Download Update multiple endocrine neoplasia type 2

Familial Cancer
DOI 10.1007/s10689-010-9320-2
Update multiple endocrine neoplasia type 2
Friedhelm Raue • Karin Frank-Raue
Ó Springer Science+Business Media B.V. 2010
Abstract Multiple endocrine neoplasia type 2 (MEN2) is
a autosomal dominat inherited tumour-syndrome caused by
germline activating mutations of the RET proto-oncogene
on chromosome 10. It is clinically characterized by the
presence of medullary thyroid carcinoma (MTC), bilateral
pheochromocytoma and primary hyperparathyroidism
(MEN2A) within a single patient. Three distinct clinical
forms have been described depending on the phenotype:
the classical MEN 2A, MEN 2B, an association of MTC,
pheochromocytoma and mucosal neuroma, (FMTC)
familial MTC with a low incidence of other endocrinopathies. Each variant of MEN2 results from different RET
gene mutation, with a good genotype phenotype correlation. Genetic testing detects nearly 100% of mutation
carriers and is considered the standard of care for all first
degree relatives of patients with newly diagnosed MTC.
Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on a classification
into four risk levels utilizing the genotype-phenotype correlations. MEN 2 gives a unique model for early prevention
and cure of cancer and for stratified roles of mutation-based
diagnosis of carriers.
Keywords Multiple endocrine neoplasia type 2 Pheochromocytoma Primary hyperparathyroidism Ganglioneuromarosis RET proto-oncogene Tyrosine kinase inhibitors
Abbreviations
MEN
Multiple endocrine neoplasia
MTC
Medullary thyroid carcinoma
Ct
Calcitonin
Pheo
Pheochromcytoma
HPT
Primary hyperparathyroidism
FMTC
Familial medullary thyroid carcinoma
RET gene Rearranged during transfection gene
CCH
C-cell hyperplasia
Introduction
Multiple endocrine neoplasia type 2 (MEN2) (OMIM
171400) is an autosomal dominant cancer syndrome that
implies a 50% risk to offspring of a carrier to inherit the
disorder. The estimated prevalence is 2.5 per 100,000 in
the general population. Predisposition to MEN2 is caused
by germline activating mutations of the RET proto-oncogene [1, 2]. MEN2 shows a high penetrance for medullary
thyroid carcinoma (MTC), a rare calcitonin (Ct)-secreting
tumour of the parafollicular or C-cells of the thyroid, which
derive from neural crest. Most patients suffer from the
sporadic (non-familial) form while 25–30% account for
hereditary MTC. Hereditary MTC is usually bilateral and
multicentric; multifocal C-cell hyperplasia is considered to
be a precursor of MTC in patients with hereditary disease.
F. Raue
Endocrine Practice, Heidelberg, Germany
Classification and clinical manifestation of MEN 2
F. Raue (&) K. Frank-Raue
Endokrinologische Gemeinschaftspraxis, Brückenstr.21,
69120 Heidelberg, Germany
e-mail: [email protected]
MEN type 2 syndrome occurs in three clinical distinct
varieties with MTC as the common manifestation
(Table 1). These three varieties of MEN2 are clinically
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F. Raue, K. Frank-Raue
Table 1 Clinical classification of MEN 2 and occurrence of MTC, associated tumours and other diseases
Subtype
% of total cases
MTC (%)
Pheo (%)
HPT (%)
Associated diseases
MEN 2A
56
100
50
25
Cutaneous lichen amyloidosis Hirschsprung’s disease
MEN 2B
9
100
50
35
95
FMTC
distinct with respect to incidence, genetics, age of onset,
association with other diseases, aggressiveness of MTC,
and prognosis. Both sexes are nearly equally affected in the
familial variety [3, 4].
1.
2.
3.
The MEN 2A syndrome (Sipple’s Syndrome), characterized by MTC in combination with pheochromocytoma
(Pheo) and hyperplasia of the parathyroids (primary
hyperparathyroidism, HPT); it is the most common form
of all MEN 2 syndromes (55% of all cases).
The MEN 2B syndrome, consisting of MTC, Pheo,
ganglioneuromatosis, and Marfanoid habitus; it is the
most rare and aggressive form of MEN 2 (5–10% of all
cases) [5].
Familial MTC (FMTC), with a low incidence other
endocrinopathies; it is the mildest variant of MEN2
more often diagnosed in recent years (35–40% of all
cases) [6].
The respective frequency of MTC in MEN2A is over
90%, approximately 40–50% for Pheo, and 10–20% for
multigland parathyroid hyperplasia with HPT. MTC is
generally the first manifestation of MEN2A between the
age of 20–30 years. At least two of the classical clinical
features of MEN 2A are required in the patient or in the
first-degree relatives of the patient to make a clinical
diagnosis of MEN 2A.
Many patients with MEN 2B have an earlier onset in the
first year of life and more aggressive MTC with a higher
morbidity and mortality than in patients with MEN2A.
Multivariate analysis suggests that the higher mortality rate
of MEN 2B reflects a more advanced tumour stage at
presentation rather than a more aggressive tumour behaviour once established [7]. HPT is not a feature of MEN2B.
Patients with MEN2B also tend to have typical phenotypic
features like mucosal neuromas and cutaneous neuromas
visible physical stigmata such as raised bumps on the lips
and tongue, intestinal ganglioneuromas, and in some
instances, a Marfanoid habitus with skeletal deformations
and joint laxity. The intestinal disturbances like chronic
constipation or megacolon from birth are often initial disease manifestations that present for medical attention.
Brauckhoff [8] reported that 86% of MEN2B patients
demonstrated the inability to cry tears. They often do not
have a family history of the disease due to de novo
mutation.
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Ganglioneuromatosis, Marfanoid Habitus
Very rare
FMTC is a variant of MEN2, in which there is a strong
predisposition to MTC in the families with a low or no
incidence of the other clinical manifestations of MEN2A.
The diagnosis of FMTC can only be considered when four
or more family members across a wide range of ages have
isolated MTC. Nowadays, FMTC is viewed as a phenotypic variant of MEN 2A with decreased penetrance of
pheochromocytoma and primary hyperparathyroidism. The
penetrance and clinical course of MTC in FMTC is more
benign than MEN2A and MEN2B with a late onset or no
clinically manifest disease, and the prognosis is relative
good. Therefore, a family history is often inadequate in
establishing familial disease. FMTC has been diagnosed
more frequently in recent years (35–40% of all cases).
The way of discovery of MTC in a patient has changed
within the last decade by using specific strategies: Ct
screening in patients with thyroid nodules and screening
with molecular methods for mutations in the RET protooncogene in patients with apparently sporadic MTC and in
family members at risk for MTC. About 1–7% of apparently sporadic cases have identifiable RET mutations,
including about 2–9% with de novo germline mutations [4,
9]. By early identification of patients with MTC, the presentation changes from clinically evident tumours to preclinical disease resulting in a higher cure rate of affected
patients with much better prognosis [10].
Medullary thyroid carcinoma: pathology
and biochemical marker
Hereditary MTC characteristically presents as a multifocal
process with C-cell hyperplasia (CCH) as precursor lesion
to MTC. Only familial primary CCH is a preneoplastic
lesion. Secondary CCH, which has been associated with
chronic lymphocytic thyroiditis, hypergastrinemia, near
other follicular cell-derived thyroid tumours, and even
aging, has a much lower, if any, potential for malignancy
[11]. The time frame of the progression from CCH to
microscopic carcinoma remains unclear but may take
years. Metastasis may be found first in central and lateral
cervical and mediastinal lymph nodes of the neck in 10%
of patients with a micro-MTC operated on after discovery
at familial screening, and in up to 90% of patients operated
on for clinical MTC. Metastases outside the neck and
Update multiple endocrine neoplasia type 2
phosphorylation of the specific tyrosine residues and activation of multiple intracellular pathways with effects on
development and differentiation occur.
Hereditary MTC is caused by autosomal dominant gainof-function mutations in the RET proto-oncogene. It was
demonstrated that mutation of the extracellular cysteine at
codon 634 causes ligand-independent dimerization of
receptor molecules, enhanced phosphorylation of intracellular substrates, and cell transformation. Mutation of the
intracellular tyrosine kinase (codon 918) has no effect on
receptor dimerization but causes constitutive activation of
intracellular signalling pathways and also results in cellular
transformation. A hereditary RET gene mutation results in
expression of abnormally overactive RET protein in all
tissues in which it is expressed; somatic RET mutations
that occur later in life and are limited to C cells are present
in 40–50% of sporadic MTCs [15, 16]. MTC is generally
the first neoplastic manifestation because of its earlier and
higher penetrance compared with pheochromocytoma or
parathyroid hyperplasia.
mediastinum may occur during the course of the disease in
the lung, liver and bone.
The primary secretory product of MTC is calcitonin
(Ct), which serves as a tumour marker for MTC. Measurement of monomeric Ct with two-site assays [12] is
widely available, accurate, reproducible, and cost-effective. Slightly elevated Ct levels might be seen in CCH,
renal failure, and autoimmune thyroiditis. Either basal or
stimulated plasma Ct levels using pentagastrin or calcium
are elevated in virtually all patients with MTC. Basal Ct
concentrations usually correlate with tumour mass and are
almost always high in patients with palpable tumours [13].
Similarly, elevated plasma Ct levels following surgery to
remove the tumour are indicative of persistent or recurrent
disease.
RET-proto-oncogene: genetic abnormalities in MEN 2
The MEN 2 gene was localized to centromeric chromosome 10 (10q11.2) by genetic linkage analysis in 1987
[14]. Point mutations of the RET proto-oncogene were first
identified in 1993 in MEN 2A, MEN 2B and FMTC in
seven closely located exons [1, 2] (Fig. 1). Analysis of
RET in families with MEN 2A and FMTC revealed that
only affected family members had germline missense
mutations and they have been found in nearly 100% of
these families. Up to now, mutation analysis in MEN 2
families has identified over 50 different missense mutations
segregating with the disease [7].
The RET gene has 21 exons and encodes a receptor
tyrosine kinase that appears to transduce growth and differentiation signals in several developing tissues including
those derived from the neural crest. The tyrosinkinase is
activated upon ligand-induced dimerization after binding of one of the four ligands known. Subsequently
Fig. 1 Germline mutations of
the RET proto-onkogene
associated with multiple
endocrine neoplasia type 2 and
familial MTC, numbers indicate
mutated codons of the RET
gene
Genotype phenotype correlation
In the majority of MEN2 families, associations between
specific RET mutations (genotype) and aggressiveness of
MTC and presence of other endocrine tumours (phenotype)
are well documented (Table 2). The most common mutation of codon 634 is TGC-CGC (Cys-Arg), it has been
associated with pheochromocytoma and parathyroid gland
involvement with MEN 2A families [17–19]. Therefore,
individuals with this mutation should be annually screened
for these endocrinopathies. Pheo is associated with exon
634 and 918 mutations in approximately 50% of patients,
with exon 10 mutations (codons 609, 611, 618, and 620) in
up to 20% patients, and rarely with mutations in exons
Common mutations
609 618
611
Exon 5
321
8
634
620
533
918
804
10
11
630
532
790 791
635
13
649
768
14
15
16
912
844
883 891
Rare mutations
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F. Raue, K. Frank-Raue
families with MEN 2A and FMTC [25]. Therefore, FMTC
associated with a RET gene exon 10 mutation constitutes a
subtype of MEN 2A with a low frequency of pheochromocytoma, rather than a separate clinical entity. The same
is true for mutations in exon 13 codon 768, 790 and 791,
and in exon 14 (Val 804 Leu) [26], which thought to be
specific for FMTC. However, some rare families with MTC
and pheo were also identified [6].
In 95% of patients and families with MEN 2B a mutation
in codon 918 in exon 16 coding for the intracellular TK2
domain was found [18]. In more than 50 percent of cases of
MEN2B with codon 918 affected, mutations occur as new
(de novo) germline mutations. In each family this mutation
resulted in an ATG (methionine) to ACG (threonine)
alteration. A germline mutation of RET codon 883 exon 15
in two cases of de novo MEN 2B was described [27].
Table 2 Genotyp and age of onset of MTC
RET
codon
Earliest age
of onset
ATA risk
level
Age of prophy.Tx
918
2 months
D
ASAP
634
13 months
C
Before 5 years
609
5 years
B
Consider before 5 years
620
6 years
B
611
7 years
B
618
7 years
B
768
790
9 years
10 years
A
A
804
12 years
A
891
13 years
A
791
15 years
A
533
21 years
A
631
22 years
A
May delay [5 years
Risk levels
13–15 (codons 791 and 804) [20, 21]. HPT in MEN 2A is
most commonly associated with codon 634 mutations, with
C634R in particular [22].
All cases of MEN 2A with Hirschspung’s diseases are
associated with mutations in exon 10 (codons 609, 611,
618, 620), and MEN 2A with cutaneous lichen amyloidosis
is associated with mutations in codon 634 [23].
The actual analysis of the RET proto-oncogene in
patients with hereditary MTC provided evidence for a
change in the spectrum of detected mutations [24]:
Meanwhile codon 634 mutations are still the most common
missense change in patients with MEN 2A but the frequently decreased to 37%. On the other hand, so called
‘‘rare mutations’’ in exon 10 codon 609, exon 13 codons
768, 790, and 791, exon 14 codon 804, and exon 15 codon
891 increased to 39%. It is of considerable interest to note
that identical germline mutations have been reported in
The association between disease phenotype and RET
mutation genotype may have important implications for the
clinical management of MEN 2 patients and their families.
This information could be used to intensify screening for
pheo or HPT in mutations associated with a higher risk of
disease or to plan the prophylactic thyroidectomy
depending on the aggressiveness of MTC associated with
different mutations [4, 7]. The mutations were divided into
four risk levels [7] (Table 3). Patients with level A mutations mostly FMTC (exon 13 codons 768, 790, and 791,
exon 14 codon 804, and exon 15 codon 891) have the
lowest risk for the development and aggressiveness of
MTC. Patients with level B mutations, mostly MEN 2A
(exons 10 codons 609, 611, 618, and 620) are at intermediate risk, and patients with level C mutations, the classical
MEN2A (exon 11 codon 634), are at higher risk of
Table 3 Codon based genotype phenotype correlation (adapted to the ATA classification [7])
ATA risk level (2009)
A
B
Codon
768, 790, 791, 804
609, 611, 618, 620, 630, 634
631
918, 883
649, 891,
MEN-2 subtype
FMTC
FMTC/MEN 2A
MEN 2A
MEN 2B
MTC aggressiveness
MTC age of onset
High
Adults
Higher
5 years
Higher
Before the age of
5 years
Highest
First year of life
Timing of prophylactic
thyroidectomy
When calcitonin rises/age 5 or
10 years
5 years
Before the age of
5 years
First months of life
Screening for Pheo
Start at 20 years, periodically
Screening for HPT
Start at 20 years, periodically
Start at 20 years,
annually
Start at 20 years,
periodically
Start at 8 years,
annually
Start at 8 years,
annually
Start at 8 years,
annually
–
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C
D
Update multiple endocrine neoplasia type 2
Table 4 Criteria for RET mutation analysis and impact on diagnosis and management
Persons
Role
Consequences
Patients with histological
proven MTC or C-cell
Hyperplasia
Distinguish between sporadic and hereditary
form of MTC
Exclude sporadic MTC from further family screening and
identify RET gene carriers for initiation of family
screening
Patients with familial
occurence of MTC and/or
Pheo
Define the particular phenotype: MEN2A,
Time of prophylactic thyroidectomy
MEN2B, FMTC and the risk to develop pheo or Screening for pheo and HPT
HPT
First-degree family members
of MEN2 patients
Distinguish gene carriers from non-carriers
aggressive MTC. Patients with level D mutations the typical MEN2B (exon 15 codon 883, and exon 16 codon 918)
are at the highest risk for early development and aggressive
growth of MTC with the youngest age of onset and highest
risk of metastases. This knowledge of the age and penetrance of MTC in the codon mutated gives informations for
timing and surgical procedure to prevent metastatic MTC.
Recommendations for the timing of prophylactic thyroidectomy and the extent of surgery are based upon a
model that utilizes these genotype-phenotype correlations
to stratify mutations into four risk levels [7] (Table 2).
Patients with level A mutations have the lowest risk for
development and aggressiveness of MTC. Operation may
be postponed beyond age 5 years until after an abnormal C
cell stimulation test result is observed (i.e. an abnormal Ct
response to calcium) and depending on the age that MTC
developed in the family members. Patients with level B
mutations (exon 11) are at intermediate risk should
undergo total thyroidectomy before the age of five. Patients
with level C mutations (exon 11, codon 634) should be
operated before the age of 5 and patients with exon 16
codon 918 (MEN 2B) are at the highest risk for early
development and aggressive growth of MTC. Thyroidectomy should be done as soon as possible during the first
year of life, if done later surgery is often not curative.
Diagnosis of MEN2
In index patients the clinical presentation and manifestation
of MEN 2 associated MTC are similar to those of sporadic
MTC. The typical age of clinical onset of MEN2 is the
third decade of life, patients present with a thyroid mass or
a cervical lymphadenopathy found incidentally during
routine examination. MTC shows hypoechogenic regions,
sometimes with calcifications, and a thyroid scan almost
always shows no trapping of radioactive iodine or technetium. Cytologic examination of the cold, hypo-echogenic
nodule, will lead to a strong suspicion of MTC. The
diagnosis of MTC in index cases is often made postoperatively when pathohistological examination may show
RET mutation analysis should be done before the age of
recommended prophylactic thyroidectomy whenever
possible
multifocal bilateral MTC accompanied by diffuse CCH. A
plasma Ct measurement can clarify the diagnosis, since,
preoperative Ct levels correlate significantly with tumour
size [13] and in the presence of a palpable MTC, the
plasma Ct concentration will usually be greater than
1000 pg/ml. CEA level will be elevated in most cases with
clinical evident tumours. Therefore, measurement of
plasma Ct in patients with thyroid nodules has been
advocated a routine procedure by some European consensus groups [28]. Genetic testing for RET mutations in
patients with suspicious MTC and elevated calcitonin
levels may also be helpful, since, if a mutation is found, it
will imply that the disease is hereditary and that the family
should be screened. All patients with a personal medical
history of primary CCH, MTC, or MEN 2 should be
offered germline RET testing [7] (Table 4). Once a
germline RET mutation has been identified in a family,
genetic counselling and RET mutation analysis should be
offered to all first-degree relatives. Mutations in the RET
proto-oncogene can be used to confirm the clinical diagnosis and identify asymptomatic family members with the
syndrome. Offspring of a RET mutation gene carrier have a
50% risk of inheriting the mutation. Those who have a
negative test can be reassured and require no further biochemical screening. At present, genetic testing is performed before the age of 5 years in all first-degree relatives
of an index case (in MEN 2B patients directly after birth).
When it is decided to delay prophylactic thyroidectomy
beyond the first 5 years of the children with MEN2A/
FMTC, basal and/or stimulated serum CT and cervical
ultrasound should be performed annually starting by the
age of 5 years.
Less common presentations of MTC include recognition
during search initiated after an associated disease such as
pheo or multiglandular hyperparathyroidism becomes
apparent. The clinical manifestation of pheo associated
with MEN2 is similar to that in sporadic cases with signs
and symptoms such as headache, palpitations, nervousness
tachycardia and hypertension. Measurement of plasma
and/or 24 h urinary excretion of catecholamines and
metanephrines should be performed. Once the biochemical
123
F. Raue, K. Frank-Raue
diagnosis is made imaging studies like MRI and/or MIBG
scanning are appropriate. The presence of Pheo must be
ruled out prior to any surgical procedure, if untreated they
can be lethal. Patients with MTC should be evaluated for
possible Pheo. A coexisting Pheo should be removed
before thyroidectomy. The possibility of bilateral disease
must be carefully evaluated. The penetrance of pheo
among different MEN 2 kindreds depends on specific RET
germline mutations (see above) [21]. Pheo have usually
become evident approximately 10 years later than manifestation of MTC. Therefore, they are usually identified
during screening in patients with MEN2 often before
clinical symptoms occur. Biochemical screening for pheo
should be performed annually in MEN 2 patients depending on the genotype (see above) beginning by the age
8 years in carriers of RET mutations associated with
MEN2B and in the other codons by the age of 20 years.
Because of high risk to the fetus and the mother, women
with a RET mutation associated with MEN 2 should be
screened for pheo before pregnancy. Other hereditary
syndromes associated with familial pheo are von HippelLindau syndrome, paraganglioma syndromes and neurofibromatosis type 1 [29].
The primary hyperparathyroidism (HPT) is often clinical occult and do not differ from those seen in mild sporadic HPT. The diagnosis is established by finding high
intact-parathyroid hormone concentrations in the presence
of hypercalcemia. Pathological findings show chief cell
hyperplasia involving multiple glands. Annual measurement of serum calcium concentration in gene carriers is
probably adequate for screening purposes beginning by the
age 8 years in carriers of RET mutations in codon 630 and
634, and by age 20 years in carriers of other MEN 2A RET
mutations. It is rarely the first manifestation in MEN2A.
Treatment
The only way to cure patients with MTC is surgery, the
multicentric and bilateral nature of hereditary MTC
implicates a total thyroidectomy. The extend of lymph
node dissection depends on the preoperative Ct and
imaging determine the extent of lymph node involvement.
In the setting of clinically detected MTC (index patient)
with Ct values more than 150 pg/ml without cervical
lymph node or distance metastases preoperatively total
thyroidectomy and prophylactic central neck dissection is
recommended. Patients with more than ten lymph nodes or
more than two lymph nodes compartments involved, a T4
tumour, or invasion in the soft tissue could not be cured by
aggressive surgery (bilateral neck dissection). Therefore, a
more palliative approach with resection of the local disease
and clearance of the central compartment for prevention of
123
future complications such as invasion into the recurrent
laryngeal nerve or aerodigestive tract with resulting loss of
speech or swallowing.
Prophylactic thyroidectomy should be performed in a
clinical asymptomatic gene carrier of a RET mutation with
a normal thyroid and no suspicious lymph node on ultrasound examination and normal Ct levels. Recommendations on the timing of prophylactic thyroidectomy and
extent of surgery are based on a classification into four risk
levels utilizing the genotype–phenotype correlations (see
above risk levels) [7].
Some authors suggest thyroidectomy at age 5 for risk
group A, some at age 10, while others, including the current authors [30], suggest that surgery may be postponed
until an abnormal C-cell stimulation test result is observed
(i.e., an abnormal Ct response to pentagastrin or calcium
stimulation). For asymptomatic patients with risk levels A
to C who are older than 5 years with Ct levels more than
40 pg/ml and thyroid nodules more than 5 mm and/or or
evidence for lymph node metastases a more extensive
disease has to be suggested, which requires total thyroidectomy plus central lymph node dissection [7]. In order to
avoid complications like recurrent laryngeal nerve injuries
or hyperparathyroidisms this operation should be done by
high-volume surgeons.
Surgery for Pheo in MEN 2 should precede surgery for
MTC. Before adrenalectomy all patients should receive
appropriate pharmacotherapy (alpha- with/or without betaadrenergic antagonist). Approximately one-third of patients
who undergo a unilateral adrenalectomy will eventually
require a second operation for contralateral pheo, but this
may not occur for many years, during which time the
patient will not be steroid dependent. Adrenal corticalsparing adrenalectomy is a promising technique for preventing adrenal insufficiency.
The parathyroid glands in MEN 2 patients are frequently found to be enlarged at thyroidectomy for MTC
and should therefore be carefully evaluated. The goal in
MEN2 patients with primary hyperparathyroidism is to
excise the enlarged glands and to leave at least one normal
parathyroid gland intact. If they are all enlarged, a subtotal
parathyroidectomy or total parathyroidectomy with autotranplantation should be performed.
Postsurgical follow-up and management
All patients should receive adequate thyroxine replacement
therapy after total thyroidectomy to restore euthyroidism
[31]. All patients should undergo Ct and CEA determination at regular intervals after total thyroidectomy. Normal
basal and pentagastrin-stimulated Ct levels suggest a
tumour-free state. These patients can be followed-up at half
Update multiple endocrine neoplasia type 2
Initial surgery
Serum calcitonin
basal and stimulated
undetectable
elevated
biochemical cured
biochemical testing
every 6-12 months
Pheo, HPT, Calcitonin
Persistent/recurrent MTC
Adequate primary surgery?
progressive disease
DT<6months
Progressive Metastases
Palliative Therapy
e.g.TK Inhibitors
stable disease
Calcitonin <150pg/ml
or Dt <24 months
Imaging negative or stable
Conservative observation
Fig. 2 Postoperative and long term follow up
yearly intervals with physical examination and Ct determination (Fig. 2). Patients with persistent elevation of
plasma Ct after total thyroidectomy should be thoroughly
evaluated to define the extent of local and distant disease
(see above). If there is no evidence of distant metastases
and if local disease is found in the neck, reoperation
(completion) could be done using meticulous dissection
and microsurgical techniques [32].
In patients remaining Ct-positive with evidence of noncurable and non-operable disease (diffuse distant metastases) or occult disease (no local recurrence is found and
adequate operation has been done), close observation of
changes in serum Ct und CEA concentration is required.
Doubling time of the tumour markers should be calculated.
Many patients may exhibit a remarkable stable course and
no further treatment is recommended; a ‘‘wait and see’’
approach is advocated, as experience with non-surgical
therapy in the management of slow growing metastatic
MTC with doubling time of Ct of more than 2 years has
been disappointing [33]. In those patients whose disease
shows rapid and steady progress, e.g. doubling of tumour
marker smaller than 6 month and progression of tumour
burden evaluated by response evaluation criteria (RECIST), intervention with palliative surgical intervention,
chemotherapy, radiotherapy, somatostatin, or nowadays
with tyrosinkinase inhibitors can be considered as a palliative therapeutic modality [34]. Compounds that block
RET kinase activity directly, or block subsequent downstream signalling molecules like tyrosinkinase inhibitors
are under evaluation in clinical trials and preliminary evidence indicates that they may have important clinical
benefit [35].
Prognostic factors
The natural history of MTC is variable and ranges from
years of dormant residual disease after surgery to rapidly
progressive disseminated disease and death related to either
metastatic thyroid tumour or complications of pheo in
MEN 2B. The 10-year survival rates for all MTC patients
range from approximately 61–76% [36–38]. The main
factors that influence survival are stage of disease at
diagnosis, size of the tumour and lymph node involvement,
the variety of the tumour (sporadic vs. familial), the age
and sex of the patient, and calcitonin doubling time.
Patients with MEN 2A have a better survival rate than do
patients with sporadic disease. In a multivariate analysis
adjusted for tumour stage, the significant difference in
survival advantage between patients with sporadic and
familial disease disappeared [36, 39, 40]. This underlines
the importance of tumour stage and age at diagnosis for
prognosis in MEN2. Early RET gene mutation analysis and
prophylactic thyroidectomy in a presymptomatic state
improve quality of life and prolonged life expectancy [10,
31, 41].
Preventing, counselling, health economics
Genetic testing in MEN2 adds much information in the
management of the tumour syndrome. In clinically
demonstrable MTC the specific RET mutation gives
information on the risk of appearance of pheo and HPT, the
aggressiveness of the MTC, and the prognosis. In screening
family members the result of genetic testing allows for
early treatment and thereby offers the chance of prophylactic thyroidectomy and cure of MTC. From a medical
point of view MEN2 is a unique model using genetic
information to cure a patient with a hereditary cancer
syndrome. From the patients view there is a loss of privacy
and autonomy and a feeling of stigmatization and discrimination. There appears to be a threshold for patients to
inform their relatives about the hereditary disease. This has
to be taken into account when counselling patients with
MEN2. The confidentiality of genetic testing is an absolute
with no exception therefore the duty to inform relatives at
risk falls to the moral obligation of the patient. However,
many guidelines do allow for disclosure of results to at-risk
individuals without the patient0 s consent when the information disclosed will prevent serious harm [7]. Our social
attitude to rare hereditary diseases has to be reconsidered.
We need precise laws preventing discrimination concerning full insurance coverage and employment. Patient
interest groups may serve in providing information, support
in emotional distress, and stand up for common political
and social aspects.
Both preimplantation and prenatal testing are available
in some/most countries to RET mutation carriers. These
methods have the fascinating potential to remove the disease from the family. In balancing the potential advantages
against the efforts and hazards of the methods most people
would agree that MEN2 nowadays, if treated properly, has
an acceptable morbidity and no excess mortality. In our
123
F. Raue, K. Frank-Raue
experience most RET mutation carriers of childbearing age
would not consider prenatal or preimplantation diagnostic
testing when offered during counselling.
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