Table Of ContentThyroid Cancer
Thyroid Cancer
A Comprehensive Guide to Clinical Management
Edited by
Leonard Wartofsky,
MD, MPH, MACP
Washington Hospital Center, Washington, DC
Foreword by
Ernest L. Mazzaferri, MD, MACP
Ohio State University Medical Center, Columbus, OH
Springer Science+Business Media, LLC
© 2000 Springer Science+-Business Media New York
0rigina11y published by Humana Press Inc. in 2000
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Cover illustration: "Histopathologic section of papillary thyroid carcinoma showing typical nuclear crowding, with
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Library of Congress Cataloging-in-Publication Data
Thyroid cancer: a comprehensive guide to clinical management / edited by Leonard Wartofsky.
p. cm.
Includes bibliographical references and index.
ISBN 978-1-4757-6845-9 ISBN 978-1-59259-199-2 (eBook)
DOI 10.1007/978-1-59259-199-2
1. Thyroid gland-Cancer-Treatment. 1. Wartofsky, L. [DNLM: 1. Thyroid Neop1asms.
WK 270 T5494 1999]
RC280.T6T527 1999
616.99'444-dc21
DNLM/DLC 99-21826
for Library of Congress CIP
Dedicated to the memory ofa great thyroidologist, teacher, and friend,
Dr. Sidney H. Ingbar, and to all of our patients who struggle under the
cloud ofa n uncertain future with their malignancies
Foreword
As the 20th century draws to a close, it seems like a propitious time to look back upon
the advances we have made in understanding thyroid carcinoma, since our knowledge
today will certainly serve to light the path of discovery in the next century. Gazing at the
world through a small looking glass focused on thyroid carcinoma seems an appropriate
way to begin thinking about the clinical management of this group of diseases. What are
the important things that we have learned in recent years that form the basis of our current
clinical knowledge? How can we best use that information in the care of our patients?
Dr. Leonard Wartofsky's new and sharply focused text, Thyroid Cancer, promises to
answer this hypothetical set of questions in a succinct and clinically relevant way.
It sometimes seems that thyroid carcinoma is a neglected orphan among human can
cers, which is at the root of some important issues. Thyroid carcinomas comprise a
diverse group of malignancies ranging from indolent microscopic papillary carcino
mas that pose no threat to survival to anaplastic carcinomas that are the most vicious
carcinomas afflicting humans. Yet, because of its low incidence, there have been no
prospective randomized clinical trials of the treatment of thyroid carcinoma. Further
more, none are likely to be done, given the prolonged survival and relatively low mor
tality rates associated with the majority of these cancers. Nonetheless, patients often
suffer greatly from this disease: many have serious recurrences and some die from
relentlessly progressive and untreatable cancer. This is a disease that knows no bound
aries, striking young and old alike. Unfortunately, management paradigms derive from
retrospective studies, and few new drugs have been added to our therapeutic armamen
tarium. One would thus anticipate a deep void in our understanding of these tumors.
Despite these shortcomings, the 20th century has seen major advances in our under
standing of their etiology, pathophysiology, and management. The good news is that
the advances have been rapidly translated into improved outcomes for many patients
with thyroid carcinoma. For example, data from the National Cancer Institute shows
that, although the incidence of thyroid carcinoma has increased significantly-almost
28o/o--since the early 1970s in the United States, cancer-specific mortality rates during
this same period have dropped significantly-by almost 21 %. In my view this results
from the earlier diagnosis of the cancer, which allows the full impact of effective
therapy, and which I believe has dramatically altered the clinical course of these tu
mors.
One of the dazzling success stories in medicine in the last half of this century is that
with medullary thyroid carcinoma, a truly orphan tumor afflicting relatively few people.
First identified in 1959 as a discrete entity, this tumor was identified before calcitonin
was known to exist and before the mystery of the mUltiple endocrine neoplasia syn
dromes had been completely unraveled. The pieces of the puzzle fell together at light
ning speed over a few decades. The Ret proto-oncogene mutations recently identified
vii
viii Foreword
in this tumor will serve as the portal to our eventual complete understanding of its
biology and are already the keystone to its diagnosis in members of afflicted kindreds.
Now children with this genetic defect can be identified with molecular testing well
before medullary thyroid carcinoma becomes clinically manifest or is identifiable by
any other test, resulting in thyroidectomy that cures the disease. What a wondrous
group of developments to pass on to the patients and physicians of the next century!
This work serves as a model for the scientific investigation of malignant tumors.
We are also acquiring a clearer view of the molecular biology of well-differentia ted-
papillary and follicular---thyroid carcinomas. Ret rearrangements found in papillary car
cinomas of humans have been shown to produce the tumor in transgenic mice,
underscoring the central role of Ret in the pathogenesis of papillary carcinoma. Study of
familial papillary thyroid carcinoma-now recognized to occur in a small but important
subset of patients in whom it may be transmitted as an autosomal dominant trait--un
doubtedly will provide important new information. These and other exciting discoveries,
such as the identification of the sodium-iodide symporter in laboratory animals and hu
mans, portend more basic discoveries that will generate currently unimaginable diagnos
tic and therapeutic tools. The latest example of this success in the laboratory is
recombinant human TSH, which was recently introduced into clinical practice and al
ready is dramatically improving and simplifying the care of patients with differentiated
thyroid carcinoma.
During the past 50 years we have learned much about the important etiologic role of
ionizing radiation in thyroid carcinoma. Introduced at the tum of the 20th century by
Roentgen, external radiation soon became routine practice in the United States for many
benign clinical conditions ranging from "status thymicolymphaticus" to acne. It took
over 50 years, however, to understand that the thyroid gland of children is extremely
sensitive to the carcinogenic effects of ionizing radiation and that this therapy itself
caused papillary thyroid carcinoma, often decades after the exposure. Studies of the
Japanese survivors of the atomic bombings of Nagasaki and Hiroshima first docu
mented thyroid carcinoma as a consequence of radioactive fallout. Nonetheless, the
notion was long held that internal radiation of the thyroid from ingested radioactive
iodine was not a thyroid carcinogen. The outbreak of papillary thyroid carcinoma
among children exposed to radioactive iodine fallout from the nuclear reactor accident
in Chernobyl, however, abruptly closed the door on this notion. This accident placed a
deadly exclamation mark after the statement that small doses of radioiodine indeed are
carcinogenic to the thyroid glands of infants and children, and sparked renewed con
cerns about the aboveground nuclear weapons testing program in Nevada between 1950
and 1960, during which radioactive iodine fallout rained down on nearly the entire
continental United States. The National Cancer Institute estimates that a substantial
excess of thyroid carcinomas has probably occurred and perhaps will continue to occur
as a result of this exposure. How clinicians will deal with this information, including
what tests should be done, is under discussion, but national screening studies are not
likely to be done.
We also have learned much about the pathology of thyroid carcinoma during the
20th century. The early observations about the prognostic implications of tumor size
and invasion through the thyroid capsule are now well accepted. In addition, patholo-
Foreword IX
gists now recognize a number of histologic variants of papillary and follicular carcinoma
that have important implications that must be carefully factored into the assessment of a
tumor's prognosis. Other important advances in our understanding of thyroid pathology
have occurred in this decade. What was once considered small-cell anaplastic thyroid
carcinoma is now recognized as thyroid lymphoma-known to be a rare complication of
Hashimoto's disease--which nevertheless seems to be occurring with increasing fre
quency. While we were busy discovering thyroid lymphoma, the incidence of anaplastic
thyroid carcinoma has been quietly declining, probably as a result of early diagnosis and
treatment of well-differentiated tumors that often serve as its forerunner. All of us breathe
a quiet sigh of relief at this improvement. Now it is well appreciated that a tumor's
prognosis cannot be fully assessed until its final histology has been carefully studied,
sometimes both histologically and imrnunochemically, to uncover the dark secrets of its
origin. This has therapeutic implications.
I think much of our success in reducing mortality from thyroid carcinoma stems
from early diagnosis. Thirty years ago the main diagnostic tests to identify a malignant
nodule were thyroid hormone suppression and radionuclide imaging. Now the stan
dard of care in a clinically euthyroid patient is to perform a fine-needle aspiration
biopsy of the nodule before any other tests are done. Though it remains a less than
perfect test, the study of fine-needle cytology has prevented unnecessary surgery in
many patients while increasing the yield of carcinoma among those undergoing thy
roidectomy. I think fine-needle aspiration of nodules has saved more lives than is
generally acknowledged-by preventing long periods of thyroid hormone suppres
sion-while malignant nodules sometimes became wildly metastatic. There is evi
dence that long delays in therapy significantly increase cancer-specific mortality rates
of papillary and follicular thyroid carcinoma. The key to fine-needle aspiration diag
nosis is to understand the diagnostic details of the cytology report and to act accord
ingly.
Much of the current debate on thyroid carcinoma has revolved around the extent of
initial therapy, both surgical and medical, that is necessary for patients with differenti
ated thyroid carcinoma. Almost everyone believes that some differentiated thyroid
carcinomas require minimal therapy, whereas others require more aggressive manage
ment. The problem lies in defining aggressive tumors. Several staging systems and
prognostic scoring systems have been devised to discriminate between low-risk pa
tients who are anticipated to have a good outcome with minimal therapy and higher
risk patients who require aggressive therapy to avoid morbidity or mortality from thy
roid carcinoma. However, most of the prognostic systems do not identify the variants
of papillary and follicular carcinoma that have remarkably different behaviors. Most
prognostic scoring systems have been created with multiple regression analysis to find
predictive combinations of factors, but almost none include therapy in the analysis.
Moreover, almost all of them have considered cancer mortality as the endpoint of
therapy, ignoring tumor recurrence or disease-free survival. This becomes problem
atic in defining risk because patients under age 40 typically have low cancer mortality
rates, but experience high rates of tumor recurrence. Because most recurrences are in
the neck and are easily treated, some clinicians regard them as trivial problems--but
my patients find this notion incomprehensible. Most patients are devastated by a re-
x Foreword
currence of tumor, regardless of its site. The greatest utility of prognostic scoring
systems lies in epidemiological studies and as tools to stratify patients for prospective
therapy trials, but they are least useful in determining treatment for individual patients.
In the past few decades most have come to believe that near-total or total thyroidec
tomy is the optimal treatment for thyroid carcinomas, even for patients at relatively
low risk of mortality from their carcinomas. The main reason not to do total thyroidec
tomy is that it is associated with higher complication rates than those of lobectomy.
However, there is now evidence documenting what most of us have known for a long
time: surgeons with the most experience have the lowest complication rates,
regardless of the extent of the thyroidectomy. Given the low frequency of this disease,
a compelling argument can be made to refer patients to centers with highly experienced
surgeons for their initial management.
Followup of differentiated thyroid carcinomas and medullary thyroid carcinoma is
greatly facilitated by sensitive serum tests-thyroglobulin and ca1citonin--and the use
of a variety of scanning techniques. I believe that what we term recurrence of tumor is
actually persistent disease that previously fell below the radar of our older, less-sensi
tive detection tools. With newer sensitive tests including, for example, thyroglobulin
measured by messenger RNA, we now have the opportunity to identify and treat thy
roid cancers at an earlier and more responsive stage. Perhaps the most vivid example
of this is the identification of diffuse pulmonary metastases among patients with high
serum thyroglobulin levels and negative diagnostic imaging studies, which are only
seen on posttherapeutic whole-body scans done after large therapeutic doses of 131 I.
Whether this enhances survival continues to be debated, but I think there are compel
ling reasons to suggest that it does improve outcome.
Thus many relatively new observations and management tools that have largely been
developed in the last half of this century are being brought to the bedside to substan
tially enhance our ability to improve the outcome of most patients with thyroid carci
noma. Many challenges remain, however. More effective therapy is urgently needed
for patients with widely metastatic disease that is unresponsive to current therapies.
We need to understand more about the molecular predictors of recurrence and death
from thyroid cancer. Nonetheless, our present state of knowledge provides clinicians a
wide variety of diagnostic and therapeutic modalities to effectively manage this group
of cancers. I believe the knowledge contained in Thyroid Cancer will give the practic
ing clinician the necessary information to provide patients the latest and best diagnos
tic and therapeutic techniques.
Ernest L. Mazza/erri, MD, MACP
Preface
Publication of a new medical text should require some justification. We
believe that no text has been published or currently exists that serves the needs of
practicing physicians for clinically relevant information about thyroid cancer. Thyroid
Cancer: A Comprehensive Guide to Clinical Management is intended to fill that need
and serve as an extensive and inclusive reference source or handbook to clinicians
managing patients with thyroid cancer. The various sections have been written by
highly knowledgeable experts, and the editor has functioned to organize and system
atize the materials into a readable and practical whole. But, equally important to the
authors' expertise is the fact that they are clinicians who are aware of the questions
being asked by practicing physicians, whether in pediatrics, family practice, internal
medicine, endocrinology, endocrine surgery, radiation therapy, or nuclear medicine.
Indeed, no one author could have the requisite clinical experience to write knowledge
ably on all of the topics covered. A word of warning is appropriate, however. Because
of the absence of large, well-controlled clinical trials on the management of thyroid
cancer, many aspects of the standard practices or recommendations of the authors will
be controversial and not universally accepted. In fact, there are differences of opinion
expressed within the various sections of the book, and the editor has not endeavored to
suppress controversy or achieve unanimity. Rather, an attempt has been made to
present evidence-based recommendations where possible, and to indicate clearly where
evidence is lacking and management might be deemed controversial.
Thyroid Cancer has a somewhat unusual format in that the same author has written
each comparable subsection within each major tumor section. For example, rather than
one chapter covering the pathology of all the thyroid cancers, there are separate pathol
ogy chapters within the broad headings of papillary cancer, follicular cancer, medul
lary cancer, etc., and separate chapters within each of these sections dealing with the
clinical presentation, surgical approach, nuclear medicine studies, chemotherapy, etc.
Thus, the arrangement should allow the reader to look up the specific cancer in his or
her patient and find everything they need to know in one convenient place in an eco
nomically concise format. This organization was not always practical and the original
plan breaks down somewhat with, for example, the surgical management of papillary
and follicular thyroid carcinomas, which is similar except for the usual need for a more
complete thyroidectomy for the latter. The minimal differences did not justify a sepa
rate chapter in our view, and in this case the surgery section is described for differenti
ated thyroid carcinoma. In either case, the emphasis is on practical clinical management
such that the volume should represent both an authoritative reference source and a
practical handbook for management.
xi
Xl! Preface
It is clear that the pace of accumulating information about thyroid cancer has
been both rapid and accelerating in recent years; Thyroid Cancer is an up-to-date sum
mary of the current state of our knowledge regarding thyroid nodules, and every known
and clinically significant variant of thyroid malignancy. Each section starts with the
clinical presentation and then proceeds through diagnostic evaluation, histopathology,
medical or surgical approaches to therapy, and then to natural history and prognosis.
After the initial sections on thyroid nodules, there is a scholarly review of the patho
genesis and epidemiology of thyroid cancer. In the latter context, we have learned
much about the risks of radiation exposure from the 1986 Chernobyl accident, and the
relevance of these data to other lesser radiation exposures is discussed. Also in the past
decade, remarkable advances have been made in our ability to diagnose and manage
thyroid cancer. Isotopic scanning modalities other than radioiodine have been devel
oped, and the recent availability of recombinant human thyrotropin is transfiguring our
management, particularly of low risk patients. Advances in our understanding of the
immunology of thyroid cancer and the genetic alterations leading to malignancy con
tinue unabated and the current state of our knowledge in these areas is also thoroughly
reviewed. Precision in diagnosis of cancer has been facilitated by fine needle aspira
tion cytology, and in cancer followup by development of more specific and sensitive
assays for serum thyroglobulin, and by sensitive imaging techniques including ultra
sound, CT, MRI, and the newer scanning modalities.
Much has been learned about the appropriate surgical procedures that permit
an optimal prognosis without unnecessary disfigurement. Recent appreciation of the
phenomenon of radio nuclide "stunning" has led to development of protocols that maxi
mize therapeutic efficacy of radioiodine therapy. Separate sections of the volume deal
with the special aspects of thyroid cancer in children, and the thorny problem of the
management of the patient with suspected residual thyroid cancer on the basis of mea
surable thyroglobulin levels but who has radioiodine scan surveys that are negative and
fail to identify a source of the thyroglobulin, i.e., the cancer. Though the major portion
of the text deals with all aspects of the most common thyroid carcinomas, the well
differentiated papillary and follicular types, there are extensive treatments as well of
the primary thyroidal cancers that do not arise from follicular epithelium, e.g., medul
lary and anaplastic cancer, and lymphoma. Separate sections also deal with the more
rare and unusual malignant thyroid tumors, both in regard to their pathology and their
clinical presentation and management. Those desiring a greater in-depth discussion are
provided a current and exhaustive bibliography in each section.
I thank the many authors for their outstanding contributions, and the efforts of
the skilled executive staff of Humana Publishers, including Thomas Lanigan, Paul
Dolgert, Craig Adams, and James Geronimo who produced the book in so professional
and timely a manner. We bring this volume to its readership with great enthusiasm and
with the sincere hope that it will prove to be of substantial utility to physicians to allow
them to provide the greatest benefit to their patients with thyroid cancer.
Leonard Warto!sky, MD
