Medullary thyroid cancer

Full text

*DNB (General Medicine) DNB (Endocrinology), Consultant
†MD MNAMS DNB (Endocrinology) FRACP (Endocrinology) FRCP (Edinburgh), Professor and Head Unit-1
Department of Endocrinology, CMC, Vellore, Tamil Nadu, India.
**MD DNB (Endocrinology), Associate Professor
Endocrine and Diabetes Unit, CMC, Ludhiana, Punjab, India.
Medullary Thyroid Cancer
HS Asha*, Jubbin Jagan Jacob**, Nihal Thomas†
MEDULLARY THYROID CANCER
Medullary thyroid cancer (MTC) is an uncommon
malignant tumor derived from the parafollicular cells
(C cells) of the thyroid. It was initially described
by Hazard et al in 1959. Sipple conceptualized
the association of MTC and pheochromocytoma,
which is now known as multiple endocrine
neoplasia (MEN)-2A, along with which primary
hyperparathyroidism is also associated. MTC
may occur in some situations in association with
pheochromocytoma, ganglioneuromas, and
marfanoid habitus in MEN-2B (Table 1).1 Mutations
in the rearranged during transfection (RET)
proto-oncogene have been identied in patients with
MEN-2 and a subset of sporadic MTCs.2,3
C cells are of neuroendocrine origin and evolve
from the neural crest, subsequently migrating to
the ultimobranchial body, which fuses with the
developing thyroid gland. The C cells constitute
1% of the cells of the thyroid gland and produce a
32-amino acid peptide named calcitonin. Calcitonin
inhibits bone resorption and protects against
hypercalcemia. Calcitonin is also produced by
neuroendocrine cells in the adrenals, pancreas,
lungs, prostate, and other tissues and in any cell
type during sepsis. Under normal physiological
conditions, C cells are the predominant source of
Table 1
Hereditary Medullary Thyroid Carcinoma
Syndrome Components
MEN-2A or Sipple’s syndrome
• MTC
• Pheochromocytoma
• Parathyroid adenomas
Variants of MEN-2A
• Familial medullary thyroid carcinoma
• MEN-2A with cutaneous lichen amyloidosis
• MEN-2A with Hirschsprung’s disease
MEN-2B
• MTC
• Pheochromocytoma
• Intestinal ganglioneuromatosis
• Marfanoid habitus
MTC: medullary thyroid carcinoma; MEN: multiple endocrine neoplasia.

Asha, Jacob and Thomas
180
calcitonin and hence are a useful tumor marker
for MTC.1
Clinical Presentation
Sporadic MTC accounts for 75–80% of all cases
of the disease.4,5 The mean age at presentation
is 45–55 years, with a female predominance in
Western literature.6,7 In the Indian setting, the mean
age at presentation was around 41–46 years, with a
male predominance.5,8 Women presented a decade
earlier than men at 1 center.8
The most common presentation is that of a
painless thyroid swelling (65%), of whom, 50% have
associated lymphadenopathy. It can also present with
isolated cervical lymph node enlargement (15%) or
be detected during evaluation for MEN-2 in a patient
with pheochromocytoma or during screening of
family members of those affected by MEN-2. Details
of the clinical presentation of patients with MTC in
a tertiary care centre are summarized in Table 2.5
Sporadic MTCs are more commonly unicentric;
hereditary MTCs associated with MEN-2A and 2B
are most often bilateral and multicentric.1 It is more
aggressive and metastasizes earlier in MEN-2B
than in MEN-2A.9 The secretion of calcitonin,
calcitonin gene-related peptide, prostaglandins, and
vasoactive intestinal polypeptide may precipitate
symptoms of diarrhea and ushing.10 About 50%
have clinically evident lymph node metastases at
diagnosis.5 The central compartment lymph nodes
(level VI) are most commonly involved, followed
by ipsilateral level II–V nodes and subsequently
the contralateral nodes. The other common sites
of metastases include mediastinal lymph nodes,
liver, lungs, and bone.11,12 Around 5% have distant
metastasis at diagnosis.4
In MEN-2, the earliest abnormality is focal C-cell
hyperplasia. These foci become nodular, evolving
into microscopic MTC and subsequently visible MTC.
MTC develops later in the course of the disease and
is less aggressive in familial MTC (FMTC) when
compared to MEN-2A.1
Molecular Pathogenesis
Germline mutations in the RET proto-oncogene have
been identied in patients with hereditary MTC and
somatic RET mutations in a proportion of sporadic
MTC.12 The RET gene encodes a receptor tyrosine
kinase that is expressed in the neural crest-derived
cell lineages. The RET receptor plays a crucial
role in regulating cell proliferation, migration,
differentiation, and survival through embryogenesis.
Under normal conditions, RET can be activated by a
complex of co-receptors and ligands, which include
the glial-derived neurotrophic factor (GDNF) family
of ligands (GFLs) and glycosylphosphatidylinositol-
anchored GDNF family α receptors (GFRα).
Interaction of GFRα/GFL complex with RET leads
to autophosphorylation of tyrosine residues. The
C cells are more susceptible to oncogenic RET
activation than the adrenal medulla or parathyroid
in MEN-2A, leading to an earlier presentation and
a higher penetrance of MTC. Mutations in the
extracellular cysteine-rich domain are generally
found in MEN-2A and convert a cysteine residue
to a non-cysteine residue. The mutation leaves
Table 2
Mode of Clinical Presentation in Patients with Medullary Thyroid Carcinoma5
Clinical presentation Number of patients (n = 40) Percentage
Goiter with lymphadenopathy 12 30
Solitary thyroid nodule 7 17.5
Isolated goiter 7 17.5
Isolated cervical lymph node enlargement 6 15
Pheochromocytoma 5 12.5
Familial screening 1 2.5
Mode of presentation unclear from medical
records 2 5

Medullary Thyroid Cancer 181
an unpaired cysteine residue in an RET monomer
to form an aberrant intermolecular disulde bond
with another mutated monomer. The two mutated
RET molecules are constitutively dimerized and
activated. Mutations in the intracellular tyrosine
kinase residues are generally found in MEN-2B
and FMTC; these activate tyrosines, leading to
aberrant phosphorylation of substrates preferred
by cytoplasmic tyrosine kinases such as C-Src and
C-Abl rather than the substrates preferred by normal
receptor tyrosine kinase. The mutated RET no longer
needs dimerization to become active and signals
independent of the ligand. This further leads to an
activation of downstream signaling pathways.13
Diagnosis
A high index of clinical suspicion is warranted in a
patient presenting with a thyroid nodule, with a family
history suggestive of MEN-2A (associated young
onset hypertension due to pheochromocytoma and
primary hyperparathyroidism with fractures or renal
stones), MEN-2B (association of pheochromocytoma,
marfanoid habitus, mucosal neuromas, or chronic
constipation due to intestinal ganglioneuromas), or
a family history of MTC.
Tumor Markers
The diagnosis of MTC is established by demonstrating
elevated serum calcitonin levels. Calcitonin is a
highly sensitive biomarker of MTC, and a majority
of patients with MTC exhibit signicantly elevated
levels. Pre-operative calcitonin levels correlate
with the tumor size and the stage of the disease.
Calcitonin levels <100 pg/mL were associated with
a median tumor size of 3 mm (98% <1 cm), while
levels >1000 pg/mL correlated with a median tumor
diameter of 2.5 cm.14 The positive predictive value
of basal calcitonin in the pre-operative diagnosis
of MTC with values >20 and <50, >50 and <100,
and >100 pg/mL were 8.3%, 25%, and 100%,
respectively.15 Nodal metastases could be rst
observed at basal calcitonin levels of 10–40 pg/
mL. Distant metastasis and extrathyroidal extension
were evident in patients with calcitonin levels of
150–400 pg/mL.16 Elevation of serum calcitonin can
occur in C-cell hyperplasia, autoimmune thyroiditis,
chronic renal failure, pregnancy, and mastocytosis.17
Calcitonin elevation is also observed in non-thyroidal
neuroendocrine tumors arising from the foregut,
pancreas, insulinoma, glucagonoma, VIPoma,
carcinoid, prostate cancer, small-cell lung cancer,
and large-cell lung cancer with neuroendocrine
differentiation.18 The glucagon-like peptide (GLP)-1
receptor agonist liraglutide has been demonstrated
to increase calcitonin release and cause C-cell
hyperplasia in rats and, to a lesser extent, in mice.
In contrast, humans and cynomolgus monkeys have
low GLP-1 receptor expression in thyroid C cells,
and liraglutide does not increase calcitonin release
in primates.19 In a study of 10,864 patients with
thyroid nodules, 0.4% had high serum calcitonin
concentrations and were proven to have MTC.20
There is no consensus regarding the usefulness of
a routine measurement of serum calcitonin levels in
individuals with thyroid nodules.
Carcinoembryonic antigen (CEA) is also secreted
by the C cells of the thyroid. Pre-operative CEA
levels >30 ng/mL have been shown to be less likely
associated with a surgical remission. The rate of
central and lateral lymph node involvement was
70% and increased to 90% if CEA levels were >100
ng/mL. CEA levels in excess of 100 ng/mL were
also associated with contralateral nodal disease and
distant metastasis.21
Ultrasound Scan
The features suggestive of MTC include solid
hypoechoic nodules, echogenic foci in 80–90%
of the tumors due to amyloid deposition, and
associated calcication. Similar deposits have also
been observed in 50–60% of nodal metastasis.
Chaotic intranodular vessels within the tumor on
color-ow imaging also indicate MTC.22 On the
other hand, sonological ndings are highly operator
dependent. They are less sensitive and specic in
detecting central lymph node metastases than when
compared to the lateral neck.23
Fine-needle Aspiration Cytology
The typical cytological features include a dispersed
cell pattern, polygonal appearance of the cells,
binucleated cells, and the presence of amyloid.24
The sensitivity of ne-needle aspiration cytology
(FNAC) in detecting MTC is 63% in comparison with
98% for serum calcitonin measurement.18
Histopathology of Medullary Thyroid Cancer
On gross examination, they are rm, white or yellow,
and inltrative. Some of them are well dened and
encapsulated. On light-microscopic examination, the
C cells are rounded, polygonal, or spindle shaped,
arranged in islands separated by brous tissue,
trabeculae, or ribbons of cells, or uncommonly
as glandular structures. The nuclei are rounded
or elongated. Amyloid deposits are the hallmark,
both in the primary tumor and within the metastatic
deposits (Figure 1). Immunostaining for calcitonin

Asha, Jacob and Thomas182
is a useful method to establish the diagnosis with
certainty (Figure 2).25
Evaluation of Metastatic Disease
The neck, chest, and abdominal computed
tomographic (CT) scan are most commonly
performed in the pre-operative staging of patients
who have a signicant elevation of calcitonin (>400
pg/mL). Arterial phase-contrast abdominal CT and
contrast-enhanced magnetic resonance imaging
(MRI) are useful in the detection of macroscopic
liver metastases. Hepatic arteriography is more
sensitive than CT abdomen in the detection of
small lesions.18,26 Direct examination and biopsy of
the liver by laparoscopy may show small deposits
of metastatic MTC in patients with normal CT
scanning and MRI. The metastases appear as
small (<5 mm), bright, white nodules on the surface
of the liver.27
Evaluation for MEN-2A and MEN-2B
Individuals with a family history suggestive of MEN-2A
should be screened for primary hyperparathyroidism
by the measurement of serum calcium, phosphorus,
and albumin. Parathyroid hormone (PTH) should
be estimated when serum calcium is elevated or
when there is a high index of suspicion of primary
hyperparathyroidism. Patients with a family history
of onset of hypertension in youth (MEN-2A or
MEN-2B) should have an estimation of 24-hour
urine metanephrines and normetanephrines to
rule out pheochromocytoma before taking up for
thyroidectomy.
Genetic Testing
Patients who present with MTC should undergo
DNA analysis for detection of mutations in the RET
proto-oncogene because the likelihood of a germline
RET mutation is relatively high (9%) in apparently
sporadic MTC in an assessment of Indian patients.28
MTC has nearly a 100% penetrance in MEN-2
syndromes and FMTC. Clinically relevant mutations
are located on exons that are 10, 11, 13, 14, 15,
and 16, and these are to be analyzed. Families at
risk of MEN-2 without identiable mutations in the
exons that are mentioned should be screened for
mutations in exons 5 and 8.13 The clinical course
and aggressiveness of MTC are based on the
mutations in different exons. RET mutations have
been stratied into 3 groups based on their clinical
behavior. Patients with MEN-2B have the most
aggressive MTCs and have mutations in codon 883
or 918. These are classied as level 3. Patients with
MEN-2A and FMTC with level 2 mutations (codons
609, 611, 618, 620, 630, and 634) are classied
as having high risk, and patients with mutations in
codons 768, 790, 791, 804, and 891 (level 1) are
classied as having the least risk for the development
of aggressive MTC.3,29
Multiple endocrine neoplasia-2 is inherited as an
autosomal dominant disorder. Hence, 50% of the
offsprings of the index case are at risk. However,
a physician cannot disclose reports of genetic
tests to a patient’s rst-degree relatives without
the patient’s consent. Hence, the physician should
inform the patient about the risk of development
of the disease in rst-degree relatives. It would
be the moral obligation of the patient to inform his
rst-degree relatives to undergo genetic testing to
ascertain their risk.18
All RET mutation carriers of reproductive
age should be counseled about the option of
pre-implantation or prenatal genetic testing.
Pre-implantation genetic diagnosis is an in vitro
Figure 1. Histopathology of medullary thyroid carcinoma
showing spindle-shaped tumor cells (white arrow) with
amorphous amyloid within the tumor (black arrow).
Figure 2. Calcitonin immunostaining showing tumor cells
staining positive for calcitonin (white arrows).

Medullary Thyroid Cancer 183
fertilization technique that isolates and tests a
single embryonic cell for RET mutation. Unaffected
embryos may then be transferred to the uterus. This
has a potential to remove the disease from the family.
Prenatal genetic testing may also be performed on
samples obtained by chorionic villus biopsies or
amniocentesis in the rst and second trimesters of
pregnancy, respectively.18
Screening for Other Components of MEN-2
among Those with Germline RET Mutations
In the absence of symptoms or an adrenal mass
to suggest the possibility of pheochromocytoma,
surveillance should include an annual
measurement of plasma free metanephrines and
normetanephrines or 24-hour urine metanephrines
and normetanephrines, beginning by the age of 8
years in those with RET mutations in codons 630,
634, 804, 883, and 918, and by the age of 20 years
in those with other mutations. Periodic surveillance
starting at the age of 20 years is also indicated in
patients with RET mutations associated with only
FMTC. Surveillance for primary hyperparathyroidism
should include annual measurement of albumin
corrected serum calcium with or without intact PTH,
beginning by the age of 8 years in carriers of RET
mutations in codons 630 and 634, and by the age of
20 years in carriers of other MEN-2A RET mutations;
those with FMTC mutations should also have a
periodic surveillance.18
Treatment
Surgery
Patients with level 3 RET mutations should undergo
a prophylactic total thyroidectomy in the rst year
of life. Individuals with level 2 mutations should
undergo surgery before the age of 5 years and
those harboring level 1 mutations between the
age of 5 years and 10 years. In those with thyroid
nodules >5 mm in size at any age, a basal serum
calcitonin >40 pg/mL when >6 months old, or with
a clinical or radiological evidence of lymph node
metastasis, further evaluation is required with
neck ultrasound, which should evaluate the central
and lateral compartments and also the superior
mediastinum. In these situations, more extensive
surgery inclusive of central and lateral compartment
lymph node dissection may be necessary. About 6%
of all children undergoing central neck dissection
suffer from hypoparathyroidism. Normal parathyroid
tissue should be identied and left in situ with an
adequate vascular pedicle, or, if it is not possible,
transplanted into the sternomastoid or non-dominant
forearm. In those with a strong family history of
primary hyperparathyroidism, it would be prudent to
transplant parathyroid into the forearm and consider
removal of the transplanted remnant in case of
hypercalcemia.18
The MTC patients with limited local disease
(with a tumor size <4 cm and metastasis to level VI
cervical lymph nodes) without or with limited distant
metastasis should undergo total thyroidectomy and
level VI compartment lymph node dissection. Those
with local metastases to the central and lateral neck
compartments should undergo total thyroidectomy
and central (level VI) and lateral neck (levels IIA, III,
IV, and V) dissection. In the presence of extensive
metastatic disease or advanced local disease, a more
palliative approach should be adopted to minimize
the risk of hypoparathyroidism and maintain normal
speech and swallowing. Surgery is indicated when
there is pain or tracheal compression.18 Somatic
RET mutations are positive in 40–50% of sporadic
MTC, and these individuals have a more aggressive
course than those without RET mutations.30
In case MTC is incidentally detected on
histopathology in a patient who underwent
hemithyroidectomy, patients at risk of contralateral
MTC or residual metastatic disease are likely to
benet from completion thyroidectomy, including
bilateral central compartment lymph node
dissection. The high-risk individuals include those
with germline or somatic RET mutation, histologic
evidence of C-cell hyperplasia, tumor multifocality
or extrathyroidal extension, positive surgical margin
or metastasis, family history of MEN-2, ultrasound
suspicious of contralateral tumor or lymph node
metastasis, or serum calcitonin levels above the
normal range. If these features are not present, the
patient can be observed and followed up. When the
postoperative serum calcitonin is undetectable, the
risk of persistent or residual disease is low and these
patients need only follow up.18
Postoperative Thyroxine Replacement
Medullary thyroid cancer is not thyroid-stimulating
hormone (TSH) dependent, and hence, only
replacement levothyroxine therapy should be
instituted postoperatively to maintain TSH levels
between 0.5 and 2.5 mIU/L.18
Postoperative Radioactive-iodine Ablation
Radioactive-iodine uptake into the follicular cells
may have a bystander effect in ablating adjacent
MTC and has been used in some centers in the
postoperative treatment of disease conned to the
thyroid.5,31

Asha, Jacob and Thomas184
Postoperative External Beam Radiotherapy
External beam radiotherapy (EBRT) does not alter
the local or regional relapse late, but in high-risk
patients with extraglandular invasion, microscopic
residual disease, or lymph node involvement, the
locoregional relapse free rate at 10 years was better
in individuals who received postoperative EBRT in
comparison with those who did not receive external
bean radiotherapy (86% vs 52%; P = 0.049).32
Postoperative Follow-up
In view of variable time duration to normalization of
serum calcitonin,33 it is recommended to check serum
calcitonin 2–3 months following surgery. Biochemical
remission is dependent on the pre-operative basal
calcitonin level and tumor size. In a large series,
postoperative serum calcitonin was normalized in
62% of patients with node-negative disease and
in 10% with node-positive disease. Remission rate
was 50% in those with primary tumor >10 mm,
node-negative disease, and pre-operative calcitonin
>300 pg/mL. No remission was noted in those with
a tumor >40 mm in diameter or basal pre-operative
calcitonin >3000 pg/mL. Undetectable postoperative
calcitonin was obtained in 57% with <10 lymph node
metastases and, in 4% with metastasis in >10 lymph
nodes.18
Calcitonin doubling time is a predictor of survival
in MTC. In a retrospective series, when the calcitonin
doubling time was <6 months, the 5- and 10-year
survival rates were in the range of 25% and 8%,
respectively; when the calcitonin doubling time was
6–24 months, the 5- and 10-year survival rates were
92% and 37%, and in those with calcitonin doubling
time >2 years, survival was 100% at 10 years.34
Biochemical cure predicts a survival rate of 97.7%
at 10 years. In a study by Modigliani et al, survival in
non-cured patients was 80.2% at 5 years and 70.3% at
10 years.35 Persistent hypercalcitoninemia indicates
a poorer prognosis (Figure 3).5 Age and stage were
independent predictive factors for survival.35
Modest calcitonin elevation <150 pg/mL indicates
locoregional disease. An ultrasound neck should be
performed to look for residual disease in the thyroid
bed or lymph nodes. In those with postoperative
calcitonin >150 pg/mL, suspicion of distant
metastasis is high and one should consider other
imaging modalities like CT scan of neck and chest,
3-phase contrast-enhanced multidetector CT of the
liver or contrast-enhanced MRI, MRI of spine and
pelvis, and bone scan to detect residual/recurrent
disease.18 131I-meta-iodobenzylguanidine (MIBG)
has a sensitivity of 65% in localizing metastatic MTC
(Figure 4).5
Figure 3. Survival curves for patients with persistent
postoperative hypercalcitoninemia compared with those
with normal postoperative calcitonin levels (time in months).
P = 0.901 (not signicant).5
Yes—persistent postoperative hypercalcitoninemia;
No—no postoperative hypercalcitoninemia.
Figure 4. Meta-iodobenzylguanidine scan in patient with
medullary thyroid carcinoma post-thyroidectomy and
lymph node dissection showing metastasis in both lungs
(black arrows).
0 24 48 72 96 120 144 168 192 216 240
1.0
0.8
0.6
0.4
0.2
0.0
Time (months)
Cum survival
No
Yes
131 I mIBG study (24 hours)
Anterior Posterior
Fluorodeoxyglucose (FDG)-positron emission
tomography (PET) and 18F-dihydroxyphenylalanine
(DOPA) PET are useful in localizing the disease, with
a sensitivity of 44% and 63%, respectively.36,37 The

Medullary Thyroid Cancer 185
sensitivity and specicity of 18F-DOPA PET/CT was
100% when serum calcitonin was >150 pg/mL.38
Treatment of Metastatic Disease
In those with local recurrence in the thyroid bed
or cervical lymph nodes (>1 cm), repeat surgical
resection is indicated, including compartmental
dissection of image or biopsy-positive disease in the
central (level VI) or lateral (level II-A, III, IV, and V)
neck compartments. Asymptomatic lymph nodes (<1
cm) can be observed. When there is no anatomic
evidence of disease on imaging despite a detectable
serum calcitonin, it would be most appropriate to
keep the patient on follow-up. Percutaneous ethanol
injection may also be considered for locoregional
MTC.18
Active treatment is often indicated in patients with
lesions in critical locations such as brain metastasis,
impending or active spinal cord compression,
airway compromise, symptomatic lesions, hormonal
hypersecretion (corticotrophin-releasing hormone
[CRH] or adrenocorticotropic hormone [ACTH]
secretion leading to Cushing’s syndrome), and
impending or active fracture of weight-bearing
bones. EBRT may be considered to treat painful
bone metastases and for clinically signicant lesions
that are not candidates for surgery. Vertebroplasty,
radiofrequency ablation with or without cementation,
cryosurgery, and arterial embolization are all
effective in reducing pain in the given patient.18
Bisphosphonates also reduce bone pain in those
subjects with skeletal metastasis.39
Lung or mediastinal lesions causing local
compression of an airway or bleeding may be
considered for surgery, EBRT, or radiofrequency
ablation. Lesions with central airway invasion
may be amenable to the addition of photodynamic
therapy or airway stenting.18
Liver metastases are usually multiple and
disseminated throughout the liver, with diarrhea
and pain. They are usually not amenable to
surgery, percutaneous ethanol ablation, or
radiofrequency ablation.18,40 They are best treated
with chemo-embolization. In a series of 12 patients
with MTC with hepatic metastasis, 42% had partial
response, 42% had stabilization, and diarrhea
improved in 40%.41
Chemotherapy: Clinical trials of chemotherapeutic
regimens in persistent or recurrent MTC have shown
limited efcacy, with the best response of partial
remission in 10–20%. The agents used include
dacarbazine, doxorubicin, and 5-uorouracil.18
Radionuclide-targeted therapies: 90Yttrium
DOTA–TOC has been used in the treatment of
metastatic MTC with rising calcitonin levels and
tumor uptake on 111In octreoscan. Twenty-nine
percent of the patients demonstrated decreasing
calcitonin levels with therapy.42 131I-MIBG is taken by
MTCs and hence may be useful for the treatment of
metastatic MTC.5 In a small series, partial remission
was achieved in 25% and meaningful palliation in
75% of patients with metastatic MTC.43
New Modalities of Therapy
Tyrosine kinase inhibitors sunitinib, sorafenib,
vandetanib, and motesanib have been used in
the treatment of MTC.44 With motesanib, only 2%
had a partial response, while 47% experienced
stable disease at 24 weeks.45 Among patients with
metastatic FMTC, vandetanib produced partial
response in 17% and stable disease in 33% at 24
weeks. Calcitonin levels dropped by >50% in 66%
of these patients. Sunitinib achieved a greater
disease stabilization rate of 83% in MTC patients.
With sorafenib, partial response was seen in 8%
and minor response (dened as 23–29% reduction
in tumor diameters) was achieved in another 19%.
The common adverse effects of these drugs include
fatigue, diarrhea, and nausea. Sunitinib causes
erythrodysesthesias, neutropenia, and hypertension.
Sorafenib is known to inhibit the growth plate in
children. Vandetanib causes asymptomatic QT
prolongation and skin rash. Motesanib increases
the requirement of levothyroxine to maintain TSH
suppression or a euthyroid state.44
Treatment of Associated Problems
Diarrhea in MTC most often occurs in the setting
of advanced disease in patients with hepatic
metastases. Diarrhea may be hypersecretory or due
to enhanced gastrointestinal (GI) motility or both.
It is debilitating both in terms of nutrition and the
quality of life. Therapy with loperamide or codeine
is the rst-line therapy. If diarrhea does not subside,
treatment with somatostatin analogs or debulking of
large tumor deposits could also be considered.18
The ACTH or CRH overproduction from MTC
leads to Cushing’s syndrome. MTC accounts
for 2–6% of ectopic ACTH-dependent Cushing’s
syndrome. Options of treatment in this situation
include debulking of large hepatic metastases
(surgery or chemo-embolization), medical therapy
with ketoconazole or mitotane, or bilateral
adrenalectomy. Treatment with somatostatin analogs
is ineffective.18
Long term Follow-up
Long term biochemical monitoring for MTC patients
who achieve a complete biochemical cure should

Asha, Jacob and Thomas186
include annual measurement of serum calcitonin.
Those with detectable serum calcitonin levels
postoperatively should have basal calcitonin and
CEA levels measured every 6 months to determine
their doubling time. Ongoing follow-up should include
physical examination and measurement of calcitonin
and CEA at one-fourth the shortest doubling time or
annually, whichever is more frequent. CEA is also
secreted by cancers of the GI tract, lung, prostate,
breast, and ovary and should be interpreted with
caution in individuals with co-existent cancers.18
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