumulates in the cytoplasm as coarse brown granules and
represents a combination of oxidized and polymerized dopamine within
lysosomal granules (Fig. 2.1G; selectively vulnerable in Parkinson disease).
Similarly, the locus ceruleus, located near the fourth ventricle in the
rostral pontine tegmentum, contains a population of large, pigmented
neurons, which serve as a major source of norepinephrine in the brain
(selectively vulnerable in Parkinson disease). Neurons located in the
raphe nuclei, located along the midline of the brainstem, are similar in
size and shape to the noradrenergic neurons of the locus ceruleus, but
lack the pigmentation. These cells produce serotonin and have diffuse
projections throughout the nervous system, but most heavily innervate
limbic and sensory regions. Within the basal forebrain, inferior to the
anterior commissure in a region called the substantia innominata, is
the nucleus basalis of Meynert, a collection of large cholinergic neurons
that project throughout the cerebral cortex (selectively vulnerable in
Alzheimer disease).
Glia
Glia account for approximately 90% of all CNS cells and have been
generally regarded as the “glue,” providing structural and functional
support for neuronal elements. In fact, they are functionally much more
diverse and biologically important than originally suspected, such that
neurobiologists have shifted away from this overly “neuronocentric”
perspective. Glia are divided into the macroglia or true glia—astrocytes,
oligodendrocytes, and ependyma—and the microglia, which are actually
of hematopoietic rather than true glial derivation.
Astrocytes
Astrocytes are the multipolar, “star-like” glial cells of the CNS (Figs.
2.2 and 2.3). They can be subdivided into protoplasmic and fibrillary
families based on their location and morphology. Protoplasmic astrocytes
reside in the cortex; fibrillary astrocytes populate the white matter. In
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 Practical Surgical Neuropathology

A B

C D

E F
Fig. 2.3  Reactive glia. (A, B) Gemistocytic astrocytes (arrows) are one form of reactive change in which the astrocytic cytoplasm is distended and eosinophilic processes are readily
identified. (C) Immunohistochemistry for GFAP highlights evenly spaced reactive astrocytes and emphasizes their “star-like” quality. (D, E) Piloid gliosis is a highly fibrillar form of
reactive gliosis that is composed of dense, elongate astrocytic processes that are tightly packed together and are often associated with numerous Rosenthal fibers; in this case,
piloid gliosis forms the wall of a pineal cyst. (F) Alzheimer type II astrocytes (arrow) have enlarged, clear nuclei and are seen in states of hyperammonemia.

22
 Normal Brain Histopathology

G H
Fig. 2.3, cont’d  (G) Bergmann gliosis occurs at the interface of the molecular and granular layers of the cerebellum, generally in response to Purkinje cell injury. In this case, a
nearly normal complement of Purkinje cells (arrow) is seen on the right, whereas Purkinje cells have been replaced by one to three layers of Bergmann glia containing oval nuclei
with long coarse cytoplasmic processes radiating toward the pial surface (left side). The patient was an infant as evidenced by the thin remnant of the external granular layer. (H)
Creutzfeldt cells (arrow) are reactive astrocytic cells with fragmented nuclear material, while thinner starburst-like forms called granular mitoses (not shown) can be mistaken for
astrocytoma-associated mitotic figures. Although not specific, both are most often seen in inflammatory-demyelinating disorders.

addition to similar cell shapes and numerous processes, all astrocytes
contain abundant cytoplasmic intermediate filaments, largely composed
of glial fibrillary acidic protein (GFAP). In the resting state, astrocyte
nuclei are recognized on H & E stained sections, but the scant, delicate
cytoplasm and processes are not readily seen because they blend with
surrounding neuropil. Nuclei are oblong with a chromatin pattern
that is lighter and looser than either oligodendrocytes or neoplastic
astrocytes (Fig. 2.2A). Nucleoli are not present in most resting astro-
cytes, in contrast to neurons. Many astrocytes have processes that
terminate as end-feet on blood vessel walls, where they contribute to
the blood-brain barrier. Others have processes that extend end-feet to
the pial surface of the brain, contributing to the glia limitans of the
brain-CSF barrier.
Astrocytes are activated in response to a variety of pathologic condi-
tions (see Fig. 2.3). The morphologic spectrum of reactive astrocytosis is
critical to recognize because (1) it focuses attention on pathologically
affected regions for further evaluation; (2) it serves as a validation
that a disease process is present in the CNS (i.e., rather than artifact);
and (3) it often causes diagnostic dilemmas due to its morphologic
overlap with neoplastic conditions. Reactive astrocytosis involves both
proliferation and hypertrophy of astrocytes and its appearance varies
with the chronicity and severity of insult. The initial response to insult
is an overall hypertrophy, including enlargement of the cell body and
processes, together with an activated appearance of the nucleus, with
dispersion of chromatin and enlargement of nucleoli. In H & E stained
sections, the presence of abundant astrocytic cytoplasm and visible
cellular processes is almost always a pathologic finding (Fig. 2.3B).
Immunohistochemistry for GFAP will highlight the reactive nature of
these astrocytes, demonstrating mostly even spacing of cells with extensive
arborizing of their processes and the orientation of the reactive cells to
the underlying injury (Fig. 2.3C). Reactive astrocytes of longer duration
often take on a gemistocytic (from the Greek word gemistos for “stuffed”)
appearance, with large amounts of brightly eosinophilic cytoplasm in their
eccentrically placed cell bodies (Fig. 2.3A). The relatively even spacing
of these astrocytes and their radially arranged processes, respecting
each other’s territorial boundaries, help to distinguish them as reactive,
rather than neoplastic.
Chronic reactive astrocytosis occurs around or within a slow-growing
lesion and is often more fibrillar in nature, with numerous long astro-
cytic processes forming a layer of dense gliosis. Rosenthal fibers are
large, flame-shaped or globular proteinaceous deposits that may be
seen in this type of long-standing process; when present, this form of
reaction is often termed piloid gliosis, due to its morphologic overlap
with the compact regions of pilocytic astrocytoma (Fig. 2.3D and E).
It is most often encountered adjacent to slow-growing neoplasms (e.g.,
craniopharyngioma, ependymoma, hemangioblastoma) and benign cystic
lesions (e.g., pineal cyst, spinal syrinx).
Alzheimer type II astrocytes are a reactive form seen in states of
elevated blood ammonia, usually related to renal or hepatic disease
(Fig. 2.3F). They are present in highest concentration in the basal
ganglia where cells show nuclear swelling, marked chromatin clear-
ing, and micronucleoli. Cytoplasmic hypertrophy is not prominent in
this form of astrocytosis and, usually, the nuclei have no appreciable
cytoplasm.
Bergmann glia are specialized astrocytes located between the
molecular and granular layers of the cerebellum. Cells are only one to
two layers thick and can go unnoticed in resting states. In response to
cerebellar injury, especially to individual Purkinje cell loss from ischemia
or hypoxia, the reactive proliferation of this cell layer is referred to as
Bergmann gliosis; on H & E stained sections, there is a replacement of
Purkinje cells with one to three layers of oval nuclei associated with coarse
GFAP-positive fibrillary processes radiating toward the pia (Fig. 2.3G).
Creutzfeldt cells are another form of reactive astrocytes that have
abundant cytoplasm, the fragmenting of nuclear material giving the
impression of multiple micronuclei (Fig. 2.3H). A related finding of
“granular mitoses” in these reactive astrocytes may mimic proliferating
astrocytoma cells [see Chapter 24 discussion of demyelinating diseases
and tumefactive multiple sclerosis (MS)]. These cells are not specific,
but are seen most often in active inflammatory diseases (classic in
demyelinating disease).
Markedly enlarged and cytologically atypical astrocytes can be seen
in many non-neoplastic conditions, although the nuclear atypia is often
most pronounced in reactions to radiation (radiation atypia; see Chapter
21) and progressive multifocal leukoencephalopathy (PML; see Chapters

23
 Practical Surgical Neuropathology
23 and 24). In both conditions, nuclei can be bizarre with marked
hyperchromasia, multilobation, and irregular outlines. The context of
additional microscopic changes and the clinical history are often required
to avoid a misdiagnosis of neoplasm.
processes, whereas in the cerebral cortex, they are scattered within the
neuropil and concentrated immediately surrounding neuronal cell bodies
(satellite cells). In the latter location, they may serve as a progenitor
population.

Oligodendrocytes
Oligodendrocytes are the myelinating cells of the CNS and are therefore
more numerous in white than in gray matter (see Fig. 2.2). With their
thin, short cellular processes extending in all directions, oligodendrocytes
provide internodes of myelination to multiple axonal processes in their
environment. In H & E stained sections, only the nucleus of oligoden-
drocytes is usually visible due to the blending of cellular processes with
the neuropil. A clear zone surrounding the nucleus, the so-called
perinuclear halo, often highlights oligodendrocytes as well as tumors
with similar cytologic features (i.e., oligodendrogliomas); in either case,
this appears due to a retraction artifact of formalin fixation. Nuclei are
generally round and regular, but vary from small and darkly basophilic
(accounting for a majority) to slightly larger with pale vesicular nuclei.
Nucleoli are not usually noted by standard light microscopy. In the
white matter, oligodendrocytes are disposed along the length of axonal
Ependyma
Ependyma are cuboidal to columnar epithelioid glial cells that form a
single-layered covering of the ventricular system (Fig. 2.4). On their
ventricular (apical) surface, ependyma have microscopically visible cilia
and microvilli, while their lateral surfaces are tethered to one another
by desmosomes, forming a functional CSF-brain barrier. Ependymal
cytoplasm is pale to eosinophilic, and nuclei are oval and hyperchromatic.
Within the supratentorial and infratentorial compartments, ependyma
are fairly homogeneous, varying slightly by anatomic location in their
cell height and degree of ciliation (Fig. 2.4C and D). Within the spine,
the central canal is lined by ependyma and serves as a conduit for
CSF during childhood. In adulthood, the central canal is collapsed
and vestigial, remaining only as a central collection of clustered
ependyma throughout the spinal cord length (Fig. 2.4E). Along the
lateral ventricles, especially posteriorly, it is fairly common to encounter

A B

C D
Fig. 2.4  Choroid plexus and ependyma. (A, B) Choroid plexus (arrowhead) is a tufted aggregate of vascular channels lined by a single layer of choroid epithelium, which contains
large pink cells with a cobblestone-like surface. Choroid plexus extends from its entry zone in the lateral ventricle, where it transitions from the ependymal lining (arrow).
(C, D) Ependyma are a single layer of cuboidal to columnar epithelioid glial cells that line the ventricular system and form the brain-CSF barrier. Cilia can usually be noted on the
ventricular surface of ependyma. The distinction between choroid plexus and ependymal cells can be seen at high magnification.

24
 Normal Brain Histopathology

E F
Fig. 2.4, cont’d  (E) In the spinal cord, a central collection of poorly organized ependymal cells forms the vestigial central canal, which can sometimes be mistaken for a neoplasm
in small biopsy specimens. (F) Extensions of the ependymal lining or “ependymal rests” (arrow) can sometimes be noted within the white matter at a distance from the ventricular
system, especially in the occipital lobe.

either entrapped outpouchings of ependyma or small clusters forming

canals (Fig. 2.4F). These do not represent hamartomas or malforma-
tions, but only remnants of imperfect development that are clinically
inconsequential.

Choroid Plexus
The choroid plexus is a functionally differentiated region of ependyma
that extends into the ventricular space as frond-like tufts of epithelium
that secrete the ultrafiltrate of CSF (see Fig. 2.4). Individual cells are
found as a single layer upon a fibrovascular core. Compared to ependyma,
they have larger, cobblestone-shaped cell bodies and contain small,
bland, basally located nuclei. Microvilli extend from the apical surface.
Tight junctions and desmosomes are present between choroid plexus
cells to assure a viable blood-CSF barrier.

Microglia A
Microglia are small, elongated cells located throughout the CNS gray
and white matter (Fig. 2.5). In the resting state, microglia are easily
overlooked because of their small size and bland appearance, yet they
account for nearly 20% of the cellular population. In standard H & E
sections, the nuclei of activated microglia are long, thin, and dark—leading
to their designation as “rod-cells”—but their cytoplasm is difficult to
visualize. Special stains based on silver carbonate or lectins provide
contrast to small processes and delicate branches that extend from their
tips. Microglia are not neuroepithelial in origin, but rather are derived
from a monocyte/macrophage lineage that incorporates into the CNS
early in development. Once established, they serve as antigen-presenting
cells for immune surveillance and participate in inflammatory responses,
particularly against viral pathogens.
Upon activation, microglia proliferate and migrate to sites of damage,
and in this state (“microgliosis”) cells are more readily identified.
Activation also causes increased expression of proteins such as major B
histocompatibility complex (MHC) I and II, which can be detected
immunohistochemically. When microglia and astrocytes aggregate Fig. 2.5  Microglia. (A) Microglia have thin, elongated, and hyperchromatic nuclei that
around a central focus of injury, such as a viral-infected neuron, they stand out from the neuropil (arrow). Microglia are most readily identified in their reactive
state, when they are referred to as “rod-cells.” (B) The rod-like quality of activated
form a microglial nodule (see Chapter 23).
microglia is also appreciated on cytologic preparations (arrows).
Another population of monocyte/macrophage–derived cells resides
in the perivascular compartment, between the outer basement mem-
brane of the vessel and the glia limitans. In distinction to parenchymal

25
 Practical Surgical Neuropathology
microglia, these perivascular macrophages are in continuity with the
circulating monocyte population. Both perivascular and circulating
populations of monocytes are recruited into the CNS parenchyma
in response to severe injury, where they differentiate into tissue
macrophages, often with foamy clear cytoplasm (i.e., gitter cells) in
order to perform phagocytic and immunologic functions. They are
sometimes referred to as the “garbage collectors” of the CNS, because
they clean up all necrotic debris, metabolic by-products, and foreign
material.

Blood Vessels
Similar to other organs, the brain has a population of vascular and
perivascular cells essential for its oxygen and nutrient supply. Compared
to their extracranial counterparts, the large arteries that run within the
subarachnoid space have thinner muscular walls, have less adventitia,
and lack external elastic lamina (Fig. 2.6). As they penetrate into the
brain parenchyma, larger arteries retain both a thin covering by the
pia-arachnoid and a perivascular space, the Virchow-Robin space, which
A
represents a continuation of the subarachnoid space, although its function
and content remain controversial. No such space exists once the vessels
become small capillaries and the endothelium is intimately associated
with neuropil. Capillaries are formed by individual endothelial cells
forming delicate tubular structures with widths suitable only for passage
of individual circulating blood cells. The physiologically critical blood-
brain barrier is formed predominantly by the specialized nature of CNS
endothelial cell junctions and cannot be identified histologically. In
particular, these endothelial cells lack fenestrations between them and
are joined by specialized tight junctions that functionally preclude the
free movement of substances between vascular and CNS spaces.
Astrocytic end-feet and basal lamina elements further contribute to the
integrity of this blood-brain barrier.
B
Meningothelial Cells
Meningothelial cells are scattered within the arachnoid membranes Fig. 2.6  Blood vessels. (A) Large arteries within the subarachnoid space supply the
throughout the neuroaxis, but have their highest concentrations at the brain by penetrating into the parenchyma, where initially they maintain a perivascular
(Virchow-Robin) space that separates the vessel from the neuropil (arrow). (B) Smaller
tips of arachnoid granulations and the outermost layers of the arachnoid
capillaries within the brain (arrows) consist of a thin, delicate tube lined by a single
just under the adjacent dura, where they are called arachnoid cap
layer of endothelial cells that either directly abut the brain parenchyma or have a smaller
cells (Fig. 2.7A and B). Meningothelial cells are epithelioid to slightly perivascular space. The blood-brain barrier is due in large part to the specialized tight
spindled and are typically seen in small clusters (10 to 20 cells), where junctions between endothelial cells.
they have a tendency to form whorls and psammoma bodies, similar
to their neoplastic counterparts in meningiomas. Cells have moderate
eosinophilic cytoplasm and oval nuclei with dispersed chromatin,
often giving the appearance of central clearing or “nuclear holes,” a
feature they have in common with meningioma cells, their neoplastic Tissue Organization
counterpart. Cerebral Cortex
The vast majority (>90%) of cerebral cortex in humans is neocortex, an
Melanocytes evolutionarily late form of cortical development that is distinguished
Melanocytes are normal, neural crest–derived constituents of the human from paleocortex (mostly limbic and olfactory cortices) and archicortex
leptomeninges that are intimately associated with pia and subarachnoid (hippocampal structures), which are more primitive. Neocortex differs
membranes (Fig. 2.7B and C). They are widely scattered in most from primitive cortex in its anatomic location and architecture. All
supratentorial regions and are noted histologically only following intense neocortical areas—also called isocortex—go through developmental
searching or fortuitous tissue sectioning. Their highest density is over periods in which their elements are laid down in six layers. Many regions
the ventral surface of the superior spinal cord, brainstem, and base of the retain this layered appearance throughout life. Paleocortex and archicortex
brain. Almost always seen as individual dendritic-shaped cells rather do not share this developmental pattern or six-layered structuring into
than clusters, leptomeningeal melanocytes are thin, elongated, and show adulthood.
slight branching and pigmentation in proportion to cutaneous pigmenta- Cerebral cortex contains two dominant neuronal types, the granular
tion. As such, these cells are often most conspicuous in patients with (stellate) cell and the pyramidal cell (see Neurons earlier in the chapter).
darkly pigmented skin and can be appreciated grossly on the ventral Pyramidal cells account for two-thirds of cerebral cortical neurons and
surface of the brainstem and spinal cord in some instances. Melanin are the primary output. They have prominent apical dendrites that
pigment is made within cytoplasmic melanosomes and premelanosomes extend toward the cortical surface. Their axons extend long distances
and is therefore similar to dermal melanocytes rather than the neu- to terminate within the ipsilateral or contralateral cortex or travel to
romelanin of the substantia nigra. subcortical regions. Granular cells are smaller and are considered to

26

A appreciated in considerably thicker sections than are normally cut for
B the “line of Gennari.”
C of approximately 5 to 10 oligodendrocytes are disposed in linear, parallel
Fig. 2.7  Meningothelial cells and melanocytes. (A) Meningothelial cells are scattered
within the arachnoid membranes and are most frequent within the outermost layers as
arachnoid cap cells. They are typically spindled to polygonal, have moderate amounts
of eosinophilic cytoplasm and bland oval nuclei, and are usually in small clusters.
(B) Melanocytes (arrowheads) are infrequent, flattened, highly pigmented cells of the pia
and arachnoid membranes that are generally dispersed individually and are in highest
density over the ventral brainstem. Meningothelial cells often form small whorls at the
outer surface of the arachnoid membranes (arrow). (C) High magnification of melanocytes.
Normal Brain Histopathology
be the primary interneurons of the neocortex. Other less common
neurons are the horizontal cells (of Cajal), common in the superficial
cortex in development; fusiform cells, most frequent in the deepest
2
cortical layers; and cells of Martinotti, present in lesser numbers in all
cortical layers.
The practice of neuropathology requires basic familiarity of neocortical
structure (Fig. 2.8A), because subtle abnormalities underlie diseases
such as developmental migration disorders/malformations, focal cortical
dysplasia, other epilepsy-associated lesions, neurodegenerative diseases,
and hypoxic/ischemic injury (see Chapters 25–27). The six layers of
the cortex, from the surface to the white matter, are I, the molecular
layer, which has very few neurons in adulthood; II, the outer granular
cell layer; III, the outer pyramidal cell layer; IV, the inner granular cell
layer; V, the inner pyramidal cell layer; and VI, the multiforme layer,
which is populated primarily by fusiform neurons. These layers are
more histologically apparent in some regions than others, often best
routine surgical neuropathology. Regions with primary output function,
such as primary motor cortex, have mostly pyramidal cells, whereas
regions with primarily integrating or sensory function contain mainly
granular cells. In either instance, dominance by a single cell type results
in less apparent layering due to a loss of architectural contrast. Regions
with nearly equal compliments of granular and pyramidal cells dem-
onstrate the most apparent horizontal layering.
Myelin staining of the cortex reveals parallel, horizontal bands of
myelinated fibers that are not as readily apparent on H & E stained
sections. The two most prominent bands are in layers IV and V, referred
to as the external and internal bands of Baillarger, respectively. Primary
visual cortex (Brodmann area 17), located on either side of the calcarine
fissure in the occipital lobe, is characterized by a greatly widened band
of Baillarger in layer IV due to the large input of visual afferent fibers
from the lateral geniculate nucleus (see Fig. 2.8B). This enlarged zone
divides layer IV into three distinct layers and can be seen grossly as
White Matter
The white matter of the CNS is relatively uniform (Fig. 2.9A). It is
generally more deeply eosinophilic than the overlying cortex, and its
matrix is coarser. Its architecture is dictated by the arrays of axonal
processes that extend to and from gray matter structures. Individual
axons themselves are difficult to appreciate on H & E sections of normal
brain because they are thin and blend with the background neuropil
(though they can be noted in disease states in which neuropil is dis-
rupted). However, neurofilament immunohistochemistry or silver stains
can highlight axons (Fig. 2.9B). Oligodendrocytes, fibrillary astrocytes,
and microglia are all oriented along the length of axons with a fairly
rigid periodicity. When viewed in the plane of white matter tracts, units
arrays along axonal processes and interrupted by single, interspersed
fibrillary astrocytes. Microglia are also located at regular intervals, albeit
with much less frequency than are oligodendrocytes, with cell bodies
oriented parallel to axons.
Basal Ganglia
The caudate, putamen, and nucleus accumbens (i.e., the neostriatum)
are developmentally related and histologically similar (Fig. 2.10A).
They contain a variety of small and large neuronal populations that
have relatively uniform density. About 95% are small and midsize
(10 to 18 µm) gamma-aminobutyric acid-ergic (GABAergic) spiny
neurons that provide projections to the globus pallidus (i.e., the paleo-
striatum). These have extensive dendritic trees packed with spines
for connection with the large array of input fibers from the cerebral
27
 Practical Surgical Neuropathology
Fig. 2.8  Cerebral cortex. (A) Cerebral neocortex
(isocortex) contains six layers, numbered sequentially
I I
from superficial to deep: I, molecular layer; II, external
II granular cell layer; III, external pyramidal cell layer; IV,
internal granular cell layer; V, internal pyramidal cell
II III layer; VI, multiforme layer. WM, White matter. (B) The
primary visual cortex of the occipital lobe has a distinc-
tive histologic arrangement. Cortical layer IV is greatly
IVa
expanded due to the high number of visual inputs and
is divided into layers IVa, IVb, and IVc. Prominent bands
III
IVb of Baillarger are present in layers IV and V in primary
visual cortex. The greatly expanded band of Baillarger
in layer IV can be seen grossly as the line of Gennari.
IVc

IV
V

V
VI

VI
WM
WM
A B

Fig. 2.9  White matter. (A) Sweeping linear arrays of

axons are the backbone of the white matter but cannot
be readily identified on hematoxylin and eosin stains.
Oligodendrocytes, astrocytes, and microglia are dispersed
linearly along the length of axons with a fairly rigid
periodicity. (B) Axons in the white matter are highlighted
in black by silver staining.

A B

cortex, thalamus, and brainstem. Other populations consist of large
cholinergic neurons (approximately 2% of neurons) and smaller cells
containing neuropeptide Y, somatostatin, or nitric oxide synthetase.
Interspersed among the neurons and neuropil of the striatum are small,
white matter bundles of the internal capsule that can only be seen
microscopically. These “pencil fibers of Wilson” are specific for this
region and serve as a guide to location when included in small biopsy
specimens.
posterior groups of nuclei. Not among these larger categories are the
midline, intralaminar, and reticular nuclei. The histologic appearance
of each lobe is relatively similar, with variations depending on specific
functions (see Fig. 2.10B). Thalamic neurons consist of two main types:
large projection neurons with axons that exit the thalamus (75% of the
neuronal population) and smaller, inhibitory (GABAergic) interneurons.
Each large projection neuron extends its process to the cerebral cortex
through the internal capsule.

Thalamus Hippocampus
The thalamus is the main integrator and relay of sensory information The hippocampal formation consists of the hippocampus proper, the
to the cortex and has over 50 individual nuclei, each with its own specific subiculum, and the dentate gyrus (i.e., dentate fascia) and is intimately
function. Classic divisions are the anterior, medial, ventrolateral, and associated with the entorhinal cortex (Fig. 2.11; see also Chapter 25).

28

A B
CA2
CA3
CA1
H is generally much more sensitive to hypoxia, toxicants, seizures, and
ALV
DF
SUB
Fig. 2.11  Hippocampal formation. The hippocampus proper consists of CA1, CA2, and
CA3 sectors of pyramidal neurons. CA1 continues as the subiculum (SUB) at the base
of the hippocampal formation. The dentate fascia (DF) contains a narrow, densely populated
band of granular cells (stratum granulosum) that surrounds the hilum (H) or CA4. The
major white matter tract emerging from the hippocampus is the alveus (ALV), located
between hippocampal pyramidal fields and the lateral ventricle.
The entorhinal cortex occupies most of the parahippocampal gyrus, is the
largest source of input into the hippocampus, and contains a distinctive
six-layered cortical architecture. Near its surface in layer II are numerous
large, round neuronal clusters that can be seen as small protrusions on
the brain’s surface. Deeper are the remainder of its six layers that contain
pyramidal cells and a diverse array of smaller neurons. The subiculum
Normal Brain Histopathology
Fig. 2.10  Basal ganglia and thalamus. (A) The caudate,
putamen, and globus pallidus contain a variety of
small and midsize neurons interspersed in a rich
2
neuropil. Pencil fibers of Wilson are small, white matter
bundles embedded within the gray matter neuropil
that are unique to these deep nuclei of the cerebrum
(arrow). (B) The thalamus has large projection neurons
as well as a less frequent population of smaller,
inhibitory interneurons.
sits at the base of the hippocampus and is a field populated largely by
pyramidal neurons with an allocortical arrangement that transitions
from the three-layered cortex of the hippocampal cornu ammonis 1
(CA1) subdivision at one end to the six-layered entorhinal cortex at the
other. The hippocampus is divided into CA1, CA2, and CA3 subfields,
each having distinct arrangements of pyramidal neurons and selective
vulnerabilities to disease. CA3 emerges from the hilum (i.e., CA4) of the
dentate gyrus and contains the largest pyramidal neurons. Pyramidal
neurons of CA2 form a narrow band that runs between CA1 and CA3.
Transition to CA1 is characterized by a wider band of slightly smaller
pyramidal neurons that are more dispersed. CA1 (i.e., Sommer sector)
degenerative diseases than are other subfields. The molecular layer of the
hippocampal CA fields faces the dentate gyrus, while its white matter
tracts form the alveus that runs along the space between the CA neurons
and the lateral ventricle. White matter tracts of the alveus converge to
form the fimbria of the hippocampus, which continues as the fornix,
traveling around the peripheral portions of the septum pellucidum of the
lateral ventricles to find their way to the hypothalamus and mamillary
bodies; this anatomic tract is also known as the circuit of Papez and
forms an important portion of the limbic system.
The densely packed smaller granular cells that form the C-shaped
structure of the dentate gyrus are the stratum granulosum. Hilar (or
CA4) neurons that occupy the inner space within the C-shaped structure
formed by the dentate fascia are a heterogeneous population of neurons
including large pyramidal and smaller interneurons.
Pineal Gland
The pineal gland has a unique morphology, unlike any other region
in the central nervous system (Fig. 2.12). At low magnification, it has
a lobulated arrangement with a prominent intralobular fibrovascular
and glial stroma. The cellular density of the normal pineal is greater
than most other brain regions, which together with the unusual archi-
tecture can lead to misinterpretation of this structure as a neoplasm.
The dominant cell type, the pineocyte is a midsize specialized neuronal
cell with round, regular “neuroendocrine” nuclei and delicate stippled
chromatin. Pineocytes contain moderate pale pink cytoplasm with
29
 Practical Surgical Neuropathology
* extension of the neurohypophysis, and the pars tuberalis, an extension
A central spaces noted, some containing mucinous or colloid content.
B Rathke cleft. In humans, it is not well developed and contains only
Fig. 2.12  Pineal gland. (A) The pineal gland (arrow) is located in the midline, posterior
and superior to the midbrain tectum (asterisk). (B) It consists of loose lobules of pineocytes
arranged in small clusters and linear arrays and separated by glial and fibrovascular
septae.
short processes and form small clusters and linear arrays. They stain
avidly with synaptophysin and neurofilament protein antibodies, the
latter of which often demonstrates small club-shaped swellings. At the
periphery of nests and surrounding blood vessels is a higher density of
fibrillarity. Interspersed among the nests and within the perivascular
region are the less common pineal astrocytes, which are highlighted with
GFAP stains.
Pituitary Gland
The relationship between normal pituitary histology and disease is also
covered in Chapter 20. Nonetheless, the pituitary gland is composed
of anterior, intermediate, and posterior lobes (Fig. 2.13). The anterior
and intermediate lobes (adenohypophysis) have differing embryology,
functions, and microscopic appearances than does the posterior lobe
(neurohypophysis). The adenohypophysis is not of neuroectodermal
origin, but rather is derived from oral ectoderm that invaginates
superiorly as Rathke pouch to eventually find its place within the sellar
compartment. Notwithstanding their non-CNS origin, diseases of the
sellar space often affect neurologic function.
30
The pituitary gland is connected to the more superior hypothalamus
by the pituitary stalk, which is composed of the infundibulum, a superior
of the anterior gland. The stalk also carries a functionally vital vascular
supply between hypophyseal and hypothalamic compartments. Arterial
supplies to the pituitary are the inferior and superior pituitary arter-
ies, which branch from each internal carotid artery. These give rise
to a network of capillary loops within the gland (gomitoli), which in
turn lead to a substantial network of venous sinuses that drain back
to the hypothalamus, carrying vital hormonal feedback. Thus, the
vascular network of the pituitary is extensive and critical to endocrine
function.
The anterior pituitary accounts for over 75% of the sellar volume. It
is composed of variably sized nodules or acini interrupted by stromal
and vascular septa (see Fig. 2.13A and B). Most are filled with cellular
elements and lack appreciable lumina. Only occasionally are glands with
Stroma surrounding individual acini can be highlighted by reticulin stains,
a helpful adjunctive test for establishing a normal glandular arrangement
and ruling out an adenoma. Individual cells of the anterior lobe can be
classified as acidophils (40%), basophils (10%), and chromophobes (50%)
based on their hematoxylin and eosin staining. However, these staining
patterns are not sufficiently specific to predict endocrine function or
hormone production. Rather, glandular cells are more often classified
based on their immunohistochemical staining properties as lactotrophs
(prolactin), thyrotrophs (thyrotrophic hormone, TSH), somatotrophs
(growth hormone, GH), corticotrophs (adrenocorticotrophic hormone,
ACTH), or gonadotrophs (follicle-stimulating hormone, FSH; luteinizing
hormone, LH; or the steroidogenic transcription factor, SF1). Whereas
gonadotrophs are diffusely spread throughout the gland with even density,
other hormone-producing cells show regional variation. Corticotrophs
and thyrotrophs are located in highest density within the central portion
of the gland, while laterally, lactotrophs and somatotrophs are in highest
density.
The thin intermediate lobe of the pituitary is derived from the posterior
glandular and colloid-filled cystic remnants within a slightly fibrous
stroma. Individual cells are cuboidal or columnar, some with apical
cilia, others containing cytoplasmic mucin (Fig. 2.13E). When large
or clinically symptomatic, these cystic spaces are termed Rathke
cleft cysts.
In distinction to the glandular anterior lobe, the posterior pituitary,
or neurohypophysis, is an extension of the CNS and has a “neural”
histology (Fig. 2.13C). It is composed of neuronal processes that
extend from their cell bodies in the hypothalamus down the pituitary
stalk (infundibulum) to occupy the posterior portion of the sella and
terminate near blood vessels. Scattered in the neuropil are Herring
bodies—subtle eosinophilic axonal dilations that are filled with lysosomes
and neurosecretory granules containing vasopressin and oxytocin (Fig.
2.13D). The most prominent nucleated cells of the neurohypophysis
are pituicytes—GFAP and thyroid transcription factor 1 (TTF1)-
expressing spindle or stellate glial cells that abut the basal lamina of
blood vessels. Their cytoplasm engulfs the nerve terminals and regulates
the release of hormones into the bloodstream. The overall histology of
the neurohypophysis is complex, with a seemingly disorganized cell
arrangement that includes sweeping axonal processes punctuated by
more cellular perivascular regions, occasionally causing confusion with
neoplastic disease.
Cerebellum
Although the circuitry of the cerebellar cortex is exceedingly intricate, its
histologic appearance is homogeneous and relatively simple throughout
 Normal Brain Histopathology

A B

C D
Fig. 2.13  Pituitary gland. (A, B) The anterior pituitary gland consists of tightly packed
acini of acidophils (pink), basophils (blue), and chromophobes (amphophilic) separated
by a fine fibrovascular stroma. (C) The posterior pituitary (neurohypophysis) is formed
by the axonal projections of neurons from the hypothalamus together with primary
glial cells, pituicytes, which are most commonly located in a perivascular distribution.
(D) Eosinophilic axonal dilations that store neurosecretory peptides (Herring bodies,
arrow) can be seen distributed throughout the posterior gland. (E) The intermediate
lobe is small and often shows mild fibrosis and contains cysts lined by flattened,
Rathke-type epithelium.

(Fig. 2.14). Outermost is the molecular layer, a rich neuropil network
containing abundant axonal and dendritic processes, but only a few
small neuronal cell bodies. The Purkinje cell layer is at the junction
of the molecular layer and the deeper internal granular cell layer (see
Figs. 2.1E and 2.3G arrows). Purkinje cells are large neurons that have
widely arborizing dendritic trees that extend into the molecular layer,
serving as synaptic input for the parallel fibers of the granular cells.
Purkinje cell axons are the main output of the cerebellar cortex, and a
majority have their termination on the neurons of the dentate nucleus.
Granular cells of the cerebellum are the most common neuronal cell in
the CNS and are present in high density central to Purkinje cells. Each
granular cell sends an axon to the molecular layer, which then bifurcates
to form the parallel fibers that synapse with numerous Purkinje cell
dendritic trees.

31
 Practical Surgical Neuropathology

WM RN

SNc
GCL ML

PCL SNr

Fig. 2.14  Cerebellum. The cerebellar cortex contains a sparsely cellular molecular layer
(ML), a Purkinje cell layer (PCL), a granular cell layer (GCL), and white matter (WM).
A CP

The deep cerebellar nuclei are set on either side of the midline
cerebellum in the midst of white matter tracts of the medullary center
that are entering and leaving cerebellar cortex. These are seen as thin,
undulating ribbons of gray matter containing large and small neurons
that encircle a central zone of white matter tracts that project out of the
cerebellum. The largest and most lateral nucleus is the dentate nucleus,
which has both developmental ties and morphologic similarity to the *
inferior olive of the medulla. It is the source of most efferent signals
traveling out of the cerebellum via the superior peduncle. The other deep
cerebellar nuclei, from lateral to medial, are the emboliform, globose, and
fastigial nuclei, although they are hard to recognize in routine sections.

Brainstem
Throughout the brainstem, anatomic regions are broadly subdivided
B
in the ventral to dorsal direction as base, tegmentum, and tectum. The
base is located ventrally and consists mostly of long white matter tracts
(cerebral peduncles, basis pontis, and medullary pyramids). The teg-
mentum lies dorsal to the base and ventral to the cerebral aqueduct or
fourth ventricle. Among other structures, it contains the reticular forma-
tion, a centrally located, relatively uniform gray matter that lacks strict
organization and boundaries, but is critical to the control of basal bodily
activities, including cardiovascular tone, respiration, and consciousness.
The tectum is the area located dorsal to the brainstem ventricular
compartments, serving as their roof. Together, the tectum and tegmentum
house most of the cranial nerve nuclei and also provide much of the
integrative function of the brainstem.
The locations of cranial nerve nuclei display the same general pattern
throughout the brainstem. Nuclei are located in the dorsal tegmentum
in the vicinity of the fourth ventricle. Motor nuclei are located medially,
sensory nuclei are located laterally, and the autonomic nuclei are found
between them. C
Midbrain Fig. 2.15  Brainstem. (A) In the midbrain, the substantia nigra is composed of the reticulata
At the most ventral aspect of the midbrain are the large cerebral (SNr), which resembles basal ganglia histologically, and the compacta (SNc), which contains
a high density of large pigmented dopaminergic neurons. Ventral to the SNr is the cerebral
peduncles, the dense white matter bundles on either side composed
peduncle (CP) and dorsal to the SNc in the superior midbrain is the red nucleus (RN).
predominantly of inferiorly projecting corticospinal and corticopontine (B) The base of the pons contains numerous, prominent pontine crossing fibers (arrow)
fibers. Immediately dorsal is the substantia nigra (SN), a thin strip that that intertwine with pontine nuclei (asterisk) and descending fibers (arrowhead), including
extends laterally and dorsally from the midline and contains large, heavily corticospinal tracts (Luxol fast blue stain). (C) The medulla contains the inferior olivary nucleus
pigmented dopaminergic neurons (see Fig. 2.1G; Fig. 2.15A). Of note, (arrow), which like the related dentate nucleus in the cerebellum is made of a thin ribbon
of undulating gray matter surrounding a white matter hilum (Luxol fast blue/PAS stain).
32

the cytoplasmic accumulation of neuromelanin in nigral neurons does
not reach sufficient levels for gross detection of pigmentation until
adolescence; therefore, the nonpigmented nigra of children should not be
confused with the depigmented counterpart resulting from neuronal loss
in Parkinson disease later in life. In the midline between the right and
left SN is the ventral tegmental area, where there is a functionally discreet
population of pigmented dopaminergic neurons. The red nuclei are paired,
round gray matter structures dorsal to the SN in the rostral midbrain.
Around the ependymal-lined cerebral aqueduct is the periaqueductal
gray matter, a collection of neurons involved in pain modulation. The
midbrain tectum is almost entirely composed of inferior and superior
colliculi, while the tegmentum contains predominantly white matter
structures.
Pons
The pons is dominated by its large base (basal pons or basis pontis) and
by its large white matter connections to the cerebellum—the superior,
middle, and inferior cerebellar peduncles. The basal pons consists of
both transversely and longitudinally oriented white matter tracts (see
Fig. 2.15B). Longitudinal fibers include corticospinal tracts that continue
as the medullary pyramids inferiorly and corticopontine tracts that
terminate on the interspersed pontine nuclei. The eye-catching transverse
fibers represent white matter bundles arising from pontine nuclei, crossing
the midline, and entering the cerebellum via the middle cerebellar
peduncle. Near the fourth ventricle on each side of the pons is the locus
ceruleus (“blue spot”), a small nucleus containing a high density of
pigmented, noradrenergic neurons that project diffusely throughout
the CNS. Near the midline throughout the brainstem, but concentrated
mostly in the dorsal pons, are the midline raphe nuclei (midline “seam”).
These nuclei contain large serotonergic neurons that project extensively
throughout the brain.
Medulla
Anterior in the medulla are the paired medullary pyramids, which
carry corticospinal tracts to their decussation at the medullary-spinal
junction, then continue as the lateral corticospinal tracts in the spinal
cord. Posterior to the pyramids in the midline is the medial lemniscus,
a white matter tract projecting from the contralateral nucleus cuneatus
and gracilis. More lateral in the rostral medulla are the dominant
olivary nuclei, seen as bulges (olives) on the anterolateral medullary
surface (see Fig. 2.15C). This ovoid structure consists of a ribbon of
convoluted gray matter with large pyramidal-type neurons surrounding
a hilus of outwardly projecting white matter tracts that extend to the
contralateral cerebellar peduncle. The olivary nucleus is developmentally
and functionally related to the cerebellar dentate nucleus and bears
resemblance to it histologically. Posteriorly, the fasciculus gracilis and
cuneatus are continuations of the posterior columns and terminate
in the nucleus gracilis and nucleus cuneatus, respectively. The medial
longitudinal fasciculus is a white matter tract that rides the midline
dorsally, while the spinothalamic tract maintains its anterolateral
position in the brainstem, immediately dorsal to the olive in the
medulla.
Spinal Cord
The spinal cord has the same basic histologic organization throughout
its length, with unique features superimposed at specific spinal levels
(Fig. 2.16). On cross section the cord contains central gray matter in
the shape of an H and surrounding white matter tracts. The white
matter tracts are functionally diverse and precisely organized in terms
of sensory and motor function. Nonetheless, they are fairly uniform
in histologic cross sections, showing mostly bundles of myelinated and
unmyelinated fibers traveling in the superior–inferior direction with
Normal Brain Histopathology
VR
ASA 2
AH
IML
PH CC
WM
DR SG
LT
FG
Fig. 2.16  Spinal cord. Cross section of the thoracic spinal cord shows anterior horns
(AH), posterior horns (PH), intermediolateral cell columns (IML), white matter (WM),
the ependymal-lined central canal (CC), substantia gelatinosa (SG), Lissauer tract (LT),
the fasciculus gracilis (FG) of the dorsal columns, anterior spinal artery (ASA), ventral
roots (VR), and dorsal roots (DR).
scattered oligodendrocytes and fibrillary astrocytes. Anterior horns are
the ventral extensions of the H-shaped gray matter and contain the
large anterior horn cells (lower motor neurons) and smaller gamma
motor neurons, which innervate muscle spindles. Anterior horns are
largest and contain the greatest number of lower motor neurons at the
cervical and lumbar enlargements due to their output to the upper
and lower extremities, respectively. The posterior horn contains large
projection neurons and smaller interneurons. The substantia gelatinosa is
a posteriorly located portion of the posterior horn that is distinguished
by its lack of myelinated fibers, giving rise to its pale appearance. It
continues dorsally into the Lissauer tract, another poorly myelinated
region of white matter.
The gray matter region between anterior and posterior horns
contains cells of the autonomic nervous system. Between levels T1
and L3 is located the intermediolateral cell column, which extends off
the central gray matter as a lateral horn. It contains the cell bodies
of preganglionic sympathetic neurons, which project out through the
ventral roots. The intermediate zone from S2 to S4 contains mostly a
parasympathetic neuronal population. Lastly, Clarke nucleus is a medial
extension of the intermediate gray matter found from spinal levels T1 to
L2. It contains large neurons important to sensory processing with the
cerebellum.
Meninges
The dura mater has a histologic appearance unlike any other region of the
nervous system (Fig. 2.17). It consists of a thick, monotonous layer of dense
fibrous connective tissue composed mostly of layered collagen with only
scattered interspersed flattened fibroblasts. Because its appearance is so
reliable, its identification within a histologic section ensures the pathologist
that the location of the surgically sampled lesion was superficial (i.e., near
or involving the dural covering); nonetheless, some caution is warranted
because markedly fibrotic leptomeninges may occasionally approach
the thickness of dura. Normally, however, the arachnoid membranes
that traverse the space between dura and underlying brain contains the
arachnoid trabeculae, which are a delicate meshwork of thin connective
tissue containing flattened fibroblast-like cells, scattered meningothelial
cells, and rare melanocytes (see Fig. 2.7; Fig. 2.17B). The most superficial
33
 Practical Surgical Neuropathology
A B
Fig. 2.17  Meninges. (A) The dura mater is a thick, dense fibrous connective tissue covering for the brain with low cellularity. (B) The arachnoid membranes are delicate fibrous
bands (arrow) that traverse the subarachnoid space (asterisk), embed subarachnoid vessels, and have attachments to both underlying pia and overlying dura. (C) The pia mater
(arrow) is a thin, fine coating on the surface of the brain that is brightly eosinophilic and merges with the arachnoid.
layer of cells (arachnoid cap cells) forms a continuous lining that is
tethered to the overlying dura and forms a restrictive barrier to the flow
of fluids between the subarachnoid space and the dura. Normally, there
is in fact no subdural space per se, but these relatively weak attachments
between arachnoid and dura are easily disrupted or pealed back by
hemorrhage (e.g., subdural hematoma) or “unnatural” forces, such as
the prying hands of a surgeon or pathologist. The pial layer is found
on the surface of the brain as a delicate fibrous coating that is slightly
eosinophilic compared to the underlying cortex and contains only rare
small flattened cells (Fig. 2.17C). It extends peripherally to fuse with
the overlying arachnoid trabeculae to form a continuous pia–arachnoid
network.
Peripheral Nerve, Schwann Cells, and Dorsal Root Ganglia
Within millimeters of their exit from the central nervous system, both
cranial nerves and spinal nerve roots transition from a central to a
peripheral nerve morphology and myelinating pattern (with the exception
of cranial nerve VIII, which transitions at the internal auditory meatus)
(see also Chapter 15). Schwann cells are the glial cell equivalents of the
peripheral nervous system that provide an insulating coat of myelin
around axons to improve conduction speeds (Fig. 2.18A). Larger (e.g.,
sural) nerves typically have multiple subunits known as fascicles, which
appear rounded on cross section and consist of ensheathed bundles of
myelinated and unmyelinated axons, along with Schwann cells, small
blood vessels, and stromal support. Together with peripheral nerve
fibroblasts and the collagen-rich network of endoneurium (within the
fascicle), perineurium (surrounding individual fascicles), and epineurium
(surrounding the entire nerve), Schwann cells provide structural support
to their underlying axonal processes. In contrast to oligodendrocytes,
the myelin-rich cytoplasm of a single Schwann cell is flattened and
concentrically laminated around a segment of a large axon at specific
intervals between nodes of Ranvier. In standard H & E stained tissue
sections, Schwann cells are the most numerous cell bodies within
peripheral nerves and are seen in longitudinal sections as elongate,
34
*
C
spindled cells containing thin, wavy hyperchromatic nuclei. On cross
section of nerve, their myelin-rich coating is seen as a clear, donut-
shaped ring around a central, tiny, eosinophilic axon (Fig. 2.18B). Stains
for myelin (Luxol fast blue) dramatically improve the visibility of the
myelin sheath.
Dorsal root ganglia are located near the spinal exit foramina, invested
within a dural sheath, and are the home of cell bodies for spinal affer-
ent sensory neurons. Individual cell bodies of ganglion cells are large,
with abundant cytoplasm, Nissl substance, prominent vesicular nuclei,
large nucleoli, and variable quantities of cytoplasmic lipofuscin pigment
(Fig. 2.18C). Peripheral extensions terminate in transducing sensory
receptors that give rise to incoming signals. Large, long processes
extend centrally via the dorsal roots into the spinal cord, with the
largest myelinated tracts becoming the ascending posterior columns.
Around the perimeter of each ganglion cell body are flattened satellite
cells (specialized Schwann cells), which most likely serve a support role
and provide a committed stem cell source for repopulation of their more
peripheral progeny.
Features of Infancy and Childhood
The germinal matrix is a neural stem cell population that is adjacent to
the lateral ventricles as a subependymal layer and gives rise to sequentially
differentiated neuronal and glial precursors that migrate to their homes
in the cerebrum (Fig. 2.19A). The germinal matrix is prominent in early
brain development and does not begin to thin out until the 26th week
of gestation. The matrix persists as scattered cell islands and perivascular
nests until term. After birth, most of the germinal matrix disappears
except for a portion called the ganglionic eminence, which is located
between the thalamus and caudate. It fragments and diminishes in size
throughout the first year of life.
The cerebral cortex derives from neuroblasts that migrate outwardly
along radial glia from the germinal matrix. The innermost neurons of
the cortex are the first to arrive and are subsequently joined by neuroblasts
migrating to progressively more superficial regions. By the 5th month
 Normal Brain Histopathology

A B C
Fig. 2.18  Dorsal root ganglia and peripheral nerve. (A) Peripheral nerve in longitudinal plane showing bundles of axons (arrow), which are only barely visible within their thicker,
clear myelin sheath. Schwann cells have elongate nuclei with slightly bulbous ends and are oriented along the length of the axon to provide its myelination. (B) On transverse
section of peripheral nerve, the clear ring of bubbly myelin is seen surrounding a central eosinophilic structure representing the axon (arrow). (C) Each large neuronal cell body
(ganglion cell) of the dorsal root ganglion is surrounded by satellite cells, a specialized Schwann cell population.

ML

LV

EGCL
E

CC
ML
GM

IGCL WM
A B WM C
Fig. 2.19  Features of development and infancy. (A) The germinal matrix (GM) is a periventricular precursor cell population located directly adjacent to the ependyma (E) of the
lateral ventricles (LV). Although heavily populated by neural precursors during fetal development, it diminishes and eventually disappears in the first year of postnatal life (germinal
matrix of 20-week-gestation fetus). (B) The cerebral cortex undergoes gradual lamination during fetal development, with individual layers emerging in the 5th month of gestation.
The cortex of a 30-week-gestation fetus shows a clearly formed molecular layer (ML), initial separation of cerebrocortical layers (CC), and demarcation of the cortex from white
matter (WM). (C) The fetal and infant cerebellum contains an external granular cell layer (EGCL, arrow), which is a precursor cell population that migrates inward through the
molecular layer (ML) to form the internal granular cell layer (IGCL) (cerebellum of 6-week-old infant).

of fetal development, the cortex shows a superficial molecular layer and
a deeper, densely cellular band (Fig. 2.19B). From the latter, a six-layered
cortex gradually emerges starting in the 6th month. Cortical layering
results from the maturation of cortical laminar neurons, the selective
cell death of neuronal populations, and expansion of the neuropil due
to the growth of dendritic fields.
Cerebellar cortical development occurs along two major pathways.
The Purkinje cells form early in embryonic life after migrating to their
final location from the alar plate. Granular cells develop from the rhombic
lip. They first form a precursor population as the external granular cell
layer, which is located at the surface of the cerebellar folia, superficial
to the molecular cell layer. External granular cells are actively dividing

35
 Practical Surgical Neuropathology
and give rise to inwardly migrating cells that then mature and form the Table 2.1  Nonpathologic Features of Normal Aging
internal granular cell layer, the granular cell population that persists in Neurons
adulthood (Fig. 2.19C). Although the external granular cell layer begins
Neurofibrillary tangles
to diminish 2 to 3 months after birth, it does not totally disappear until Granulovacuolar degeneration
12 months after birth. Hirano bodies
Neuritic plaques
Features of the Aging Nervous System Ferrugination
A wide range of histologic features may be encountered in the aging Marinesco bodies
nervous system, often becoming most prominent in elderly patients; Lipofuscin accumulation
they are summarized in Table 2.1 and illustrated in Figs. 2.20 and 2.21. Pigment incontinence of substantia nigra
Recognition of these structures is critical to avoid misinterpreting them Glial
as pathologic. In the case of neurofibrillary tangles (Fig. 2.21A) and Corpora amylacea adjacent to ependyma, subpial regions, and vasculature
neuritic plaques (Fig. 2.21B), the distinction between normal aging
Meninges
and disease becomes a matter of quantity and location. Whereas small
numbers of tangles in the mesial temporal lobe are considered part of Fibrous thickening
normal aging, widespread neocortical involvement is a sign of Alzheimer Hyaline plaques
disease (AD) and extensive subcortical deposits are characteristic of other Arachnoid granulation collagenization (Pacchionian bodies)
Meningothelial hyperplasia (reactive proliferation)
neurodegenerative disorders such as progressive supranuclear palsy (see
Psammoma body formation
Chapter 27). In fact, the precise number and type of neuritic plaques
(and tangles) needed for a definitive diagnosis of AD has been a topic of Pituitary Gland
great debate over the years, although fortunately most cases of advanced Squamous cell metaplasia of pars tuberalis
disease contain numerous widespread plaques and tangles, making the Adenohypophyseal fibrosis
diagnosis relatively simple. Similarly, while corpora amylacea (Fig. 2.20A) Other
are extremely common and are considered totally innocuous, similar
Perivascular mineralization, globus pallidus
structures may be seen within neuronal cells or their processes in rare
Micronodular mineralization, globus pallidus, and hippocampal molecular layer
disorders such as Lafora disease and adult polyglucosan body disease. Choroid plexus mineralization and cystic change
Pineal mineralization and cystic change

A B
Fig. 2.20  Findings of normal aging. (A) Corpora amylacea (arrow) are spherical basophilic polyglucosan bodies that accumulate as astrocytic inclusions during the aging process.
Their highest density is around blood vessels, under the pial surface, and adjacent to the ventricles—locations where astrocytic foot processes are most common. These eye-catching
laminated bodies are not always recognized as being intracellular, and they can accumulate to striking densities during aging. (B) Perivascular mineralization of the large vessels
of the globus pallidus is a common aging process and can begin as early as childhood (arrow).

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 Normal Brain Histopathology

C D E
Fig. 2.20, cont’d  (C) Microvascular mineralization also occurs with increasing age and is seen most frequently in the hippocampus and the basal ganglia (arrow). (D) The arachnoid
membranes become thicker and more fibrous with age. (E) Fibrohyaline plaques are thick, densely hyalinized forms of fibrosis that occur in the most superficial layer of the arachnoid
membranes. These are noted most often over the median aspects of the superior frontal and parietal lobes and covering the spinal cord.

A B C
Fig. 2.21  Findings that may occur in limited fashion in normal aging. (A) Neurofibrillary tangles are slightly basophilic, crystalline inclusions that fill the neuronal cytoplasm, generally
taking the shape of a flame (arrows). (B) Amyloid plaques represent the extracellular accumulation of beta-amyloid that deposits in Alzheimer disease and, to a lesser extent, in
the normal aging process (arrow). (C) Granulovacuolar degeneration consists of small cytoplasmic vacuoles and basophilic granules and is noted most often in the hippocampal
pyramidal cells of elderly individuals (arrows).

Suggested Readings Ortiz-Hildago C, Weller RO. Peripheral nervous system. In: Mills SE, ed. Histology for Pathologists.
Felten DL, O’Banion MK, Maida MS. Netter’s Atlas of Neuroscience. 3rd ed. Philadelphia, PA: Elsevier; 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012.
2016. Vanderah TW, Gould DJ. Nolte’s The Human Brain: An Introduction to Its Functional Anatomy. 7th
Fuller GN, Burger PC. Central nervous system. In: Mills SE, ed. Histology for Pathologists. 4th ed. ed. Philadelphia, PA: Elsevier; 2016.
Philadelphia, PA: Lippincott Williams & Wilkins; 2012.
Lopes MBS, Pernicone PJ, Scheithauer BW, et al. Pituitary and sellar region. In: Mills SE, ed. Histology
for Pathologists. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012.

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