Table Of ContentMolecular Pathology Library
Series Editor: Philip T. Cagle
José Javier Otero
Aline Paixao Becker Editors
Precision
Molecular
Pathology of
Glioblastoma
Molecular Pathology Library
Series Editor
Philip T. Cagle
Houston, TX, USA
Creating a diagnostic, prognostic, and therapeutic treatment strategy precisely
tailored to each patient’s requirements is the fundamental idea behind precision
medicine. The Molecular Pathology Library series integrates molecular biology
with clinical data for treatment designed for the patient’s individual genetic makeup.
This approach is widely recognized as the future of medicine and it is vital for
practicing pathologists to know the molecular biology, diagnostics and predictive
biomarkers for specific forms of cancer or other diseases and their implications for
treatment. Each volume focuses on a specific type of cancer or disease and provides
concise essential information in a readily accessible, user friendly, convenient
format. Each volume is oriented towards the pathologist who needs this information
for daily practice, tumor boards, and conferences or for preparation for certification
boards or other tests. Written by experts focusing on patient care, these books are
indispensible aids to pathologists’ participation in precision medicine in the 21st
century.
More information about this series at http://www.springer.com/series/7723
José Javier Otero • Aline Paixao Becker
Editors
Precision Molecular
Pathology of Glioblastoma
Editors
José Javier Otero Aline Paixao Becker
Neuropathology Radiation Oncology
The Ohio State University The Ohio State University
Columbus, OH Columbus, OH
USA USA
ISSN 1935-987X ISSN 1935-9888 (electronic)
Molecular Pathology Library
ISBN 978-3-030-69169-1 ISBN 978-3-030-69170-7 (eBook)
https://doi.org/10.1007/978-3-030-69170-7
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
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To our patients, who selflessly permitted
tissue procurement for research and
contributed to all of the knowledge in
this book.
To our families, who provide us the support
to carry on in happy and in difficult times.
J.J.O. and A.P.B.
Foreword
The modern practice of neuropathology is both stimulating and overwhelming.
Making a diagnosis can be difficult enough, but the standard of care has gone far
beyond simply providing a diagnosis. Over the last decade, the practice of diag-
nostic medicine has become increasingly complex. This was reflected in the
restructuring of the 2016 WHO Classification of Tumours of the Central Nervous
System to include an integrated diagnosis format combining histologic and molec-
ular genetic data. As such, pathologists and treating physicians are necessarily
becoming more familiar with the molecular pathogenesis of brain tumors and how
it relates to diagnosis, prognosis, and treatment. Nowhere is this more relevant
than in the study of the most common primary malignant brain tumor,
glioblastoma.
Precision Molecular Pathology of Glioblastoma focuses on various aspects of
cancer neuroscience, tumor pathology, epidemiology, molecular genetics, and cut-
ting-edge treatment of this deadly disease. This book provides a deep dive into the
current understanding of the neurobiology of glioblastoma and the clinical applica-
bility of its molecular underpinnings. The authors address current obstacles in diag-
nosis and the barriers to implementing molecular diagnostic techniques in pathology
laboratories, particularly in developing countries. Other timely topics include
machine learning and learning-based automated methods for brain tumor classifica-
tion and stem cell-based modeling of glioblastoma. The editors and contributing
authors are a renowned group of neuroscientists, pathologists, and physicians who
are experts in their fields, across many different institutions, states, and even
countries.
While great strides have been made in the fields of molecular biology and neuro-
science, there are still many challenges facing clinicians and pathologists in the
pursuit of more accurate and prognostically relevant diagnoses. Drs. Jose Otero and
vii
viii Foreword
Aline Becker, both outstanding physician-scientists and neuropathologists, have
edited a state-of-the-art book to aid us in the quest for precision medicine. I know
you will find it informative and useful in your practice.
Michelle Madden Felicella, MD
Associate Professor of Pathology/Neuropathology,
University of Texas Medical Branch
Galveston, TX, USA
Preface
Very few human diseases require as much of an integrated approach to patient man-
agement than primary brain cancers. Primary brain tumors are the first solid tissue
cancer for which widely accepted diagnostic guidelines require molecular pathol-
ogy for diagnosis. The information obtained from the genomic testing is important
for both prognostication and treatment planning, as well as to assist in making deci-
sions to enroll a patient into a clinical trial that may involve targeted therapy.
Implementing these diagnostic workflows creates several problems for patient care.
First, in the USA, the number of pathologists per 100,000 people has declined, with
now only 439 formally trained neuropathologists reported in the USA per recent
reports. Formal training in neuropathology is needed to provide optimal patient care
at the point of neurosurgical intraoperative consultations as well as integration of
histopathological and molecular pathological testing. Exacerbating this challenge is
the fact that current reimbursement rates for neuropathological intraoperative con-
sultation is only $63.17 per consult (CPT code = 88331)1, rendering it financially
unfeasible to staff neuropathologists to be on-call in most community clinical set-
tings, ultimately leading to non-neuropathologists commonly fielding neurosurgical
intraoperative consultations throughout the USA; neuropathology staffing problems
are even worse worldwide. Furthermore, treatment planning by neuro-oncologists
and radiation oncologists requires integrated histopathological/molecular patho-
logical reports by trained neuropathologists. As primary brain cancers are rare, gli-
oma-specific biomarkers are not commonly stocked in community and academic
pathology laboratories. This even includes basic diagnostic and prognostic neuro-
oncologic biomarker tests such as ATRX, H3K27M, or even IDH1R132H assays, all of
which can be implemented on routine immunohistochemistry platforms which are
widely deployed globally. A third challenge includes the US regulatory and finan-
cial landscape of molecular pathology testing. In contrast to most immunohisto-
chemical assays which may obtain reimbursement from the same CPT code
1 Current Procedural Terminology (CPT) codes, also known as service codes, are a universal sys-
tem that identifies medical procedures in the USA. Reimbursement is in US Dollars as of December
28, 2020.
ix
x Preface
regardless of biomarker detected, each molecular pathology test in the USA requires
a unique CPT code for each new biomarker in order to obtain reimbursement. This
generates a high bar for individual molecular pathology laboratories in cancer cen-
ters to bring on new, “home-brewed” molecular assays. Also, modern technologies
such as chromosomal microarray to date have not been, and will likely never be,
reimbursed by most Medicare and private insurance providers. In addition, next
generation sequencing (NGS) platforms have poor history of reimbursement and is
therefore rarely performed outside major cancer centers in the USA. Furthermore,
insurance companies in most US states that cover molecular testing will only reim-
burse FDA-approved NGS tests once per patient per cancer. This is problematic
given the natural evolution of gliomas and the tendency to develop different molec-
ular subclones later in the disease course.
These challenges have led to some entrepreneurial data monetization strategies,
where NGS testing is cost-subsidized by private companies so that their data scien-
tists may access patient data. Although such innovative approaches may represent
positive short-term solution, instituting such an approach globally that is self-sus-
tainable has several challenges. Furthermore, single-gene molecular pathology
assays and NGS technologies benefit from economies of scale, resulting in the need
to perform “batch testing.” All of these factors result in excessive turnaround times
(TATs) in neuropathology. At our own institution, our average TAT for neuropathol-
ogy exceeds 6 business days to “result” a patient diagnosis, with molecular pathol-
ogy information “resulted” typically over 12 business days following surgery. In the
case of community pathologists, the TAT is even longer, as these cases would be
sent out to expert neuropathologists for consultation. The net result of these chal-
lenges is delayed treatment plan generation by the neuro-oncologists and radiation
oncologists.
It is with these issues in mind that we began to work on the design of this book.
Although molecular sub-typing of primary brain cancers has been extremely impor-
tant in providing accurate information regarding the patient diagnosis and progno-
sis, its implementation has not been fully equitable throughout the world. For these
reasons, we attempted to provide a balanced and realistic approach review of the
current state of glioblastoma understanding, ranging from traditional histological
review, molecular pathology of glioma, modern radiomics, neurosurgical focus, and
integration of treatment plans by neuro-oncologists. We also include chapters
focused on implementing molecular pathology programs in developing countries
and immunohistochemical surrogates for molecular pathology. This book is there-
fore aimed for a wide audience ranging from medical students and residents to
practicing neuro-oncologists, radiologists, pathologists, and neurosurgeons. We
hope that after reading this book, you will be inspired to work towards improving
the lives of patients with high-grade glioma.
Columbus, OH, USA José Javier Otero, MD, PhD
