Neoplasia Endocrina Múltiple

S P E C I A L
F E A T U R E
R e v i e w
Multiple Endocrine Neoplasia Type 2 and Familial

Medullary Thyroid Carcinoma: An Update
Samuel A. Wells, Jr, Furio Pacini, Bruce G. Robinson, and Massimo Santoro
Cancer Genetics Branch (S.A.W.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland
20814; Section of Endocrinology and Metabolism (F.P.), Department of Internal Medicine, Endocrinology,
and Metabolism, and Biochemistry, University of Siena, 53100 Siena, Italy; University of Sydney School of
Medicine (B.R.), The University of Sydney, Sydney, New South Wales 2065, Australia; and Dipartimento di
Medicina Molecolare e Biotecnologie Mediche (M.S.), Universita di Napoli Federico II, Edificio 19, Torre
Biologica, Via S. Pansini 5, 80131, Napoli, Italy
Context: Over the last decade, our knowledge of the multiple endocrine neoplasia (MEN) type 2
syndromes MEN2A and MEN2B and familial medullary thyroid carcinoma (FMTC) has expanded
greatly. In this manuscript, we summarize how recent discoveries have enhanced our understanding of the molecular basis of these diseases and led to improvements in the diagnosis and management of affected patients.
Evidence Acquisition: We reviewed the English literature through PubMed from 2000 to the
present, using the search terms medullary thyroid carcinoma, multiple endocrine neoplasia type 2,
familial medullary thyroid carcinoma, RET proto-oncogene, and calcitonin.
Evidence Synthesis: Over 70 RET mutations are known to cause MEN2A, MEN2B, or FMTC, and recent
findings from studies of large kindreds with these syndromes have clouded the relationship between
genotype and phenotype, primarily because of the varied clinical presentation of different families
with the same RET mutation. This clinical variability has also confounded decisions about the timing of
prophylactic thyroidectomy for MTC, the dominant endocrinopathy associated with these syndromes. A
distinct advance has been the demonstration through phase II and phase III clinical trials that molecular
targeted therapeutics are effective in the treatment of patients with locally advanced or metastatic MTC.
Conclusions: The effective management of patients with MEN2A, MEN2A, and FMTC depends on
an understanding of the variable behavior of disease expression in patients with a specific RET
mutation. Information gained from molecular testing, biochemical analysis, and clinical evaluation
is important in providing effective management of patients with either early or advanced-stage
MTC. (J Clin Endocrinol Metab 98: 3149 3164, 2013)
ince the seventh International Workshop published

the Consensus Guidelines for the Diagnosis and
Therapy of Multiple Endocrine Neoplasia types 1 and 2
over a decade ago, there has been a marked expansion
in our knowledge of the basic and clinical aspects of
these syndromes (1). This is particularly true of multiple
endocrine neoplasia (MEN) type 2A, MEN2B, and familial medullary thyroid carcinoma (FMTC), where extensive studies of large families, often from national
consortia, have led to the identification of new germline
or somatic activating RET mutations that either alone

or in association with a second RET mutation, characterize modified phenotypes (2 4). There have been additional studies addressing the indications and timing of
prophylactic thyroidectomy in family members who
have inherited a mutated RET allele. Also, completed
phase II and phase III clinical trials of molecular targeted therapeutics (MTTs) have shown efficacy in patients with advanced (MTC), a disease stage for which
there has been no effective therapy.
ISSN Print 0021-972X ISSN Online 1945-7197

Printed in U.S.A.
Copyright 2013 by The Endocrine Society
Received January 22, 2013. Accepted May 30, 2013.
First Published Online June 6, 2013
Abbreviations: CCH, C-cell hyperplasia; CEA, carcinoembryonic antigen; CLA, cutaneous

lichen amyloidosis; FMTC, familial medullary thyroid carcinoma; HD, Hirschsprungs disease; MEN, multiple endocrine neoplasia; MTC, medullary thyroid carcinoma; MTT, molecular targeted therapeutic; RET, rearranged during transfection.
doi: 10.1210/jc.2013-1204
J Clin Endocrinol Metab, August 2013, 98(8):3149 3164
jcem.endojournals.org
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 15 December 2014. at 19:13 For personal use only. No other uses without permission. . All rights reserved.
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Hereditary Medullary Thyroid Carcinoma
The RET proto-oncogene comprises 21 exons and is located on chromosome 10

(10q11.2). Homologs of RET are present in
higher and lower vertebrates, as well as in
Drosophilia melanogaster (12, 13). RET encodes a single-pass transmembrane receptor of
the tyrosine kinase family of proteins, and at
several stages of development, it is expressed in
cells derived from the branchial arches (parathyroids), from the neural crest (the brain,
parasympathetic and sympathetic ganglia, thyroid C-cells, adrenal medulla, and enteric ganglia), and from the urogenital system (14). RET
is the integral component of a tripartite cellsurface complex including a member of the glial-derived neurotrophic factor (GDNF) family
ligands (GFL) (Figure 1), to which it binds in
conjunction with its cognate glycosylphosphatidylinositol-linked GDNF family receptors (GFR 1 4). Ligand binding, requiring
calcium ions chelated to the RET extracellular
domain, induces dimerization and phosphorylation of the RET receptor with downstream
activation of several signal transduction pathways (15) (Figure 1). In MEN2A, MEN2B, and
FMTC, the mutations are activating, unlike
most other hereditary cancer syndromes,
which are associated with DNA mismatch repair genes or inactivation of tumor suppressor
genes. The recent discovery that somatic
HRAS, KRAS, and NRAS mutations occur in
Figure 1. The RET protein. Abbreviations: ART, artemin; CLD, cadherin-like
domains; CRD, cysteine-rich domain; GDNF, glial-derived neurotrophic factor; GFL,
approximately 10% to 45% of sporadic
glial-derived neurotrophic factor family ligands; GFR (1 4), GDNF family
MTCs, and are almost always mutually exclureceptors; Ki, kinase insert region; NTN, neuturin; PSP, persephin; SP, signal peptide;
sive with somatic RET mutations, suggests an
TK, tyrosine kinase domain; TM, transmembrane domain. The position of major RET
phosphorylation sites (Y905, Y1015, and Y1062) are marked, as are other
important alternate molecular pathway for the
phosphorylation sites and signaling pathways.
development of this malignancy (16, 17). A recent exomic sequencing study demonstrated
Recently, several professional groups have published ad- that besides RET and rarely RAS, no other gene is comditional guidelines defining the management of patients with monly targeted by point mutations in MTC (18).
MTC or neuroendocrine tumors (57). Accordingly, our
Approximately 50% of patients with familial Hirschpurpose is not to develop another set of guidelines, or to sprungs disease (HD) have RET mutations, and chromorevise existing guidelines, but to provide an overview of the somal translocations that activate RET occur in approxcurrent knowledge of the MEN2 syndromes and FMTC.
imately 30% of patients with papillary thyroid carcinoma
and less often in patients with lung cancer and chronic
myelomonocytic leukemia (19 22).
The Molecular Genetic Basis of MEN2A,

MEN2B, and FMTC
Each of the MEN2 syndromes and FMTC is inherited in
an autosomal dominant pattern and is caused by mutations in the RET (rearranged during transfection) protooncogene (8 11). Over 1000 kindreds with these endocrinopathies have been identified throughout the world.
Clinical Manifestations of MEN2A, MEN2B,

and FMTC
MEN type 2A
MEN2A (OMIM 171400) accounts for 80% of hereditary MTC syndromes. Virtually all patients develop
doi: 10.1210/jc.2013-1204
MTC, up to 50% develop pheochromocytomas, and up to

30% develop hyperparathyroidism depending on the RET
codon mutation (23). Patients with MEN2A may also develop cutaneous lichen amyloidosis (CLA), HD, or rarely
prominent corneal nerves (24). Despite the facts that RET
is highly expressed in human fetal kidney during morphogenesis and that ret-knockout mice (ret/) display renal
agenesis or severe dysgenesis, there are few reports of genitourinary abnormalities in patients with MEN2A,
MEN2B, or FMTC (25, 26).
MTC accounts for approximately 5% of all thyroid
cancers and occurs either sporadically (75% of cases) or in
a hereditary pattern. The MTC arises from the neural
crest-derived C-cells and up to 50 C-cells per low-power
field are present in the normal adult thyroid gland (27). In
the early stage of pathogenesis these cells proliferate, as
C-cell hyperplasia (CCH), the only histological manifestation of incipient disease. The so-called secondary CCH,
occurring in association with diseases such as hyperparathyroidism, hypergastrinemia, and renal insufficiency, or
after the administration of certain drugs, is not a premalignant condition (28). The maximum C-cell surface area
in the adult thyroid gland is twice as high in men as
women (29). The C-cells secrete the 32amino-acid
polypeptide calcitonin and the glycoprotein carcinoembryonic antigen (CEA), which serve as excellent tumor
markers for MTC. The serum calcitonin level, both in
the basal state and after iv administration of the secretagogues calcium or pentagastrin is higher in men compared with women, almost certainly a reflection of the
gender difference in C-cell mass.
Unlike sporadic MTC, which presents as a solitary unilateral thyroid nodule, hereditary MTC is multicentric and
occupies the upper and middle portions of each thyroid
lobe. The tumor remains confined to the thyroid gland for
a variable period of time before spreading to the regional
lymph nodes and subsequently to the liver, lung, bone, and
brain. Histologically, 20% of the tumors have a predominantly cellular growth pattern, 40% have a fibrous pattern with more than half of the cellular component replaced by a calcified acellular stroma, and the remaining
40% display an intermediate pattern with neoplastic nests
of cells separated by bands of fibrous tissue. The stroma is
composed primarily of full-length calcitonin, which has
staining properties similar to amyloid (30). There is a
graded progression in tumor histology with a cellular
growth pattern developing early and progressing to intermediate and fibrous patterns as the MTC ages.
Pheochromocytomas develop in approximately 50%
of patients with MEN2A and MEN2B, the clinical presentation and behavior being similar in the 2 syndromes.
The mean age of presentation is 36 years, and the diagnosis
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is made after MTC in 50% of cases, concurrently with

MTC in 40% of cases, and before MTC in 10% of cases.
The tumors are almost always benign and confined to the
adrenal gland. In 65% of cases, they are multicentric and
bilateral. Patients with unilateral pheochromocytomas
usually develop a contralateral pheochromocytoma within
10 years (31).
There is significant morbidity and mortality associated
with an undiagnosed pheochromocytoma; thus, in patients with known MEN2A or MEN2B, it is critical to rule
out this tumor before interventional procedures. Before
the introduction of biochemical and genetic testing, pheochromocytoma, not MTC, was the most common cause of
death in patients with MEN2A. The deaths were commonly associated with surgical procedures or childbirth
(23, 32). After the introduction of biochemical and genetic
screening in families with hereditary MTC, deaths due to
pheochromocytoma markedly decreased.
Patients suspected of having a pheochromocytoma
should have measurement of plasma-free or urinary-fractionated metanephrines or both (33, 34). Computed tomography scanning and magnetic resonance imaging are
used to localize pheochromocytomas. The sensitivity
(90%100%) and specificity (70% 80%) are similar for
the 2 procedures (35, 36).
Excepting very unusual circumstances, a pheochromocytoma should be resected before the MTC if both
are present. Preoperative preparation is with -adrenergic blockade and if necessary -adrenergic blockade.
Unilateral adrenalectomy is indicated in patients with a
single pheochromocytoma, because there is a significant
incidence of Addisonian crisis associated with bilateral
adrenalectomy (31, 37). In patients with bilateral pheochromocytomas, both adrenals are resected under corticosteroid coverage preoperatively and continuously postoperatively. The standard procedure is laparoscopic
adrenalectomy (38, 39). Because of the substantial morbidity and occasional mortality associated with bilateral
adrenalectomy for pheochromocytoma surgeons have explored procedures such as subtotal adrenalectomy to preserve adrenocortical function (40). Although the concept
of preserving adrenal cortical function in this clinical setting has merit, there has been a limited experience with the
procedure and there are few reports of long-term follow-up in treated patients (40, 41).
Hyperparathyroidism develops in 20% to 30% of patients with MEN2A. The mean age of onset is 36 years
(42). In most cases, hyperparathyroidism is diagnosed
concurrently with MTC, being the first manifestation of
the syndrome in less than 5% of cases. The hypercalcemia
is usually mild, and 85% of patients are asymptomatic
(43). The size of the parathyroid glands may vary greatly
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with from 1 to 4 being enlarged. Histologically, the enlarged parathyroid glands contain multiple hyperplastic
nodules in a pattern best defined as pseudonodular hyperplasia (44). During thyroidectomy for MTC, the surgeon often finds 1 or more enlarged parathyroid glands
even though the patient is asymptomatic and normocalcemic. There is no single satisfactory operation for hyperparathyroidism in MEN2A, the options being subtotal
parathyroidectomy with preservation of a small remnant
of one gland or total parathyroidectomy with heterotopic
autotransplantation (45, 46).
CLA occurs in approximately 10% of families with
MEN2A. The skin lesions are particularly evident in the
scapular region of the back corresponding to dermatomes
T2 to T6. The inciting lesion appears to be notalgia paresthetica, a sensory neuropathy involving the dorsal spinal
nerves. Secondary changes characterized by the deposition
of amyloid result from pruritus and repetitive scratching.
The CLA may be present at a young age and before the
onset of clinically evident MTC, thus serving as a precursor for the syndrome (47, 48).
HD can occur in patients with MEN2A and FMTC and
is characterized by the failure of neural crest cells to migrate, proliferate, and differentiate into submucosal
(Meissner), myenteric (Auerbach), and deep submucosal
(Henles) enteric plexuses. Several genes have been implicated in HD, the major ones being RET and endothelin
receptor B (EDNRB). (49) Whereas EDNRB mutations
are present in approximately 5% of patients with HD,
RET mutations are found in 15% to 20% of sporadic
cases and 50% of familial cases (50). HD occurs in approximately 7% of patients with MEN2A and FMTC (4).
Conversely, 2% to 5% of patients with HD have hereditary MTC (51, 52). The RET mutations associated with
HD disable the activation or expression of RET, resulting
in loss-of-function in contrast to the RET mutations associated with MEN2A, MEN2B, and FMTC, which induce constitutive activation and gain-of-function. The
generally accepted explanation for the concurrence of HD
and MEN2A or FMTC is that a dual effect is induced by
the associated RET mutations, which through constitutive
activation, are sufficient to trigger neoplastic transformation of the thyroid C-cells and adrenal chromaffin cells yet,
because of impaired expression of the RET protein at the
cell surface, are insufficient to generate a trophic response
in the precursor neurons (53).
MEN type 2B
MEN2B (OMIM 162300) accounts for 5% of hereditary MTCs. Patients with MEN2B also develop pheochromocytomas and a definitive phenotype characterized by
typical facies, a marfanoid habitus, ocular abnormalities
(enlarged corneal nerves, conjunctivitis sicca, and the

inability to cry tears), musculoskeletal manifestations
(bowing of the extremities and slipped capital femoral
epiphysis), and generalized ganglioneuromatosis. Over
90% of patients have gastrointestinal symptoms characterized by abdominal pain, constipation, and alternatively diarrhea, bloating, and megacolon. The gastrointestinal symptoms are particularly evident in
children and young adults and may require a surgical
procedure to relieve symptoms (54, 55).
It is important that clinicians who first see children with
MEN2B recognize the characteristic signs and symptoms
associated with the syndrome, because the MTC is highly
aggressive in this setting and there is a narrow window
during which thyroidectomy may be curative (56 59). In
approximately 50% of MEN2B cases, a de novo germline
RET mutation gives rise to the disease. Newborns are at a
particular disadvantage in this setting, because their parents appear normal, and the disease is unexpected. In one
series of 21 patients with sporadic MEN2B, the mean age
at diagnosis was 14.2 years (60). Even in the most advantageous setting where thyroidectomy is performed in the
neonatal period, the outcome is often dismal (61). In patients with de novo MEN2B, the mutated allele arises from
the father. This is also true of the 10% of cases of de novo
MEN2A (62, 63).
Familial MTC
FMTC (OMIM 155240) accounts for 15% of hereditary MTCs. This entity is characterized by the presence of
only MTC, which has a late age of onset and a less aggressive clinical course compared with MEN2A and
MEN2B (64). As defined in the Guidelines for Diagnosis
and Therapy of MEN Type 1and Type 2 (1), a diagnosis
of FMTC would apply to kindreds with more than 10
carriers, multiple carriers, or affected members over the
age of 50 and an adequate medical history to exclude the
presence of pheochromocytoma and hyperparathyroidism, especially in older subjects (1). These criteria are more
rigorous than those set forth by the International RET
Mutation Consortium Analysis, which defined FMTC as
a kindred with a minimum of 4 family members with MTC
and no objective evidence of pheochromocytoma or hyperparathyroidism (65).
Genotype-Phenotype Correlations in
MEN2A, MEN2B, and FMTC
Clinical studies have provided an important framework
for understanding the relationship of genotype to phenotype, especially in MEN2A. For example, in 95% of pa-
doi: 10.1210/jc.2013-1204
tients with MEN2A, RET mutations occur in codons 609,

611, 618, and 620 in exon 10 or in codon 634 in exon11.
The presence of any germline mutation at codon 634 is
highly associated with the development of hyperparathyroidism and also pheochromocytoma, the frequency of the
latter depending on the RET codon mutation: 609 (4%),
611 (0%), 618 (22%), 620 (9%), and 634 (50%) (66). The
presence of CLA in MEN2A is almost always associated
with a C634 RET codon mutation; however, it has also
been reported in a subject with a V804M germline mutation (65, 67). The HD associated with MEN2A almost
always involves the cysteine codons in exon 10, including 609 (15%), 611 (5%), 618 (30%), and 620 (50%)
(68, 69).
The large majority of patients with MEN2B have mutations in exon 16 (M918T) and less often exon 15
(A883F). The clinical behavior of the MTC appears to be
less aggressive in patients with the A883F mutation, compared with those with a M918T mutation, and despite the
generally poor prognosis, rare long-term cures after early
thyroidectomy have been reported (59, 70, 71). Patients
with rare double RET mutations involving codon V804M
and either codon Y806C, S904C, or E805K present with
atypical MEN2B, characterized by MTC with a late age of
onset and varying aggressiveness (7274).
The most common FMTC mutations affect extracellular cysteine codons in RET exon 10, or intracellular RET
codons other than A883 and M918.
The reported RET germline point mutations and their
associated clinical phenotypes are shown in Figure 2, and
the list of all reported RET mutations, deletions, insertions, duplications, homozygous mutations, and multiple
codon mutations associated with MEN2A, MEN2B, and
FMTC are listed in Supplemental Table 1 (published on
The Endocrine Societys Journals Online web site at
http://jcem.endojournals.org).
Early reports evaluating the association between genotype and phenotype occurred at a time when many RET
mutations causing hereditary MTC were yet to be discovered (65, 75, 76). It was expected that as a larger number
of families were studied, the relationship between genotype and phenotype would become clearer; however, in
many ways, the opposite has happened. It has become
apparent that different families with MEN2A due to the
same RET mutation often have significant variability in
the clinical expression of disease and aggressiveness of the
MTC. This is presumably due to coexpression of diseasemodifying alleles.
Although the original criteria defining MEN2A and
MEN2B have remained unchanged, there has been a particular problem with FMTC, where already there are 2 sets
of criteria defining the syndrome (1, 65). It has become
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evident that many kindreds first designated as FMTC,

with longer follow-up, or upon study of other kindreds
with the same mutation, are found to have MEN2A. This
situation is exemplified by a 6-generation Brazilian kindred of 229 family members, 76 of whom had MTC due
to a G533C mutation but no evidence of pheochromocytoma or hyperparathyroidism (77). The family appeared
to have FMTC; however, it was subsequently reported
that a 62-year-old member of this kindred developed a
pheochromocytoma (78). Furthermore, 2 Greek families
with the G533C mutation were reported to have MTC and
pheochromocytoma, thus clarifying that this RET mutation is associated with MEN2A (79, 80).
The matter of nomenclature has been further complicated as various investigators have used FMTC to define
families, most commonly those with the noncysteine RET
mutations in codons 768, 790, 791, or 804, who predominantly manifest MTC and have a much lower frequency
of pheochromocytoma or hyperparathyroidism (5, 81
83). If these broader criteria were followed, the incidence
of FMTC would comprise 30% to 60% of patients with
hereditary MTC.
Thus, a clear definition of FMTC is needed. Considering the rigid criteria proposed by the Guidelines for Diagnosis and Therapy of MEN Type 1and Type 2 (1),
there are at present only 3 documented families that would
be classified as FMTC (Supplemental Table 1) (1, 84 86).
One solution is to retain the definition of FMTC with
the strict criteria originally proposed, realizing that after
long-term follow-up, a family suspected of having FMTC
may develop hyperparathyroidism or pheochromocytoma and be reclassified as MEN2A (1). A second alternative is to expand the definition of FMTC to include
families with certain RET mutations who have late-onset
MTC with the infrequent occurrence of pheochromocytoma or hyperparathyroidism. A third alternative is to
discard the term FMTC and classify all patients with hereditary MTC, other than those with MEN2B, as MEN2A
and designate them by a specific RET mutation, for example MEN2A_RET C634R (87). With this option, there
would be two MEN2 syndromes, with approximately
95% classified as MEN2A, which would be a remarkably
heterogeneous group with over 70 different RET mutations in families that express MTC, pheochromocytomas,
and hyperparathyroidism over a wide range of frequencies, times of onset, and clinical behavior. This would not
address the issue of a number of small families, or single
individuals, many with rare germline RET mutations, who
defy classification.
All considered, it seems reasonable to retain the term
FMTC and include within it 1) families with a RET germline mutations who meet the original strict criteria for
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Wells, Jr et al
Figure 2. The RET gene, the RET protein, and RET point mutations associated with MEN2A, MEN2B, and FMTC. RET gene structure with coding
exons numbered 1 to 20 is shown as the central figure in gray. Alternative splicing in exon 19 generates 2 alternative mRNAs, coding for RET-51
(1114 residues) when exon 19 is spliced to exon 20 or RET-9 (1072 residues) when exon 19 remains unspliced. Moreover, alternative splicing to
another exon (exon 21) causes the synthesis of the C-terminal part of another less abundant RET isoform, RET-43. In this figure, only RET-51 is
represented, whereas RET-9, RET-43, and the alternative exon 21 are not. The RET protein is represented on the left in blue and red. Amino acid
residues, numbered 1 to 1114, are shown to the left of the figure. The extracellular RET domain (with the signal peptide [SP], 4 cadherin-like
domains [CLD1 4], and a cysteine-rich domain [CRD]), the transmembrane domain (TM), and the intracellular tyrosine kinase domain (TK) are
represented. The RET TK is split into 2 subdomains (TK1 and TK2) by an insert region (Ki). The positions of reported RET point mutations associated
with MEN2A, MEN2B, and FMTC are shown to the right of the RET gene. The mutations causing MEN2A and MEN2B are shown in black, whereas
the mutations for FMTC are shown in red. An asterisk denotes homozygous mutations. Some of the reported RET mutations have no function
studies demonstrating that the specific mutation is a bona fide gain-of-function mutation. Not included in Figure 2 are reports of deletions,
insertions, duplications, or multiple mutations. This information, as well as references for each point mutation or genetic alteration, is included in
Supplemental Table 1. [Modified from Figure 5 in J. W. de Groot et al: RET as a diagnostic and therapeutic target in sporadic and hereditary
endocrine tumors. Endocr Rev. 2006;27:535560 (163), with permission. The Endocrine Society.]
doi: 10.1210/jc.2013-1204
FMTC (1), 2) small families (at least 2 generations, with at

least 2 but fewer than 10 RET gene carriers) with MTC but
no pheochromocytoma or hyperparathyroidism, or 3)
small families or single individuals with 2 or fewer members with MTC in a single generation without pheochromocytoma or hyperparathyroidism.
According to this classification, the reported families or
single individuals with only MTC, and associated specific
RET germline mutations, are listed in Supplemental Table
1. It is important to note that to designate a family with a
specific RET germline mutation, eg, C611F, as FMTC,
there must be no other reported family with this specific
mutation that has either a pheochromocytoma or
hyperparathyroidism.
Although this modified nomenclature may add clarity
to the disease phenotypes and genotypes, clinical investigators still need to be aware of the substantial variability
in the clinical expression of disease within MEN2A and
FMTC families. This is especially relevant in patients considered for prophylactic thyroidectomy.
The Diagnosis of Hereditary and Sporadic

MTC
Serum calcitonin
Formerly, measurement of serum calcitonin levels, especially after the iv administration of the provocative
secretagogues calcium or pentagastrin, or a combination
of the two, served as the primary method for screening
family members at risk for hereditary MTC (88). Since the
introduction of direct DNA analysis for detecting RET
mutations, the determination of serum calcitonin levels is
rarely used alone for the early diagnosis of hereditary
MTC; however, in some clinics, it is the basis for timing
prophylactic thyroidectomy in family members who have
inherited a mutated RET allele. The preferred assays for
quantitating serum calcitonin are 2-site, 2-step, chemiluminescent, immunometric assays that are highly specific
for monomeric calcitonin. With these assays, the risks of
a hook effect, or cross-reactivity with other peptides or
byproducts of inflammatory or infectious reactions are
minimal (89 91). The reference values for basal serum
calcitonin levels are 10 pg/mL for males and 5pg/mL
for females. The reference values for children are more
varied, especially in neonates, where they can be as high as
40 pg/mL (89). The normal range of basal and stimulated
serum calcitonin levels may vary from laboratory to laboratory; thus, for serial measurements of calcitonin, it is
best that clinicians use the same laboratory with its established reference range.
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In many European centers, it is standard practice to

measure serum calcitonin levels in patients presenting with
nodular goiters to exclude MTC, although this has not
become common practice in the United States or Australia
(9295).
Direct DNA analysis for mutations in the RET
proto-oncogene
Approximately 98% of index patients with MEN2 and
FMTC have an identifiable RET mutation (81, 96). Figure
2 lists the currently known RET point mutations (within
exons) documented in hereditary MTC. Unlike the characteristic mutations in exons 10, 11, 15, and 16 associated
with MEN2A and MEN2B, little is known about the mode
of activation of extracellular mutations in RET exons 5
and 8 (97100). Also, the mechanisms by which intracellular codon mutations in exons 13 and 14, and less commonly non-MEN2B mutations in exons 15 and 16, activate RET are unclear, although in the latter case, it has
been suggested that they disrupt the autoinhibited dimer
conformation of wild-type RET, thereby enabling RET
kinase (101).
In families with a known germline RET mutation, testing of family members at risk is relatively easy because a
targeted approach can be focused on the specific codon
housing the mutation. In new families with hereditary
MTC where the RET status is unknown, the usual strategy
for testing family members at direct risk is to sequence the
most commonly affected exons and, if negative, to extend
sequencing to additional exons. If no RET mutation is
found, it may be necessary to sequence the entire coding
region of the gene. As the extent of sequencing increases,
so does the cost. Gene sequencing technology, however, is
becoming cheaper, and clinicians may find that rather
than a tiered approach, it may be more practical in new
families with hereditary MTC to sequence the entire RET
coding region, because this would allow the detection of
not only uncommon RET mutations but also double mutations, deletions, and insertions.
One cannot overemphasize the importance of direct
DNA sequencing to detect RET mutations in kindred
members at risk for hereditary MTC. There are 69 laboratories internationally that perform direct DNA analysis
for RET mutations (102). The large majority of them sequence selected exons (most commonly 10, 11, 13, 14, 15,
and 16, and in some laboratories, exon 8) or the entire
coding region. Prenatal diagnosis is offered in some
laboratories.
Approximately, 3% to 7% percent of patients with presumed sporadic MTC actually have hereditary MTC;
thus, it is important to test for germline RET mutations in
new patients with MTC regardless of their family history
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(103, 104). Genetic counselors and physicians are responsible for providing information to patients regarding the
clinical expression of hereditary MTC, the patterns of inheritance, the role of genetic testing, and available therapeutic options. The physician has a duty to warn the patient that family members may be at foreseeable harm
(105, 106). Also, adult patients, or parents of minors,
should inform family members at risk that they should be
tested. The issue of an affected subjects reluctance to provide information to family members or to prevent minors
at risk from having genetic testing is a more difficult issue,
which is conflicted by recent provisions inherent in the
Health Insurance Portability and Accountability Act
(HIPAA) (105).
Management of Medullary Thyroid

Carcinoma in Patients With MEN2A,
MEN2B, and FMTC
The strongest predictor of survival in patients with MTC,
whether hereditary or sporadic, is stage of disease at diagnosis. In a population-based study the 10-year diseasespecific survival exceeded 90% in patients with localized
disease; however, it decreased to 78% and 40%, respectively, in patients with regional or distant metastases (107).
Only 10% of patients with metastases to cervical nodes are
cured by thyroidectomy and extensive lymph node dissection
(108 110). The postoperative serum calcitonin falls within
the normal range in 60% of patients with node-negative
disease but in only 10% of patients with node-positive
disease (108). The prognosis is excellent in patients who
have a preoperative serum calcitonin less than 150 pg/
mL, an MTC smaller than 1 cm, and no lymph node
metastases (108). The 10-year survival approaches
100% in patients with undetectable basal and stimulated calcitonin levels after initial thyroidectomy (111).
In patients with tumor confined to the thyroid gland,
the standard operation is total thyroidectomy with resection of lymph nodes in the central zone of the neck, an area
bounded by the hyoid superiorly, the sternal notch inferiorly, and the carotid arteries laterally. The neck dissection is more extensive in patients with evident cervical
lymph node metastases.
Prophylactic thyroidectomy
In patients with hereditary cancer, several criteria
should be met when considering removal of an organ destined to become malignant. There should be 1) near-complete penetrance of the mutated gene, 2) a reliable method
of detecting family members who have inherited a mutated
allele, 3) minimal morbidity associated with removal of
the organ at risk, 4) excellent replacement therapy for the

function of the removed organ, and 5) a reliable method
for determining whether the operative procedure has been
curative. Few hereditary malignancies meet all of these
criteria; fortunately, MEN2A, MEN2B, and FMTC meet
each of them.
Direct DNA analysis of family members at risk for hereditary MTC can detect those who have inherited a mutated RET allele, and they can be offered thyroidectomy
before the development of MTC or while it is still confined
to the thyroid gland. In many cases, the procedure is not
prophylactic, because CCH, with or without small foci of
MTC, may be present in the resected gland. Nevertheless,
prophylactic or early thyroidectomy in patients found to
have a mutated RET allele characteristic of hereditary
MTC can be preventative or curative and has become standard management throughout the world.
A major consideration is the age at which to perform
thyroidectomy. Several professional groups have developed guidelines for the timing of thyroidectomy, all of
which are based on the perceived clinical behavior of the
specific RET mutation causing hereditary MTC (Table 1)
(1, 57).
With some RET mutations, the course of action is
straightforward. For example, in patients with MEN2B
and an M918T or A883F RET mutation, the MTC is
highly aggressive and thyroidectomy should be performed
as soon as the diagnosis is established, even in the first
months of life. Also, most patients with MEN2A have
mutations in RET codon 634 and even though malignant
transformation can occur as early as 1 year of age, involvement of regional lymph nodes rarely occurs before 11
years of age (2, 112). Most clinicians agree that in this
setting, the thyroid gland should be removed at or before
5 years of age, and to decrease the risk of hypoparathyroidism, a central compartment lymph node dissection is
unnecessary (112).
Excepting these 2 examples, the task is more challenging considering the large number of RET mutations identified in subjects with MEN2A and FMTC (Supplemental
Table 1). It is important that the treating physician study
the pattern of disease presentation in a new family, assuming that it is of sufficient size to yield meaningful information. Even in large kindreds, the pattern of disease
presentation may not become evident until evaluation of
several family members, and even then it may vary with
reports of other kindreds with the same RET mutation.
For example, in previous studies of kindreds with MEN2A
caused by mutations in RET codon C609S, there were no
reported cases of pheochromocytoma (1, 65). Over the
last decade, however, not only has there been documentation of pheochromocytomas in families with this muta-
doi: 10.1210/jc.2013-1204
3157
Table 1. Guidelines for Timing Prophylactic Thyroidectomy in Hereditary MTC
tion but in one kindred, pheochromocytoma was the dominant endocrinopathy, there being no clinically evident
MTC (113115). Furthermore, the age of CCH or MTC
onset in the youngest patient varied from 9 years in one
kindred to 48 years in another, and in all but 1 kindred, the
age of MTC onset in the youngest patient was above 20
years (116). In some reports of kindreds with the V804L
RET mutation, there was low penetrance of MTC,
whereas in other kindreds with the same mutation, or the
V804M mutation, the MTC was more aggressive (117
119). MEN2A kindreds such as these, and they are not
unusual, present a conundrum and a challenge for clinicians when considering timing of thyroidectomy.
Realizing the difficulty of determining the age when
prophylactic thyroidectomy should be performed in sub-
jects with a given RET germline mutation, some investigators have based the timing on the level of basal or
stimulated serum calcitonin (120). This approach is controversial, however, because there are reports of subjects
at risk for hereditary MTC with elevated calcitonin levels,
whose thyroidectomy specimens showed no CCH or MTC
and subsequent RET mutation analysis was negative
(121123). At present, there are no accepted guidelines for
the use of basal or stimulated calcitonin levels to determine
the timing of thyroidectomy in subjects at risk for hereditary MTC. The issue is of great importance, however, and
rigorous guidelines need to be defined, especially for clinicians who choose a watchful waiting approach for subjects who have inherited a certain mutated RET allele.
3158
Wells, Jr et al
Physicians caring for families with hereditary MTC

must consider the risks associated with thyroidectomy
performed at a very young age, compared with the risks
associated with delaying the procedure, possibly losing
patients to follow-up, or finding at thyroidectomy that the
MTC has spread beyond the thyroid gland (118, 124).
The operative procedure
In patients with MEN2B regardless of age, and patients
with MEN2A and FMTC who are above 8 years of age, a
total thyroidectomy with resection of lymph nodes in the
central compartment of the neck is indicated. In patients
with MEN2A or FMTC who are less than 5 years of age,
with no enlarged cervical lymph nodes, total thyroidectomy alone is the preferred procedure. Regardless of the
operative approach, care must be taken to protect the
parathyroid glands, the recurrent laryngeal nerves, and
the external branch of the superior laryngeal nerves. Generally, the results of prophylactic thyroidectomy in this
clinical setting have been very satisfactory. The European
Multiple Endocrine Neoplasia Study Group evaluated
207 patients from 145 kindreds with MEN2A, MEN2B,
and FMTC. In patients with RET codon 634 mutations,
malignant transformation was present as early as 1 year of
age and the cumulative age-related risk of MTC increased
progressively with age, but there was no evidence of lymph
node metastases before 14 years of age (2). In another
study of 50 patients with MEN2A followed for a minimum of 5 years after prophylactic thyroidectomy, no
lymph node metastases were present in children less than
11 years of age. In 44 children, the serum calcitonin was
undetectable after stimulation with combined calcium and
pentagastrin infusion; however, 3 children developed permanent hypoparathyroidism, emphasizing the risk of performing a central lymph node dissection below 5 years of
age (112).
Postoperative evaluation
Patients should be evaluated within 6 months postoperatively by physical examination and determination of
serum levels of calcitonin and CEA. If the serum levels of
tumor markers remain undetectable or within the normal
range for 5 years, there is no need for additional studies,
and patients can be followed at yearly intervals. A reliable
indicator of the rate of MTC progression is the doubling
time of serum calcitonin or CEA. A calcitonin doubling
time between 6 months and 2 years is associated with 5and 10-year survival rates of 92% and 37%, whereas a
calcitonin doubling time less than 6 months is associated
with 5- and 10-year survival rates of 25% and 8%, respectively (125, 126). The serum levels of calcitonin and
CEA are strongly correlated; however, in some cases, the
CEA increases progressively, whereas the calcitonin does

not. This suggests cellular dedifferentiation, a hypothesis
supported by immunohistochemistry studies of CCH,
MTC confined to the thyroid gland, and metastatic MTC
(127, 128).
If during the postoperative period the serum calcitonin
level increases above 150 to 200 pg/mL, a total body computed tomography scan is indicated. Patients who develop
metastases to regional lymph nodes but have no distant
metastases are candidates for resection of the recurrent
tumor. There have been several reports of repeat surgery
for MTC, but to date, there are no randomized trials comparing repeat neck surgery to either watchful waiting or
other therapies. Compartmental dissection was originally
thought to be curative in approximately 30% of patients
(129). Recent studies, however, have shown that the serum calcitonin falls within the normal range postoperatively in one-third of patients, yet surgical cure, indicated
by undetectable serum calcitonin levels after pentagastrin
or calcium stimulation is rare (129 131). Some single-arm
studies suggest that external beam radiotherapy administered postoperatively decreases the incidence of locoregional disease; however, it has not improved overall survival (132, 133).
Complications of hormonal excess from MTC
Approximately 30% of patients with MTC develop diarrhea, and it is more common in patients with high levels
of serum calcitonin (134). Mild diarrhea can be managed
with loperamide or codeine; however, severe diarrhea is
more difficult to control. Tumor debulking or selective
arterial chemoembolization may provide benefit in selected cases (135, 136).
The development of Cushings syndrome due to inappropriate ACTH secretion occurs in less than 3% of patients with MTC (137). The treatment is resection of the
primary tumor, or in patients with metastases, the administration of adrenal enzyme inhibitors such as ketoconazole, metyrapone, aminoglutethimide, mitotane, etomidate, or more recently, mifepristone (138). In many cases
bilateral adrenalectomy is necessary to control the excess
glucocorticoid production. The prognosis is poor because
most patients die within a year of the diagnosis.
The management of distant metastases
The development of distant metastases from MTC is an
ominous sign because survival after discovery is 51% at 1
year, 26% at 5 years, and 10% at 10 years (111, 139). In
patients with an indolent rate of progression, local treatment of distant metastases, either by surgical resection,
chemical ablation, or radiotherapy, depending on the an-
doi: 10.1210/jc.2013-1204
3159
Table 2. Clinical Trials With MTT in Patients with MTC

Drug (Ref.)
Study
No.
Patients
PR, %
Stable
Disease, %
PFS,
mo
Axitinib (151)
Motesanib (152)
Sorafenib (153)
Sunitinib (162)
Vandetanib (161)
Vandetanib (100 mg/d) (154)
Cabozantinib (155)
Vandetanib (300 mg/d) (159)
Cabozantinib (160)
Imatinib (156)
Imatinib (157)
Sorafenib plus Tipifarnib (158)
Phase II
Phase II
Phase II
Phase II
Phase II
Phase II
Phase II
Phase III
Phase III
Phase II
Phase II
Phase II
11
91
16
6
30
19
37
231/100
219/111
15
9
13
18
2
6.3
50
20
16
29
0.46 (HR)
0.28 (HR)
0
0
38
27a
48b
87.5a
NA
53b
53b
41b
0.46 (ORR)
0.28 (ORR)
27b
56a
31b
NA
12
17.9
NA
27.9c
NA
NA
30.5c
11.2c
0
0
17
Abbreviations: HR, hazard ratio comparing progression-free survival in treated compared with placebo control patients; NA, not available; ORR,
overall response rate; PFS, progression-free survival; PR, partial response Response Evaluation Criteria in Solid Tumors, (RECIST).
a
4 mo.
6 mo.
Estimated PFS in months.
atomical site involved, may provide benefit for variable

periods of time.
Systemic therapy for metastatic MTC
Single-agent or combination chemotherapy has yielded
short-term responses in the range of 10% to 20% in patients with advanced MTC. Until recently, doxorubicin
was the only drug approved by the U.S. Food and Drug
Administration (FDA) for the treatment of patients with
advanced MTC, and it is still used for this indication today
but much less frequently as frontline therapy (140, 141).
Other therapeutic agents, ranging from angiogenesis
inhibitors and epigenetic-modulating agents to selective
COX-2 inhibitors, have been relatively ineffective in patients with differentiated thyroid carcinoma, and there is
little or no experience in phase II trials of patients with
MTC (142144). Various immunotherapeutic regimens
have been evaluated in patients with advanced MTC, including 2 trials of dendritic cells, pulsed with either calcitonin and CEA or tumor lysate. Responses were variable, but partial remissions were noted in 4 of 17 patients
in the 2 trials (145, 146). Pretargeted radioimmunotherapy with bispecific monoclonal 131I antibody against
CEA has shown promise in early clinical studies but has
not yet been studied in prospective randomized phase III
trials (147). The lack of effective systemic therapeutic
agents has been a major problem for physicians and their
patients.
In the normal state, external growth factors transmit
signals within the cell through a series of reactions that
transfer phosphate from ATP to tyrosine residues in polypeptides. The reactions are catalyzed by protein tyrosine
kinases, which when mutated become constitutively acti-
vated, leading to immortalization of the cell. The protein

tyrosine kinases were recognized as vulnerable therapeutic
targets and attracted the interest of clinical oncologists as
well as the pharmaceutical industry. The first example that
an MTT had efficacy was documented in a randomized
trial of patients with chronic myeloid leukemia (CML)
comparing the tyrosine kinase inhibitor imatinib with interferon alfa plus cytarabine. The results with imatinib
were far superior to those with interferon alfa plus cytarabine, and at 60 months, 96% of 362 patients still on
imatinib experienced a complete cytogenetic response
(148). This trial was a major landmark in cancer care and
created great enthusiasm and cautious expectation that
novel MTTs would show similar efficacy in patients with
other liquid and solid tumors, where the initiating oncogenic event was known and druggable. Although clinical
trials of MTTs in patients with solid organ malignancies
has not replicated the striking success achieved with imatinib in CML, some drugs have been effective with significant improvement in progression-free survival or overall
survival (149, 150).
Currently, there are over 20 published phase II or phase
III clinical trials of MTTs in patients with locally advanced
or metastatic thyroid cancer. Twelve of these document
the efficacy of various MTTs in patients with MTC (Table
2) (151162). Although not all MTTs have shown activity, most have with confirmed partial remissions ranging
from 2% to 50%. Two of the compounds, vandetanib and
cabozantinib, have been evaluated in prospective, randomized, double-blind phase III clinical trials, and each
demonstrated significantly improved progression-free
survival compared with placebo. Recently, the FDA ap-
3160
Wells, Jr et al
proved the 2 compounds for treatment of patients with

advanced MTC (159, 160). Virtually all MTTs are associated with toxicities, which in some cases lead to dose
reductions or even cessation of therapy. Currently, treatment with MTTs has reached a plateau in patients with
advanced MTC and improved therapeutic efficacy will
come only through the development of drugs that bind
the mutated kinase with greater specificity or the design
of combinatorial therapeutic regimens that improve efficacy while impeding drug resistance.
Unfortunately, in trials of MTTs for advanced MTC,
clinical responses have been characterized by partial, not
complete, remissions, and in time, resistance to the drug
develops and the tumor progresses. Clinical trials of MTTs
have not required the collection of tumor tissue from participating patients; thus, associated correlative studies are
lacking and mechanisms of resistance remain unknown.
Preclinical studies and the molecular analysis of tumor
tissues from patients with a range of other tumors have
shown that mechanisms of resistance to MTTs are multifactorial, often complex, and mostly lineage-specific. Information from these studies has been critical to the development of second- and third-generation MTTs and
most importantly in the design of effective combinatorial
therapeutic regimens.
With the remarkable and continuing advances in biotechnology, the amount of genomic information available
to clinical investigators and the practicing endocrine oncologist will increase at a rapid pace. In the age of personalized medicine, the development of a new class of
molecular targeted therapeutics holds great promise for
patients with advanced malignancies, and especially those
with hereditary cancer syndromes.
Acknowledgments
Address all correspondence and requests for reprints to: Samuel
A. Wells, Jr, MD, Cancer Genetics Branch, National Cancer
Institute, National Institutes of Health, Building 37, Room
10106A, 37 Convent Drive, Bethesda, Maryland 20814. E-mail:
wellss@mail.nih.gov.
Disclosure Summary: B.G.R. has served on advisory boards
for AstraZeneca, Eisai, and Bayer. M.S. has received research
support from AstraZeneca and Roche and participated in a collaborative study with Ariad. F.P. and S.A.W. have nothing to
declare.
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S P E C I A L

Multiple Endocrine Neoplasia Type 2 and Familial

ince the seventh International Workshop published

or somatic activating RET mutations that either alone

ISSN Print 0021-972X ISSN Online 1945-7197

Abbreviations: CCH, C-cell hyperplasia; CEA, carcinoembryonic antigen; CLA, cutaneous

J Clin Endocrinol Metab, August 2013, 98(8):3149 3164

Hereditary Medullary Thyroid Carcinoma

J Clin Endocrinol Metab, August 2013, 98(8):3149 3164

The RET proto-oncogene comprises 21 exons and is located on chromosome 10

The Molecular Genetic Basis of MEN2A,

Clinical Manifestations of MEN2A, MEN2B,

MTC, up to 50% develop pheochromocytomas, and up to

is made after MTC in 50% of cases, concurrently with

Hereditary Medullary Thyroid Carcinoma

J Clin Endocrinol Metab, August 2013, 98(8):3149 3164

(enlarged corneal nerves, conjunctivitis sicca, and the

tients with MEN2A, RET mutations occur in codons 609,

evident that many kindreds first designated as FMTC,

Hereditary Medullary Thyroid Carcinoma

J Clin Endocrinol Metab, August 2013, 98(8):3149 3164

FMTC (1), 2) small families (at least 2 generations, with at

The Diagnosis of Hereditary and Sporadic

In many European centers, it is standard practice to

Hereditary Medullary Thyroid Carcinoma

Management of Medullary Thyroid

J Clin Endocrinol Metab, August 2013, 98(8):3149 3164

the organ at risk, 4) excellent replacement therapy for the

Table 1. Guidelines for Timing Prophylactic Thyroidectomy in Hereditary MTC

Hereditary Medullary Thyroid Carcinoma

Physicians caring for families with hereditary MTC

J Clin Endocrinol Metab, August 2013, 98(8):3149 3164

CEA increases progressively, whereas the calcitonin does

Table 2. Clinical Trials With MTT in Patients with MTC

Estimated PFS in months.

atomical site involved, may provide benefit for variable

vated, leading to immortalization of the cell. The protein

Hereditary Medullary Thyroid Carcinoma

proved the 2 compounds for treatment of patients with

J Clin Endocrinol Metab, August 2013, 98(8):3149 3164

43. Raue F, Kraimps JL, Dralle H, et al. Primary hhyperparathyroidism

Hereditary Medullary Thyroid Carcinoma

effects in multiple endocrine neoplasia type 2B. Am J Hum Genet.

J Clin Endocrinol Metab, August 2013, 98(8):3149 3164

MEN2A and MEN2B mutations. Oncogene. 1995;11:2419

sivity of familial medullary thyroid carcinoma (FMTC) due to a

Hereditary Medullary Thyroid Carcinoma

noma. Prognostic significance and impact on treatment of clinical

J Clin Endocrinol Metab, August 2013, 98(8):3149 3164

152. Schlumberger MJ, Elisei R, Bastholt L, et al. Phase II study of safety

Take advantage of The Endocrine Societys online ABIM approved

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