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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1382_Библиотеки_им_академика_М_И_Перельмана.pdf
Fig. 11.1. A lymph node metastases from medullary thyroid
cancer. The node is firm to palpation and the cut surface
reveals the characteristic chalky-white appearance.
mutation is required for malignant transformation. In patients with hereditary disease, this
point mutation is in the germline, but sporadic
cases have been found to have somatic mutations of RET in 25–45% of cases. The first germline mutation of the RET gene was identified in
patients in 1993, and since that time there has
Fig. 11.2. Histologic view of medullary thyroid cancer (20
magnification), displaying the characteristic stromal amyloid
deposition.
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been a growing number of RET mutations that
have been associated with hereditary MTC. The
most common mutation in MEN2A is in codon
634 occurring in 80% of patients. The codon
most frequently associated with MEN2B is a
codon 918 mutation.
Diagnosis
Almost all patients with MTC, who are not
detected through genetic screening, present
with a palpable neck mass. Sporadic disease
tends to present in the fifth or sixth decade of
life and there is a slight female preponderance.
The disease has spread to the lymph nodes in
35–50% of patients at initial diagnosis, so frequently the neck mass that is appreciated is
actually a metastatic lymph node. Neck ultrasound should be performed as part of the initial
evaluation to look both for additional thyroid
tumors as well as the presence of suspicious
neck lymphadenopathy.
Given the posterior location of many of these
tumors, they can compress or invade local
structures and patients can present with complaints of hoarseness, dysphagia, or respiratory
difficulty. As with all patients with thyroid cancer, direct laryngoscopy should be performed to
evaluate vocal cord mobility as part of the preoperative evaluation. Calcitonin levels, if markedly elevated, can cause symptoms including
flushing, diarrhea, and weight loss. If patients
have MEN2, they may present with symptoms of
either pheochromocytoma (headaches, palpitations, or sweating) or hyperparathyroidism
(fatigue, bone pain, or kidney stones).
Distant metastases are present in 10–15% of
patients at the time of diagnosis [1]. The most
common locations for metastatic disease
include the mediastinum, liver, lungs, and
bone. A contrast-enhanced CT of the chest,
mediastinum, and abdomen is recommended
as part of the metastatic evaluation of a patient
with an initial diagnosis of MTC. Metastatic
lesions may be large and calcified and readily
apparent on imaging, but can also display a
military pattern of small micrometastases that
are unable to be seen on imaging. Bone metastases may present with pain or fractures.
Screening for known RET mutations and
sequencing of DNA looking for rare RET
151
MEDULLARY THYROID CANCER
Fig. 11.3. Fine needle aspiration of medullary thyroid cancer.
mutations are now readily available. Subsequently, many patients with hereditary disease
are now identified through genetic screening of
at-risk individuals. Family members of
patients with a germline mutation of the RET
gene have a 50% chance of inheriting the mutation. If patients are identified to be genetic
carriers, their lifetime risk of malignancy
approaches 100%. Even patients with apparently sporadic disease have a significant
chance of having a germline RET mutation
and should undergo genetic testing and screening for pheochromocytoma.
The diagnosis of MTC is most frequently
obtained from a fine needle aspiration (FNA)
of a new thyroid nodule. On FNA, MTC is characterized by the presence of stromal amyloid
and the absence of thyroid follicles (Fig. 11.3).
If a FNA of the thyroid does not reveal thyroid
follicles, then it should be stained for calcitonin,
chromogranin A, or CEA which can confirm the
diagnosis of MTC. If immunohistochemistry
is not performed, it is not uncommon for an
FNA of a MTC to be misinterpreted as a parathyroid tumor or a poorly differentiated thyroid
carcinoma.
Serum Markers
If a patient has a clinical history or FNA that is
suspicious for MTC, serum calcitonin levels can
be useful to confirm the diagnosis. Calcitonin
levels may be slightly elevated in a small percent
of normal patients, but most patients with an
elevation >100 pg/ml have a diagnosis of MTC
[2]. In patients with borderline basal calcitonin
levels, a stimulated calcitonin can be obtained to
help clarify the diagnosis. Stimulated calcitonin
levels are obtained after the administration of
either calcium gluconate (2 mg/kg) or pentagastrin (0.5 mg/kg). Pentagastrin is currently only
available in the USA on experimental protocols.
Prior to widespread genetic testing, basal and
stimulated calcitonin testing was the standard
for following patients at risk for MTC. Testing
was started at age 5 and performed annually
until 35 years of age. The administration of
pentagastrin and calcium is associated with the
development of nausea, diaphoresis, agitation,
and urinary urgency. Given the unpleasant side
effects, many patients were noncompliant with
long-term follow up, and this technique has
largely been abandoned.
The degree of calcitonin elevation correlates
well with tumor burden. Nodal metastasis starts
emerging at basal calcitonin levels of 10–40 pg/ml
(normal range <10 pg/ml). Distant metastases
are typically associated with calcitonin levels
of greater than 150 pg/ml and frequently
>1000 pg/ml [3]. Patients with calcitonin levels
>3000 pg/ml are likely to have extensive meta-
static disease and are unlikely to be cured of their
disease [4]. If patients have a preoperative calcitonin level less than 50 pg/ml, they have a 98%
chance of achieving an undetectable calcitonin
level with surgery alone [5].
Some groups have advocated routine serum
calcitonin testing in all patients with a new thyroid nodule. Unfortunately, falsely elevated calcitonin levels can be seen in both autoimmune
thyroiditis and multinodular goiter, causing up
to 4% of patients to have elevated basal calcitonin levels. Further evaluation of patients with
elevated basal calcitonin levels reveals that only
5% actually have MTC (95% false positive)[2].
Since most of the MTC that is detected by serum
calcitonin measurements is also picked up by
FNA, the diagnostic yield of routine calcitonin
measurement appears to be very low, identifying only one new diagnosis out of 1383 patients
[2]. Although early diagnosis affords these
patients earlier intervention and perhaps
improved outcomes, the cost effectiveness of
routine calcitonin screening must be carefully
examined.
CEA has also proven to be a useful tumor
marker in patients with MTC. CEA levels are
elevated in >50% of patients with MTC.
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ENDOCRINE SURGERY
Preoperative CEA levels can be useful for risk
stratification of patients. A preoperative serum
CEA level >30 ng/ml is highly predictive of
inability to cure a patient with operative intervention [6]. CEA levels >100 are highly associated with extensive lymph node involvement
and distant metastasis. An increasing CEA level
in the presence of a stable calcitonin can be a
sign of dedifferentiation of the tumor and is
associated with a worse prognosis.
Other tumor markers, such as plasma catecholamines, serotonin, and chromogranin A,
may be elevated in patients with MTC; however,
their clinical utility is limited [7]. Plasma calcitonin and CEA are the most useful markers for
following patients with MTC and should be
obtained in all patients.
Associated Conditions
While the majority of MTC is sporadic, approximately 20% of cases are due to a hereditary form
of the disease. The hereditary forms of MTC are
MEN2A, MEN2B, and FMTC. All of these disorders are inherited in an autosomal dominant
pattern and have variable penetrance. MEN2A is
the most common disorder and accounts for
75% of hereditary MTC.
MEN2A is associated with MTC in >95% of
cases. The MTC in MEN2A is typically multifocal and bilateral. The age of onset varies with
the specific genetic mutation, but it typically
presents in early adulthood. Pheochromocytomas can be seen in up to 50% of cases and they
are frequently multifocal and associated with
adrenal medullary hyperplasia. Pheochromocytomas can be screened for using either
plasma metanephrines or 24-h urine collections for catecholamines and metanephrines.
If identified, pheochromocytomas should be
treated and resected prior to proceeding with
a neck operation. Preoperative alpha blockade
should be initiated and blood pressure normalized prior to proceeding with a laparoscopic
adrenalectomy. Hyperparathyroidism occurs
in 20–35% of patients with MEN2A and is
most common in patients with codon 634
mutations. Screening for hyperparathyroidism
can be performed with annual calcium and
parathyroid hormone (PTH levels). While historically felt to be due to hyperplasia, the disease is frequently very asymmetric and may be
due to a single enlarged gland. Patients should
be treated as other patients with primary
hyperparathyroidism with removal of only the
grossly abnormal parathyroid glands. Some
variants of MEN2A are also associated with
either cutaneous lichen amyloidosis or Hirschsprung’s disease. Most of the mortality associated with MEN2A is from the MTC, therefore
early recognition and treatment is essential.
In MEN2B, nearly 100% of patients develop
MTC. MTC develops at a very young age
(infancy) and has a very aggressive course.
Because of the early age of onset and the frequent delay in diagnosis, patients with MEN2B
are rarely cured of their disease. Pheochromocytomas are seen in 50% of patients, but no
patients develop hyperparathyroidism. A distinguishing feature of MEN2B is the development of diffuse ganglioneuromas of the lips,
tongues, eyelids, and gastrointestinal tract.
These patients have a characteristic appearance
including a marfanoid habitus, everted eyelids,
and thick lips. These patients also have problems
with megacolon, skeletal abnormalities, and
markedly enlarged peripheral nerves. Due to the
aggressive nature of the MTC in these patients,
many die at a young age and never reproduce.
Therefore, most of the MEN2B diagnoses seen
today are de novo germline mutations.
Familial MTC occurs when families develop
only MTC. Since there is significant overlap in
the genetic mutations that lead to either FMTC
or MEN2A, the definition of FMTC is strict. In
order to consider a family to have FMTC and
not MEN2A, there must be no evidence of
either pheochromocytoma or hyperparathyroidism in more than 10 carriers and multiple
members need to be affected after the age of 50.
Since MTC is often the first manifestation of
MEN2A, with pheochromocytomas lagging
significantly behind, distinguishing between
MEN2A and FMTC can be difficult. Especially
in smaller kindred it is safer to label a family as
MEN2A than FMTC, which ensures that
patients are screened and monitored for the
development of pheochromocytomas.
Since the results of genetic testing may not be
available prior to operative intervention, every
patient must be evaluated for a potential pheochromocytoma. Pheochromocytoma can be
tested for with either plasma metanephrines or
a 24-h urine collection for catecholamines,
metanephrines, and vanillyl mandelic acid.
153
MEDULLARY THYROID CANCER
It is essential torule this out prior to proceeding
with general anesthesia, as an undiagnosed pheochromocytoma can provoke a life-threatening
hypertensive crisis. Since hyperparathyroidism is
present in 20–35% of patients with MEN2A, all
patients should also have a serum calcium and
PTH checked prior to operative intervention.
Genetic Testing
Germline genetic mutations in the RET gene will
be found in 6–10% of patients with apparently
‘‘sporadic’’ MTC. Therefore, routine genetic
screening should be performed in all patients
with a diagnosis of MTC. Genetic testing of the
RET gene is performed by PCR amplification of
the patient’s germline DNA usually obtained
from white blood cells. Mutations are screened
for in exons 10, 11, 13, 14, 15, and 16. If no
mutations are found, the remaining 15 exons
of the RET gene should be sequenced. Currently
known mutations encode over 95% of cases of
hereditary MTC. Commercial testing for the
most common mutations is widely available,
but more thorough analyses are required to
identify the less common mutations. The predicted risk of hereditary MTC in a patient with a
negative screen is estimated to be only 0.18%.[8]
If patients are not found to have a RET mutation, but remain concerned about the risk of an
unidentified mutation, they can be screened
with periodic basal/stimulated calcitonin levels.
The significance of a genetic mutation for a
patient and their family cannot be underestimated. It is important that prior to screening
for genetic mutations that patients receive
appropriate genetic counseling. The risks and
benefits of genetic testing should be carefully
discussed with the patient and their family.
Patients need to understand the significance of
a genetic mutation, the limitations of the testing,
and the potential adverse affects (including
genetic discrimination and effects on family relations). Once a patient is found to be positive for a
RET mutation, they must be carefully counseled
regarding the risks to additional family members. At-risk family members need to be identified and should undergo genetic testing as soon
as possible. Patients that are identified as RET
mutation carriers should undergo prophylactic
thyroidectomy. The timing of genetic testing and
prophylactic surgery should be determined after
a careful assessment of the risks of malignancy
and the aggressiveness of the disease associated
with the genetic mutation as well as its expression within the family.
Among RET mutations, there is significant
variationintheaggressivenessoftheMTCthat
develops. As we gain a better understanding of the
genotype–phenotype relationships among RET
mutations, we are better able to tailor the treatment of our patients. Currently, RET mutations
are classified into three groups based on level of
risk (or aggressiveness) of MTC (Table 11.1).
Table 11.1. RET mutations
Risk level for MTC Codon mutation Youngest age of MTC
Level 3 (highest) 883
918
922
Level 2 (higher) 611
618
620
634
Level 1 (high) 609
630
768
790
791
804
891
Source: Data compiled from [8, 15, 46, 47]
9 mo 1 Within first 6 months of life
7
7
5
15 mo
5
1
22
10
21
6
13
Youngest age
of nodal disease Age of prophylactic surgery
(preferably in the first month)
By age 5
11
10
5
By age 5–10
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Patients with level 3 mutations have the most
aggressive disease. Level 2 mutations are associated with a slightly later onset and a less aggressive course, while level 1 mutations are associated
with the most indolent course.
Patients with mutations in codon 883, 918,
and 922 are classified as level 3 mutations and
have the most aggressive course, with metastatic
disease presenting in the first years of life.
Because of the high risk of malignancy at an
early age, thyroidectomy is recommended
within the first 6 months and preferably within
the first month of life. Microscopic MTC is frequently seen by age 1 and metastatic disease has
been reported prior to age 1. Because of the
early risk of nodal involvement, patients with
MEN2B should also undergo a central neck dissection [8].
Level 2 RET mutations, including codon
611, 618, 620, and 634 mutations, are considered high risk for MTC and the current recommendation is that these patients undergo
thyroidectomy before age 5 [8]. Whether or
not patients with MEN2A should undergo a
prophylactic central neck dissection is not
clear and currently there is no consensus on
this issue. It is important to consider the specificmutationthatthepatienthasaswellasthe
course of disease within the family to estimate
the risk of malignancy and nodal disease and
then balance the risks and benefits of adding a
nodal dissection. Codon 634 mutations are the
most common cause of MEN2A and have a
strong association with both pheochromocytoma and hyperparathyroidism.
Level 1 RET mutations, including codon 609,
768, 790, 791, 804, and 891, are still considered
high risk for MTC, but are the lowest risk of the
RET mutations. MTC in these patients tends to
develop later in life and takes on a more indolent course. These patients are still best treated
with a prophylactic thyroidectomy, but the optimal timing of surgery is not clear. Since clinically apparent disease is rarely reported prior to
10 years of age, many recommend waiting until
then to perform the thyroidectomy. However,
there remains variability and unpredictability in
some families, hence many surgeons recommend treating all patients with MEN2A the
same and perform their prophylactic operation
by age 5 whenever possible. An alternative to
using a strict age cutoff is to perform periodic
stimulated calcitonin testing and to proceed to
thyroidectomy when the calcitonin becomes
elevated.
While the genetic mutations associated with
MEN2B are distinct, there is significant overlap
in the mutations that are associated with
MEN2A and FMTC. MEN2A has been associated with mutations in both level 1 (790, 791)
and level 2 (609, 611, 618, 620, 634) categories.
FMTC has been described in all of the mutations
associated with MEN2A and additionally in
families with codon 532, 533,768, 804, 844, 891,
and 912 mutations [9, 10].
Somatic mutations of RET have also been
found in up to 25% of sporadic MTC tumors.
The most common mutation is in codon 918
which is associated with a poorer patient
prognosis.
Prognosis
Unlike papillary thyroid cancer, which has been
increasing in incidence, the incidence and mortality from MTC has remained very stable over
the last few decades [11]. Overall, the prognosis
of patients with MTC is good. The 10-year survival of patients with MTC is 75–85% [12, 1, 10].
Approximately half of patients with MTC present with disease localized to the thyroid gland,
and these patients have a 10-year survival of
95.6% [1]. A third of patients will present with
locally invasive tumors or clinically apparent
spread to the regional lymph nodes. Patients
with regional disease have a 5-year overall survival rate of 75.5%. Distant metastases are present in 13% of patients at initial diagnosis and
portend a poor prognosis with a 10-year survival of only 40%.
Independent prognostic factors include
advanced patient age, extraglandular invasion,
gross residual disease, and advanced disease
stage [1, 13]. The most commonly used staging
system for MTC is the TNM system, which is
outlined in Table 11.2. When matched for age
and stage, hereditary and sporadic patients have
similar life expectancies. Calcitonin doubling
time has also been proposed as a significant
negative prognostic factor. Patients with calcitonin doubling times of less than 6 months have
a 5-year survival of 25% in comparison to
patients with a doubling time greater than 2
years who have a 100% 5-year survival [14].
155
MEDULLARY THYROID CANCER
Table 11.2. TNM staging of medullary thyroid cancer
Stage Tumor size Node status Metastasis
IT1 N0 M0
II T2 N0 M0
III T3
T1
T2
T3
IVA T4a
T4a
T1
T2
T3
T4a
IVB T4b Any N M0
IVC Any T Any N M1
Source: Reprinted from AJCC Cancer Staging Atlas, 2006, p. 73.
N0
N1a
N1a
N1a
N0
N1a
N1b
N1b
N1b
N1b
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
Tumors with minimal calcitonin staining or
tumors that present with rapidly increasing
CEA levels (with stable calcitonin levels) have
also been shown to have a worse prognosis.
Prophylactic Surgery
Prophylactic surgery removes the at-risk organ
prior to it developing clinically significant disease. When determining the timing of prophylactic surgery, it is important to balance the risk
of clinically significant disease with the risks of
operative intervention. In hereditary MTC,
there is a clear age-related progression from
C-cell hyperplasia to MTC and ultimately to
nodal spread. However, the optimal timing of
prophylactic thyroidectomy is not clear. Hopefully as we gain a better understanding of the
phenotype–genotype relationships amongst the
RET mutations, we will be better able to predict
when disease is likely to develop and therefore
plan operative intervention prior to that time.
The RET mutations associated with hereditary MTC are listed in Table 11.1 with guidelines
as to when to perform a prophylactic thyroidectomy for each mutation. In general, it is
reasonable to intervene in children with
MEN2A and FMTC by age 5, while patients
with MEN2B should be operated on during
infancy whenever feasible. In a recent study
looking at long-term follow up of patients who
have undergone prophylactic thyroidectomy,
no patient with MEN2A who was operated on
under the age of 7 has had evidence of recurrent
disease, with over 5 years of follow up [15]. If a
family does not want to proceed with prophylactic surgery in a young child, then it is reasonable to follow the patient closely with stimulated
plasma calcitonin levels, and then proceed with
operation when there is a rise in the stimulated
calcitonin levels.
The extent of surgery that is necessary in the
prophylactic setting hasbeen debated. Everyone
agrees that at a minimum all patients should
undergo a total thyroidectomy. The debate
involves whether or not a central neck lymphadenectomy should be performed. Advocates of
routine central neck dissection argue that even
in screened patients, clinically occult disease
with nodal metastasis can be present in 6% of
patients [15]. They argue that the best opportunity to cure a patient is at their initial operation.
With the use of routine autotransplantation of
the parathyroid glands, the long-term complications of a central neck dissection can be
minimized. Opponents of routine central neck
dissection argue that while nodal disease has
been seen in the occult setting, it is very rare in
children under 10 [15]. They suggest that a more
selective approach can be performed utilizing
preoperative ultrasound and tumor markers to
further risk stratify patients. With a normal
preoperative ultrasound and serum calcitonin
(basal and/or stimulated) and CEA level, the
risk of occult nodal disease is very low and the
potential benefits of a prophylactic neck dissection are outweighed by the risks of permanent
hypoparathyroidism. In a recent series from
Washington University where they have performed 85 prophylactic total thyroidectomies
with bilateral central neck dissections (with
routine parathyroidectomy with autotransplantation), they found two (2.4%) patients with
nodal disease and three patients with permanent hypoparathyroidism (3.5%) [16]. While
the incidence of nodal disease is low, those
patients who have nodal disease at the time of
their prophylactic dissection often end up having persistently elevated calcitonin levels and
are not cured of their disease [15]. In order to
minimize the risks of this prophylactic operation, it is essential that these procedures be
performed only by experienced surgeons.
Since the first prophylactic thyroidectomies
were performed in the early 1990s, the risk of
recurrence after a prophylactic thyroidectomy
156
ENDOCRINE SURGERY
is still unknown. Preliminary results suggest
that the risk of recurrence is very low, especially
when surgery is performed prior to age 10 [15].
However, since the long-term outcomes are not
known, it is recommended that after a prophylactic thyroidectomy, patients be followed every
1–2 years with plasma calcitonin and CEA
levels. In addition, patients at risk for MEN2
need to be screened for the development of
both pheochromocytoma (MEN2A and 2B)
and hyperparathyroidism (MEN2A only),
which can occur decades later.
Clinically Evident Disease
Patients who have clinically evident disease are
best treated with a minimum of a total thyroidectomy and bilateral central neck dissection.
Ipsilateral lateral neck dissection should be
added if the primary tumor is greater than 1 cm
in size or there is evidence of positive nodes in
the central neck. A contralateral lateral neck dissection should be considered in patients with
bilateral tumors or extensive lateral adenopathy
on the side of the tumor (Fig. 11.4).
Central neck nodal disease is present in up to
81% of patients with palpable tumors [17]. Addition of a central neck dissection improves cure
rates over a thyroidectomy alone in patients with
clinically evident MTC [18]. A central neck dissection consists of a complete clearing of all
lymph nodes and fibrofatty tissue from the level
VI compartment. Level VI extends from the
hyoid bone superiorly to the innominate vessels
inferiorly; laterally it is bound by the carotids.
A level VI lymphadenectomy requires careful
Fig. 11.4. An algorithm for the treatment of clinically apparent MTC.
157
MEDULLARY THYROID CANCER
dissection of the recurrent laryngeal nerve along
its entire length; it also requires meticulous dissection of the parathyroid glands. Many surgeons argue that it is impossible to do a complete
central neck dissection without removing the
parathyroids and/or their blood supply. Some
surgeons routinely remove the parathyroid
glands with the specimen and then carefully dissect them free from the nodal tissue and autotransplant them. If patients have sporadic MTC,
FMTC, or MEN2B, then the autotransplant can
be performed in the sternocleidomastoid. In
patients with MEN2A, due to the risk of hyperparathyroidism in the remnant, the parathyroid
tissue should be autotransplanted to the nondominant forearm. Placement of the autograft in
the forearm facilitates the work-up and management of any hyperparathyroidism that may
develop. Autotransplanted parathyroid glands
usually do not function for 4–8 weeks, so calcium
and vitamin D replacement is required during
this period of recovery.
The role of a lateral dissection in MTC is less
clear. Ipsilateral nodal metastasis are present in
14–80% of patients, [17, 19] and contralateral
lateral nodal metastasis have been reported in
19–49% of patients [17, 20]. Since there is a high
incidence of lymph node disease, even in
tumors <1 cm, some surgeons advocate a bilateral lateral neck dissection for all patients with
MTC [20, 17]. Unlike papillary thyroid cancer,
where microscopic nodal disease may be effectively treated with radioactive iodine, the only
effective treatment for MTC is surgical resection. While many patients with MTC have an
indolent course, some patients suffer from a
much more aggressive variant of disease, and
early surgical intervention gives them the best
chance for a long-term cure. The significance
of microscopic disease in the lymph nodes is
not fully known, but a significant number of
patients will have recurrent or persistent disease
based on the presence of an elevated calcitonin
after primary operation. Despite an aggressive
surgical resection of all neck lymph nodes, only
32% of patients with nodal disease at the time of
their operation have undetectable calcitonin
levels postoperatively [20].
The morbidity of a bilateral neck dissection
can be significant, and because of this, many
surgeons advocate a more selective approach
to the lateral neck. Preoperative neck ultrasound is highly sensitive for detecting lateral
lymphadenopathy. An ipsilateral lateral lymphadenectomy is advocated when ultrasound
or physical exam suggests the presence of lateral
lymphadenopathy, when central compartment
lymph nodes are involved, or when the primary
tumor is 1 cm. Contralateral lateral neck dissections are then added when patients have
bilateral tumors or there is extensive lymphadenopathy on the primary tumor side. Contralateral lymph node involvement is almost never
seen in the absence of ipsilateral lymph node
disease; therefore in patients with a unifocal
tumor and no ipsilateral lymph node disease,
there is likely no benefit to a contralateral neck
dissection [20]. Lateral neck dissections can be
performed at the time of the initial total thyroidectomy and central neck dissection or can be
done in a staged procedure after the initial
operation.
Recent NCCN guidelines [21] recommend
that patients who have demonstrable MTC or
MEN2B should be treated with a total thyroidectomy with bilateral central neck dissection.
Ipsilateral lateral neck dissections should be
added in patients with primary tumors 1cm
or if the central nodes are involved. Interestingly, according to the SEER database, over
half of patients treated for MTC over the last
several decades had less than the recommendation operation, suggesting that many patients
with persistent calcitonin elevations may have
had an inadequate initial operation [1, 22].
Postop Surveillance
Patients with disease confined to the thyroid
gland without nodal disease have a very low
risk of recurrence and rarely die of their disease
[23]. However, many patients with MTC have
nodal disease at presentation, and these patients
have a very high risk of developing recurrent or
persistent disease. Therefore, they must be followed closely postoperatively.
Follow up should start 2–3 months postoperatively by obtaining a new baseline calcitonin and CEA. However, if values are markedly
elevated preoperatively, it may take up to
4 months to clear, so if the levels are still elevated
at 2–3 months, they should be repeated prior to
pursuing further work-up. Patients who have
undetectable calcitonin levels postoperatively
can be followed with annual measurements of
serum calcitonin and CEA. Routine cervical
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ENDOCRINE SURGERY
ultrasound can be added, but is of no proven
benefit. If there is a rise in serum markers, then
additional imaging can be pursued as indicated.
There is no one combination of tests that best
serves all patients. A reasonable algorithm can be
determined after considering the individual
patient as well as the quality of studies available
at your institution. Thyroid hormone replacement is required after a total thyroidectomy;
however, TSH suppression is not indicated in
patients with MTC.
Persistent/Recurrent Disease
The natural history of MTC varies greatly. Some
patients have a very indolent disease course and
may live years with a mildly elevated calcitonin
level with no imageable disease. Then there are
others who present with a very aggressive variant, that is widely metastatic and/or locally
invasive and these patients warrant a more
aggressive surgical approach to minimize their
risk of dying of their disease.
Patients with MTC must be followed closely
as approximately 50% of patients will develop
recurrent disease. Calcitonin and stimulated
calcitonin levels are very sensitive ways for
detecting either residual or recurrent disease.
When the postoperative calcitonin level is elevated, a careful examination must be performed
prior to proceeding with operative exploration.
Patients with isolated cervical disease may be
operated on for a curative intent, but patients
with metastatic disease should only undergo
operative intervention for palliative reasons.
Therefore, it is essential to perform a thorough
search for metastatic disease prior to embarking
on a neck reexploration.
Since surgery is the mainstay of therapy for
MTC, an adequate initial operation is essential
in order to optimize patient outcomes. However, approximately 50% of patients treated in
the USA each year undergo an inadequate initial
operation and many of these patients are found
to have persistently elevated calcitonin levels
postoperatively. Patients with an inadequate
initial operation may be best served with a
repeat neck operation.
In order to optimize outcomes and potentially cure patients of their disease, some surgeons advocate a very aggressive approach for
the treatment of persistent disease after an
inadequate initial surgery. Using a technique
of ‘‘microdissection’’ of all compartments of
the neck, Tisell and colleagues [24] were able
to normalize calcitonin levels in one third of
patients and substantially reduce them in an
additional third. Other more recent studies
have confirmed that with good patient selection,
neck reoperation can normalize calcitonin
levels in about a third of patients and significantly reduce levels in 40% of cases [25]. The
key to successful neck reoperation is careful
patient selection and recognition of metastatic
disease. Evaluation of metastatic disease can
include anatomic imaging with neck US, CT
scan of the chest and abdomen, and MRI of the
neck and mediastinum. Functional imaging can
also help to identify distant sources of disease.
Both PET and MIBG scans have been used to
localize metastatic disease in patients with
MTC. Since these tumors produce CEA, an
anti-CEA-labeled antibody scan has also been
utilized.
Often metastatic disease to the liver takes on
a miliary pattern and is not detectable by conventional imaging. Therefore, some have advocated the use of more invasive studies as part of
the metastatic work-up. Selective venous catheterization can be performed to obtain basal and/
or stimulated calcitonin levels from various
sites in the neck, chest, and abdomen. If disease
localizes to the neck, then patients can be successfully treated with surgical resection of the
appropriate neck region. While small reports
have found this technique to be beneficial,
others have found that hepatic measurements
can be spuriously elevated and misleading,
bringing to question the utility of this method
of evaluation [16]. Since most patients with
persistently elevated calcitonin levels either
have neck disease or metastatic disease to the
liver, some advocate doing a diagnostic laparoscopy to examine the liver surface prior to cervical reoperation. Using routine laparoscopy to
evaluate the liver, one group found that 21.3% of
patients had occult liver disease that altered the
approach to the patient’s cervical disease [26].
Neck reoperations are associated with significant risks. Therefore, reoperation should only be
pursued if there is significant likelihood of benefiting the patients. If patients had an inadequate
initial operation or are found to have only locoregional disease, then surgical resection should be
pursued. Patients with tracheal or mediastinal
159
MEDULLARY THYROID CANCER
invasion can die of local compression/invasion if
the disease is not resected. Therefore, if patients
develop symptomatic locoregional recurrence,
even in the setting of metastatic disease, then
they should be offered surgical resection when
feasible and external beam radiation when surgery is not possible [27].
If a patient had an adequate first operation
and postoperatively they have persistently elevated calcitonin, but all imaging is negative, it is
appropriate to follow them clinically without
further intervention. These patients should be
followed annually and reimaged if there is a
progressive increase in the serum markers.
Radiation Therapy
External beam radiation does not currently play
a significant role in the treatment of patients
with MTC. The primary treatment modality for
all patients who are candidates is surgical resection. However, radiation therapy has been
applied to help palliate local disease when surgery is not a feasible option. Radiation therapy
has also been used to palliate bony metastases.
Given the high risk of cervical recurrence in
these patients, especially those with microscopic residual disease, nodal involvement, or
extraglandular spread, some have advocated for
postoperative treatment with external beam
radiation. There have been several studies
examining the role of adjuvant external beam
radiation in MTC. One study found that in highrisk patients, surgery plus external beam radiation had a recurrence rate of 14% compared to
48% in the surgery alone group [13]. While this
study suggests that a subset of patients may
benefit from adjuvant external beam radiation,
this needs to be further evaluated.
Despite the paucity of evidence regarding the
utility of postoperative radiation therapy, a significant number of patients are treated with it.
Interestingly in a recent review of the SEER
database, 18% of patients were treated with
adjuvant radiation. Radiation therapy not only
didn’t improve survival, but it was associated
with decreased survival [1]. External beam
radiation causes extensive scarring and fibrosis
within the neck making future surgical interventions both difficult and potentially dangerous. Since the benefits of radiation therapy are
not clear and its use limits future surgical intervention, its use should be reserved for cases of
known residual disease in which complete surgical resection is not possible.
Radioactive iodine is part of the standard
treatment for papillary thyroid cancer, but
since C-cells are not of thyroid follicular origin,
radioactive iodine is not taken up in the C-cells
and radioactive iodine treatment plays no role
in the management of MTC. Interestingly, there
has been some interest in using radioactive
iodine, not to treat significant disease, but to
ensure that all C-cell containing thyroid tissue
was removed during the initial operation [28].
After a total thyroidectomy, even in the most
experienced hands, there is a small amount of
residual thyroid tissue, which may contain
C-cells, which theoretically could form a new
focus of MTC in a patient with a germline predisposition. Radioactive iodine is only taken up
by thyroid follicle cells but affects tissue in the
surrounding 2 mm of tissue via ß-ray emission.
One small study has suggested that in patients
with disease confined to the thyroid, who have
an elevated calcitonin level postoperatively,
radioactive iodine may decrease calcitonin
levels [28]. While interesting, further studies
need to be performed to clarify the possible
role of radioactive iodine in the treatment of
MTC in this subset of patients.
Radioimmunotherapy has been proven efficacy in other neuroendocrine tumors and several targets have been investigated in MTC. CEA
and Somatostatin receptors are both present on
MTC cells. A preliminary study using anti-CEAtargeted radioimmunotherapy has shown some
efficacy in high-risk patients (calcitonin doubling times <2 years) in comparison to historical controls. Unfortunately this therapy is
associated with significant toxicity including
grade four neutropenia and thrombocytopenia
in >20% of patients[14, 29].
Systemic Therapy
Surgery has been the mainstay of therapy for
patients with MTC. An aggressive surgical
approach has been advocated because once
patients develop systemic disease, treatment
options are very limited.
Conventional chemotherapy has shown limited efficacy in patients with MTC. Complete
responses are very rare and partial responses
have been seen in less than a third of patients.
The side effect profile of chemotherapy is often