Ebook Escourolle poirier’s manual of basic neuropathology Part 1

(BQ) Part 1 book Escourolle poirier’s manual of basic neuropathology presentation of content: Basic pathology of the central nervous system, tumors of the central nervous system, central nervous system trauma, neuropathology of vascular disease, human prion diseases,... and other contents.

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3

Oxford University Press is a department of the University of Oxford

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© Françoise Gray, Charles Duyckaerts, Umberto De Girolami 2014

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Library of Congress Cataloging-in-Publication Data

Escourolle & Poirier’s manual of basic neuropathology / [edited by] Françoise Gray, Charles Duyckaerts, Umberto De Girolami ; foreword by Martin A Samuels – 5th ed.

p ; cm.

Escourolle and Poirier’s manual of basic neuropathology

Manual of basic neuropathology

Rev ed of: Escourolle & Poirier’s manual of basic neuropathology / Françoise Gray, Umberto De Girolami, Jacques Poirier c2004 Includes bibliographical references and index.

ISBN 978–0–19–992905–4 (alk paper)—ISBN 978–0–19–933048–5 (alk paper)—ISBN 978–0–19–933049–2 (alk paper)

I Gray, Françoise II Duyckaerts, C III De Girolami, Umberto IV Escourolle, Raymond, 1924– V Gray, Françoise Escourolle

& Poirier’s manual of basic neuropathology VI Title: Escourolle and Poirier’s manual of basic neuropathology VII Title: Manual of basic neuropathology

[DNLM: 1 Central Nervous System Diseases—pathology WL 301]

9 8 7 6 5 4 3 2 1

Printed in the United States of America

on acid-free paper

6 Human Prion Diseases 149

James W. Ironside, Matt hew P. Frosch, and Bernardino Ghett i

7 Multiple Sclerosis and Related Infl ammatory Demyelinating Diseases 161

Hans Lassmann, Raymond A. Sobel, and Danielle Seilhean

8 Pathology of Degenerative Diseases of the Nervous System 173

Charles Duyckaerts, James Lowe, and Matt hew Frosch

2 Tumors of the Central Nervous System 20

Keith L. Ligon, Karima Mokhtari, and

Th omas W. Smith

3 Central Nervous System Trauma 59

Colin Smith

4 Neuropathology of Vascular Disease 76

Jean-Jacques Hauw, Umberto De Girolami, and

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12 Pathology of Skeletal Muscle 278

Hart G W Lidov, Umberto De Girolami, Anthony A Amato, and Romain Gherardi

13 Pathology of Peripheral Nerve 313

Jean-Michel Vallat, Douglas C Anthony, and Umberto De Girolami

14 Diseases of the Pituitary Gland 343

Vânia Nosé and E Tessa Hedley-Whyte

Appendix: Brief Survey of Neuropathological Techniques 365

Homa Adle-Biassett e and Jacqueline Mikol

Index 379

9 Acquired Metabolic Disorders 205

Leila Chimelli and Françoise Gray

10 Hereditary Metabolic Diseases 227

Frédéric Sedel, Hans H. Goebel, and

Douglas C. Anthony

11 Congenital Malformations and

Perinatal Diseases 257

Féréchté Encha-Razavi, Rebecca Folkerth,

Brian N. Harding, Harry V. Vinters, and

Jeff rey A. Golden

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brain could react to disease My roadmap in this new

terrain was the then-new litt le blue book, Escourolle

and Poirier’s Manual of Basic Neuropathology My

heavily worn copy remains on my bookshelf

A  second edition appeared in 1977 and a third in

1989, with Françoise Gray succeeding Raymond Escourolle, who had died in 1984 Th en, aft er a lon-ger interval, Umberto De Girolami joined Françoise Gray and Jacques Poirier for the fourth edition, pub-lished in 2003 In the foreword to the fourth edition

I noted how dependent I was on the original manual and bemoaned the loss of intense neuropathology training in the making of modern neurologists

In the past decade, neuroimaging and lar medicine have become even greater parts of the routine life of the clinician At our daily morn-ing report conferences, it is diffi cult to prevent our residents from showing the images fi rst, skip-ping the history and the neurological examination entirely Some have even argued that listening

molecu-to the patient, performing a careful neurological examination, and trying to localize the lesion have

It has been a decade since the previous edition of

the Manual of Basic Neuropathology was published

in 2003 In 1971, Raymond Escourolle and his

student, Jacques Poirier, published a book on the

basic aspects of neuropathology, the English

ver-sion of which was translated by Lucien Rubinstein

and published in 1973 I  was in the midst of my

neurology residency at the time and on July 1,

1973, I was embarking with trepidation on a year of

neuropathology, a requirement of my training

pro-gram in that era Knowing only the pathology that

I  had learned in medical school and having

virtu-ally no concept of neuropathology, I  found myself

immersed in an alien world Litt le did I  know that

this was to be one of the most infl uential years in my

career Th e ritual of removing the brains, obtaining

the appropriate sections for microscopic analysis,

and wading through the slides converted me from

an internist into a neurologist Neuropathology was

the basic science of clinical neurology I learned how

to correlate clinical symptoms and signs with fi

nd-ings in the brain and the various ways in which the

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For the fi ft h edition of the Manual , the

distin-guished neuropathologist Charles Duyckaerts, himself an expert in neurodegenerative diseases, par-ticularly Alzheimer’s disease, joins Drs Gray and De Girolami as the editors Over 30 additional experts have writt en authoritative but characteristically brief and clear chapters on the full array of major topics in the fi eld Th e organization of the book remains reas-suringly unchanged Th e fi rst chapter reviews the basic pathology of the nervous system, followed by chapters on tumors, trauma, vascular diseases, and infections A separate chapter deals with the increas-ingly important prion diseases, followed by chap-ters on multiple sclerosis, degenerative disorders, acquired metabolic diseases, hereditary metabolic diseases and congenital malformations, and peri-natal diseases Separate chapters follow on skeletal muscle, peripheral nerve, and the pituitary gland

Th e book ends with a modernized survey of pathology techniques

Th is newly updated version of a truly venerated book will be valued by students, trainees, and practi-tioners in all of the fi elds related to the nervous sys-tem, including neurology, neurosurgery, psychiatry, neuroradiology, neuroendocrinology, neuropathol-ogy, and neuroscience Th e new edition will have

an honored place on my bookshelf, right next to the litt le blue book that got me started over 40 years ago

Martin A. Samuels, MD, DSc (hon),

FAAN, MACP, FACP Chairman, Department of Neurology, Brigham and Women’s Hospital Professor of Neurology, Harvard Medical School

Boston, Massachusett s, USA

become quaint fossils of times past Th is has led

to a new problem, the “incidentaloma,” a fi nding

on imaging or other testing that is unrelated to the

patient’s actual problem Th e only way to put

“inci-dentalomas” in perspective and to prevent harm

to patients is to fully understand what is actually

possible in the nervous system; in other words,

neuropathology

Other powerful societal forces aimed at saving

time and money have put pressure on the eff ort

it takes to think through complex patient

prob-lems carefully and to correlate them rigorously

with the real pathology found in the nervous

sys-tem Fortunately for us, Umberto De Girolami has

championed the continuing need to use

modern-ized neuropathology as a powerful tool for bett er

patient care and for progress in understanding the

causes of diseases of the nervous system His

suc-cessor as Chief of Neuropathology at the Brigham,

Rebecca Folkerth (a co-author of the chapter on

congenital malformations and perinatal diseases,

in the Manual ), has continued this tradition Each

week at our neuropathology conference we are

impressed with how much is learned from the

neu-ropathological analysis of patients, whether that be

autopsy or biopsy material With the prudent

appli-cation of modern techniques, including molecular

and genetic analysis, we repeatedly learn that we

oft en did not have a full grasp of clinical problems,

even with the most skilled application of modern

technology

My own clinical practice and education is

contin-uously in fl ux based largely on the refl ection on our

clinical analysis using the powerful tools of modern

neuropathology

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Th is fi ft h edition of the Manual att empts to

delib-erately maintain the general intention of the fi rst and subsequent editions of Professors Escourolle and Poirier’s monograph—that is, to provide a basic description of the lesions underlying the diseases of the nervous system and to limit pathophysiological considerations to essential principles Historical, clinical, neurological, and radiologic imaging data, once again, are specifi cally excluded, as well as refer-ence listings, while recognizing this to be essential information for the erudite and informed practice

of neuropathology Our premise, however, has been that it would be presumptuous for us to do justice to this vast body of information, well beyond the scope

of a basic overview of neuropathology We also have made the assumption that the reader has some familiarity with general concepts of neuroanatomy, neurohistology, and the principles of anatomical pathology as well as clinical neurology

With these guidelines in mind, our aim has been

to produce a text that mainly presents those aspects

of neuropathology that are morphologic, and to

Elémentaire de Neuropathologie , published in 1971

and 1977, were conceived, writt en, and edited by

Raymond Escourolle and Jacques Poirier Aft er

the death of R. Escourolle in 1984, Françoise Gray

joined Jacques Poirier for the third edition; in

addi-tion, Jean-Jacques Hauw and Romain Gherardi

contributed to selected chapters Th e fi rst three

edi-tions reached the English-speaking public thanks

to the friendship and translating ability of the

now-deceased Lucien Rubinstein For the fourth

edition, Umberto De Girolami joined as co-editor

and the scope of the monograph was expanded

with the collaborative eff orts of multiple experts

throughout the world to write the English-language

text Jacques Poirier is now retired, and we are

delighted that Charles Duyckaerts has agreed to join

the editorial team for the fi ft h edition Th ere have

also been some changes in the authorship of several

chapters in response to the changing status of senior

authors and the need to recruit active investigators

to replace them

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degenerative and metabolic disorders, mental disorders, and neuromuscular diseases Morphologic neuropathological data, obtained

develop-at biopsy or develop-at postmortem examindevelop-ation, fore need to be integrated with this new knowl-edge for the reinterpretation and reclassifi cation

there-of many diseases For example, cal information obtained at biopsy, combined with molecular biology and genetic data, is now required for the diagnosis, prognosis, and guid-ance of the choice of treatment modalities for cerebral tumors

• Lastly, an urgent responsibility to present an updated synopsis of neuropathology is that this knowledge is important to allied disciplines, as there is a constant need for surveillance of newly recognized diseases, including iatrogenic ones

We need to thank fi rst of all Susan Pioli, who although now retired from the publishing business was instrumental in the prior edition and led us to Craig Panner with Oxford University Press, who has given fundamental support Secondly, we thank the contributing authors and their staff for the text and illustrations provided in this new edition

In the Introduction to the First Edition, Professors Escourolle and Poirier off ered an apology

to the reader that is still valid 40 years later:

Th e compilation of a basic work designed to iarize physicians-in-training with such a highly specialized discipline as Neuropathology entails two opposing risks:  in att empting to compress the maximum amount of information within the minimum space, the text is liable to become unin- telligible to beginners; if on the contrary, one tries to maintain too elementary a level, the danger is that only the obvious will be stated In presenting to the non-initiated reader neuropathological informa- tion that some may fi nd too simple, we have pre- ferred the hazard of the second pitfall

Françoise Gray Charles Duyckaerts Umberto De Girolami

demonstrate these with accurate descriptions and

good illustrations, all within the scope of a concise

and inexpensive “manual.”

For several reasons, we think that the time is now

right for a new edition since the last one in 2003

Over the past decade, specialty training in

neu-rology, neurosurgery, and pathology has changed

throughout much of the world, such that in these

disciplines less time is being devoted to

neuro-pathology Th is has been due in large part to the

tremendous expansion of knowledge in allied

sub-specialty areas, requiring that more time be devoted

to them As a result, the trainee is now very much in

need of a concise introductory text

In addition, several other important changes in

medicine and society have had an impact on the

fi eld of neuropathology and need to be addressed in

this text

• For a variety of social and scientifi c reasons,

autopsy studies are currently being performed

much less frequently than in years past Th is

change has been brought about in part because

the progress in radiological imaging, both

struc-tural and functional, has decreased the need to

draw on clinical–anatomical correlations derived

from autopsy data to guide medical practice

Oddly enough, conversely, autopsy-derived

knowledge of the anatomical distribution and the

neuropathological basis of lesions continues to

be a valuable body of information for the

inter-pretation of imaging data To this aim we have

made ample use of macroscopic illustrations and

whole-brain celloidin-/paraffi n-embedded

sec-tions from our archives

• Progress in molecular biology and genetics has

revolutionized the laboratory diagnosis of many

groups of neurological diseases Neuropathology

stands at the vanguard of the development and

implementation of these diagnostic studies

In the past decade, progress in

immunohisto-chemistry methods for in situ identifi cation of

abnormal proteins, and the enormous advances

in molecular biology to uncover specifi c gene

mutations, have led to greater understanding of

many hereditary neurological diseases, including

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Umberto De Girolami, MD

Professor of Pathology Harvard Medical School Neuropathologist, Brigham and Women’s Hospital; Consultant Neuropathologist

Boston Childrens’ Hospital, Boston, MA

Maitre de Conférence en Anatomie Pathologique,

University of Paris VII

Neuropathologiste, Practicien Hospitalier, APHP,

Hopital Lariboisière, Paris, France

Anthony A. Amato, MD

Professor of Neurology

Harvard Medical School

Vice-chairman, Department of Neurology;

Chief, Neuromuscular Division

Brigham and Women’s Hospital,

Boston, MA

Douglas C Anthony, M.D., PhD

Professor, Alpert Medical School of Brown University

Pathologist-in-Chief, Lifespan Academic Medical

Center,

Providence, RI

Leila Chimelli, MD, PhD

Professor of Pathology

Federal University of Rio de Janeiro

Neuropathologist, National Cancer Institute,

Massachusett s General Hospital, Boston, MA

James W Ironside, FRCPath

Professor of Clinical Neuropathology School of Clinical Sciences

University of Edinburgh, UK Honorary Consultant Neuropathologist Lothian University Hospitals Division and TaysideUniversity Hospitals

Scotland, UK

Hans Lassmann, MD

Professor of Neuroimmunology Center for Brain Research Medical University of Vienna Vienna, Austria

Hart G. W Lidov, MD, PhD

Associate Professor of Pathology Harvard medical School Director of Neuropathology Department of Pathology ;  Boston Children’s Hospital  Neuropathologist Brigham and Women’ Hospital  Boston, MA

Keith L. Ligon, MD, PhD

Assistant Professor of Pathology Harvard Medical School Investigator, Dana-Farber Cancer Institute Center for Molecular Oncologic Pathology

Neuropathologist, Brigham and Women’s Hospital, Boston Children’s Hospital

Boston, MA

Rebecca Folkerth, MD

Associate Professor of Pathology

Harvard Medical School

Director, Neuropathology Service, Brigham and

Women’s Hospital;

Consultant Neuropathologist, Boston Childrens’

Hospital,

Boston, MA

Matt hew P. Frosch, MD, PhD

Lawrence J. Henderson Associate Professor of

Pathology and Health Sciences & Technology

(HST); Associate Director, HST

Harvard Medical School

Director, Neuropathology Service

C.S Kubik Laboratory for Neuropathology

Massachusett s General Hospital,

Boston, MA

Bernardino Ghett i, MD

Distinguished Professor and Director of

Neuropathology

Department of Pathology and Laboratory Medicine

Indiana University School of Medicine

Indianapolis, Indiana

Romain K Gherardi, MD

Professor of Histology

Reference Center, INSERM U955

Henri Mondor University Hospital

Paris-Est University, F-94010 Créteil, France

Jeff rey A. Golden, MD

Harvard Medical School

Chair,

Brigham and Women’s Hospital

Boston, MA

Françoise Gray, MD, PhD

Professeur d’Anatomie Pathologique,

University of Paris VII

Praticien Hospitalier, AP,HP, Hôpital Lariboisière,

Paris, France

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Electron Microscopy, UMass Memorial Medical Center Worcester, MA

Raymond A. Sobel, MD

Professor of Pathology (Neuropathology) Stanford University School of Medicine Neuropathologist, Veterans Aff airs Health Care System

Palo Alto, CA

Jean-Michel Vallat, MD, PhD

Professor of Neurology University of Limoges Department of Neurology University Hospital Dupuytren Limoges, France

Harry V. Vinters, MD, FRCPC, FCAP

Distinguished Professor of Pathology & Laboratory Medicine, and Neurology,

David Geff en School of Medicine at University of California Los Angeles (UCLA),

Chief, Section of Neuropathology, Ronald UCLA Medical Center

Member, Brain Research Institute, UCLA Los Angeles, CA

Kum Th ong Wong, MBBS, MPath, FRCPath, MD

Dept of Pathology, Faculty of Medicine, University of Malaya,

Kuala Lumpur, Malaysia

Emeritus Professeur d’Anatomie Pathologique,

University of Paris VII

Praticien Hospitalier, AP, HP, Hôpital Lariboisière,

Paris, France

Vânia Nosé, MD, PhD

Associate Professor of Pathology

Harvard Medical School

Director of Anatomic and Molecular Pathology

Massachusett s General Hospital

Boston, MA

Francesco Scaravilli, MD, PhD, FRCPath, DSc

Emeritus Professor of Neuropathology

Institute of Neurology, UCL, London, UK

Frédéric Sedel, MD, PhD

Professor of Neurology

Fédération des Maladies du Système Nerveux

APHP, Pitié-Salpêtrière Hospital

New Jersey Medical School

Neuropathologist, University Hospital,

Newark, NJ

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D A N I E L L E S E I L H E A N , U M B E R T O D E G I R O L A M I , A N D F R A N Ç O I S E   G R AY

AUTOPSY DIAGNOSIS in neuropathology is

based on the macroscopic and microscopic study

of the brain, brainstem, cerebellum, and spinal cord

Increasingly, the ability to reach greater diagnostic

precision is butt ressed by the new laboratory

consecutive steps are involved in reaching a

diagno-sis and these are, in fact, closely interrelated: (1) a

morphologic/laboratory analysis of the lesions;

(2) a topographic analysis of the lesions; and (3) a

critical integration of these fi ndings and their

subse-quent correlation with the clinical data and the

gen-eral autopsy fi ndings, thus permitt ing an etiological

diagnosis to be made in most instances

1 MORPHOLOGIC ANALYSIS

OF CENTRAL NERVOUS

SYSTEM LESIONS

With the exception of tumors and malformations, most

disorders of the central nervous system (CNS) are

characterized morphologically by the co-expression of multiple reactions to injury that may not be diagnos-tic in themselves Th ese reactions aff ect the cellular elements of the nervous system (neurons, astrocytes, oligodendrocytes, and microglia) and/or the support-ing structures (meninges, connective tissue, or blood vessels) Basic cellular reactions are demonstrable only

on microscopic examination, whereas tissue lesions that can be associated with more extensive destructive

or atrophic changes are recognized macroscopically or with the help of a magnifying lens

Although, for didactic purposes, the reactions

to injury seen in the neurons, glia, connective sue, and vascular structures will be described sepa-rately in the text below, it is essential to emphasize that there is a close functional interdependence of the various cellular elements of the nervous system

tis-Th is is particularly important in the case of nerve cell alterations where, except for very acute injury, the possibility of artifactual change should be enter-tained whenever the reaction is not accompanied by

a glial cell response

sclerosis) It is also seen in anterograde and grade transsynaptic degeneration, as may occur in the lateral geniculate body following a lesion of the optic nerve

Programmed cell death (apoptosis) is an active, genetically controlled, energy-consuming process frequent in neurodegeneration and involving pri-marily the nucleus of the cell Neurons undergoing simple neuronal atrophy or apoptosis have similar

morphologic features and may show positive in situ

end labeling of internucleosomal DNA tation ( Fig.1 1 ) or be demonstrable by activated caspase-3 immunostaining

Nerve cell atrophy should not be mistaken for what is referred to as “dark neurons.” Th is phenom-enon is now recognized to be an artifactual change

of the neuron cell body, seen particularly in brain biopsies fi xed in formalin by immersion, and charac-terized by shrunken cytoplasm and deeply-stained and irregularly-shaped nucleus without other cellular alterations

1.1.1.2 Acute Neuronal Necrosis (Anoxic/ Ischemic Neuronal Change) Th is type of cell death occurs in a variety of acute injuries, including anoxia and ischemia, but may also be seen in many other acute pathological processes (e.g., hypoglycemia or

1.1 BASIC cellular reactions to

CNS injury

1 1 1 N E U R O N A L L E S I O N S

Neuronal injury may suffi ciently severe to result in

irreversible damage (cell death) or may be transient

or minimal and cause reversible functional

dam-age Destruction of neurons may be focal, or extend

diff usely, involving many populations of neurons

throughout the nervous system In acute

neuro-nal injury, when the tissue is examined with H&E

preparations at a time shortly aft er a lethal insult to

the cell, one observes eosinophilia of the cytoplasm,

shrinkage and hyperchromasia of the nucleus, and

disappearance of the nucleolus; subsequent to the

disintegration of the cell, neuronophagia by

scav-enger cells ensues In chronic diseases, evidence of

cell death is recognized morphologically as

neuro-nal “cell loss” or, alternately, as “atrophy” when the

irreversible injury has occurred relatively slowly and

has progressively involved ever greater numbers of

cells In some degenerative diseases of the nervous

system in which there is progressive loss of neurons

over variable time periods, the aff ected cells have

distinctive morphologic hallmarks (e.g., neurofi

bril-lary degeneration, neuronal storage of metabolic

products, disorders associated with intracellular

inclusion bodies)

Th e end stage of all irreversible lesions that

aff ect the nerve cells is neuronal loss, evidenced

by an appreciable reduction in the number of cell

bodies in a particular area, as compared to normal

Th is assessment can be diffi cult to estimate in the

absence of rigorous morphometric analysis, when

it involves less than 30% of the normal cell

popula-tion Th is estimate depends on the thickness of the

section and on the normal cytoarchitectonics of the

region examined

1.1.1.1 Nerve cell “atrophy” Neuronal

“atro-phy” is the descriptive term that is given to a wide

range of irreversible neuronal injuries that give

rise to a relatively slowly-evolving death of the

cell Neuronal “atrophy” is characterized

morpho-logically by retraction of the cell body with

dif-fuse basophilia of the cytoplasm and pyknosis and

hyperchromasia of the nucleus of the neuron, in

the absence of an infl ammatory reaction Neuronal

“atrophy” is thought to occur in many

degenera-tive disorders that involve several interconnected

neuronal systems (i.e., multiple system atrophy, in

Friedreich ataxia, and even in amyotrophic lateral

FIGURE 1.1 Two neurons undergoing

apopto-sis are positively stained by in situ end labeling to

demonstrate internucleosomal DNA fragmentation

In one neuron, on the left , only the nucleus is stained, whereas in the other, which is at a later stage of the programmed cell death process, the entire cell body is stained Compared to a normal neuron, on the right, both apoptotic neurons have similar morphologic features and show pyknotic nucleus and shrunken cytoplasm

preserved human tissue at postmortem, by light

and electron microscopy, the following sequence of

changes is noted over the course of 12 to 24hours aft er

the insult:  (a)  cytoplasmic microvacuolation due to

swelling of mitochondria and endoplasmic reticulum;

(b) shrinkage of cell body with retraction of the

cel-lular outlines, and disappearance of Nissl bodies with

eosinophilic condensation of the cytoplasm (“red

neuron”); (c) condensation of nuclear chromatin and

nuclear pyknosis ( Fig. 1 2 ) ; (d) late disappearance of

the nuclear chromatin, resulting in increased

acido-philia of the nucleus, which appears to merge into the

surrounding cytoplasm (karyorrhexis)

Occasionally, dead neurons, especially those

adjacent to old, mostly hemorrhagic, infarcts, or to

traumatic scars, become encrusted with basophilic

mineral deposits, chiefl y iron and calcium salts Th is

condition is referred to as mineralization or

ferrugi-nation of neurons ( Fig.1.3)

1.1.1.3 Central chromatolysis Central

chroma-tolysis is characterized morphologically by swelling

of the cell body, disappearance of Nissl bodies

begin-ning centrally and extending outward, and fl att

en-ing and eccentric displacement of the nucleus to the

periphery ( Fig. 1.4) It is seen usually in lower motor

neurons (anterior horns of the spinal cord, cranial

nerve nuclei), where it represents a reparative

reac-tion of the cell body to a lesion of the axon (retrograde

interpret Axonal lesions of neurons whose axons do not leave the confi nes of the CNS apparently either

do not produce changes in perikaryal cell body phology or result in “simple” type of atrophy Oddly

mor-enough, some metabolic disorders that do not a priori

involve axons (e.g., Wernicke encephalopathy, pellagra encephalopathy, porphyria) may be accompanied by central chromatolysis in cortical neurons

A confi dent diagnosis of central chromatolysis requires comparison with the normal morphology

FIGURE 1.4 Central chromatolysis (Nissl stain) Note the cellular swelling, the eccentric displace-ment of the nucleus, and the margination of the Nissl bodies

1.1.1.5 Binucleated neurons Th ese lesions are seen rather infrequently, sometimes under normal circumstances, at the edge of old focal destructive lesions, as a dysplastic/malformation phenomenon (e.g., tuberous sclerosis), or in certain neoplasms (e.g., ganglion-cell tumors)

1.1.1.6 Neuronal storage In some hereditary metabolic diseases related to enzymatic defects involving synthetic or degradative pathways for lip-ids or carbohydrates, interruption of the pathway leads to cytoplasmic accumulation of intermediate substrates or their byproducts, resulting in swelling and distention of the cell body of nerve cells, with eccentric displacement of the nucleus ( Fig. 1.8) In several neuronal storage disorders, the stored mate-rial has distinctive histochemical and ultrastruc-tural features that may help characterize clinically

of the aff ected gray matt er structure because the

nerve cell-body in some nuclei (e.g., the

mesen-cephalic nucleus of the fi ft h cranial nerve, Clarke’s

column) normally contains rounded neurons with

marginated Nissl bodies

1.1.1.4 Vacuolated neurons and neuropil

Vacuolated neurons and neuropil are observed

in Creutzfeldt-Jakob disease ( Fig.  1.6) In rare

instances, swelling with vacuolization of the nerve

cell is thought to result from transsynaptic

degen-eration—for example, in the neurons of the inferior

olive in olivary hypertrophy, secondary to a lesion of

the ipsilateral central tegmental tract, or of the

con-tralateral dentate nucleus—so-called “fenestrated

neurons”( Fig. 1.7)

Normal

neuron

Complete central chromatolysis

Cell death Recovery

Stages of hyperchromasia

FIGURE 1.5 Nerve cell changes in central

FIGURE 1.8 Distended nerve cell bodies in a case

of neuro-lipidosis (combined Luxol fast blue and Bodian silver impregnation)

Tangles are particularly well demonstrated by tau immunocytochemistry, which is now used routinely

in diagnostic work Some NFTs can also be noreactive for ubiquitin On electron microscopic examination most NFTs consist of paired helical fi l-aments measuring around 20 nm across, with a regu-lar constriction to 10nm occurring every 80nm In Alzheimer disease, they may also be associated with straight fi laments In progressive supranuclear palsy, NFTs have been found to consist mainly of straight

immu-fi laments measuring 15 nm in diameter

Granulovacuolar degeneration is a neuronal

altera-tion found in pyramidal cells of Ammon’s horn; this abnormality is seen in normal aging as well as in Alzheimer disease and Pick disease It consists of an accumulation of small clear vacuoles measuring 4 to 5μm in diameter, containing an argyrophilic granule that is also well stained by hematoxylin ( Fig. 1 11) Some of the granules are immunoreactive for phos-phorylated neurofi laments tubulin, tau, and ubiq-uitin, suggesting that the vacuoles are autophagic lysosomal structures in which cytoskeletal compo-nents are being degraded

1.1.1.8 Intraneuronal inclusion bodies Intracytoplasmic or intranuclear inclusion bodies are important indicators of neuronal injury Th ey occur in degenerative, metabolic, and viral diseases and oft en have diagnostic immunocytochemical and ultrastructural features

Pick bodies are round homogenous

intracytoplas-mic neuronal inclusions ( Fig. 1.12) , characteristic of Pick disease, where they may be seen in pyramidal neurons and dentate granule cells of the hippocam-pus, as in aff ected regions of the neocortex Th ey are intensely argyrophilic and are immunoreactive for ubiquitin, tau, and tubulin Ultrastructurally, they consist of poorly circumscribed masses of interme-diate fi laments, 15-nm straight fi laments, and some paired helical fi laments, as well as entrapped vesicu-lar structures

( Fig.  1.9) It is autofl uorescent and rich in acid

phosphatase Th e pigment is PAS-positive and can

be stained by Luxol fast blue It has distinctive

ultra-structural features (see Chapter 10)

1.1.1.7 Alzheimer neurofi brillary

degenera-tion and granulovacuolar degeneradegenera-tion Alzheimer

neurofi brillary degeneration is characteristically seen

in the brains of aged individuals and in patients with

senile dementia of Alzheimer type but has also been

described in a variety of other cerebral disorders

Th is degenerative change is manifest by the

forma-tion of neurofi brillary tangles (NFTs), structures

that are well demonstrated by silver impregnation

and by immunohistochemical techniques and

con-sists of thickened and tortuous skeins within the

neuronal perinuclear cytoplasm Th e confi guration

of the tangle may vary according to the anatomical

site, the type of neuron aff ected, and the stage of its

development ( Fig.1.10) A  band-shaped perikaryal

NFT can be seen both in large and small

pyrami-dal cells and is perhaps an early stage of NFT

for-mation ( Fig.1 10A ) A  triangular fl ame-shaped

perikaryal NFT is seen mainly in large pyramidal

FIGURE 1.9 Lipofuscin in neuronal cell

body (H&E)

( Fig.1 13A , B ) Th ey may also be oval or elongated structures, especially when they occur in axonal

processes or in sympathetic ganglia ( Fig.1 13C , D )

Cortical Lewy bodies are less clearly circumscribed and consist of a homogenous zone of hypereosino-philia that usually lacks the characteristic surrounding

“halo” ( Fig.1 13E , F ) Lewy bodies are

immunoreac-tive for ubiquitin, αB-crystallin, and α-synuclein

inclu-sions; their appearance varies depending whether

they are found in the perikaryon or in the nerve cell

processes, in the cortex, brainstem, or sympathetic

ganglia ( Fig.  1 13) Typical (brainstem) Lewy

bod-ies are roughly spherical with an eosinophilic core

surrounded by a paler “halo.” One or more inclusions

may be present in the cytoplasm of a single neuron

FIGURE 1.10 Diff erent types of NFTs (Bodian silver impregnation combined with Luxol fast blue)

(A) Band-shaped perikaryal NFT (B, C) Triangular, fl ame-shaped perikaryal NFT (D) Small, compact, globose perikaryal NFT (E) Large globose NFT (F) “Ghost NFT.”

rosis Ultrastructurally, they consist of bundles of

fi laments of 15 to 25 nm in diameter, with a tubular profi le on cross section

Marinesco bodies are small eosinophilic

intranu-clear inclusions located chiefl y in melanin-containing brainstem neurons ( Fig.  1.16A ) Th ey are strongly ubiquitin positive

When ubiquitinated intranuclear inclusions occur in other regions of the brain they suggest various other disorders Small round eosinophilic inclusions (about the same size of the nucleo-lus) are found in neurons of CAG-repeat dis-eases (including SCA, Huntington, and DRPLA)( Fig.  1.16B ) Larger, eosinophilic, ubiquitinated inclusions are found in association with CGG

repeats (fragile X) and NIID ( neuronal

intranu-clear inclusion disease ) Similar large intranuintranu-clear

inclusions are found in INIBD ( intranuclear

inclu-sion body disease )

Lafora bodies are rounded structures composed

of polyglucosan (polymers of sulfated charides) and are similar to corpora amylacea (see further on) in composition and staining character-istics Th ey are found in large number in myoclonic epilepsy both in the CNS (chiefl y in the dentate nucleus) and in tissues outside the nervous system, such as sweat glands, liver, and skeletal muscle Th ey usually have a dense, intense periodic-acid-Schiff (PAS)-positive core surrounded by fi lamentous, fainter PAS-positive structures ( Fig.1 17)

inclusions that occupy a variable volume of the nucleus and be surrounded by a clear halo are associated with some viral infections of the CNS

infections, particularly in necrotizing encephalitis caused by herpes simplex virus, and in subacute sclerosing panencephalitis In rabies, the viral inclusions are intracytoplasmic and are referred

to as Negri bodies In some instances (e.g., 

cyto-megalovirus infection) both intranuclear and

By electron microscopy, they consist of an

amor-phous electron-dense core surrounded by a corona

of radiating fi laments Th eir presence defi nes several

conditions termed “Lewy body disorders”; the most

common disorder in this group is Parkinson disease

rod-shaped or elliptical cytoplasmic inclusions that

appear to overlap the cell border of a neuron cell

body Th ey are mostly found in the CA1 fi eld of

the hippocampus and are particularly numerous in

Alzheimer disease, Pick disease, and in patients with

are immunoreactive for actin and actin-associated

proteins Ultrastructurally, they consist of parallel

fi laments 60 to 100  nm in length, which alternate

with a longer sheet-like material

Bunina bodies are eosinophilic, nonviral

intra-cytoplasmic inclusions found in motor neurons

in cases of familial or sporadic amyotrophic lateral

sclerosis ( Fig.1 14A , B ) Th ey are immunoreactive

FIGURE 1.11 Granulovacuolar degeneration

(Bodian silver impregnation)

FIGURE 1.12 Neuronal argyrophilic inclusion in

Pick disease (Bodian silver impregnation)

1.1.1.9 Axonal alterations Following focal axonal lesions that disrupt the integrity and con-tinuity of the nerve fi ber, the distal part of the cell process undergoes Wallerian degeneration, which will be described further on (see basic lesions of the peripheral nervous system; Chapter 13)

intracytoplasmic inclusion bodies may be seen

Viral inclusion bodies are immunoreactive with

appropriate antivirus antibodies, allowing for a

specifi c diagnosis Electron microscopy may also

be used to identify virions; however, it is now used

less oft en in diagnostic work

In conditions associated with nerve cell phy” as described above, the destruction of the cell body of the neuron results in degeneration of all of its processes, including the dendrites and the axon, which become swollen, then fragmented, and even-

if widespread, as occurs in system degenerations, results in rarefaction of the white matt er demonstra-ble with myelin and axon stains In these diseases, the phenomenon probably begins at the most distal portions of the longest axons

Axonal swellings or spheroids are localized

eosino-philic enlargements of the axon At these sites along the axon there is a condensation of neurofi laments, organelles, and other materials that are normally conveyed along the axon by an anterograde trans-port system, but accumulate focally when the trans-port system is interrupted Spheroids are a feature

FIGURE 1.14 Bunina bodies in anterior horn cells of the spinal cord, in a case of motor neuron disease (H&E) (A) Immunocytochemistry for ubiquitin (B)

FIGURE 1.15 Skein-like inclusion in an anterior

horn cell, in a case of motor neuron disease

(immuno-cytochemistry for ubiquitin)

FIGURE 1.16 Intranuclear inclusions (A) Marinesco bodies: small intranuclear inclusion in a pigmented neuron of the substantia nigra (H&E) (B)Ubiquitin-positive intranuclear inclusion in a case of spinocerebellar degeneration with CAG repeat expansion (courtesy of Professor Francesco Scaravilli)

amyloid protein (beta APP) ( Fig. 1 18C ) Th e latt er

is transported by axonal fl ow and accumulates when this process is disrupted Th e term torpedo is applied

to Purkinje cell axonal swellings and is a feature of

a many metabolic and degenerative cerebellar eases Torpedoes are well demonstrated by silver impregnation and by the immunohistochemical methods Th ey are most notable in the initial por-tion of the axis cylinder before the origin of the col-lateral branches ( Fig. 1 18 C)

Th e axonal swellings that develop when axonal transport is disrupted by neuronal metabolic dys-function are usually termed dystrophic Th is occurs

in some acquired (e.g., vitamin E defi ciency) or inherited metabolic diseases Extensive formation

of axonal swellings is characteristic of neuroaxonal dystrophy and of some leukodystrophies

Th e term dystrophic neurite is used to describe

neuronal cytoplasmic processes distended by tau protein or other abnormal ubiquinated material

Th ese occur in several neurodegenerative diseases

of axonal damage by diverse extrinsic insults and

are well demonstrated by either silver impregnation

( Fig.  1 18A ) or by immunostaining with

ubiqui-tin ( Fig. 1 18B ) and with the precursor of the beta

FIGURE 1.17 Lafora body in a case of myoclonic

their cytoplasmic network of cell processes is more extensive and can best be appreciated with immu-nostaining for glial fi brillary acidic protein (GFAP)

An older term, isomorphorphic fi brillary gliosis,

refers to the alignment of reactive astrocyte cesses conforming to a degenerating fi ber tract

1.1.2.2 Alzheimer type II glia Alzheimer type

II glia is seen particularly in hyperammonemic

states such as occur in Wilson disease and in liver

unit area, eosinophilia of the cytoplasm around the

nucleus, and expansion and distortion of the

astro-cytic cytoplasmic arborization For reasons that are

not understood, mitotic fi gures are only rarely

iden-tifi ed in gliotic tissue, and techniques that bring out

dividing cells (Mib-1/Ki 67) also confi rm the slow

turnover

Th e morphologic aspects of the process of gliosis

will vary depending on the location, stage of

evolu-tion, and nature of the pathological process Th e

early stages are characterized by hypertrophy of the

C

FIGURE 1.19 Gliosis Fibrillary gliosis, (A) hypertrophy of nucleus as of cytoplasm and processes that are well seen on GFAP stain Gemistocytic astrocytes with large homogenized and eosinophilic cytoplasm (H&E) (B), (GFAP) (C)

pilocytic astrocytomas, particularly of the lum) (cf Chapter 2), and of Alexander disease (cf

cerebel-Chapter 10 )

Eosinophilic granular bodies are rounded hyaline

droplets that occupy the cytoplasm of astrocytes and are seen in pilocytic astrocytomas and ganglion-cell tumors

1.1.2.4 Inclusions and storage material

Accumulation of lipofuscin occurs in astrocytes as

part of aging as it does in neurons Similarly, in lipid

storage diseases, glial lipid storage may accompany

neuronal storage

Tau protein , which is the main component of

NFTs, can also accumulate in astrocytes,

particu-larly in progressive supranuclear palsy (PSP) and

cor-ticobasal degeneration (cf Chapter 8)

Tuft ed astrocytes are considered to be highly

char-acteristic of PSP (see Fig. 8 5A ) Th e whole length

of their processes contains tau protein and they are

Gallyas stain or tau immunocytochemistry Th orn

astrocytes have an argyrophilic cytoplasm with a few short processes (see Fig. 8 5 B) and oft en a small eccentric nucleus Th ey are commonly seen in PSP but are not specifi c to this disease and may be seen

in other neurodegenerative conditions

In corticobasal degeneration, the accumulation

of tau protein in astroglial cells results in distinctive

structures in gray matt er which are termed astrocytic

plaques In these plaques, tau protein accumulates at

the end of the astrocytic processes, while the center

of the plaque is devoid of tau immunoreactivity (see Fig. 8 11 )

Viral inclusion bodies may also be found in astrocytes, particularly in subacute sclerosing pan-encephalitis and cytomegalovirus (CMV) infection (cf Chapter 5)

PAS-positive inclusions, 10 to 50  μm in diameter, that are predominantly found in astrocytic pro-cesses, although they occasionally occur within axons Ultrastructurally, they consist of densely packed 6- to 7-nm fi laments that may be admixed with amorphous granular material and are not membrane bound Corpora amylacea increase in number with aging, particularly in the subpial and subependymal regions, around small blood vessels and in the posterior columns of the spinal cord Adult polyglucosan body disease (cf Chapter  10)

is characterized by diff use accumulation of corpora amylacea, involving the cortex and white matt er,

failure from acquired or hereditary metabolic

dis-ease, but it can also be found in other systemic

metabolic disorders (e.g., renal failure) Th is

reac-tion of astrocytes is characterized by enlargement

of the nucleus, reaching 15 to 20 μm in diameter,

which appears irregular in shape and pale and

empty-looking because of the disappearance of

chromatin granules ( Fig. 1 20) One or two dense

rounded PAS-positive bodies resembling

nucle-oli are oft en seen next to the nuclear membrane,

which is always sharply outlined Th e cell body is

not usually visible on conventional preparations

and stains poorly with GFAP Alzheimer II glia

(unrelated to Alzheimer disease) occur in the gray

matt er, involving particularly deep gray nuclei,

especially the pallidum and the dentate nuclei and

also the cerebral cortex Alzheimer type II glia are

metabolically active cells engaged in the detoxifi

-cation of ammonia; on ultrastructural study, they

are shown to contain numerous mitochondria

1.1.2.3 Rosenthal  fi bers By light microscopy,

Rosenthal fi bers are rounded, oval, or elongated,

beaded structures, measuring 10 to 40μm, which

appear homogenous, and brightly eosinophilic On

electron microscopy, they consist of swollen

astro-cytic processes that are fi lled with electron-dense

amorphous granular material and glial fi laments

With immunohistochemical methods peripheral

labeling for GFAP, ubiquitin, and ΑBcrystallin can

be demonstrated Rosenthal fi bers are seen in

vari-ous pathological conditions that have in common

intense fi brillary gliosis of long standing, as seen

throughout the brain in multiple sclerosis plaques,

in the spinal cord in syringomyelia, and in the

are also characteristic of certain neoplasms (e.g.,

FIGURE 1.20 Alzheimer type II glial cells (H&E)

cerned with antigen presentation and infl ammation Microglial basic reactions to injury are typically seen in three situations:

• Macrophage proliferation and phagocytosis (the

cells are also known as compound granular puscles, foam cells, lipid phagocytes, or gitt er cells) Th is is a frequent fi nding in many brain lesions, particularly those associated with demy-elinating processes or with traumatic or ischemic tissue destruction Aft er a destructive or demy-elinating insult, macrophages invade the dam-aged region within 48 hours of injury Th ese are rounded cells with distinct cytoplasmic borders and measure 20 to 30 μm in diameter Th ey have

cor-a smcor-all, dcor-arkly-stcor-aining cor-and sometimes eccentric nucleus, and a clear, granular cytoplasm that can contain lipids, hemosiderin pigment, or any other phagocytized material ( Fig. 1 21A , B) Th e num-ber of these scavenger cells increases over a period

of days and weeks, and they may still be present in injured tissue many months aft er the injury Most derive from blood monocytes

chromatic leukodystrophy)

Cytoplasmic inclusions involving mainly

oligo-dendrocytes have been shown to be a characteristic

feature of multiple system atrophy (cf Chapter 8)

Th ese inclusions are usually fl ame- or sickle-shaped

and can be demonstrated by silver impregnation and

are immunoreactive for ubiquitin, αB-crystallin,

and α-synuclein

Th e accumulation of tau protein in

oligodendro-cytes, known as “coiled body,” may be found in PSP,

corticobasal degeneration, and argyrophilic grain

disease (cf Chapter8) Th ese are fi brillary structures

“coiling” around the nucleus

1 1 4 M I C R O G L I A L L E S I O N S

Microglial cells are of monocyte lineage and have

important phagocytic functions Th ey can be

dem-onstrated by silver impregnation, lectin-binding

techniques, and immunohistochemical techniques

using antibodies that react with

monocyte/macro-phages (e.g., CD68) ( Fig. 1 21B )

FIGURE 1.21 Perivascular lipid-laden macrophages (compound granular corpuscles, foam cells, or gitt er cells) in a demyelinating lesion (Luxol fast blue combined with Bodian silver impregnation) (A) and with CD68 immunostaining (B)

specifi c pathological processes (i.e., vascular,

degenerative) As will be described in the ing chapters, these may accompany one or more of the specifi c pathological processes visible under the microscope that are described above or may result

forthcom-in more extensive changes that can be visible to the naked eye

1 2 1 C E R E B R A L AT R O P H Y

Cerebral atrophy is the end-stage of a

is lighter than a normal age-matched control Macroscopically, there is narrowing of the gyri and widening of sulci On section, the cortical ribbon

is thinned, and ventricular dilatation is oft en ent Th e histological substratum consists of a vari-able loss of neurons oft en associated with gliosis, depending on the underlying illness, and a variety

pres-of neuronal alterations, which will be discussed in turn in subsequent chapters

1 2 2 C E R E B R A L   E D E M A

Cerebral edema is defi ned as an increase in brain volume due to an increase in water and sodium con-tent Depending on its pathogenesis, brain edema has been classifi ed as vasogenic, cytotoxic, or inter-stitial (hydrocephalic) Combination of these proto-types of edema is frequent

• Vasogenic edema , probably the most common type

of brain edema, complicates head injury, abscess, tumors, and hemorrhages Both vasogenic edema and cytotoxic edema occur with ischemia Vasogenic edema results from blood–brain barrier injury lead-ing to increased permeability of the microcircula-tion to macromolecules, particularly to proteins

By radiological imaging, sites of vasogenic edema are marked by contrast enhancement, because the injected contrast medium leaks across the perme-able vascular lining Biochemically, the edema fl uid resembles a plasma fi ltrate It is located chiefl y in the extracellular spaces of the white matt er

• In cytotoxic edema , excessive amounts of water

enter one or more of the intracellular ments of the CNS (neurons, glia, endothelial cells,

compart-or myelin sheaths) because the cellular tration of osmotically active solutes is increased

concen-Th is usually results from an injury impairing the

• Rod cell proliferation ( Fig. 1.22 and 5.25) is a form

of microglial response to subacute parenchymal

injury in which necrosis is minimal or absent Rod

cells are elongated, spindle-shaped cells that can

be recognized on H&E preparations by the

pres-ence of a cigar-shaped nucleus Th e best

descrip-tions of this glial change are found in reports of

cases of general paresis in the older literature (cf

Chapter 5) Rod cells are also seen in cases of

sub-acute encephalitis and evolving ischemic lesions

• Microglial nodules consist of discrete clusters of

microglial cells that are typically found in subacute

viral encephalitis, in and around sites of neuronal

destruction— neuronophagic nodules (cf Chapter 5)

1 1 5 E P E N D Y M A L   C E L L S

Ependyma have a limited range of reactions to

injury Along with neurons and other glial cells,

ependymal cells may be infected in viral diseases In

the adult CNS, ependymal cells do not proliferate

in response to injury and cell loss Th eir destruction

leaves bare stretches of the ventricular lining; this

is accompanied by proliferation of subependymal

astrocytes that form small hillocks along the

ventric-ular surface— ependymal granulations Occasionally,

surviving ependymal cells may be overgrown by the

astrocytic reaction and appear as clusters of tubules

buried within the ependymal granulations

of the CNS to Injury and Herniations

A set of general tissue reactions are known to occur

in the CNS that stand apart from the reactions to

FIGURE 1.22 Rod-shaped microglia in a case of

general paresis of the insane (Nissl stain)

and reabsorption Rarely, it results from increased production of CSF (e.g., choroid plexus papilloma) More commonly, it is the consequence of altered

fl ow and absorption of the CSF as a result of tion of CSF pathways within the ventricular system (noncommunicating hydrocephalus) or in the sub-arachnoid space (communicating hydrocephalus) Obstruction at “bott leneck” areas such as the foram-ina of Monro, the aqueduct of Sylvius, and the exit foramina of the fourth ventricle (lateral foramina

obstruc-of Luschka and midline foramen obstruc-of Magendie) can occur when there is extension of blood or tumor into the ventricular system Subarachnoid pathways most oft en become blocked over the cerebral con-vexities and around the rostral brainstem (incisural block) as a result of infl ammation or hemorrhage

In the acute phases, the blood clot or infl ammatory exudate forms a barrier to fl ow Subsequently, orga-nization of the clot or exudate leads to fi brous oblit-eration of the subarachnoid space

Hydrocephalus is oft en associated with increased intracranial pressure In children, in the absence of appropriate shunting procedures, the head can become enlarged when hydrocephalus develops before the cranial sutures close When the progres-sive obstructive lesion causing the hydrocephalus

is not severe, the hydrocephalic process may lize and the CSF pressure returns to normal limits (“normal-pressure hydrocephalus”)

Several alterations in the brain are common to all forms of hydrocephalus Th ese include dilation

of the ventricular system, interstitial edema, tion of the volume of the white matt er, accentuation

reduc-of the primary, secondary, and tertiary cerebral sulci

because the blood-brain macromolecular barrier

remains intact, disease processes that give rise to

cytotoxic edema are not associated with

radio-logical enhancement aft er injection of contrast

medium

• Interstitial or hydrocephalic edema is the

accu-mulation of cerebrospinal fl uid (CSF) in the

extracellular spaces of the periventricular white

matt er resulting from obstructive hydrocephalus

As fl uid collects within the obstructed ventricles,

pressure increases and the CSF is forced across

the ependymal lining into the adjacent

extracel-lular spaces

Macroscopically, the edematous areas of brain

are swollen and soft ( Fig.  1 23) Th e swelling

increases the volume of the intracranial contents,

with consequent increased intracranial pressure (see

below) When the brain is cut, the slice surfaces may

be wet and shiny If the edema is diff use, the

ventri-cles are compressed; in severe cases they are reduced

to slit-like cavities

Under light microscopy, myelin stains

demon-strate pallor of the white matt er Th e cerebral tissue

has a loose appearance and is split by vacuoles of

variable size Glial cells are swollen, and perivascular

spaces are dilated

Th ese macroscopic and microscopic features

cor-respond to ultrastructural features that vary

accord-ing to the etiological and pathogenetic mechanism

Th ey include dilatation of the perivascular and

extra-cellular spaces, swelling of astrocytic cell processes,

and splitt ing of the myelin lamellae ( Fig. 1 24)

1 2 3 H Y D R O C E P H A L U S

Hydrocephalus is an abnormal increase in the

intra-cranial volume of CSF associated with dilatation of

all or some portion of the ventricular system It is

sec-ondary to a dysequilibrium between CSF formation

FIGURE 1.23 Cerebral edema of the left cerebral hemisphere with swelling of the parenchyma that appears paler, fl att ening of the gyri, narrowing of the sulci and left lateral ventricle

fl ow and blood volume, or the development of space-occupying lesions such as tumors, abscesses, hematomas, or large, recent infarcts accompanied

by edema Th e eff ects of space-occupying lesions

on intracranial pressure are the result not only of the mass of the lesion, but also of the accompany-ing edema and obstruction of venous or CSF path-ways In children with still-open cranial sutures,

an increase in volume of intracranial contents will lead to splaying of the sutures, resulting in

an increase in the size of the skull and in digital convolutional markings In older children and in adults when the bony skull can no longer expand, intracranial hypertension leads to compression

of the brain surfaces against the inner table of the skull, with consequent fl att ening of cerebral gyri, narrowing of intervening sulci, and accentuation

of foraminal and tentorial markings on the rior cerebellar and medial temporal surfaces The expanding cerebral mass will also insinuate itself into the anatomical openings that can accom-modate it These compensatory displacements

infe-of brain from one intracranial compartment to

(producing a prominent gyral patt ern), and

perfora-tion of the septum pellucidum Disrupperfora-tion and loss of

the ependymal lining, with localized subependymal

astrocytic proliferations protruding into the

ventricu-lar cavities— ependymal granulations —is frequent

(see above) Proliferation of the subependymal glia

may bring about stenosis of the aqueduct, which is a

cause of obstructive hydrocephalus in childhood

1.2.4 INCREASED INTRACRANIAL

Aft er closure of the sutures, the volume of the cranial

cavity is fi xed by rigid bony walls and

compartmen-talized by partitions of bone and dura Th e normal

contents of the cranial cavity (blood, brain, and

CSF) are relatively incompressible Under these

circumstances, an increase in the volume of the

cranial contents will result in increased intracranial

pressure

Th e intracranial contents may expand because

of diff use brain edema, increased cerebral blood

A A

E.C.S B.M.

N.

FIGURE 1.24 Cerebral edema: principal ultrastructural forms

a hemiparesis contralateral to the lesion may

ensue; when the contralateral peduncle is

dis-placed and compressed against the free edge of the tentorium (Kernohan’s notch), an ipsilateral hemiparesis may follow; if the adjacent posterior cerebral artery is compressed, there can be sec-ondary infarction anywhere along its territory of distribution

• Compression due to temporal herniation and the downward thrust of central diencephalic hernia-tion may result in stretching of the blood vessels, especially the veins, that supply the midbrain and pons, which may be torn and cause potentially lethal brainstem hemorrhages; these are called

Duret hemorrhages

• External cerebral herniation through cal or traumatic defects in the calvarium may also occur

surgi-Bilateral cerebral lesions or circumstances that  result in a global increase of the volume

of  both hemispheres will ordinarily result in central diencephalic herniation and/or bilateral temporal lobe herniation A  midline, expanding lesion will likely result in central diencephalic herniation

1.2.4.2 Cerebellar herniations in infratentorial lesions

Two types of herniations exist:

• Upward herniation of the mesencephalon and

cere-bellum through the tentorial notch Direct

mesence-phalic lesions may result from this complication,

another, caused by an increase in the volume of

intracranial contents, are referred to as cerebral

herniations The site of herniation differs

depend-ing on whether the space-occupydepend-ing lesion is

supratentorial or infratentorial ( Fig. 1 25 )

1.2.4.1 Cerebral herniations in supratentorial

lesions A unilateral lesion ( Fig. 1 26 )that increases

the hemispheric volume is likely to cause a

hernia-tion of the cerebral hemisphere through openings

limited by the inferior border of the falx and by the

free edge of cerebellar tentorium on the ipsilateral

side of the lesion Depending on the size and the site

of the expanding lesion within the hemisphere, one

of several forms of herniation will occur, sometimes

in combination:

• Herniation of the cingulate gyrus under the falx

(subfalcine herniation) with lateral displacement

of the anterior cerebral arteries

• Lateral displacement of the midline structures

(i.e., the third ventricle, pineal gland, vein

of Galen)

• Downward herniation of the diencephalon

through the tentorial notch with downward

dis-placement of the fl oor of the hypothalamus and

of the mammillary bodies (central, diencephalic

herniation)

• Herniation of the hippocampal gyrus in the

tentorial notch between the brainstem and the

free edge of the tentorium cerebelli Th e

herni-ated temporal lobe can compress and stretch the

third and sixth cranial nerves When the

ipsilat-eral cerebral peduncle is compressed directly,

2 TOPOGRAPHIC ANALYSIS

OF CNS LESIONS

Topographic analysis of the lesions observed is just as important as the study of their morphologic aspects

It constitutes a crucial step in the att empt to arrive at

an etiological diagnosis and necessitates a rigorous and systematic examination of all the neural structures Systematic sampling of multiple anatomical levels is necessary and, wherever possible, techniques that allow for whole-brain sections provide invaluable material that permits the synchronous study of various areas of the CNS under the dissecting and the light microscope

as well as secondary lesions due to vascular

compression

• Cerebellar tonsillar herniation through the foramen

magnum is the most frequent and most

danger-ous complication of an infratentorial expanding

process, regardless of the nature of the insult or,

in case of a neoplasm, the degree of malignancy

Th e result of increased intracranial pressure in the

posterior fossa is the herniation of the cerebellar

tonsils downward through the foramen magnum

( Fig. 1 27 ), culminating in medullary

compres-sion with compromise of vital cardiorespiratory

FIGURE 1.26 Cerebral herniations (A) Inferior aspect of the cerebral hemispheres; note the herniated rim

of the right hippocampal gyrus compressing the oculomotor nerve and displacing the brainstem (B) Cerebral metastases causing temporal herniation; note displacement of the midline structures and cingulate herniation (C) Midbrain; note hemorrhagic lesion in the crus of the peduncle contralateral to the temporal herniation (Kernohan’s notch) (D,E) Midbrain and pontine hemorrhages involving mostly the tegmentum, secondary to temporal herniation

systems—for example, involvement of upper and lower motor neurons in amyotrophic lateral sclero-sis, spinocerebellar involvement in Friedreich ataxia

3 SYNTHETIC INTEGRATION

Th e fi ndings in the two components of the pathological examination, artifi cially set apart as

morphologic and topographic analyses, need to be

integrated Furthermore and most importantly, correlation of these fi ndings with the clinical data, laboratory and radiological data, general autopsy

fi ndings, and all other available diagnostic data must occur to arrive at an accurate etiological diagnosis

Th us, for example, a thorough neuropathologic understanding of cerebral infarcts is possible only aft er careful and complete postmortem examination

of the vascular tree, heart, and lungs and aft er paring the anatomical fi ndings with information provided by the clinical picture, the chronology of the functional disturbances, and data from cerebral and vascular imaging

Likewise, the study of the lipidoses cannot be based solely on neuropathological fi ndings It neces-sitates detailed correlation with data from the gen-eral postmortem examination and neurochemical/genetic analysis

As a further example, the interpretation of phologic fi ndings in hereditary disorders of the CNS

mor-or peripheral nervous system and of diseases of etal muscles requires correlation with molecular and genetic data

2.1 Diffuse Distribution

Lesions that are diff usely distributed thought the

brain may be seen in systemic diseases such as

meta-bolic or circulatory disorders or also can be the

result of blood-borne, infective processes Some of

the degenerative diseases may likewise cause diff use

lesions of the CNS Nevertheless, it is important to

emphasize that, despite the diff use character of these

changes, lesions oft en show regional predominance

2.2 Focal Distribution

Lesions may be localized to an anatomically

well-defi ned area (lobe of the cerebral hemisphere,

basal ganglia, brainstem), and certain preferential

sites of involvement are linked to specifi c

etiologi-cal entities (e.g., some cerebral tumors preferentially

occur in certain locations of the brain) Lesions may

also be localized to a vascular territory

2.3 Disseminated Distribution

Th is is seen essentially in multifocal processes, of

which multiple sclerosis is the most characteristic

example

2.4 Systematized Distribution

A number of nervous system disorders,

espe-cially degenerative diseases, cause changes that

involve certain functionally related morphologic

FIGURE 1.27 Cerebellar tonsillar herniation (A) Posterior view (B) Anterior view

2

K E I T H L L I G O N , K A R I M A M O K H TA R I , A N D T H O M A S W S M I T H

1 CLASSIFICATION

Th e basis of classifi cation of nervous system tumors

remains the histological appearance of a particular

neoplasm by light microscopic examination

(sup-plemented by immunohistochemical and electron

microscopic observations where appropriate) It is

becoming clear, however, that information derived

from cytogenetics and molecular genetics will play

an increasingly important role in tumor classifi cation,

particularly with respect to providing more precise

diagnostic and prognostic information about a

par-ticular tumor Underlying most histology-based

clas-sifi cation approaches has been an implicit assumption

that the phenotypic appearance of a particular tumor

accurately refl ects its cellular origins (e.g., low-grade

astrocytomas are derived from mature astrocytes,

etc.) Recent evidence, however, suggests that at least

some CNS tumors, such as glioblastoma and

medul-loblastoma, might be derived from neural progenitor

cells that persist throughout adult life It is also clear

that, as with other human cancers, CNS tumors arise

when alterations occur in growth regulatory genes, such as oncogenes and tumor suppressor genes Th us

it is paramount that any classifi cation scheme be fl ible enough to allow for the inclusion of new diagnostic categories as well as the modifi cation and even removal

ex-of prior categories on the basis ex-of information derived from newer methodologies Th e classifi cation scheme used in this book is based on the current (2007) World Health Organization (WHO) classifi cation of nervous system tumors

CNS tumors can be grouped into two major

categories:  primary tumors and secondary tumors

Primary tumors arise from cells that are intrinsic to the CNS or its coverings, including the calvarium, and include tumors of neuroepithelial origin and non-neuroepithelial origin Secondary tumors arise from sites elsewhere in the body and involve brain or spinal cord mainly by hematogenous dissemination (metastases) or less oft en by contiguous extension CNS tumors can also be grouped according to location and their corresponding incidence by age

In adults , approximately 70% of all brain tumors

astrocytic neoplasms Th ey can aff ect all age groups but are mainly tumors of adults, with 25% occurring between the ages of 30 and 40 Th ey most commonly occur in the cerebral hemispheres (especially frontal and temporal lobes), followed by brainstem and spi-nal cord, and are rarely seen in the cerebellum Th e clinical features refl ect the location of the tumor, with seizures being a frequent presenting symptom Imaging studies usually show an ill-defi ned, homo-geneous, non–contrast-enhancing lesion; the pres-ence of focal contrast enhancement may suggest progression toward anaplasia and a higher grade Macroscopically, these tumors enlarge and dis-tort involved brain structures, oft en with blurring of normal anatomical landmarks ( Fig. 2.1A ) Cysts of varying sizes and focal calcifi cations may be present Microscopically, diff use astrocytomas are low to moderately cellular tumors composed of well-diff er-entiated astrocytes ( Fig. 2 1B ) Some degree of nuclear atypia is almost always present, which should help dis-tinguish the neoplastic cells from reactive astrocytes Mitoses are extremely rare or absent Microvascular proliferation and necrosis are never present Th e back-ground matrix may be loose, vacuolated, or even micro-cystic Th e Ki-67/MIB-1 labeling index (a measure of cellular proliferation) is usually less than a few percent

mas, and gliomas (ependymoma, astrocytoma) in

decreasing order of frequency

2 PRIMARY NEOPLASMS

2.1 Tumors of Neuroepithelial Tissue

2 1 1 A S T R O C Y T I C T U M O R S

2.1.1.1 Diff usely Infi ltrating Astrocytoma s

As a group these astrocytomas share the following

features:  widespread occurrence throughout the

CNS, clinical presentation in adults, diff use infi

ltra-tion of adjacent and oft en distant brain structures,

and tendency for progression to anaplasia over time

A number of histological grading schemes have

been used for diff usely infi ltrating astrocytomas;

however, the Sainte Anne/Mayo grading system and

its adaptation to the current WHO classifi cation has

proved to be the most reproducible and predictive

of tumor behavior Th e Sainte Anne/Mayo criteria

are based on the presence or absence of four easily

recognizable histological features:  nuclear

pleomor-phism , mitoses , microvascular proliferation , and

necro-sis While the Sainte Anne/Mayo system recognizes

a grade I  diff use astrocytoma (lacking all of the

Table 2.1 Grading of Diffuse Astrocytoma

W H O G R A D E D E S I G N AT I O N H I S T O L O G I C A L C R I T E R I A ( S T E A N N E / M AY O )

mitoses*

mitoses, microvascular proliferation, AND/OR necrosis **

* Th e presence of a single mitosis in a diff use astrocytoma that only exhibits nuclear pleomorphism is not usually suffi cient to reclassify it as a WHO grade III tumor (except in the case of very small samples)

** Necrosis is not required for the diagnosis of glioblastoma as long as microvascular (endothelial) proliferation is present

Th ree histological variants of diff use astrocytoma have

been recognized, although in practice most have a

mix-ture of cell types By far the most common variant is

the fi brillary astrocytoma , which is composed of

neo-plastic cells with scant perikaryal cytoplasm within a

loose but consistently GFAP-positive fi brillary matrix

Gemistocytic astrocytoma is defi ned as a tumor in which

at least 20% of the neoplastic cells resemble

gemisto-cytic astrocytes (i.e., have abundant eosinophilic

cyto-plasm and peripherally-displaced nuclei)( Fig.  2 1C )

Th ese tumor cells strongly express GFAP Although

gemistocytic astrocytomas are highly associated with

progression to anaplastic astrocytoma and

glioblas-toma, they should not automatically be assigned a

higher grade unless the appropriate histological

cri-teria are fulfi lled Th e protoplasmic astrocytoma is the

least common (and most controversial) variant It is

an astrocytic tumor composed mainly of small round

cells with scant, minimally GFAP-reactive processes

in a prominent mucoid or microcystic background

matrix Th is patt ern bears a striking resemblance to the

loose/spongy tissue of pilocytic astrocytomas and may

also be focally seen in other tumors (e.g., glioma, dysembryoplastic neuroepithelial tumor) For

oligodendro-this reason the inclusion of protoplasmic astrocytoma as

a distinct variant of astrocytoma has been challenged Characteristic molecular changes in grade II astrocytomas include polysomy of chromosome 7 PMID:  21343879 (~76% of cases), mutations of

isocitrate dehydrogenase genes 1 or 2 ( IDH1/2) in more than 70% of tumors, mutations in the TP53

tumor suppressor gene in about 50% of cases, expression of the platelet-derived growth factor and its receptor, and loss of portions of chromosome

over-22 Most adult diff use low-grade astrocytomas will

progress to a higher-grade tumor such as anaplastic astrocytoma WHO grade III Th e average interval to malignant change is about 4 to 5 years, but this may vary considerably

2.1.1.1.2 Anaplastic Astrocytoma (WHO Grade III) Th ese tumors oft en arise in the sett ing of a preexisting low-grade diff use astrocytoma but can

also present de novo without clear evidence of a

FIGURE 2.1 Diff use astrocytoma (A) Th alamic astrocytoma (gross) Microscopic features: (B) Low-grade fi

bril-lary astrocytoma (H&E) (C) Gemistocytic astrocytoma (H&E) (D) Anaplastic astrocytoma (H&E)

site hemisphere Th e tumor may be surrounded by considerable vasogenic edema manifested as hyper-intensity on a T2-weighted MRI scan

Macroscopically, GBMs oft en appear as tively well-defi ned mass lesions, although there is almost always signifi cant microscopic infi ltration

typically have a “variegated” appearance with solid gray-pink tissue at the periphery and yellow zones

of central necrosis ( Fig.  2 2A ) Some have old and recent hemorrhage In common with other diff use astrocytomas, GBMs may widely infi ltrate adjacent tissue and extend for long distances within fi ber tracts Th ey may sometimes form additional masses

at distant sites, creating the impression of a cal or “multicentric” glioma on neuroimaging stud-

multifo-ies (see below discussion of gliomatosis cerebri ) True

multifocal gliomas probably do occur, although their exact frequency has been diffi cult to establish and may actually be much lower than their previously estimated range (2.4% to 7.5% of all gliomas) Th ese tumors would by defi nition be polyclonal and, at present, can only be proved by the use of molecular markers Some GBMs extend into the subarachnoid space or ventricles with the potential for cerebro-spinal fl uid (CSF) dissemination, although this appears to be a relatively infrequent phenomenon Extracranial extension and hematogenous dissemi-nation are very rare in patients who have not had prior surgery GBMs are among the most malig-nant tumors, having a mean survival ranging from less than 1 year to 18 months, with less than 2% of patients surviving longer than 3 years

All GBMs share in common the histological features of high cellularity, marked nuclear atypia, mitoses, microvascular proliferation, and necro-sis However, their microscopic appearance can be highly variable, with considerable regional heteroge-neity In some GBMs the tumor cells may show con-siderable nuclear and cytoplasmic pleomorphism with multinucleated giant cells ( Fig. 2 2B ), whereas

activity in comparison to its low-grade counterpart,

but microvascular proliferation and necrosis are

absent ( Fig. 2 1D ) Many but not all tumor cells may

express GFAP and OLIG2 Ki-67/MIB-1 labeling

indices are generally increased (usually 5% to10%)

but can overlap with both low-grade diff use

astro-cytoma and glioblastoma Th ese tumors are

aggres-sive, with typical survivals of only 2 to 3 years from

diagnosis

At a molecular level, anaplastic astrocytomas

share the molecular features of diff use astrocytoma

grade II lesions including chromosome 7 polysomy,

IDH1/2 mutation, and TP53 mutations However,

in addition they also acquire events critical to

malig-nant progression, such as inactivation of cell cycle

control pathway genes CDKN2A/p16/ARF and RB ,

amplifi cation of CDK4/6, losses on chromosome

10, as well as loss of parts of the long arm of

chromo-some 19 Given that these mutations are also seen

in glioblastoma, no alterations specifi c to anaplastic

astrocytoma have yet been proposed Conversely,

it is generally felt that the glioblastoma-associated

molecular alterations of EGFR amplifi cation and

EGFRvIII should be present only rarely in WHO

grade III tumors

2.1.1.1.3 Glioblastoma (WHO grade IV)

Glioblastoma (also known as glioblastoma

multi-forme and still abbreviated as GBM) is a malignant,

rapidly progressive, and fatal astrocytic neoplasm It

is the most common primary brain tumor,

account-ing for approximately 10% to 15% of all intracranial

most commonly arise de novo in the absence of a

preexisting astrocytic tumor (“primary GBM”, more

than 90% of tumors) but may also develop from a

less-malignant diff use astrocytoma typically

associ-ated with IDH 1/2 mutation (“secondary GBM”)

GBMs occur in all age groups, but most arise in

adults, with a peak incidence between the ages of

45 and 70 years Th ey may arise in any region of the

small undiff erentiated cells Necrosis is a istic feature of GBM and can consist of either large confl uent foci of coagulative necrosis and/or small band-like or serpiginous “geographic” necrotic foci surrounded by a rim of densely packed tumor cells imparting the characteristic and highly diagnostic pseudopalisading patt ern ( Fig. 2 2C ) Microvascular proliferation is defi ned as the presence of abnormal vessels with walls composed of two or more lay-ers of mitotically active endothelial (and/or other vascular wall) cells, oft en forming glomeruloid structures ( Fig.  2 2D ) Microvascular proliferation has also been referred to as “capillary endothelial proliferation,” although it is likely that other vas-cular components besides the endothelial cells undergo proliferation Microvascular proliferation

character-others may consist mainly of small “undiff erentiated”

cells with scant cytoplasm and oft en poor GFAP

expression (see small cell GBM below) While many

GBMs contain zones having bett er-diff erentiated

fi brillary and gemistocytic astrocytes, all

astrocy-tomas, including GBM, have signifi cant

oligoden-droglial cell populations in almost all cases and are

positive for OLIG2 like other diff use gliomas Other

cell types that may be infrequently present in GBM

include cells with glandular or epithelioid features,

PAS-positive granular cells, and heavily lipidized

cells Proliferative activity is prominent in GBM and

both typical and atypical mitoses are found Ki-67/

MIB-1 labeling indices are likewise high, commonly

averaging 15% to 20% Proliferative activity is

usu-ally greatest in tumors composed predominantly of

A

B

C

D

FIGURE 2.2 Glioblastoma (A) Glioblastoma (gross) Microscopic features: (B) Cellular anaplasia, mitoses

(H&E) (C) Necrosis with pseudopalisading (H&E) (D) Microvascular proliferation with glomeruloid tures (H&E)

struc-frequent clinical problem, and genetic testing has emerged as a reliable means for predicting patient

that increased methylation of the promoter of the

MGMT gene is associated with increased

progres-sion-free survival in adult GBM Subsequent ies have expanded on this fi nding to determine that such tests likely identify patients with an increased methylation state, not just at the MGMT locus but throughout the tumor genome, consistent with a

stud-“methylator phenotype” (G-CIMP), which is ciated with or may result from mutations in IDH1/2 Detection of IDH1/2 mutations by immunohisto-chemistry or sequencing has therefore emerged as the most eff ective means of identifying patients with

asso-a more fasso-avorasso-able prognosis

2.1.1.1.4 Glioblastoma variants Giant cell blastoma (WHO grade IV) Th is is a rare tumor, accounting for less than 5% of all GBMs Th ey usually

glio-arise de novo without evidence of a preexisting

astrocy-toma and are otherwise similar in clinical presentation

to typical GBMs Radiologically and macroscopically they tend to be bett er circumscribed than ordinary GBMs Th ey are characterized histologically by the presence of giant and multinucleated cells that may show variable expression of GFAP Many examples have an abundant stromal reticulin network Th ey have other histological features typical of GBM, includ-ing mitoses, necrosis, and microvascular proliferation, which distinguishes them from the morphologically similar pleomorphic xanthoastrocytoma (see below)

Genetically this tumor has a high frequency of TP53

mutations Giant cell GBMs generally have a poor prognosis, although some reports have suggested a somewhat bett er clinical outcome, possibly due to their greater resectability and less infi ltrative behavior

Gliosarcoma (WHO grade IV) Gliosarcomas

are tumors having a biphasic patt ern of both plastic glial and mesenchymal tissue Th ey represent

neo-cursors However, based on recent human and

ani-mal studies, it is now suggested that they arise from

neuroepithelial progenitor cells, including

oligoden-droglial progenitor cells, that are present throughout

adult life,

GBM represents one of the best-characterized

cancers at the molecular level in all of oncology and

was one of the fi rst cancers to be studied in

large-scale integrative genomic approaches Collectively,

these molecular studies have consistently identifi ed

three core signaling pathways that are disrupted in

GBM:  increased activation of receptor tyrosine

TP53 signaling, and reduced signaling of the RB

pathway, Th e activation of RTK/RA S/PI3K

signal-ing is evident in 88% of GBMs and most

character-istically occurs due to amplifi cation of the EGFR

gene, along with rearrangements and

overexpres-sion of mutant EGFRvIII and extracellular domain

mutants Additional activation of these pathways

can occur through amplifi cation of PDGRA , MET,

AKT, or PIK3CA and aberrations that lead to loss

of function for the PTEN tumor suppressor gene

Studies of the TP53 gene have shown that rates

of mutation and inactivation of this pathway are

higher than once previously thought in adult GBM,

and TP53 is now known to be the most frequently

mutated gene in GBM, occurring in at least 42% of

adult tumors Th e RB pathway is targeted through

a number of diff erent means, including genomic

losses and mutation of RB1, along with genomic

losses targeting the CDKN2A family of genes or

amplifi cation of the negative regulators of the RB

pathway, such as CDK4

Molecular studies have shown that primary and

secondary GBMs oft en have diff erent sets of genetic

alterations:  primary GBMs are commonly

charac-terized by EGFR gene amplifi cation/overexpression

while secondary GBMs arising from lower-grade

precursors have a sequential series of genetic

altera-tions, including concurrent IDH1/2 and TP53 gene