Table Of ContentRecent Results in Cancer Research
Series Editors: P.M. Schlag · H.-J. Senn
Friedhelm Raue
Editor
Medullary Thyroid
Carcinoma
Biology—Management—Treatment
Recent Results in Cancer Research
Volume 204
Series editors
P.M. Schlag, Berlin, Germany
H.-J. Senn, St. Gallen, Switzerland
Associate Editors
P. Kleihues, Zürich, Switzerland
F. Stiefel, Lausanne, Switzerland
B. Groner, Frankfurt, Germany
A. Wallgren, Göteborg, Sweden
Founding Editor
P. Rentchnik, Geneva, Switzerland
More information about this series at http://www.springer.com/series/392
Friedhelm Raue
Editor
Medullary Thyroid
Carcinoma
— —
Biology Management Treatment
123
Editor
Friedhelm Raue
Endocrine Practice andMolecular
Laboratory,Medical Faculty
University of Heidelberg
Heidelberg
Germany
ISSN 0080-0015 ISSN 2197-6767 (electronic)
Recent Resultsin Cancer Research
ISBN978-3-319-22541-8 ISBN978-3-319-22542-5 (eBook)
DOI 10.1007/978-3-319-22542-5
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Foreword
Sixty-five years ago Hazard, Hawk, and Crile first described medullary thyroid
carcinoma (MTC) as a specific histological entity. Initially, it was thought that the
tumor only occurred sporadically; however, 48 years ago, Steiner and associates
first reported that MTC also occurs as an integral part of a familial polyendocrine
disorder,whichtheynamedmultipleendocrineneoplasia(MEN)type2,incontrast
tothepreviouslydescribedMEN1.TherearetwosubtypesofMEN2:MEN2Aand
MEN2B.
AlthoughMTCaccountsforlessthan5%ofthyroidcancers,ithasattractedan
inordinate amount of interest for several reasons:
The most significant driver mutations causing MTC are known. Virtually all
patients with hereditary MTC have germline mutations in the RET protooncogene,
and almost all patients with sporadic MTC have either somatic RET mutations or
somatic RAS mutations. Direct DNA analysis to detect RET mutations has proved
invaluableintheearlydiagnosisofpatientsatdirectriskforhereditaryMEN2,and
in the detection of hereditary MTC in patients with presumed sporadic MTC.
Furthermore,thereisacorrelationbetweengenotypeandphenotypethatisusefulin
predictingtheclinicalexpressionofdiseaseinpatientswiththeMEN2syndromes.
MTC cellssecretethepolypeptidecalcitonin,which serves asasensitive serum
tumormarkerforMTC.YoungsterswhohaveinheritedamutatedRETallelecanbe
monitored by serum calcitonin measurements to determine the timing of a pro-
phylactic thyroidectomy, which is curative when done before MTC develops or
spreads beyond the thyroid gland. Serum calcitonin measurements are also useful
for detecting persistent or recurrent MTC following thyroidectomy, and for
monitoring response to therapies in patients with advanced disease.
AlthoughtotalthyroidectomyisthetreatmentofchoiceforprimaryMTC,there
had been no effective therapy for extensive regional or distant metastases until
recently, when prospective randomized trials demonstrated prolongation of
progression-free survival in patients treated with tyrosine kinase inhibitors, com-
pared to placebo. At present, these novel agents are first-line treatment of patients
with advanced MTC.
The International MEN Workshop was formed in 1984. The Workshop meets
biannuallyandprovidesavaluableforumwherecliniciansandbasicscientistsmeet
v
vi Foreword
to discuss new developments in basic science and clinical research related to the
MEN1 and MEN2 syndromes.
Dr. Friedhelm Raue, of the Department of Endocrinology at the University of
Heidelberg, is an internationally respected investigator in endocrinology. He is the
editorofthisoutstandingbookonmedullarythyroidcarcinoma,andhisco-authors
are international leaders in the field of endocrinology and thyroid cancer.
The initial part of the book is devoted to MTC, beginning with a chapter on
C-cell molecular biology and the molecular genetics of MTC, and continues with
chaptersonpathology,epidemiologyandclinicalpresentation,imaging,andtumor
markers. Subsequent chapters concern the MEN2 syndromes including the rela-
tionship between genotype and phenotype in patients with MEN2A and MEN2B,
and the management of pheochromocytoma and hyperparathyroidism. The final
chapters address the surgical management of MTC, the long-term evaluation of
patients following thyroidectomy, and the use of tyrosine kinase inhibitors in the
treatment of patients with advanced MTC.
This is an excellent book, primarily because of the expertise of the contributors
andtheirthoroughandtimelycoverageofallaspectsofMTCandtheMENtype2
syndromes. This book will be a valuable resource for medical students, post-
graduate students, basic scientists, clinical investigators, and practicing clinicians.
S. Wells
National Institutes of Health
Bethesda, MD, USA
Contents
Thyroid C-Cell Biology and Oncogenic Transformation . . . . . . . . . . . 1
Gilbert J. Cote, Elizabeth G. Grubbs and Marie-Claude Hofmann
Histopathology of C Cells and Medullary Thyroid Carcinoma. . . . . . . 41
Kurt Werner Schmid
Epidemiology and Clinical Presentation of Medullary
Thyroid Carcinoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Friedhelm Raue and Karin Frank-Raue
Medullary Thyroid Carcinoma: Imaging . . . . . . . . . . . . . . . . . . . . . . 91
Stefan Delorme and Friedhelm Raue
Calcitonin as Biomarker for the Medullary Thyroid Carcinoma . . . . . 117
Yoon Ju Bae, Michael Schaab and Juergen Kratzsch
Hereditary Medullary Thyroid Cancer Genotype–Phenotype
Correlation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Karin Frank-Raue and Friedhelm Raue
Pheochromocytomas in Multiple Endocrine Neoplasia Type 2 . . . . . . . 157
Venessa H.M. Tsang, Lyndal J. Tacon, Diana L. Learoyd
and Bruce G. Robinson
Primary Hyperparathyroidism in MEN2 Syndromes. . . . . . . . . . . . . . 179
Maria Alevizaki and Katerina Saltiki
Surgical Treatment of Medullary Thyroid Cancer. . . . . . . . . . . . . . . . 187
Andreas Machens and Henning Dralle
Long-Term Follow-up in Medullary Thyroid Carcinoma. . . . . . . . . . . 207
Friedhelm Raue and Karin Frank-Raue
vii
viii Contents
Use of Tyrosine Kinase Inhibitors for Treatment
of Medullary Thyroid Carcinoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
Ramona Dadu, Mimi N. Hu, Elizabeth G. Grubbs
and Robert F. Gagel
Thyroid C-Cell Biology and Oncogenic
Transformation
Gilbert J. Cote, Elizabeth G. Grubbs and Marie-Claude Hofmann
Abstract
Thethyroidparafollicularcell,orcommonlynamed“C-cell,”functionsinserum
calcium homeostasis. Elevations in serum calcium trigger release of calcitonin
from the C-cell, which in turn functions to inhibit absorption of calcium by the
intestine, resorption of bone by the osteoclast, and reabsorption of calcium by
renal tubular cells. Oncogenic transformation of the thyroid C-cell is thought to
progress through a hyperplastic process prior to malignancy with increasing
levels of serum calcitonin serving as a biomarker for tumor burden. The
discovery that multiple endocrine neoplasia type 2 is caused by activating
mutations of the RET gene serves to highlight the RET-RAS-MAPK signaling
pathway in both initiation and progression of medullary thyroid carcinoma
(MTC).ThyroidC-cellsareknowntoexpressRETathighlevelsrelativetomost
cell types; therefore, aberrant activation of this receptor is targeted primarily to
theC-cell,providingonepossiblecauseoftissue-specificoncogenesis.Therole
of RET signaling in normal C-cell function is unknown though calcitonin gene
transcription appears to be sensitive to RET activation. Beyond RET, the
modeling of oncogenesis in animals and screening of human tumors for
candidategenemutationshaveuncoveredmutationofRASfamilymembersand
inactivation of Rb1 regulatory pathway as potential mediators of C-cell
transformation. A growing understanding of how RET interacts with these
G.J.Cote(&)(cid:1)M.-C.Hofmann
DepartmentofEndocrineNeoplasiaandHormonalDisorders,TheUniversityofTexasMD
AndersonCancerCenter,1515HolcombeBlvd.,Unit1461,Houston,TX77030,USA
e-mail:[email protected]
E.G.Grubbs
DepartmentofSurgicalOncology,TheUniversityofTexasMDAndersonCancerCenter,
1515HolcombeBlvd.,Unit1484,Houston,TX77030,USA
©SpringerInternationalPublishingSwitzerland2015 1
F.Raue(ed.),MedullaryThyroidCarcinoma,
RecentResultsinCancerResearch204,DOI10.1007/978-3-319-22542-5_1
