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Neuro-Oncology
for the Clinical
Neurologist
Roy E. Strowd, III

MD, MEd, MS
Associate Professor of Neurology and Oncology
Department of Neurology, Internal Medicine, and Translational Sciences Institute
Wake Forest Baptist Comprehensive Cancer Center
Wake Forest School of Medicine
Winston-Salem, North Carolina
Elsevier
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NEURO-ONCOLOGY FOR THE CLINICAL NEUROLOGIST ISBN: 978-0-323-69494-0

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This book is dedicated to our patients and their caregivers—to those thriving after
20 years and those battling at 3 months; to those who have returned to fantastic
trips around the world and to those who are struggling after having lost work, friends,
and a former life; to caregivers who are excited by the opportunity of aclinical trial
and to those who are estranged by a disease that can at times seem to take away the
very soul. You asked that we tell your story and excite the world to find treatments,
make advances, and improve care. It is a privilege and honor to humbly present these
cases, tell parts of your story, and teach others.
v
Contributors List
Prakash Ambady, MD Ugonma N. Chukwueke, MD Federica Franchino, MD

Department of Neurology Center for Neuro-Oncology Department of Neuro-Oncology
Oregon Health and Science University Dana-Farber/Brigham and Women’s University and City of Health and Science
Portland, Oregon Cancer Center Hospital
Boston, Massachusetts Turin, Italy
Stephen J. Bagley, MD, MSCE and Harvard Medical School
Assistant Professor Boston, Massachusetts Jennifer L. Franke, BS
Department of Medicine, Division of Department of Neurosurgery
Hematology/Oncology Christina K. Cramer, MD Johns Hopkins University School of
University of Pennsylvania Perelman Department of Radiation Oncology Medicine
School of Medicine Wake Forest School of Medicine Baltimore, Maryland
Philadelphia, Pennsylvania Winston-Salem, North Carolina
Carol Parks Geer, MD
Jaishri Blakeley, MD Daniel E. Couture, MD Department of Radiology
Department of Neurology Department of Neurosurgery Wake Forest School of Medicine
Johns Hopkins University School of Wake Forest School of Medicine and
Medicine Winston-Salem, North Carolina Department of Radiology
Baltimore, Maryland Wake Forest Baptist Medical Center
Tiffany L. Cummings, PsyD Winston-Salem, North Carolina
Taylor Brooks, MD Department of Neurology
Wake Forest Baptist Medical Center Wake Forest School of Medicine Elizabeth R. Gerstner, MD
Winston-Salem, North Carolina Winston-Salem, North Carolina Division of Neuro-Oncology
Department of Neurology
Marc R. Bussière, MSc Sonika Dahiya, MBBS, MD Massachusetts General Hospital
Department of Radiation Division of Neuropathology Boston, Massachusetts
Oncology Department of Pathology and
Massachusetts General Hospital Immunology Stuart Grossman, MD
Boston, Massachusetts Washington University School of Medicine Sidney Kimmel Comprehensive Cancer
St. Louis, Missouri Center
Jian L. Campian, MD, PhD Johns Hopkins University
Department of Medicine Peter de Blank, MD, MSCE Baltimore, Maryland
Division of Oncology Associate Professor of Pediatrics
Washington University School of Department of Pediatrics Jacob J. Henderson, MD
Medicine University of Cincinnati Medical Center Section of Pediatric Hematology/Oncology
St. Louis, Missouri and Mary Bridge Children’s Hospital
Cincinnati Children’s Hospital Medical Tacoma, Washington
Michael D. Chan, MD Center
Department of Radiation Oncology Cincinnati, Ohio Lauren L. Henke, MD, MSCI
Co-Director, Gamma Knife Department of Radiation Oncology
Program Luisa A. Diaz-Arias, MD Washington University School of
Wake Forest School of Medicine Postdoctoral Research Fellow Medicine
Winston-Salem, North Carolina Department of Neurology St. Louis, Missouri
Johns Hopkins University School of Medicine
Baltimore, Maryland
vii
Contributors List
Matthias Holdhoff, MD, PhD David E. Kram, MD Nimish Mohile, MD

The Sidney Kimmel Comprehensive Section of Pediatric Hematology- Associate Professor of Neurology and
Cancer Center at Johns Hopkins Oncology Oncology
The Johns Hopkins University School of Wake Forest School of University of Rochester
Medicine Medicine Rochester, New York
Baltimore, Maryland Winston-Salem, North Carolina
Maciej M. Mrugala, MD, PhD, MPH
Wesley Hsu, MD Priya Kumthekar, MD Department of Neurology and Medical
Department of Neurosurgery Assistant Professor Oncology
Wake Forest Baptist Health Department of Neurology Mayo Clinic Cancer Center
Winston-Salem, North Carolina Northwestern University Feinberg School Phoenix, Arizona
of Medicine
Jiayi Huang, MD, MSCI Chicago, Illinois Carl M. Nechtman, MD
Department of Radiation Oncology Department of Neurosurgery
Washington University School of Shannon Langmead, CRNP Wake Forest Baptist Hospital
Medicine Department of Neurology Winston-Salem, North Carolina
St. Louis, Missouri Johns Hopkins University School of
Medicine Sapna Pathak, MD
Christina Jackson, MD Baltimore, Maryland Department of Neurology
Department of Neurosurgery Wake Forest Baptist Medical Center
Johns Hopkins University School of Adrian W. Laxton, MA, MD, FRCSC, Winston-Salem, North Carolina
Medicine FAANS
Baltimore, Maryland Department of Neurosurgery Joao Prola Netto, MD
Wake Forest School of Medicine Providence St Vincent’s Medical Center
Justin T. Jordan, MD, MPH Winston-Salem, North Carolina Portland, Oregon
Stephen E. and Catherine Pappas Center
for Neuro-Oncology Emily S. Lebow, MD David M. Peereboom, MD
Massachusetts General Hospital Department of Radiation Oncology Professor
Boston, Massachusetts Memorial Sloan Kettering Cancer Center Brain Tumor and Neuro-Oncology Center
New York, New York Cleveland Clinic
David Olayinka Kamson, MD, PhD Cleveland, Ohio
Department of Neurology Michael Lim, MD
Johns Hopkins Hospital Department of Neurosurgery Alessia Pellerino, MD
Baltimore, Maryland Johns Hopkins University School of Department of Neuro-Oncology
Medicine University and City of Health and Science
Ahmad N. Kassem, MD Baltimore, Maryland Hospital
Resident Physician Turin, Italy
Department of Internal Medicine Mary Jane Lim-Fat, MD
Metrohealth Medical Center Center for Neuro-Oncology John C. Probasco, MD
Cleveland, Ohio Dana-Farber/Brigham and Women’s Associate Professor of Neurology
Cancer Center Department of Neurology
Albert E. Kim, MD Boston, Massachusetts and Johns Hopkins University School of
Division of Neuro-Oncology Harvard Medical School Medicine
Department of Neurology Boston, Massachusetts Baltimore, Maryland
Massachusetts General Hospital
Boston, Massachusetts K. Ina Ly, MD Amy Pruitt, MD
Stephen E. and Catherine Pappas Center Department of Neurology
Teddy E. Kim, MD for Neuro-Oncology University of Pennsylvania
Department of Neurosurgery Massachusetts General Philadelphia, Pennsylvania
Wake Forest Baptist Hospital Hospital
Winston-Salem, North Carolina Boston, Massachusetts Shakti Ramkissoon, MD, PhD
Department of Pathology
Molly Knox, MD Sarah E. Mancone, MD Wake Forest School of Medicine
Department of Neurology Department of Neurology Winston-Salem, North Carolina and
Mayo Clinic Arizona Yale School of Medicine Foundation Medicine, Inc.
Scottsdale, Arizona New Haven, Connecticut Morrisville, North Carolina
viii
Contributors List
David Wayne Robinson, MD Michael H. Soike, MD Cristina Valencia-Sanchez, MD, PhD

Department of Radiology Hazelrig-Salter Radiation Oncology Department of Neurology
Wake Forest Baptist Medical Center Center Mayo Clinic Arizona
Winston-Salem, North Carolina University of Alabama at Birmingham Scottsdale, Arizona
Birmingham, Alabama
Carlos G. Romo, MD Courtney M. Vaughn, MPhil
Department of Neurology Roy E. Strowd, III, MD, MEd, MS Department of Radiation Oncology
Brain Cancer Program Associate Professor of Neurology and UNC School of Medicine
The Johns Hopkins University School of Oncology Chapel Hill, North Carolina
Medicine Department of Neurology, Internal
Baltimore, Maryland Medicine and Translational Sciences Thuy M. Vu, MS, CGC
Institute Department of Genetics
Roberta Rudà, MD Wake Forest Baptist Comprehensive Wake Forest Baptist Medical Center
Department of Neuro-Oncology Cancer Center Winston-Salem, North Carolina
City of Health and Science Hospital Wake Forest School of Medicine
Turin, Italy Winston-Salem, North Carolina Andrea Wasilewski, MD
Assistant Professor of Neurology
Colette Shen, MD, PhD Shivani Sud, MD University of Rochester,
Department of Radiation Oncology Department of Radiation Oncology Rochester, New York
UNC School of Medicine UNC School of Medicine
Chapel Hill, North Carolina Chapel Hill, North Carolina Patrick Y. Wen, MD
Center for Neuro-Oncology
Helen A. Shih, MD Laszlo Szidonya, MD, PhD Dana-Farber/Brigham and Women’s
Department of Radiation Oncology Department of Diagnostic Radiology Cancer Center
Massachusetts General Hospital Oregon Health and Science University Boston, Massachusetts and
Boston, Massachusetts Portland, Oregon Harvard Medical School
Boston, Massachusetts
Mary Silvia, MD Stephen B. Tatter, MD, PhD
Tuberous Sclerosis Clinic Department of Neurosurgery Michelle Marie Williams, MD
Wake Forest Baptist Medical Center Wake Forest School of Medicine Department of Neurosurgery
Winston-Salem, North Carolina Winston-Salem, North Carolina Wake Forest School of Medicine
Winston-Salem, North Carolina
Ananyaa Sivakumar Jigisha Thakkar, MD
The Sidney Kimmel Comprehensive Assistant Professor
Cancer Center at Johns Hopkins Department of Neurology and
The Johns Hopkins University School of Neurosurgery
Medicine Stritch School of Medicine
Baltimore, Maryland Loyola University Chicago
Maywood, Illinois
Riccardo Soffietti, MD
Department of Neuro-Oncology Kutluay Uluc, MD
University and City of Health and Science Department of Neurology
Hospital Oregon Health and Science University
Turin, Italy Portland, Oregon
ix
Foreword
Neuro-oncology is an exciting field. Providers from across medicine work collaboratively to provide
multidisciplinary care to patients who suffer from some of the most complex, life-changing, and at
times devastating diseases. Tumors of the brain, spinal cord, and leptomeningeal space are among
the most difficult to diagnose, refractory to treatment, and complex to manage. Patients and their
caregivers who are afflicted by these tumors are amongst the most engaged in their care of any
population that I have encountered. As new advances are made, novel techniques discovered, and
models of care refined, it is critical that providers in all areas of medicine understand the practice of
neuro-oncology and help provide unparalleled care to this population.
Who is this book for?
This book is intended for clinicians—providers who see patients in outpatient and inpatient medi-
cine. While the title speaks to neurologists, the audience of the book is much broader and includes:
1. Physicians: internists, medical oncologists, radiologists, emergency medicine physicians
2. Advanced practice providers: physicians assistants and nurse practitioners
3. Trainees: medical students, residents in neurology, neurosurgery, radiation oncology, radiology,
pathology, neuropsychology, pediatrics, and other fields
Importantly, while the text is focused on many aspects of tumor management in adults, selected
chapters heavily represent the clinical scenarios that are relevant for pediatric patients. These sec-
tions (Chapters 7, 11, 16, 17, 18, 25, and 27) include both common tumors in pediatric patients,
as well as late adult sequelae of pediatric brain tumor treatment that are critical for adult providers
who manage these patients into adulthood.
How should this book be used?
This is a case-based review of neuro-oncology. Each chapter is organized into real world cases that
reflect the diseases, clinical questions, and consultations that are encountered in clinical practice.
While the book is organized with the intention that you may read the text cover-to-cover, it is
written more with the intention to provide a quick clinical reference that clinicians can use in the
clinic just in time to manage new consultations, address patient care questions, and answer clinical
conundrums. The text is formatted to allow providers to quickly reference case scenarios when they
are referred a new patient with an abnormal MRI that might be tumor (Section 2); when they are
seeing a brain tumor patient and need to integrate their recommendations into standard of care
treatment algorithms (Section 3); when they are seeing a patient with a tumor syndrome that runs in
the family (Section 4); or when they are sent a cancer patient who may have a suspected neurologic
complication of cancer and its treatment (Section 5–8).
xi
Foreword
1. Section 1 is a neuro-oncology primer.

This section reviews the foundational clinical principles for taking care of neuro-oncology pa-
tients. Read at your leisure or when you have the following questions:
a. How do I interpret a neuropathology report? (Chapter 1)
b. What are the surgical options for my patient with a new brain mass? (Chapter 2)
c. What should I monitor when my patient is receiving radiation or chemotherapy?
(Chapters 3–4)
2. Section 2 is to be used when seeing a new imaging consult for a patient with an abnormal scan.
This section reviews common abnormal images. A new dural-based mass; is it a meningioma?
A new spinal cord lesion; what is it? Each case provides a differential diagnosis and practical
steps for managing the patient, including:
a. Dural-based lesions (Chapter 5)
b. Lesions in the brain parenchyma (Chapter 6)
c. Lesions in the posterior fossa (Chapter 7)
d. Lesions in the spinal cord (Chapter 8)
e. Lesions of the peripheral nerves (Chapter 9)
3. Section 3 is for managing patients with a known central nervous system tumor diagnosis.
This section summarizes the clinical scenarios that arise for patients with common tumors of the
nervous system and discusses how these patients are evaluated and treated, including:
a. Meningiomas (Chapter 10)
b. Low-grade gliomas (Chapter 11)
c. High-grade gliomas (Chapter 12)
d. Central nervous system lymphomas (Chapter 13)
e. Brain metastasis (Chapter 14)
f. Leptomeningeal disease (Chapter 15)
4. Section 4 focuses on familial tumor syndromes that affect the nervous system.
These patients often present first to a neurologist or primary care physician and require famili-
arity with the myriad manifestations that are often characteristic of these conditions. These
chapters review common clinical scenarios for patients with:
a. Neurofibromatosis type 1, type 2, and schwannomatosis (Chapter 16)
b. Tuberous sclerosis (Chapter 17)
c. Von Hippel Lindau disease (Chapter 18)
d. Cowden syndrome (Chapter 18)
e. Li-Fraumeni syndrome (Chapter 18)
f. Lynch syndrome (Chapter 18)
5. Sections 5–7 are for when providers are seeing consults of known cancer patients with neu-
rologic complaints.
Neurologic symptoms are the second most common reason for a cancer patient to be admitted
to the hospital (behind admission for scheduled chemotherapy!). Neurologic deficits can
occur from the cancer itself (Section 5) or from treatment of the cancer (Sections 6 and 7).
a. Section 5 reviews neurologic complications of the cancer itself including direct effects of
tumors that involve the nervous system and indirect effects of tumors that do not involve
the nervous system. These latter disorders may contribute to neurologic deficits through
paraneoplastic syndromes which are reviewed.
i. Neurologic complications in brain tumor patients including seizures, cerebral edema,
stroke, hydrocephalus (Chapter 19)
ii. Non-neurologic complications to watch out for in brain tumor patients including
endocrinopathy and hypercoagulability (Chapter 19)
iii. Neurologic complications of hematologic malignancies including leukemia and lym-
phoma (Chapter 23)
iv. Direct perineural cancer invasion causing cranial neuropathy in head and neck cancer
patients (Chapter 21)
v. Brachial plexopathy from cancer spread to the brachial plexus (Chapter 22)
vi. Paraneoplastic neurologic syndromes (Chapter 20)
xii
Foreword
Sections 6 and 7 review common neurologic complications of cancer treatment including

b.
radiation and systemic therapies. Both the central nervous system (CNS) and peripheral
nervous system (PNS) can be affected. These chapters review common CNS symptoms
(neurocognition), PNS symptoms (neuropathy), and other relevant complications includ-
ing:
i. Post-treatment radiation necrosis (Chapter 24)
ii. Treatment-induced neurocognitive dysfunction (Chapter 25)
iii. Chemotherapy induced peripheral neuropathy (Chapter 28)
iv. Complications of systemic therapies (Chapter 27)
v. Complications of immune-based therapies for cancer (Chapters 29–30)
vi. And rare complications of radiation therapy (Chapter 26)
What is included in this book?
In addition to the chapters highlighted above, several additional resources are included to provide
a quick review and reference of teaching points in neuro-oncology. These are intended to help the
practicing clinician as a quick guide and include:
1. Summary of clinical pearls: this is a summary of all of the clinical teaching points from each
chapter of the book. This is intended to be a quick reference guide on important, clinically rel-
evant, actionable items for managing patients. This is a quick and easy read to jog your memory
of key points in neuro-oncology.
2. Reference list of clinical cases: this is a list of the clinical cases that are covered in this book. Do
you want to read a case about how to manage recurrent glioblastoma? Do you need a refresher
case about how to diagnose a patient with tuberous sclerosis complex or neurofibromatosis? Do
you need to review a case of the neurologic complications of immune checkpoint inhibitors?
The list of cases is organized alphabetically by tumor type to serve as a quick reference to teach-
ing cases that are covered in this book. Not all brain and spinal cord tumors are intended to be
covered in this text and this reference list highlights the key and clinically relevant tumors that
are included in these cases.
xiii
Acknowledgements
It is only through the generous efforts and tireless work of the authors and coauthors that this
text is available and will improve care for patients. The future of our field lies in the next genera-
tion of practitioners. This text draws from the seasoned expertise of senior practitioners who have
decades of experience, as well as from the excitement of early career clinicians and investigators—it
is through these opportunities that the future of our field grows.
xv
Contents
Section 1: Basic principles of Section 3: Approach to patients

neuro-oncology with primary and secondary CNS
tumors
1. F undamentals of neuropathology:
introduction to neuropathology and 10. Approach to the meningioma patient�� 118
molecular diagnostics��1 Jennifer L. Franke, Christina Jackson, and Michael Lim
Sonika Dahiya and Shakti Ramkissoon 11. Approach to the low-grade glioma patient��136
2. S urgical considerations for brain and Carlos G. Romo, Ananyaa Sivakumar, and Matthias Holdhoff
spine tumors��18 12. A
pproach to the high-grade glioma
Michelle Marie Williams, Stephen B. Tatter, patient��153
and Adrian W. Laxton David Olayinka Kamson and Stuart Grossman
3. Introduction to radiation therapy��28 13. A
pproach to the patient with CNS
Emily S. Lebow, Marc R. Bussière, and Helen A. Shih lymphoma��172
4. E
vidence-based approaches to Ahmad N. Kassem and David M. Peereboom
chemotherapy for gliomas��38 14. A
pproach to a patient with brain
Alessia Pellerino, Federica Franchino, Roberta Rudà, metastasis��186
and Riccardo Soffietti Michael H. Soike and Michael D. Chan
15. A
pproach to the patient with
leptomeningeal metastases��197
Section 2: Neuro-oncology Jigisha Thakkar and Priya Kumthekar
imaging consults
Section 4: Inherited tumor
5. Evaluation of a dural-based lesion��53
David Wayne Robinson and Carol Parks Geer syndromes in neuro-oncology
6. E
valuation of a supratentorial
parenchymal lesion��69 16. A
pproach to patients with the n eoplasms
Albert E. Kim and Elizabeth R. Gerstner associated with neurofibromatosis type 1,
7. Evaluation of an infratentorial lesion�� 81 neurofibromatosis type 2,
David E. Kram, Jacob J. Henderson, and and schwannomatosis�� 210
Daniel E. Couture Jaishri Blakeley, Shannon Langmead, and Peter de Blank
8. Imaging of spinal lesions��93 17. A
pproach to the patient with tuberous
Teddy E. Kim, Carl M. Nechtman, and Wesley Hsu sclerosis��229
9. Evaluation of peripheral nerve lesions�� 104 Mary Silvia and Roy E. Strowd, III
K. Ina Ly and Justin T. Jordan 18. A
pproach to von Hippel Lindau, Cowden
disease, and other inherited conditions��242
Sapna Pathak, Thuy M. Vu, and Roy E. Strowd, III
xvii
Contents
Section 5: Neurologic complications Section 7: Neurologic complications

of cancer of systemic therapy
19. Neurologic complications of cancer�� 251 27. A

pproach to the patient with a delayed
Andrea Wasilewski and Nimish Mohile posttreatment CNS neurotoxicity�� 341
20. P
araneoplastic neurological disorder Amy Pruitt
syndromes�� 261 28. A
pproach to chemotherapy-induced
Luisa A. Diaz-Arias and John C. Probasco peripheral neuropathy��356
21. Perineural spread of cancer��285 Taylor Brooks and Roy E. Strowd, III
Kutluay Uluc, Laszlo Szidonya, Joao Prola Netto,
and Prakash Ambady
22. Cancer-associated plexopathy��293 Section 8: Neurologic complications
Mary Jane Lim-Fat, Patrick Y. Wen, and
of immune-based cancer therapies
Ugonma N. Chukwueke
23. C
ancer complications in patients with
hematologic malignancies��304 29. N
eurologic complications of immune
Cristina Valencia-Sanchez, Molly Knox, and Maciej M. Mrugala checkpoint inhibitors�� 371
Sarah E. Mancone and Roy E. Strowd, III
30. N
eurologic complications associated with
Section 6: Neurologic complications CAR T-cell therapy�� 381
of radiation therapy Stephen J. Bagley
Appendix 1: Summary of clinical pearls 389

24. A
pproach to the patient with radiation
Appendix 2: Reference list of clinical cases
necrosis�� 314
covered in this book 406
Jiayi Huang, Lauren E. Henke, and Jian L. Campian
25. Neurological complications of radiation�� 321 Index 412
Christina K. Cramer and Tiffany L. Cummings
26. Uncommon radiation-induced
neurological syndromes��328
Shivani Sud, Courtney M. Vaughn, and Colette Shen
xviii
Section | 1 | Basic principles of neuro-oncology
Chapter |1|
Fundamentals of neuropathology: introduction
to neuropathology and molecular diagnostics
Sonika Dahiya and Shakti Ramkissoon
CHAPTER OUTLINE Introduction

Introduction 1
Histologic classification of central nervous
In typical cases, the clinical workflow for brain tumors begins
system tumors 2
with imaging studies; however, despite the increased sensitiv-
Molecular characterization of central nervous ity and capabilities of these methodologies, diagnosing brain
system tumors 3
tumors requires histopathologic evaluation of tissue. It is
Clinical cases 4 imperative for clinicians to understand how brain tumors are
Case 1.1 Characteristic Histopathological classified so that they can better counsel patients at the time
and Molecular Features of Glioblastoma 4 of initial presentation, accurately describe prognosis, and pri-
Case 1.2 Use of Molecular Testing to Define oritize management of medical or neurological comorbidi-
the Diagnosis of WHO Grade 2, ties based on the anticipated behavior of the tumor.
Olidoendroglioma 5 Tumor classification has historically relied primarily
Case 1.3 Use of Genomic Profiling to upon morphologic features identified by light microscopy.
Establish a Diagnosis of WHO In the past decade, integration of high-throughput genomic
Grade 2, Astrocytoma 9 testing into routine clinical workflows has refined the
Case 1.4 Histopathological and Molecular approach to diagnosing brain tumors.1 In this chapter, we
Findings for WHO Grade 3, explore tumor classification from traditional microscope-
Anaplastic Astrocytoma 11 based approaches to currently available methodologies. We
Case 1.5 Pathologic Assessment of review genomic profiling and introduce the concept of an
Dural-Based Meningioma 13 integrated diagnosis.
Case 6 Histopathology of a Benign The chapter begins with a discussion of the histologic
Peripheral Nerve Sheath Tumor: assessment of brain tumors, which is often the first data
Schwannoma VS Neurofibroma 15 to be reported after a tumor surgery. This is followed by a
Conclusion 16 discussion of molecular profiling, which is used to further
classify these tumors, guide prognosis, and predict response
to therapy. Molecular data typically returns in the weeks
following surgery. Finally, we review a series of common
case scenarios and integrate the histologic and molecular
data into a final integrated diagnosis that clinicians can use
to help manage and counsel these patients.
1
Section |1| Basic principles of neuro-oncology
nervous system (CNS). Instead, gliomas are graded from

Histologic classification of central grade I to IV and are broadly divided into low- and high-
nervous system tumors grade tumors. Grade I and II are considered “low grade”
and grade III and IV as “high grade”; of these, grade I
tumors are generally well circumscribed, whereas grades
The primary method of diagnostic neuropathology and II–IV are diffusely infiltrating, albeit with some exceptions
brain tumor classification remains microscopic evaluation such as ependymoma and pleomorphic xanthoastrocytoma
of hematoxylin and eosin (H&E)–stained tissue sections by which tend to be well circumscribed despite conforming to
light microscopy. This approach has experienced relatively grade II. The histologic features assessed to establish glioma
few changes over the past several decades with generations of grading include atypia, mitoses, endothelial or microvas-
pathologists still undergoing specialized training focused on cular proliferation, and necrosis. Grade I tumors such as
learning to read or interpret stained sections on glass slides. pilocytic astrocytomas are most commonly encountered
The process of converting a portion of resected brain tis- in the pediatric setting. Although such tumors do occur in
sue to an H&E stained section is the first step to achieve a the adult population, the use of the term “lower-grade glio-
tissue-based diagnosis. Brain tissues removed at the time of mas” in adults largely refers to infiltrating grade II tumors
surgery can range from small biopsies, such as needle core such as diffuse astrocytoma and oligodendroglioma. Grade
biopsies, to large resections that often occur during a tumor III tumors include anaplastic astrocytoma (AA3) and ana-
debulking surgery. Once the fresh tissue reaches the labora- plastic oligodendroglioma (AO3), whereas glioblastoma
tory, the sample is subjected to fixation in formalin-based (GBM) is considered a grade IV astrocytoma. Progression
solutions that serve to preserve tissues and cells. of brain tumors from low to high grade does occur, most
Formalin-fixed tissues then undergo a series of steps, commonly in adults from grade II diffuse astrocytoma
commonly referred to as tissue processing, which prepares to higher-grade gliomas such as AA3 or GBM, which are
the formalin-fixed tissues for embedding into a block of termed “secondary” GBM. Not all GBMs present as progres-
paraffin wax. Once the tissue fragment is embedded in sion from a lower-grade neoplasm. In fact, the vast major-
paraffin and mounted into a cassette, this “block” serves as ity of GBMs present as de novo tumors without any prior
the final medium where the tissue can be safely stored for history of a lower-grade glioma and are referred to as “pri-
years (even decades). Importantly, this processing method mary” GBMs. Ependymomas are also considered a subtype
preserves the integrity of the tissues for later use. Forma- of glioma, albeit with combined glial and epithelial lineage,
lin-fixed paraffin-embedded (FFPE) samples are the main- and are graded from I–III; these are generally well circum-
stay of both traditional microscopic analysis and serve as scribed, with the exception of WHO grade III tumors.
the starting medium for most tissue-based molecular and Tumor Lineage. Tumor lineage is another important
genomic assays currently available. concept that goes hand in hand with grading. Lineage refers
Once a tissue sample is converted to an FFPE block, to the presumed cell of origin to which a tumor morpho-
sections (5 microns thickness) can be cut from the block, logically resembles. This designation then leads to broad
placed onto glass slides, and subjected to staining with the categories of tumors such as astrocytoma, oligodendrogli-
dyes hematoxylin and eosin. Hematoxylin stains nucleic oma, and ependymoma among others.
acids a deep blue-to-purple color, which readily highlights When reviewing H&Es for tumor classification, the first
the nuclei of cells. Eosin stains other cellular components, step is determining whether tumor cells are present. An ini-
like proteins, with a bright pink color that contrasts with the tial feature to assess is the overall cellularity of the tissue com-
blue hematoxylin-stained nuclei—together these two dyes partment (white matter, cortex, thalamus, cerebellum) being
serve as the basis for all H&E-based tumor classification. analyzed. This cellularity should then be compared to what
Brain tumor classification based on H&E features relies is normally expected for these tissues. When a tumor is mod-
on the fact that the histologic appearance of these tumors erate-to-densely cellular, this step can be trivial; however, in
is consistent from one patient to another. In fact, the fea- instances of low tumor content or scattered tumor cells infil-
tures are so reproducible that they have been codified into trating white matter (e.g., gliomatosis pattern), this step can
the World Health Organization (WHO) Classification of be surprisingly difficult, as these tumors can be indistinguish-
Tumors of the Central Nervous System, which outlines able from reactive processes (gliosis) seen in the brain.
the microscopic features present in all brain tumors and Once tumor cells are recognized, a grade must be
serves as the central resource to ensure all patients around assigned. Among diffuse gliomas, this is accomplished by
the world are diagnosed and graded using the same criteria. cataloging the presence or absence of low- and high-grade
Tumor Grading. Unlike other tumors, which are staged histologic features, including nuclear atypia, presence/
based on size, lymph node involvement, and presence or absence of mitotic figures, microvascular proliferation, and
extent of metastases (e.g., TNM classification), staging is not necrosis. Grade II diffuse gliomas are typically moderately
used for gliomas, which rarely spread beyond the central cellular tumors that can occur as both solid lesions with
2
Fundamentals of neuropathology Chapter |1|
diffuse infiltration of adjacent brain tissues or as largely astrocytes and glial cells, NeuN (neuronal nuclei), a marker
diffusely infiltrating tumors. Grade II diffuse gliomas by of neuronal differentiation, and OLIG2 (oligodendrocyte
definition lack mitoses, microvascular proliferation, and transcription factor 2), a nuclear marker of glial lineage.
necrosis but show increased cellularity and nuclear atypia. In recent years, antibodies capable of detecting specific
The presence of mitoses (a marker of cell division) in a dif- mutant proteins, such as H3F3A(K27M), BRAF(V600E),
fuse glioma warrants upgrading to an anaplastic glioma and IDH1(R132H), have become widely available for rou-
(grade III), and if necrosis and/or microvascular prolifera- tine clinical use. Integrating IHC results with histologic fea-
tion are present in astrocytic lineage tumors, a diagnosis of tures provides neuropathologists with critical information
GBM (grade IV) would be warranted. that is used to accurately assign a tumor lineage and grade.
It should be noted that there are differences in grading Additionally, as we will discuss below, determining muta-
based on tumor lineage. For example, oligodendrogliomas tional status can also provide therapeutic and prognostic
are restricted to grade II and III tumors, with no grade I information for the patient and clinical providers.
or IV oligodendroglioma categories; in contrast, astrocyto-
mas are graded on a scale of I to IV. Oligodendrogliomas
with necrosis and microvascular proliferation are grade III, Molecular characterization of
whereas astrocytomas with the same features are consid- central nervous system tumors
ered grade IV.
In addition to features important to grading, other his-
tologic features readily apparent on H&E sections include Understanding the genomic drivers of each patient’s tumor
tumor cell morphology and growth features, which are is important to achieving the goals of precision medi-
characteristic of certain lineages. Oligodendroglioma cine. Traditional methodologies for understanding onco-
tumor cells are classically associated with round nuclei genic drivers have been limited to single gene sequencing
within cells that have clear cytoplasm, resulting in a “fried methods that interrogate hotspot mutations in specific
egg” appearance. These tumor cells are often distributed genes such as BRAF or IDH1/2. Moreover, fluorescence in
within a network of fine capillary-like vessels reminiscent situ hybridization (FISH) analyses allow for gene level or
of a “chicken wire” pattern. Astrocytomas often have irregu- arm-level evaluation to identify copy number alterations
larly shaped nuclei that may be eccentrically displaced (or commonly associated with CNS tumors such as EGFR
pushed to the side of the cell); when associated with abun- amplification in GBMs or chromosome 1p/19q co-deletion
dant amounts of pink cytoplasm, it is commonly referred in oligodendrogliomas. Although these methodologies
to as gemistocytic morphology. provide powerful insights into the molecular mechanisms
For many decades, the assessment of histologic features driving gliomagenesis, they require significant tumor input
by H&E has been the foundation by which tumors were if multiple probes need to be tested, and need specialized
defined and served as the basis for much of our current personnel for interpretation, all of which can limit the
understanding of natural history of diseases. Although this availability of testing.
approach has proven invaluable, it is not without known The ability to extract nucleic acids (DNA and RNA) from
limitations. Such challenges include tumors that dem- FFPE samples has revolutionized integration of genomic
onstrate overlapping features between different lineages, data into diagnostic algorithms. Extracted FFPE DNA can
thereby creating a challenge when attempting to assign a now be used in massively paralleled or next-generation
diagnosis and grade. Additionally, classification is entirely sequencing (NGS) assays that have largely replaced the need
dependent on the tissue sampled, which introduces the for single gene assays or FISH testing in brain tumors. Com-
concept of “under sampling.” In some cases wherein neu- mon approaches to NGS testing of DNA range from tar-
roimaging studies highlight tumors that likely represent geted panels that interrogate 30–500 cancer-related genes to
high-grade gliomas, on H&E sections the resected tissue whole-exome (WES) or whole-genome sequencing (WGS).
may only demonstrate low-grade glioma characteristics. RNA testing options range from gene expression profiling
The discrepancy frequently results from undersampling of to whole transcriptome RNA sequencing. In many cases,
the more overtly malignant portions of the tumor. the amount of tissue (and DNA) needed to perform a single
In practice, H&E analysis is paired with immunohisto- gene assay is equivalent to that needed for a large panel that
chemistry (IHC) to support tumor classification particu- includes over 300 genes. The benefit of panel-based sequenc-
larly for lineage assignment and, more recently, to identify ing or WES lies in the ability to identify single nucleotide
specific mutations that can be detected at the protein level. variants, small insertion-deletions (indels), rearrangements,
IHC is a method of applying antibodies against specific and even, in some cases, copy number alterations in hun-
protein antigens that are evaluated using light microscopy. dreds of genes in parallel compared to single gene assays.
Common markers that are assessed by IHC include GFAP Application of these advanced technologies has iden-
(glial fibrillary acidic protein), a cytoplasmic marker of tified key genomic signatures of specific tumor lineages.
3
Seminal studies from The Cancer Genome Atlas demon- data to support diagnosis and prognosis, and guide clinical
strated that adult gliomas are driven more by copy number decision-making.
alterations than mutations contrary to what is observed
in other malignant tumors such as lung, colon, or breast
carcinomas. Indeed, adult GBMs are typically character-
ized by polysomy of chromosome 7, EGFR amplification, CASE 1.1 CHARACTERISTIC
CDKN2A/B deletion, and monosomy of chromosome 10 HISTOPATHOLOGICAL AND
(leading to single copy loss of PTEN).2 Conversely, oligo- MOLECULAR FEATURES OF
dendroglial lineage tumors harbor IDH1/2 mutations in GLIOBLASTOMA
association with chromosome 1p/19q co-deletion and fre-
quent alterations involving CIC and FUBP1. Young adult Case. A 69-year-old male presented to the emergency depart-
diffuse astrocytomas are characterized by a combination ment with new onset seizures and rapidly progressive right
of IDH1/2, TP53, and ATRX mutations. In the pediatric sided weakness. Brain MRI with contrast revealed a centrally
setting, grade I pilocytic astrocytomas are frequently char- necrotic, multifocal ring-enhancing lesion in the left posterior
acterized by BRAF alterations, including point mutations frontal lobe (Fig. 1.1).
(BRAF V600E) or gene fusions (KIAA1549-BRAF). Pediatric Histology. Microscopic examination of H&E sections
midline high-grade gliomas are now categorized based on (Fig. 1.2 A,B) demonstrates a densely cellular glial neoplasm
composed of cells with irregular and hyperchromatic nuclei
their mutational profile. The presence of an H3 mutation
associated with moderate amounts of eosinophilic cytoplasm.
(e.g., H3F3A K27M) in a midline diffuse glioma now war-
Mitoses are readily identified. Multifocal microvascular prolif-
rants a grade IV designation independent of other histo-
eration is present, as well as areas of multifocal necrosis in-
logic features. Focused analysis of rare glioma subtypes has
cluding palisading necrosis (Fig. 1.2B, black arrows). Immu-
also identified novel oncogenic drivers, as is the case with nohistochemistry reveals positive staining in tumor cells for
angiocentric gliomas, which are essentially defined by the GFAP (Fig. 1.2F), retained expression of ATRX (Fig. 1.2D), and
presence of MYB alterations such as MYB-QKI fusions. negative staining for IDH1(R132H) (Fig. 1.2C).
By recognizing that many brain tumors can be readily Genomic and molecular analyses. Genomic profiling of tu-
distinguished from each other based on genomic signa- mor DNA by NGS reveals EGFRvIII amplification, TERT promot-
tures, tumor classification has been refined to incorporate er mutation and homozygous deletion of CDKN2A/B. Altera-
these data. The field is moving toward a model of an “inte- tions were not detected in the following genes: IDH1, IDH2,
grated diagnosis” that combines histologic findings with BRAF, ATRX, TP53, PDGFRA. Arm-level copy number analysis
those of genomic/molecular data. In this approach, tumors revealed polysomy of chromosome 7 and monosomy of chro-
are classified and graded first based on H&E and IHC fea- mosome 10. There was no evidence of 1p/19q co-deletion.
tures which yields a histopathologic diagnosis. In parallel, Additionally, MGMT promoter methylation analysis demon-
a portion of tissue is subjected to NGS testing that yields strated no evidence of methylation.
genomic characteristics such as mutations, fusions, and Integrated Diagnosis: GLIOBLASTOMA, WHO Grade IV,
copy number alterations identified in the tumor. The his- IDH1/2 wild-type, EGFRvIII amplified; MGMT promoter un-
tologic and genomic findings are then collected together methylated
into a unified final and integrated diagnosis—often several Teaching Points. This case illustrates the classic clinical,
histologic, and genomic presentation of adult glioblastoma.
weeks after a histopathologic diagnosis has been rendered.3
Patients present with neurologic symptoms, typically non-
Given the time required to perform genomic testing, treat-
specific but which can include new-onset seizures in the fifth
ment is typically initiated based on the histopathologic diag-
to seventh decades of life. Imaging studies reveal important
nosis; however, the value of additional genomic and molecular
characteristics such as location, size, enhancement, and in-
data is to enhance diagnostic accuracy, provide prognostic volvement of adjacent brain tissues. The histologic analysis of
biomarkers (e.g., IDH1/2 mutational status), and refine the the tumor in this case demonstrated characteristic features of
treatment plan to better align with the patient’s genomic pro- GBM including increased cellularity, cells with irregular nuclei,
file. In this approach, the integrated diagnosis serves to over- and high-grade features (mitoses, microvascular proliferation,
come limitations associated with traditional histopathology and necrosis). Immunohistochemical stains for GFAP, OLIG2,
diagnoses and ensures optimal clinical management. and SOX2 support a glial lineage. The genomic profile of
this tumor also demonstrates the classic alterations associ-
ated with adult GBM, notably gains of chromosome 7, single
Clinical cases copy loss of chromosome 10, and homozygous deletion of
CDKN2A/B. Amplification of EGFR is detected in approximate-
ly 40% of adult GBMs and the EGFRvIII variant is seen in half
In the following case presentations, we will explore how of these cases. The EGFRvIII variant results from deletion of
histopathologic findings can be combined with genomic exons 2–7, which generates a constitutively activated, ligand-
4
A B
Fig. 1.1 MRI Brain including (A) axial T2-weighted sequence showing a 2.9 × 2.4 cm mass with surrounding edema in the left
posterior frontal lobe, and (B) axial T1-weighted gadolinium enhanced sequence showing multiple foci of ring-enhancement with
central necrosis concerning for a diagnosis of high-grade glioma.
independent kinase that promotes cell proliferation through Clinical Pearls

the PI3 kinase, RAS, and MAPK signaling pathways. Although
1. Microvascular proliferation and palisading necrosis are
no specific therapies have demonstrated utility against EG-
pathologic hallmarks of glioblastoma and, when present,
FRvIII, it is an active area of investigation and serves as a key
establish the diagnosis of GBM.
player of tumor growth. Loss of one copy of chromosome 10
2. IDH1/2 gene mutation is rare in glioblastoma; EGFR
is the most frequently detected genomic alteration in GBM,
amplification and MGMT promoter methylation are
occurring in 60–80% of cases.2 The tumor suppressor PTEN is
observed in approximately 40% of GBMs.
located at 10q23.3 and considered a critical candidate gene in
gliomagenesis as it is an important negative regulator of the
PI3 kinase pathway. TERT promoter mutations are detected in
70–80% of GBMs and are associated with a worse prognosis
in the absence of IDH1/2 mutations. CASE 1.2 USE OF MOLECULAR
As standard of care, patients diagnosed with GBM are TESTING TO DEFINE THE
treated with combination chemo- and radiation (adjuvant) DIAGNOSIS OF WHO GRADE 2,
therapy (see Chapters 4 and 12 for further discussion of treat- OLIDOENDROGLIOMA
ment regimens for GBM). Analysis of the MGMT promoter is
typically performed to evaluate the tumor’s sensitivity to the Case. A 39-year-old female presenting with new onset head-
alkylating agent temozolomide. O6-methylguanine methyl- aches. Brain MRI reveals a nonenhancing temporal lobe lesion
transferase (MGMT) is a DNA repair enzyme that is associated (Fig. 1.3).
with resistance to alkylating agents when expressed. Methyla- Histology. Microscopic examination of H&E sections (Fig.
tion of the MGMT promoter leads to reduced protein expres- 1.4A) reveals a moderately cellular glial neoplasm composed of
sion in tumor cells allowing for accumulation of alkylating- cells with centrally located round nuclei associated with modest
induced DNA damage that promotes cell death. In this tumor, amounts of clear cytoplasm. Mitoses are not readily identified
the absence of MGMT promoter methylation (unmethylated) and occur in less than 1 per 10 high-power fields (HPFs). High-
indicates decreased responsiveness to temozolomide. grade features including microvascular proliferation and ne-
In summary, this case highlights the classic pathologic crosis are not detected. Immunohistochemistry reveals positive
features of adult GBM and illustrates how the genomics can staining in tumor cells for IDH1 (R132H) (Fig. 1.4B) and OLIG-2
inform the signaling pathways driving gliomagenesis and pro- (Fig. 1.4D), and negative staining for TP53 (image not shown),
vide potential therapeutic targets and important prognostic with low Ki-67 proliferation index (Fig. 1.4E). An immunostain
information that can inform clinical decision-making. for ATRX shows positive staining in tumor nuclei (Fig. 1.4C).
5
H&E H&E
A B
IDH1 ATRX
C D
P53 GFAP
E F
Fig. 1.2 Microscopic examination showing histologic features consistent with glioblastoma including H&E stained sections (A,B)
showing microvascular proliferation (A, black arrowheads), and palisading necrosis (B, black arrows). Immunohistochemistry shows
negative staining for IDH1(R132H) (C), retained expression of ATRX (D), negative staining for p53 (E), and positive staining in
tumor cells for GFAP (F).
6
A B
Fig. 1.3 MRI Brain including (A) axial fluid attenuation inversion recovery sequence showing a nonenhancing mass with minimal
surrounding edema in the left anterior temporal pole, and (B) axial T1-weighted gadolinium enhanced sequence showing no
evidence of contrast enhancement.
Genomics and molecular analysis. Genomic profiling of receptor tyrosine kinase pathways. The absence of an ATRX
tumor cells reveals IDH1 p.R132H and CIC p.R215W muta- mutation, and therefore retained ATRX protein expression,
tions. Alterations were not detected in the following genes: also supports an oligodendroglial lineage tumor. In general,
IDH2, BRAF, ATRX, TP53, or EGFR. Arm-level copy number oligodendrogliomas are slow-growing tumors and have rela-
analysis revealed co-deletion of chromosomes 1p/19q without tively favorable prognostic indications compared to diffuse
evidence of deletions involving CDKN2A/B. MGMT promoter astrocytic tumors; however, recurrence and progression to a
methylation was detected. more malignant neoplasm can occur. The detection of MGMT
Integrated Diagnosis. OLIGODENDROGLIOMA, WHO promoter methylation indicates a more favorable response to
Grade II, IDH1(R132H)-mutant, 1p/19q co-deleted; MGMT alkylating chemotherapy agents.
promoter methylated In summary, this case illustrates how the presence of
Teaching Points. This case illustrates the classic histo- specific genomic alterations now defines a tumor diagnosis.
logic and genomic presentation of oligodendroglioma. In Classification of oligodendrogliomas now requires presence
contrast to glioblastoma, these tumors typically present at of 1p/19q co-deletion and an IDH1/2 mutation. Given the
younger ages, with a peak incidence in the fourth decade. overlapping histologic features or limitations of sampling, in-
Clinical symptoms can vary greatly but often include head- corporation of molecular data provides critical information for
aches, seizures, and other signs of increased cranial pressure. diagnosis and, importantly, prognosis.
Combined CT and MRI studies frequently demonstrate well-
circumscribed lesions often associated with calcifications. Clinical Pearls
Histologic analysis revealed the classic cellular appearance of 1. When molecular profiling of a brain tumor reveals the
oligodendroglial lineage tumor cells, with round nuclei sur- presence of 1p/19q co-deletion and IDH1/2 mutation, a
rounded by abundant clear cytoplasm. A low mitotic index diagnosis of oligodendroglioma is made.
and absence of microvascular proliferation and necrosis sup- 2. Histologically, oligodendrogliomas are characterized by
port classification as a lower-grade glioma. The genomic pro- the presence of round nuclei and perinuclear halo that
file is diagnostic of an oligodendroglial neoplasm as evidenced has a “fried egg” appearance.
by 1p/19q co-deletion and presence of an IDH1 (R132H) mu- 3. Grading of oligodendrogliomas is restricted to
tation. In addition to the diagnostic alterations, CIC mutations grade II and III tumors; there is no grade I or IV
are typically observed in oligodendrogliomas and rarely pre- oligodendroglioma; oligodendrogliomas with necrosis and
sent in astrocytic tumors. CIC functions as a transcriptional microvascular proliferation are grade III.
repressor to counteract activation of genes that are targets of
7
H&E IDH1
A B
ATRX OLIG2
C D
Ki-67
Fig. 1.4 Microscopic examination showing histologic features consistent with low-grade oligodendroglioma including H&E stained
sections (A) demonstrating infiltrating tumors cells with circular nuclei and perinuclear halos (A). Immunohistochemistry shows
positive staining for IDH1(R132H) (B), retained expression of ATRX (C), positive staining in tumor cells for OLIG2 (D), and low Ki-67
proliferation index (E).
8
Genomic and molecular analyses. Genomic profiling of tu-

mor cells identifies IDH1 (R132H), TP53 (R273H), and ATRX
CASE 1.3 USE OF GENOMIC PROFILING (R1426*) mutations. Alterations were not detected in the fol-
TO ESTABLISH A DIAGNOSIS OF lowing genes: IDH2, BRAF, CIC, FUBP1, or EGFR. Arm-level
WHO GRADE 2, ASTROCYTOMA copy number analysis revealed no evidence of 1p/19q
co-deletion, polysomy 7 or monosomy 10. MGMT promoter
Case. 24-year-old male who presented with new-onset sei- methylation was detected.
zures. Imaging studies reveal a large right frontal lobe lesion Integrated Diagnosis. DIFFUSE ASTROCYTOMA, WHO
with no enhancement (Fig. 1.5A–C). Grade II, IDH1(R132H)-mutated; MGMT promoter methylated;
Histology. Microscopic examination of H&E sections Negative for 1p/19q co-deletion
(Fig. 1.6A) reveal a moderately cellular glial neoplasm composed Teaching Points. This case highlights a typical presenta-
of cells with irregular-to-ovoid eccentric nuclei and associated tion of an adult low-grade diffuse astrocytoma. Similar to
with abundant amounts of eosinophilic cytoplasm. Mitoses, oligodendrogliomas, these tumors present earlier in life, with
microvascular proliferation, and necrosis are not detected. a peak incidence in the third and fourth decades. On CT and
Immunohistochemistry reveals positive staining in tumor cells MRI scans, tumors present as low-density masses with little
for p53 (Fig. 1.6D) and IDH1 (R132H) (Fig. 1.6B), and negative or no contrast enhancement. Histologically low-grade dif-
staining for ATRX (loss of nuclear staining in tumor cells, Fig. fuse astrocytomas demonstrate moderately increased cellu-
1.6C). The overall Ki-67 proliferation index is low (Fig. 1.6E). larity and the presence of nuclear atypia. Mitotic indices are
A B
C
Fig. 1.5 MRI Brain including (A) axial T2-weighted sequence showing a small right anterior frontal mass with minimal surrounding
edema (arrowhead), and (B) axial fluid attenuation inversion recovery sequence showing this same mass (arrowhead), and (C) axial
T1-weighted gadolinium enhanced sequence showing no associated contrast enhancement (arrow).
9
H&E IDH1
A B
ATRX P53
C D
Ki-67
Fig. 1.6 Microscopic examination showing histologic features consistent with a low-grade astrocytoma including H&E stained
sections (A) showing infiltrating irregularly shaped tumor cells with pleomorphic irregularly shaped nuclei. Immunohistochemistry
shows positive staining for IDH1(R132H) (B), loss of nuclear staining in tumors cells of ATRX (C), positive staining for p53 (D), and
low Ki-67 proliferation index (E).
10
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for I insist, that she has for years been practising the most heroic
virtues by suffering in silence, to preserve the peace and tranquillity
of her husband and son.
But, my dear friend, if such be the penalty annexed to the
concealment of error and duplicity by an ingenuous mind, even when
that concealment is qualified by the powerful motives of preserving
the peace and interest of all around us, what, I ask, must be the
horrors of the mind, which covers, with a veil of darkness, the fraud
intended to ruin the innocent, to betray the unsuspecting, and to
defraud the ignorant? What must be the state and condition of those
whose life is a lie? I cannot form a more appalling idea of a state of
future punishment, than in the contemplation of the hypocrite’s
terrors even in this life. What must be the life of a person, whom
deceit and treachery have made responsible for his safety to a
confederate, as depraved and dishonest as himself; living under the
dread of the chance of every moment for open detection; harassed
with the conviction that a more immediate interest, or more specious
promises, will convert the sharer of his crimes into an informer and
accuser, whom he dares not confront? What can equal the pang
which must at times pierce his bosom when he recollects, that he
enjoys the confidence and favour of his fellow creatures, only
because they do not know him for a monster to be shunned! But I
must check this train of thought.
Lady Maclairn thanks you for your soothing letter. Her mind is
relieved by the participation of its burden. She can now, to use her
own words, live without devouring her griefs, lest they should be
seen. Sir Murdoch smiles and tells her, she is his rival with Rachel
Cowley. We shall yet be more comfortable I trust.
I enclose for your amusement and Mary’s perusal, a letter we
received on Monday from Mr. Serge. Well may this poor man apply
to himself the words of the son of Sirach!
“The father waketh for the daughter when no man knoweth, and
the care for her taketh away sleep when she is young, lest she pass
away the flower of her age; and being married, lest she should be
hated.” I only regret that Mr. Serge did not study the same author, or
at least one as wise, for the means to prevent the watchfulness and
parental anxiety, so admirably described in the above mentioned
words: for had he understood better how to chuse a wife, he might
have slept in peace. A woman without understanding can hardly be
called a virtuous woman, and we well know the price of a virtuous
woman is far above rubies.
Miss Flint goes on deplorably; her sufferings have subdued the
baronet, who sees with augmenting admiration the unremitting
attentions of his “excellent Harriet.” Even Malcolm relents, and this
morning most cordially wished his mother to urge her to send for
advice to London, thinking her case a chirurgical one.
I am growing somewhat displeased with the winds and waves; but
I remember Canute, and submit to a power which I cannot control.
Mrs. Allen sends her love; she is constantly engaged with her invalid.
Miss Flint is not easy without her.
I remain, faithfully your’s,

Rachel Cowley.
LETTER LVII.
Jeremiah Serge to Sir Murdoch Maclairn.
My Dear Friend, Putney, Oct. 27.
I am certain, if you knew the consolation I have in your counsels

and advice, you would rejoice; for it is the command of a master we
both wish to serve and obey, that the “strong help the weak.” God
knows I am weak, and my talents few; you are a chosen servant, to
whom many are intrusted; but yet, Sir Murdoch, we are of the “same
household,” and the children of the same father; and, blessed be
God! you do not, like some men, scorn the relationship, because one
is appointed to a lower station than another, by that wisdom which
will accept the lowest, who performs what is required of him. I am
again brought to the trial of my strength by a new sorrow, from
which, my good friend, neither my money, nor my wisdom, can
altogether shelter me. Yet both shall be tried, as the means of relief;
for both have their use, when in the discharge of that duty, which I
am bound to perform as a Christian parent. My daughter, Caroline,
encourages me to open my heart to you; she says, she will be
answerable for the event, for that Sir Murdoch Maclairn is a man as
well as a baronet, and that he will feel as a father the troubles of a
father; and she is sure, that you will approve of my conduct; I think
also that you will; for I have been governed by her; and surely
Heaven, in its mercy, has preserved her life for my good; and has
arrested the hand of death, until she was more than ripe for the
blessed state prepared for her. Such a child! and yet so wise! so good!
I cannot proceed——
I have taken up my pen again. It is only five o’clock, and not a soul
stirring in the house but myself. So I will try and disburthen my
mind a little!—I do not now remember whether I told you, that some
few weeks since, Mrs. Tomkins, after passing a day or two with my
dear child, during her mother’s absence from home, took Lydia to
town with her, her dear sister thinking, as she told me, that the poor
girl was losing her spirits. I, knowing that she thought of every one’s
comforts, consented to my good friend’s wish of showing Lydia some
kindness. The very evening they left us, Caroline turned her
discourse on Nora, praising the letters she had written to us, and,
with her perfect charity, hoping all things. “I do not repent, my good
child,” said I, “of the kindness I have shown her: I am not the poorer
nor the worse man, if I have purchased with seven thousand pounds,
the gratitude of one, on whom she depends for the comfort of her
life. Would to God, that I could purchase health for you!” She smiled,
and said, “Then indeed would you be in danger of a bankruptcy; for I
believe my father would give his last shilling for his children’s
benefit. But let this pass. My health is not at present what troubles
me. Promise me, my dear father, that, should Lydia stand in need of
your support, you will remember, “That, where much is given, much
may justly be required;” but that where nothing has been sown, we
cannot reasonably except an harvest to rise.” “Make your mind easy
in regard to her,” replied I, “thinking she had in her thoughts the
little favour Lydia stands in with her mother, I pity and love her.” “I
understand what you mean; and I promise you, I will be her father
and her mother too, when occasion serves. She shall not be brow-
beaten and neglected as she has been of late.” “Alas! my dear father,”
answered Caroline, “you must promise more, or I cannot die in
peace. You must promise to forgive another offending child: you
must promise”—She threw her arms around me, Sir Murdoch, and
weeping, added, “to shelter her from reproach and shame.” I turned
faint and giddy; and my daughter gave me her salts. Oh! if you could
but have heard what she said, you would not wonder at what I have
done. In a word, my child was satisfied; and she lives to tell me
again, that she was going to a Heavenly Father, from one who
imitated him in lenity to his offending offspring. There was, in her
look, something which poured joy and comfort into my broken heart.
I only wish I could go to heaven with her.
“Well, I saw my weak unhappy girl; and Mrs. Tomkins advised me
to let her manage; for she was certain the terror of seeing her mother
would be fatal to her and the unborn infant. I could not reproach her,
Sir Murdoch, indeed, an afflicted man is not an angry man: and
after all, had not I been deficient in my duty? Has not my indolent
temper, and love of peace, been more considered than the good of
my family? I have been too passive, Sir Murdoch, too indulgent.
“I found the young spark who had taken Lydia’s fancy was
William, who was with us at Fairfield Hall, and whom we all liked, as
a very sober well behaved young man. His sister, my wife’s favourite
maid, introduced him to us some time before we went to Bath. She
said he was like many foolish young men, tired of being remote from
temptation; and that he had gained, with much difficulty, her father’s
consent to seek a place in London, as a valet, or a butler, being well
qualified for both; she was quite unhappy that he should be left to his
own guidance till he was fixed in a sober family; seeing he was a very
likely young man, and quite a stranger. So my wife, who never is
behind hand in good nature, said he might come to Putney, and we
were well pleased with him, and engaged him to attend us to Bath.
Poor Lydia has been honest with Mrs. Tomkins. The young fellow
was not so much in fault as herself: she confessed that she sought
him. However, this was not the question with me; we might perhaps
have hushed up this business; such things are done, as they say,
every day: but what follows? a crime, in my opinion, ten times worse
than Lydia’s; being, as it were, committed in cool blood; for what can
be more dishonest than passing off a deluded girl for a chaste one?
and depriving a poor innocent babe of a father, and a name. I could
not do such an act of injustice; being convinced that it would be
doing what I should not think just in another to do by me.
I consulted our friend counsellor Steadman, however, on this
vexatious business; for notwithstanding I have little to be proud of as
one may say, yet it went some how to my heart, that a child of mine
should be pointed at by scorn and derision. He is a worthy and a wise
man, and agrees with Mr. Tomkins, that the best thing I can do, is to
let these young simpletons be married; the girl being half distracted
with the fear of losing sight of William; and he being willing to take
her, as he told the friend we employed, Mrs. Tomkins’s mother, that
he would work for her to his life’s end, and show his good master
that it was not his money he wished for. I find his parents are honest
people, though low in the world; they had a farm within six miles of
York, but by losses amongst their cattle things went backward, and
being in arrears for rent when their lease expired, they lost the farm.
William was then about eighteen, had received good learning, and
was a sober, steady lad; but a little pride made him discontented; and
he did not like to work as a gardener, in a piece of ground, which his
father cultivated in that way, near York, and which, as he says, in
excuse for his leaving his parents, could only produce a maintenance
for them, and that he was only a burden on the ground. So all was
fixed for the marriage, and we thought no time was to be lost.
I am not quite pleased with my wife, Sir Murdoch, although I know
she is as harmless as an infant; yet it grieves me to see that she will
always be an infant. She was absent a whole month from Putney;
and whilst Caroline was thus employed, and thus disturbed, she was
taking her pleasure with people she knew nothing of, and whom all
honest and sober minded persons would shun. During eight days she
waited forsooth, for the captain, who could not think it proper for
Mrs. Serge to travel without an escort, as he calls a puppy. I
remembered the time, when much younger, she could travel by land
and by water without such a conundrum in her head. However they
arrived here, and the captain, to my great satisfaction, refused to
lodge with us, pleading business in town; and intending to be absent
only three days from his Nora and his friends.
I shall say nothing of my poor wife’s hysterics, when I told her how
matters stood with Lydia. She was terribly bad indeed! But, thank
God, these fits are not dangerous, as the doctors say; and experience
seems to justify them in their opinion; for, I know one of my wife’s
old friends, who has been subject to them twenty years. No sooner
had my poor Lydia got the better of hers on this trying occasion, than
she lamented her hard case, saying, with many tears and much
anger, that she should never be able to shew her face again amongst
fashionable people; and that no one but myself would ever have
thought of sinking their family by such a dunghill connexion. I lost
my temper, Sir Murdoch, for it frets a man to be always doing for the
best, and who is said never to do right. And I very roundly told her,
that all the plagues of my life were owing to fashionable people, as
she called gamblers and pickpockets; and if, added I, that were all
the mischief, I should be tempted to thank William Willet for his
good services. You have now, continued I, been a month under a roof
which the honest would shun; whilst under your own, Mrs. Serge,
the prop and stay of my life, is sinking to the grave. You might have
learned a lesson of more value than what your fashionable people at
Reveland Park have been teaching you. She looked confounded, and
wept in silence. No man loves peace more than I do; my heart
relented; and I only added, that she knew this was my temper; that,
whatever I thought, or rather felt to be right, that I would do; and
that the following morning Lydia would be Mrs. Willet. I kept my
word, Sir Murdoch, and last Thursday by means of a licence, I saw
the young couple united. I do not know how it was, but they quite
softened me by their tears and thanks. Mrs. Tomkins was so good as
to accompany them to her mother’s; they set out as soon as the
ceremony was over, and I returned to Putney to dinner, contented
and relieved in my mind. On entering the parlour I found my
fashionable son-in-law there; he was reading the newspaper, and I
asked him, by way of saying something, “what news?” “None,”
replied he, “of importance; but I understand, Sir, we may expect a
curious article to-morrow.” He smiled, and, as I thought, insolently;
adding, “Miss Lydia Serge, second daughter to Jeremiah Serge, Esq.
married to William Willet, late butler and gardener at Putney in her
father’s house, will make a curious paragraph!” “Very likely,”
answered I gravely; “and the article may farther say, that the
marriage ceremony was performed in St. Martin’s Church, by the
minister of the parish, and in the presence of the bride’s father. I
shall contentedly leave to the public their opinions; some may be
found who will perceive nothing wonderful in a marriage between
Serge the taylor’s daughter, and Willet the farmer’s son.” “You are
to judge for yourself, Sir,” replied he, “but I conceive few will think
Miss Lydia’s character redeemed by this twofold disgrace to herself
and family. Upon my honour I pity Mrs. Serge; and I dread the
effects of this intelligence on Mrs. Fairly.” “Look ye, captain!”
answered I, “neither your mode, nor William Willet’s, of getting a
footing in my family has been such as will make either of you my
counsellors or guides. I shall act as I please, do as I please; but as I
am a just man, be it your case so to conduct yourself, as to make it
pleasant to me to be your friend. My children, except one, who is too
good for this miserable world, have both chosen for themselves. The
same lenity has been employed for the one, whom weakness has
betrayed to folly, as to the other, whom vanity and presumption
rendered ungrateful and disobedient.” “I hope, Sir,” returned he with
a fierce air, “you do not pretend to compare—” “We will do what is
better,” answered I, ringing the bell, “we will drop the enquiry, and
have our dinner.” My gentleman was surprised, I believe; by my
manner he took the hint, however, and followed me to the dining
parlour. Our meal was not a cheerful one, and I went to my dear girl
the moment the cloth was withdrawn.
I see, Sir Murdoch, how things are turning. My wife is cajoled and
flattered by this fellow to such a degree as would surprise you; she
fancies he has done her a great favour by running away with her
daughter! Poor soul! it will be well if he does not run away with her
simple understanding! However, all these troubles call upon me for
diligence in the settling my worldly concerns, as well as those, for
another and a better state. I have already spoke to counsellor
Steadman on this subject. My property is very considerable, and
much caution is necessary in the disposal of it, so as to render it a
lasting benefit to my family. Now, my good Sir Murdoch, I think
nothing would give me more comfort in my last hour, I believe it is
not far distant, than to know that I had left you, and my dear friend
Mr. Malcolm with Mr. Steadman, guardians and trustees for the
support of the ignorant and helpless, and a wall of defence for the
innocents who may spring from my daughter’s imprudent marriages.
I am led to hope that you will not refuse me this kindness. You shall
hear from the counsellor when all is prepared. He has been my right
hand lately; I am directed by him in all that relates to William’s
settlement; but Lydia shall have the same allowance as Nora; and we
are on the look-out for something for her husband.
God preserve you all in health,

prays your faithful friend,
Jeremiah Serge.
P. S. My wife begs to be remembered, she is out of spirits, and

fancies the air of Putney unwholesome. My Caroline is a miracle! It is
astonishing to think how nature is supported! I am far from being
well; you will not wonder at this.
CHAP. VIII.
LETTER LVIII.
From Miss Cowley to Miss Hardcastle.
It is with no small satisfaction, my dearest Lucy, that I find my
“enthusiasm of mind and ardency of temper,” (to avail myself of your
gentle terms for a spirit too often governed by the impulse of a heart,
which, in its promptitude is apt to take the lead of judgment) have
met with your approbation and concurrence, in regard, at least, to
the conduct I mean to pursue with Lady Maclairn: to say the truth,
Lucy, I could practise no other; for she hourly rises in my estimation,
and esteem with me is the basis of affection. The relief which she
finds in communicating her thoughts to me, has given to her very
language a frankness which appears to be her natural character; and
in her account of the various occurrences of her life, since she
married Sir Murdoch, she omits not even her conjectures, as these
arose from the circumstances in which she has been placed. “I long
since had proofs,” said she this morning, when speaking of the
suffering Miss Flint, “that Lucretia was not devoid of feeling. My
brother, for reasons of his own, had so contrived it, that she firmly
held an opinion which he, it is probable, only affected to have.
Illegitimate birth he considered as an indelible disgrace on the
innocent; and Miss Flint adopted this notion, firmly believing that
neither fortune, talents, nor even virtue could screen an unfortunate
being, who stood in this predicament, from the reproach and insults
of the malicious. Her affection for her child was unbounded; and I
saw with comfort, that I had at least gained her gratitude, by my
apostacy from truth. The conduct she maintained with my brother, in
the mean time, puzzled me. It was obvious, he was no longer the
favoured lover; and one day, observing Philip much disturbed from
an interview he had with her in the garden at Kensington, I ventured
to say to Lucretia, that I was sorry to see Philip unhappy.” “I
understand you,” replied she, “and I will be explicit with you. I shall
never be his wife; nor will I be to him what I unfortunately have
been. I am a mother, Harriet, and I will prove myself one, by
remaining what I am, and what I can contrive to be, the guardian of
my son. I have no passions to gratify, no desires to control, since I
beheld the face of my child; to love and cherish him, and to bless you
for your goodness, shall fill up the measure of my miserable days.”
She burst into tears and left me abruptly. Her sincerity wanted no
evidence stronger than her conduct, continued Lady Maclairn. For
some time all went well. I was made happy through her mediation,
and amongst the delusive hopes, which led me to Farefield Hall as
Maclairn’s wife, was the flattering one, that, by the influence I had
acquired over Lucretia, I might in time reconcile her to Mrs. Howard.
Mr. Flamall frustrated these designs. His affections, as a parent, were
so artfully, so effectually brought forward, and his conduct was so
specious, that Lucretia insensibly gave him a confidence, which as
gradually subjected her to his will and pleasure as myself; and she
observed, that nature had yet preserved one strong hold in Flamall’s
bosom; for that he loved his child; and that would prove to her a
source of future comfort; for that no man was more capable of the
office of preceptor. Even I assented to this opinion, Miss Cowley, as it
related to his talents; and I was still the dupe of that affection, which
nature had interwoven with my frame for my brother. He became
more serious and reserved from the hour of Philip’s birth, and in the
regularity of his conduct, and the instances I had of his growing
parsimony, I scrupled not to think that he was a changed man in
many respects, although still unsubdued in his love of power. As
Philip became of an age to receive his lessons, his visits at the hall
might be called a residence; but you know already how little these
visits were productive of comfort to me, and, I may likewise add, of
comfort to Miss Flint; for my brother was a rigid disciplinarian; and
had not the child’s temper been one of the most docile and sweet, he
would have been miserable; for my brother, guided by his
acquaintance with vice, understood not that the path to virtue is
pleasant, and to unperverted feet, and a pure heart, has allurements
far superior to any that his lectures and vigilance could furnish.
You may judge of the difficulties I had to encounter in this period
of my life; and the condition to which I was reduced by a brother’s
reminding me, from time to time, that it was best for me to be
“prudent.” There was little need of a conscience like mine to draw the
inference; his tone and manner were sufficient, and he repeatedly
roused Lucretia to stand forth as my champion, on a ground which
had made me a coward, and the slave of the wretch who had led me
into the crooked path. “Her conduct was, at least, uniformly
generous on this point,” continued Lady Maclairn; “she never,
directly nor indirectly, mentioned Duncan, nor did I, till very lately,
know to what extent her knowledge went of this unhappy affair. I
breathed like one freed from death, when I found that Mr. Flamall
had determined to leave England with Philip. From the time I had
the unfortunate Mr. Duncan’s narrative before me, my soul abhorred
the sight of my brother; and I so entirely secluded myself in my
husband’s apartment, that we did not meet twice in a week, and his
reserve and coldness when we did, went not beyond mine. Again, my
dear Miss Cowley, truth obliges me to give a good report of Miss
Flint. In proportion as my spirits flagged she redoubled her attention
to my wants, and her purse was ever open to me. I believe, that my
brother’s reason for going to Jamaica, originally sprung from a
serious quarrel with Lucretia. The death of his wicked wife left him
free to marry, and he was very pressing on that subject with Miss
Flint. Lucretia had her secrets as well as myself; but accident led me
within reach of hearing her say, “Never; urge me no further; for by all
that is sacred, if you do, Percival shall know all.” I retreated, fearing
to be discovered; and, from that time, his voyage was mentioned as a
decided matter. After my brother’s departure, Lucretia fatigued me
with her importunities, to draw me from my husband’s room.” “I
should have a servant to watch him; and one I could rely on,
although it cost her an hundred pounds per annum.” I was firm, and
she submitted. Left to herself, she thought of her niece, and I was
consulted on the expediency of her inviting this poor girl to live with
her; I was distressed for a reply; knowing the bitter resentment
which she had nourished even to the name of Howard; and her
hatred to those who had sheltered this unfortunate and excellent
couple. I evaded the question as well as I could, contenting myself
with observing, that I had always thought it an act of duty on her part
to take care of her niece. “I am willing to do so;” answered she
colouring; “but I must first know what she is good for; and whether
the people with whom she lives have not taught her to believe I am a
monster.” I saw the rising storm, and timidly shrunk from it, saying,
that I could not give her my advice, without incurring the censure of
being swayed by a sordid consideration for my reputed son. “But you
know,” added I, “that you can provide for both these young people;
and you must determine their respective claims.” Poor Mary soon
after exchanged her abode of peace, for this, and the event has
confirmed my fears. The gentle and timid Mary neither gained spirits
here, nor strove to amuse her aunt’s. She had but one path, it was to
submit in silence to her aunt’s temper, and to anticipate her
commands by her diligence. She soon perceived the fatal habit which
Lucretia indulged; and this produced terror and disgust in her
innocent mind, which, as you will believe, did not tend to conciliate
her to her aunt’s hardships. I did all that I could do, to soften the one
and encourage the other; but my interference was resented, and I
was reproached, as being allied to her enemies, and blinded by
Malcolm to favour the Heartleys.
I was tempted, Lucy, to hazard some questions, with a direct
reference to Sir Murdoch’s suspicion of having been poisoned; but a
moment’s reflection checked my curiosity; and I diverted her
attention from perceiving my embarrassment, by asking her,
whether she knew what was become of the gentleman’s portrait, and
the papers, which so obviously appeared to have belonged to Mr.
Duncan’s story? She unaffectedly answered, that, “Sir Murdoch had,
when in London to meet me, consigned them into the hands of the
Spanish minister, then resident there; and in the interview,” added
she, “he learned that this nobleman was not totally a stranger to the
fate of Duncan’s parents; they were dead; and a distant branch of the
family was in possession of the title and immense estate; but there
was a sister of the Duke still living, who was abbess of a convent; and
to her he engaged to deliver these melancholy memorials of her still
adored brother. Can you wonder, Miss Cowley,” continued she with
emotion, “that I wish for death! think of my meditations, when
darkness and repose conceal me from all eyes but those of a merciful
Being, who witnesses my agonies. Such has been the ruin effected by
a wretch I dare not curse! He is the child of my parents; the ties of
blood still flow around my heart; and I implore Heaven’s sparing
mercy for him, whilst my soul sickens at the thought of the injuries
his hands have wrought, and which no time nor repentance can
remedy. Think of his dreadful account with outraged humanity,
violated truth, and every law of justice! I endeavour to hope that
Charles has found his peaceful grave. I dream of him; and this frame
of mind lays me open to superstition: my imagination presents him,
as exultingly hovering over me on angel’s wings, smiling with
ineffable complacency, and beckoning me to follow him. I try to obey
him, and awake trembling. Such are the visions of my sleeping
hours! You need not be told the meditations of my waking ones. One
single principle of action has counteracted the fatal effects of these
perturbations. I love my husband, my dear Miss Cowley, with an
affection exclusively his; and I wish to live, whilst that life is useful to
him. I am prepared for the event of being hateful to his eyes. God will
have compassion on me!”
My tears composed her; and my arguments were listened to. She
promised me to be all I wished; and I broke up the conversation by
proposing a walk in the avenue. Her husband joined us there, and I
told him I had been chiding my mother. He smiled tenderly, and
placed himself between us, observing, that he would keep the peace.
“You will not succeed,” replied I with assumed gaiety; “nor will I
accept of you for an ally; you are too much like your wife; but I have
blustered her already into obedience to my will; and she had
promised to be good, and to walk with me every day the sun shines,
instead of sitting in Miss Flint’s room to hear of pains which she
cannot alleviate. He thanked her, and blessed your
Rachel Cowley.
LETTER LIX.
From Miss Cowley to Miss Hardcastle.
I am glad you agree with me in thinking it proper that our dear
Mary should know the doctor’s opinion of her aunt’s precarious life.
She has consented with great reluctance to see Doctor Tufton; he
confirms our fears, and has made no change in her medicines. She
told Douglass that she hoped he was satisfied by her compliance with
his wishes, and added, “Do not think I am to be deceived; I have
done with medicines and doctors.” “I told her that in that case I
should think myself dismissed from her presence as well as favour,”
said the doctor. “She answered that the visits of a friend would still
be useful and acceptable;” but added she dejectedly, “your
prescriptions may not be more infallible for a sick mind, than a
diseased body.” “I took her burning hand,” continued the good
doctor, “and with sincerity of heart I told her, that in both my
characters, as her physician, and as her friend, I still hoped to be
salutary to her, on condition she did not desert herself. You are too
low now, added I, pouring out an untasted cordial at my hand; you
ought to have taken this two hours since. She put the cup aside, and,
shaking her head, said, you know it will do me no good; these are not
the cordials I need. I know there are others within your reach, replied
I with seriousness, that would contribute to give efficacy to this, and
which you refuse from a despondency of mind which you ought to
check. Wherefore is it, that with a brother nigh you, and whose
conversation would cheer you, you refuse to see him? His heart is
melting with compassion at the intelligence of your dejection and
sufferings.” “Why then does he not come and tell me so? asked she
with agitation. But I know what keeps him at a distance! he cannot
say, Lucretia, I forgive you! he cannot say, be comforted!”
“The offence which produced your intemperance, and his too
warm resentment, has been fully expiated by the pain which both
have experienced from it,” observed the doctor; “both were in fault,
and both have regretted the fault. Percival thinks only of a sick and
afflicted sister. I will pledge my life on the sincerity of his affection
for you; and I know his soul seeks to meet you in peace and love.”
She was oppressed, and gasped for utterance. “Oh! why does he
delay?” said she, “I long to see him before I die!” “You shall see him
to day,” replied I, “on condition that you will be composed. I am
confident that you will find comfort and amusement from his society.
She named the hour, and requested that I would come with him, not
knowing how the sight of him might affect her. I thought it better to
avoid the suspense of procrastinating the interview,” continued the
doctor, “and Mr. Flint has been with her. Poor Percival was
extremely shocked when he saw the alteration that sickness had
made in her person. She gave him her hand, and told him, with more
composure than I expected, that she took his visit kindly. He spoke
with emotion, and said something of his hopes, and the ensuing
summer. I shall not live to see it, answered she, looking stedfastly on
him; but it will comfort you, Percival, to know that the prospect of
the grave no longer terrifies me; I am not without hope. He
interrupted her. Cherish it, said he, eagerly, and, kissing her cheek,
cherish it, my dear Lucretia! and may its salutary influence restore
your health as well as your peace! Is this your wish? replied she,
bursting into tears. Do you, can you forgive me? You had not seen me
here, Lucretia, answered the captain with solemnity, had any
resentment lurked in my bosom: as I hope for pardon for my own
errors and mistakes, so certain is it, that affection and compassion
brought me hither. Forget, as I have done, the past; live to be my
comfort; and may this hour cancel from your mind every thought
that retards your recovery! He again kissed her, and she hung on his
neck, groaning with her agitations. Percival, overcome by this scene,
permitted me to lead him from the chamber, and he was not able to
see the family; I parted with him in the avenue. My patient, fatigued
by these exertions, is fallen into a dose. She is sinking gradually; and
will probably be lethargic.”
Mary will be anxious to hear the result of this first interview; her
aunt requested that the captain would visit her daily.
I have only time to sign the name of your
Rachel Cowley.
P. S. Has Alice informed you that Mr. Snughead is dead? either his
son-in-law’s return, or his grief for his wife was too much for him: he
died at Bath of the gout in his stomach.
LETTER LX.
From the same to the same.
Our good father has no doubt communicated to Mary the news of
her uncle Oliver Flint’s death. Peace to his manes! He has left behind
him a good report, and we are much pleased with the last proof of his
being an honest and friendly man. His heir, Mr. Philip Flint, has
written a very handsome letter to the captain, to inform him of his
legacy of five thousand pounds, and Mary’s of three, adding, that,
believing it was the intention of the donor, that there should be no
delay in the payment of these bequests, he had transmitted to him
the first six months interest of the sum, in order to answer the
present unavoidable retardment of the principal sum whilst waiting
for his precise orders. Mr. Flamall still remains obdurate; a
circumstance which Mr. Philip Flint in his letter to his mother
regrets, as a draw-back on his comforts, and peculiarly oppressive to
his mind at a time when he might have been useful as a consoler.
There were letters for Miss Flint from Mr. Flamall and her brother;
some precautions were judged requisite in regard to the delivery of
these. Doctor Douglass undertook the business, as well as to prepare
her for the sable dress of the captain. He asked her how long her
brother Oliver had left England; she took this hint, and replied with
calmness, that he had been dead to her more than thirty years; but,
added she sighing, when we are re-united, this period will appear
nothing! Encouraged by her composure he proceeded to mention his
honourable acquittal of his promise to Mr. Philip Flint, and the
regrets of his friends for his loss; and giving her the letters destined
for her was on the point of retiring, after recommending to her to be
careful of fatiguing her spirits. “Remain a moment,” replied she,
taking the two letters. “You shall see that I mean to preserve my
tranquillity. This comes from a hand that never administered to me,
aught but comfort.”—She placed Mr. Flint’s letter under her pillow.
“This from a man who, miserable in himself, is the common
disturber of the peace of others. I will not read his letter: put it into
the fire.” “I hesitated, in obeying her,” continued the doctor; “she
perceived it, and tore it into fragments.” Now burn them, and judge,
said she, that I can be firm. Mr. Flamall has nothing to do with this
hour! I will not be disturbed by his resentments. She paused, and
saw the mutilated letter consumed. “I shall not have the comfort my
brother Oliver had,” observed she, “but I do not murmur. Percival is
very kind to me, tell him that I am calm and composed; but that I
shall be busy to day, and cannot see him; and send Lady Maclairn
hither.”
It appears that her ladyship’s commission was to send off an
express to Durham for an attorney whom Miss Flint named. Mary
will have a letter from the captain to-morrow. I am going to pass the
day at the Abbey; Sir Murdoch droops a little, he dreads the
consequence of his wife’s perpetual fatigue; she has a cough not very
pleasant to my ears.
Mrs. Allen is of great use to the invalid. She regulates the sick
room with her usual address, and has convinced Miss Flint of the
utility of quitting her bed for the sopha during some part of the day.
She thinks it refreshes her spirits; and some interval of ease at
present enables her to make the exertion.
I remain Lucy’s affectionate,

Rachel Cowley.
CHAP. IX.
LETTER LXI.
From the same to the same.
This letter will contain little beyond the particulars of a scene which
recently passed in Miss Flint’s room. Our dear Mary’s solicitude is
unavoidable, and her wish to know what passes here ought to be
indulged.
Mrs. Allen was requested to witness the signing of Miss Flint’s will,
she cheerfully complied; Douglass and Mrs. Warner joining with her.
When this business was terminated, she requested the doctor to
inform the captain that she wished to see him after dinner; and, with
a languid smile, she added, tell him that Mrs. Allen shall give him his
coffee.
When alone with our friend she begged of her to be the witness to
the conversation she meditated on for the evening. “Do not refuse
me,” continued she. “I have a few instructions to leave with my
brother, and you will be useful; you will hear nothing to grieve you,
although it may affect him, and flatter me; but I wish to finish my
business with this world!”
The captain, in Mrs. Allen’s words, was punctual to his time. His
sister was on the sopha, but looked flushed and fatigued. “He was
agitated,” continued Mrs. Allen, “and I said, we are doing well to day,
Sir.” He took his seat by her, and pressed her offered hand with his
lips. She immediately spoke of Mr. Oliver Flint’s death, making some
obvious reflexions on the event. Then suddenly looking at her
brother’s dress, she said, I hope, Percival, you do not mourn that
poor Oliver has given to a brother who stood by him as a son, an
inheritance that ought in the eye of justice to have been yours. The
captain coloured, and replied with eagerness, that he was perfectly
contented with the proofs he had received of his brother’s
consideration. He has rendered me comfortable, added he, for the
remainder of my life, and has placed Mary in a condition fully
adequate to her ambition. I am grateful, and sincerely hope, that
Philip Flint will live to show the world he was worthy of the man
whom he has succeeded. Miss Flint was softened to tears. God grant,
said she with emotion, that my will may be thus satisfactory to you! I
have done for the best, Percival, I have been governed by only one
principle. Let me die in the hope that you will accept it as an
evidence of my repentance for having so long overlooked your just
claims!—She spoke this with agony.
My dear Lucretia, said the captain hastily, and startled at the
disorder she was in, let us drop a subject so useless. I have no wants,
no wishes ungratified, but that of seeing you well. I cannot bear your
kindness, replied the poor weeping Miss Flint; I have not deserved it!
Say not so to me, answered the brother with tenderness. We have all,
my dear sister, to make this acknowledgment to our Maker. We have
all of us errors to regret, and something for contrition, but we have a
merciful Judge, who knows that we are weak and fallible: let me
conjure you to endeavour to recover your spirits. Let us employ the
allotted space allowed us in acts of love and mutual aid. Your friend,
as well as physician, assures me, that your malady is augmented by
the depression of your mind. Exert your faith; animate your spirits
by reflecting, that you are in the hands of a Being infinite in mercy.
Would you like to have Mary with you? She wishes to see you, and
might be useful to you. I could not bear to see her, answered Miss
Flint with a voice broken by sorrow; but it is not from unkindness,
that I reject her, it is not hatred nor cruelty that govern me. I am
certain it is not, replied the captain; No: my dear sister! their empire
is over; and a temper, to which worlds would be nothing in the
balance, has now a place in your heart. Oh! live to enjoy the blessed
exchange! live for my comfort!
“I thought his sister must have fainted,” continued Mrs. Allen,
wiping the tears of sympathy from her honest face; and I hinted that
she wanted her cordial. The captain understood me, and I believe
would have gladly retired himself and left her to my care; for he rose

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Neurologist 1st Edition Roy E. Strowd

Roy E. Strowd, III

NEURO-ONCOLOGY FOR THE CLINICAL NEUROLOGIST  ISBN: 978-0-323-69494-0

Library of Congress Control Number : 2020941988

Senior Content Strategist: Melanie Tucker

Printed in the United States of America

Last digit is the print number: 9 8 7 6 5 4 3 2 1

Prakash Ambady, MD Ugonma N. Chukwueke, MD Federica Franchino, MD

Matthias Holdhoff, MD, PhD David E. Kram, MD Nimish Mohile, MD

David Wayne Robinson, MD Michael H. Soike, MD Cristina Valencia-Sanchez, MD, PhD

Who is this book for?

How should this book be used?

1. Section 1 is a neuro-oncology primer.

Sections 6 and 7 review common neurologic complications of cancer treatment including

What is included in this book?

Section 1: Basic principles of Section 3: Approach to patients

Section 5: Neurologic complications Section 7: Neurologic complications

19. Neurologic complications of cancer������������� 251 27. A

Appendix 1: Summary of clinical pearls 389

CHAPTER OUTLINE Introduction

nervous system (CNS). Instead, gliomas are graded from

independent kinase that promotes cell proliferation through Clinical Pearls

Genomic and molecular analyses. Genomic profiling of tu-

I remain, faithfully your’s,

I am certain, if you knew the consolation I have in your counsels

God preserve you all in health,

P. S. My wife begs to be remembered, she is out of spirits, and

I remain Lucy’s affectionate,

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NEURO-ONCOLOGY FOR THE CLINICAL NEUROLOGIST ISBN: 978-0-323-69494-0

1. Section 1 is a neuro-oncology primer.

19. Neurologic complications of cancer�� 251 27. A

Appendix 1: Summary of clinical pearls 389