DynaMed Plus - Medullary Thyroid Cancer

4/3/2019 DynaMed Plus: Medullary thyroid cancer
Medullary thyroid cancer

Overview and Recommendations
Background
Medullary thyroid cancer (MTC) is a neuroendocrine carcinoma that arises from thyroid parafollicular C
cells, and accounts for about 4%-8% of thyroid cancers.
75%-80% of MTC is sporadic and occurs as an isolated condition, typically presenting in the fifth or
sixth decade of life.
20%-25% of MTC is genetic and occurs as an isolated condition (familial MTC) or as part of
multiple endocrine neoplasia type IIa or IIb syndrome; it typically presents at earlier ages than
sporadic MTC.
MTC must be differentiated from other thyroid carcinomas, including:
differentiated thyroid cancers (papillary and follicular), which arise from thyroid follicular cells and
account for ≥ 90% of thyroid cancers
anaplastic thyroid cancer, the least common and most aggressive thyroid carcinoma, arising de novo
or from differentiated thyroid cancer
Risk factors for malignancy in patients with thyroid nodules (in addition to a family history of thyroid
cancer or multiple endocrine neoplasia [MEN 2]) include age < 14 years or > 70 years, or a history of head
or neck irradiation.
Common presentations of MTC include:
a neck mass (a thyroid nodule or lymph node metastasis) palpated on a physical exam, detected as
an incidental finding on imaging, or identified during screening of patients with familial thyroid
cancer, MEN 2A, or MEN 2B and their at-risk family members
compressive symptoms such as dysphagia and hoarseness
symptoms of tumor hormone secretion (calcitonin, adrenal cortical releasing hormone) such as
flushing, diarrhea, Cushing syndrome, or weight loss
Evaluation
Suspect thyroid malignancy in patients with thyroid nodules that are firm, fixed, growing, or associated
with cervical adenopathy, dysphonia, dysphagia, or dyspnea.
Measure serum thyroid-stimulating hormone (TSH) in all patients with thyroid nodules (Strong
recommendation).
Perform a radionuclide scan (scintigraphy) if TSH is low (Strong recommendation); pregnant women
should avoid the use of radioactive agents for diagnostic purposes (Strong recommendation).
Perform a thyroid ultrasound in most patients with known or suspected thyroid nodules (Strong
recommendation).
Perform a fine-needle aspiration (FNA) biopsy of nodules seen on ultrasound if:
the nodule is > 1 cm in diameter or has ultrasound features suspicious for malignancy (Strong
recommendation)
the patient has risk factors for malignancy or abnormal cervical lymph nodes (Strong
recommendation)
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Do not perform a FNA of nodules classified as hyperfunctioning ("hot") on scintigraphy (patients with
hyperfunctioning nodules have a low risk for malignancy and should be evaluated for hyperthyroidism)
(Strong recommendation).
Measure serum calcitonin in patients with FNA biopsy findings suggestive of medullary thyroid cancer
(MTC), a family history or clinical suspicion of MTC, or multiple endocrine neoplasia type 2 (MEN 2)
(elevated calcitonin may suggest MTC [reference ranges vary by age and gender]) (Strong
recommendation).
If FNA biopsy or calcitonin levels are suspicious for MTC, perform:
a neck ultrasound by a technician skilled in neck imaging (Strong recommendation)
a check of serum basal calcitonin, calcium (ionized or albumin-corrected), and carcinoembryonic
antigen (CEA) levels (Strong recommendation)
a rearranged during transfection (RET) gene analysis (Strong recommendation)
Consider additional imaging to detect metastatic disease if MTC is suspected and local lymph node
metastases are detected, or if the serum calcitonin is ≥ 400 pg/mL (Weak recommendation).
Management
Perform surgery in most patients with medullary thyroid cancer (MTC).
Total thyroidectomy with neck dissection is the preferred first-line treatment in most patients
without advanced local disease or extensive distant metastases (Strong recommendation).
Consider less aggressive neck surgery to preserve parathyroid function, speech, and swallowing in
patients with advanced local disease or distant metastases (Weak recommendation).
Perform palliative neck surgery for pain or tracheal compromise in patients with extensive distant
metastatic disease, but otherwise surgery may be deferred (Weak recommendation).
Screen for and, if present, resect any pheochromocytoma before performing surgery for MTC (to
avoid a hypertensive crisis) (Strong recommendation).
For metastatic, progressive, or unresectable MTC:
Systemic therapy is usually not needed for asymptomatic patients with stable or slowly progressive
small volume metastatic disease (Strong recommendation).
Treatment for patients with lesions in critical locations may include:
tyrosine kinase inhibitors, such as vandetanib or cabozantinib (Strong recommendation)
surgery for some brain and bone metastases (Strong recommendation)
external beam radiation therapy for clinically significant metastases not amenable to surgery
(Weak recommendation)
chemotherapy in selected patients with rapidly progressive disease that is not amenable to
clinical trials or palliative therapies (Strong recommendation) (chemotherapy is discouraged
for routine use in MTC [Strong recommendation])
Radioactive iodine (RAI) treatment is not recommended because MTC cells do not concentrate
RAI.
Provide follow-up treatment and monitoring.
After thyroidectomy:
Provide adequate thyroxine replacement therapy (Strong recommendation) and keep thyroid
stimulating hormone levels at 0.5-2.5 milliunits/L (Strong recommendation).
Monitor for persistent or recurrent disease with serum calcitonin, carcinoembryonic antigen
(CEA) (Strong recommendation), and imaging as indicated based on the clinical and
biochemical findings.
Monitor patients with rearranged during transfection (RET) mutations for pheochromocytoma and
hyperparathyroidism.
Take measures to prevent or detect MTC and identify associated disorders.
Perform prophylactic thyroidectomy in all persons with RET mutations, preferably before age 5
years (Strong recommendation).
Offer genetic testing and counseling to family members of patients with MTC (Weak
recommendation).
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Screen at-risk family members of patients with clinical multiple endocrine neoplasia (MEN) type
MEN 2A, MEN 2B, or familial medullary thyroid cancer but no RET mutation for MTC,
hyperparathyroidism, and pheochromocytoma (Weak recommendation).
Related Summaries
Multiple endocrine neoplasia type 2A or type IIb
Papillary thyroid cancer
Follicular thyroid cancer
Anaplastic thyroid cancer
Metastatic thyroid cancer - American Thyroid Association (ATA) guidelines
General Information
Description
carcinoma of thyroid gland(4, 5)

less common form of thyroid cancer, accounting for 4%-8% of all thyroid cancers
arises from parafollicular C cells (unlike differentiated thyroid cancers, which arise from follicular
cells) and therefore is a neuroendocrine tumor
about 20%-25% due to inherited genetic defect, often as part of multiple endocrine neoplasia type
IIa or IIb syndrome
Also called
medullary carcinoma of thyroid
Definitions
thyroid nodule - discrete lesion in thyroid gland that is radiologically distinct from surrounding normal
thyroid tissue
may be caused by both benign and malignant disease
often discovered on physical exam or incidentally on imaging studies
see Thyroid nodule for additional information
Types
types of thyroid cancer(4, 5)

differentiated thyroid cancer - arises from thyroid follicular cells
papillary thyroid cancer accounts for 80% of thyroid cancer
follicular thyroid cancer accounts for 10%-20% of thyroid cancer
medullary thyroid cancer - neuroendocrine tumor accounting for 4%-8% of thyroid cancer, arises
from parafollicular C cells
anaplastic thyroid cancer - least common and most aggressive form of thyroid cancer, arises de novo
or as progression of differentiated thyroid cancer
types of medullary thyroid cancer(5)
isolated (familial or sporadic)
syndromic (familial)
Epidemiology
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Who is most affected
for sporadic medullary thyroid cancer - adults in fifth or sixth decade of life(3)
for hereditary forms of medullary thyroid cancer - children and adults < 50 years old(3)
Incidence/Prevalence
medullary thyroid cancer incidence

4% of all thyroid cancer in United States(4)
medullary thyroid carcinoma incidence by race and gender in United States
based on analysis of United States National Cancer Institute Surveillance, Epidemiology, and
End Results (SEER) database for 1992-2006
Incidence of Medullary Thyroid Carcinoma per 100,000 Person-Years:
Race Men Women
Non-Hispanic White 0.17 0.22
Black 0.1 0.11
Hispanic 0.18 0.03
Asian 0.1 0.02
American Indian/Alaska
Not calculated Not calculated
Native
Reference - Thyroid 2011 Feb;21(2):125
overall thyroid cancer incidence
thyroid cancer incidence in United States
based on analysis of United States National Cancer Institute Surveillance, Epidemiology, and
End Results (SEER) database
incidence per 100,000 person-years between 1992 and 2006
7.7 overall
11.3 in females
4.1 in males
Reference - Thyroid 2011 Feb;21(2):125
5.5% mean annual increase in incidence between 2002 and 2011 (SEER Fact Sheet accessed
2014 May 9)
estimated 62,980 new cases of thyroid cancer expected in United States in 2014
47,790 in females
15,190 in males
Reference - American Cancer Society Cancer Facts & Figures 2014
overall age-adjusted incidence of thyroid cancer doubled from 1970-72 to 1994-96 in Canada
based on analysis of Canadian Cancer Registry (CCR)
increase from 3.3 to 6.8 per 100,000 in women
increase from 1.1 to 2.2 per 100,000 in men
Reference - Br J Cancer 2001 Nov 2;85(9):1335 full-text
Likely risk factors
risk factors for thyroid malignancy include(1, 2)

age < 14 years or > 70 years
first-degree relative with medullary thyroid carcinoma or multiple endocrine neoplasia (MEN) type
IIa or MEN type IIb
nodular fixation, firmness, or ongoing growth
dysphonia, dysphagia, dyspnea
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Associated conditions
simultaneous medullary and papillary thyroid carcinoma in two case reports (J Med Case Reports 2007
Nov 12;1:133 full-text)
Etiology and Pathogenesis

Causes
20%-25% due to autosomal dominant inheritance of gene mutation(5)

germline activating mutations of RET (rearranged during transfection) proto-oncogene located on
chromosome 10q11.2 cause all of the following
multiple endocrine neoplasia type IIa - syndrome of medullary thyroid cancer,
pheochromocytoma, and hyperparathyroidism
multiple endocrine neoplasia type IIb - syndrome of medullary thyroid cancer,
pheochromocytoma, ganglioneuromatosis of gut and oral mucosa, and Marfanoid habitus
familial medullary thyroid cancer
mutation of NTRK1 (neurotrophic tyrosine kinase receptor type 1) gene located on chromosome
1q21-q22 can also cause familial medullary thyroid cancer (OMIM accessed 2014 May 8)
75%-80% sporadic
without known cause(5)
no associated genetic inheritance pattern, but somatic RET mutation present in up to 80% of tumors,
usually at codon 918 (mutation at codon 634 and other sites also occurs, but less common)(3, 4)
Pathogenesis
pathogenesis in all forms of medullary thyroid cancer(4)

initial process is primary C-cell hyperplasia (secondary C-cell hyperplasia, for example due to
aging, hyperparathyroidism, or chronic lymphocytic thyroiditis, has minimal malignant potential)
C-cell hyperplasia progresses to early invasive microcarcinoma
microcarcinoma progresses to grossly invasive medullary thyroid cancer
in inherited medullary thyroid cancer syndromes, RET (rearranged during transfection) proto-oncogene
normally encodes production of receptor tyrosine kinase, which appears to transduce signals for growth
and differentiation in several developing tissues including those derived from neural crest (see also
Multiple endocrine neoplasia type 2A or Multiple endocrine neoplasia type IIb)
History and Physical

History
Chief concern (CC)
common presentations include(4, 5)

palpable neck mass (thyroid nodule or metastasis to lymph node)
compressive symptoms (due to local tumor extension) such as dysphagia and hoarseness
symptoms of tumor hormone secretion (calcitonin, adrenal cortical releasing hormone) such as
flushing, diarrhea, weight loss, Cushing syndrome
History of present illness (HPI)
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typical age at onset of medullary thyroid cancer(3)

about 55 years for sporadic medullary thyroid cancer
genetic medullary thyroid cancer usually develops earlier
20-30 years in multiple endocrine neoplasia type IIa (MEN) IIa
0-20 years in MEN IIb
40-50 years in familial medullary thyroid cancer
Past medical history (PMH)
ask about history of radiation exposure

environmental exposure(5)
total body irradiation for bone marrow transplantation
head or neck irradiation (AACE/AME/ETA Grade B, Level 2)
Family history (FH)
ask about family history of

multiple endocrine neoplasia type IIa (MEN IIa), MEN IIb, or conditions suggestive of MEN, such
as medullary thyroid cancer, pheochromocytoma, or hyperparathyroidism(5)
thyroid disease and cancer (AACE/AME/ETA Grade B, Level 2)
see also Thyroid nodule
Physical
General physical
may have normal exam if diagnosed by rearranged during transfection (RET) testing
assess for signs of tumor hormone secretion such as weight loss and flushing(5)
findings suggestive of multiple endocrine neoplasia (MEN) type II may include
elevated blood pressure and tachycardia due to pheochromocytoma in MEM type IIa or MEN type
IIb
marfanoid body habitus in MEN type IIb
Skin
cutaneous lichen planus amyloidosis of central upper back may suggest multiple endocrine neoplasia type
IIa
HEENT
findings suggestive of multiple endocrine neoplasia type IIb include

mucosal neuromas (lumps on lips, anterolateral surface of tongue, and conjunctiva)
prominent, thickened corneal nerves on slit lamp exam
Neck
perform examination of the thyroid gland and cervical lymph nodes (AACE/AME/ETA Grade A, Level 3)
(1)
look for
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location, consistency, and size of nodule

fixation of nodule to surrounding tissue
neck tenderness
check for characteristics suggesting malignancy
nodule characteristics
fixed nodule
firm or hard consistency
growing nodule (slow but progressive growth over weeks to months)
cervical lymphadenopathy
see also Thyroid nodule
Chest
pes cavus or pectus excavatum may suggest multiple endocrine neoplasia type IIb
Extremities
proximal muscle weakness may occur in multiple endocrine neoplasia type IIb
Diagnosis
Making the diagnosis
suspect in patient with

palpable or incidentally detected thyroid nodule
known or suspected multiple endocrine neoplasia type IIa (MEN IIa), MEN IIb, or familial
medullary thyroid cancer
diagnosis based on biopsy findings of(3)
malignant parafollicular cells
immunostaining for calcitonin, carcinoembryonic antigen, or chromogranin A
Differential diagnosis
other thyroid nodules/lesions

benign thyroid nodule
thyroid cyst (DynaMed commentary -- bleeding into cyst is common cause of sudden appearance of
nodule)
colloid goiter
multinodular goiter
thyroiditis
Riedel thyroiditis
Hashimoto thyroiditis
postpartum thyroiditis
granulomatous disease
hemorrhagic tumors
other thyroid carcinoma
papillary thyroid carcinoma
follicular thyroid cancer
anaplastic thyroid carcinoma
thyroid adenoma (follicular, Hürthle cell, atypical)
thyroid lymphoma
other causes of cervical lymphadenopathy
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Testing overview
recommendations for evaluation of thyroid nodules based on expert panel reports from American
Association of Clinical Endocrinologists/Associazione Medici Endocrinologi/European Thyroid
Association (AACE/AME/ETA) and American Thyroid Association (ATA)(1, 2)
measure serum thyroid-stimulating hormone (TSH) in all patients with thyroid nodules
(AACE/AME/ETA Grade A, Level 3; ATA Grade A)
if TSH low, perform radionuclide scan (scintigraphy), but avoid use of radioactive agents for
diagnostic purposes in pregnant women
perform thyroid ultrasound if
TSH high or normal
scintigraphy shows hypofunctioning ("cold") or indeterminate lesions (which have 3%-15%
risk of malignancy)
patient has known or suspected thyroid nodule (ATA Grade A)
patient has palpable nodule, multinodular goiter, risk factors for thyroid malignancy, or
lymphadenopathy suggestive of malignancy (AACE/AME/ETA Grade B, Level 3)
perform fine needle aspiration (FNA) biopsy if ultrasound confirms nodule > 1 cm, nodule < 1 cm
in patients with risk for thyroid malignancy, or features suspicious for malignancy (do not perform
FNA biopsy of nodules classified as hyperfunctioning ["hot"] on scintigraphy)
measure serum calcitonin in patients with FNA biopsy findings suggestive of medullary thyroid
cancer (MTC), family history or clinical suspicion of MTC, or multiple endocrine neoplasia type 2
(AACE/AME/ETA Grade A, Level 2)
see Thyroid nodule for details
ATA recommendations for additional testing if FNA biopsy or calcitonin levels diagnostic or suspicious
for MTC, or if MTC diagnosed after hemithyroidectomy(4)
skilled neck ultrasound (ATA Grade A)
serum basal calcitonin, calcium (ionized or albumin-corrected), and carcinoembryonic antigen
(CEA) levels (ATA Grade A)
rearranged during transfection (RET) gene analysis (ATA Grade A)
consider additional imaging if local lymph node metastases detected or serum calcitonin ≥ 400
picograms/mL (ATA Grade C)
Blood tests
thyroid-stimulating hormone (TSH)

check TSH at initial evaluation in all patients with thyroid nodules (AACE/AME/ETA Grade A,
Level 3, ATA Grade A)(1, 2)
if TSH decreased, evaluate for hyperthyroidism(1)
if TSH increased, evaluate for hypothyroidism(1)
serum thyroglobulin not recommended in initial evaluation or diagnosis of thyroid nodules
(AACE/AME/ETA Grade C, Level 3) (ATA Grade F)(1, 2)
serum calcitonin(1, 3, 4)
calcitonin level required for patients with thyroid nodule and family history or clinical suspicion of
medullary thyroid cancer thyroid cancer or multiple endocrine neoplasia type 2 (AACE/AME/ETA
Grade A, Level 2)
most useful biochemical marker for medullary thyroid cancer (may correlate with tumor burden)
normal calcitonin is generally < 10 pg/mL, but reference ranges vary with age and gender
testing recommendations
basal or stimulated serum calcitonin ≥ 100 picograms/mL suspicious for medullary thyroid
carcinoma and requires further evaluation (ATA Grade A)
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basal serum calcitonin > 40 picograms/mL in child > 6 months old may suggest extensive
medullary thyroid carcinoma
interpret results in children < 3 years old with caution due to limited data on normal range
(ATA Grade B)
use sex-specific reference ranges to interpret results in adults (ATA Grade C)
use same assay over time for follow-up (ATA Grade C)
causes of inaccurate calcitonin levels may include(4)
heterophilic antibodies may cause falsely elevated (and rarely falsely lowered) calcitonin
levels
other causes of elevated calcitonin
parafollicular cell hyperplasia
chronic kidney disease
autoimmune thyroiditis
mastocytosis
non-thyroid neuroendocrine neoplasms
widely disseminated disease may cause falsely low calcitonin ("hook effect")
if calcitonin levels are increased, confirm results in the absence of modifiers, including
(AACE/AME/ETA Grade B, Level 3)(1)
alcohol use
smoking
sepsis
heterophilic anti-calcitonin antibodies
other tumor markers(3, 4)
carcinoembryonic antigen (CEA)
may be preferentially expressed in less differentiated tumors
preoperative serum CEA level > 30 ng/mL may suggest spread outside of thyroid
CEA level > 100 ng/mL associated with extensive lymph node involvement and distant
metastasis
chromogranin A elevated in medullary thyroid cancer and used to monitor disease progression
serum calcium level - elevated albumin-corrected or ionized calcium may indicate primary
hyperparathyroidism due to multiple endocrine neoplasia (MEN) type IIa(4) (measure serum intact
parathyroid hormone level if MEN IIa suspected)
if symptomatic, check hormones and other proteins which may be secreted by medullary thyroid tumors(3)
corticotropin
somatostatin
vasoactive intestinal peptide
serotonin
Imaging studies
Ultrasound
thyroid ultrasound indicated for evaluation of thyroid nodules in all patients with(1, 2)
known or suspected thyroid nodules (including nodules found incidentally on other imaging studies)
(ATA Grade A)
palpable thyroid nodules or multinodular goiters (AACE/AME/ETA Grade B, Level 3)
risk for thyroid malignancy (AACE/AME/ETA Grade B, Level 3)
lymphadenopathy suggestive of malignant lesions (AACE/AME/ETA Grade B, Level 3)
ultrasound useful to(1)
detect ultrasound features suggestive of malignancy
select lesions for fine-needle aspiration (FNA) biopsy
look for coincidental thyroid nodules or diffuse thyroid changes
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measure baseline volume of thyroid gland and of lesions that will be treated medically
ultrasound for assessing malignancy risk
nonpalpable nodules detected by ultrasound have similar risk of malignancy as palpable nodules of
same size(2)
nodule ultrasound characteristics associated with malignancy (risk greatly increased if > 1
characteristic present, but no feature has high sensitivity and no feature is 100% predictive of
malignancy)(1, 2)
marked hypoechoic pattern (specificity 41%-92%)
irregular microlobulated margins (specificity 48%-92%)
presence of microcalcifications (specificity 44%-95%)
chaotic vascular spots inside nodule (specificity 80%)
nodule shape taller (anteroposterior) than wide (transverse)
size > 1 cm
other lesion characteristics associated with malignancy
extension beyond thyroid capsule
invasion of the pre-thyroid muscles
infiltration of recurrent laryngeal nerve
preoperative neck ultrasound recommended if fine needle aspiration (FNA) biopsy or calcitonin levels
diagnostic or suspicious for medullary thyroid carcinoma(4)
perform skilled neck ultrasound, including (ATA Grade A)
superior mediastinum
central and bilateral lateral neck compartments
perform additional imaging if local lymph node metastases detected or serum calcitonin ≥ 400
picograms/mL (ATA Grade C)
preoperative neck ultrasound recommended for all patients
Thyroid scintigraphy (radionuclide scanning)
classifies nodules as hot (hyperfunctioning), cold (hypofunctioning), or indeterminate(1)

indicated for(1)
single thyroid nodule with low thyroid-stimulating hormone (TSH) levels
multinodular goiter
even without suppressed TSH, so cold or indeterminate areas can be targeted for fine-needle
biopsy, and hot areas can be found that don't need biopsy
especially if there is substernal extension in large multinodular goiter
consider for patient with normal TSH living in iodine-deficient region to exclude autonomy for a thyroid
nodule or multinodular goiter (AACE/AME/ETA Grade C, Level 3)(1)
do not perform fine needle aspiration (FNA) biopsy of nodules classified as hyperfunctioning ("hot") on
scintigraphy (hyperfunctioning nodules have low risk for malignancy, patient should be evaluated for
hyperthyroidism)
Other imaging
ATA recommendations for imaging (in addition to neck ultrasound) if FNA biopsy or calcitonin levels
diagnostic or suspicious for medullary thyroid carcinoma, and local lymph node metastases detected or
serum calcitonin ≥ 400 picograms/mL (ATA Grade C)(4)
computed tomography (CT) scan of chest and neck
three phase contrast-enhanced multidetector CT scan or contrast-enhanced magnetic resonance
imaging (MRI) of liver
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magnetic resonance imaging (MRI) or computed tomography (CT) scans not recommended for routine
evaluation of thyroid nodules (AACE/AME/ETA Grade D)(1)
positron emission tomography (PET) and/or CT may be useful for detecting lung or bone metastases in
patients at risk for metastatic thyroid cancer(5)
negative result on fluorodeoxyglucose-positron emission tomography (FDG-PET) may help rule out
thyroid cancer in patients with indeterminate fine needle aspiration biopsy of thyroid nodule,
especially in lesions > 15 mm (level 2 [mid-level] evidence)
based on systematic review limited by clinical heterogeneity
systematic review of 6 studies evaluating FDG-PET in 241 patients with indeterminate fine needle
aspiration biopsy of thyroid nodule
definition of positive FDG-PET varied across studies
definition of malignancy varied across studies, and may or may not include papillary
microcarcinomas and malignant lesions located distant from index nodule
reference standard was final histopathological diagnosis in all studies
pooled prevalence of malignancy in thyroid nodule was 26% (range 14%-42%)
pooled performance of FDG-PET for detection of malignancy in thyroid nodule in analysis of 225
patients from 6 studies
sensitivity 95% (95% CI 86%-99%)
specificity 48% (95% CI 40%-56%), results limited by heterogeneity (p < 0.001)
negative likelihood ratio 0.24 (95% CI 0.1-0.59)
positive predictive value was 39% and negative predictive value was 96%, assuming 26%
prevalence of malignancy
in subgroup analysis of 164 lesions > 15 mm in greatest dimension, sensitivity was 100% and
specificity was 47%
Reference - Cancer 2011 Oct 15;117(20):4582 full-text
Biopsy and pathology
Biopsy
fine needle aspiration (FNA) biopsy

expert panels recommend fine-needle aspiration (FNA) biopsy to rule out malignancy in suspicious
lesions(1, 2)
expert panels include American Association of Clinical Endocrinologists/Associazione
Medici Endocrinologi/European Thyroid Association (AACE/AME/ETA) and American
Thyroid Association (ATA)
do not perform FNA if nodules are hot on scintigraphy (AACE/AME/ETA Grade B, Level 3)
indications for FNA
nodule of any size if
abnormal cervical lymph nodes (AACE/AME/ETA Grade B, Level 3; ATA Grade
A)
extracapsular growth on ultrasound (AACE/AME/ETA Grade B, Level 3)
patient has history of neck irradiation in childhood or adolescence
first degree relative with papillary or medullary thyroid carcinoma or multiple
endocrine neoplasia type 2
increased calcitonin levels in the absence of interfering factors (such as alcohol,
smoking, sepsis, heterophilic anti-calcitonin antibodies)
nodule > 5 mm
with suspicious findings on ultrasound in patient with risk factors (ATA Grade A)
insufficient evidence to recommend for or against FNA without suspicious
findings on ultrasound in patient with risk factors (ATA Grade I)
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nodule < 1 cm with findings on ultrasound suggestive of malignancy

(AACE/AME/ETA Grade B, Level 3)
nodule ≥ 1 cm if microcalcifications present (ATA Grade B)
solid nodule > 1 cm
hypoechoic on ultrasound (AACE/AME/ETA Grade B, Level 3; ATA Grade B)
isoechoic or hyperechoic on ultrasound (ATA Grade C)
nodule ≥ 1.5-2 cm, mixed cystic-solid, and suspicious findings on ultrasound (ATA
Grade B)
nodule ≥ 2 cm, mixed cystic-solid, without suspicious findings on ultrasound (ATA
Grade C)
nodule ≥ 2 cm and spongiform (ATA Grade C)
for multinodular thyroid glands or multinodular goiters
preferentially aspirate lesions with suspicious appearance on ultrasound if there
are multiple nodules > 1 cm (ATA Grade B)
if none of the nodules appear suspicious on ultrasound and there are multiple
coalescent nodules that appear similar on ultrasound with no intervening normal
parenchyma present, aspirate largest nodules only and observe others with serial
ultrasound examinations (ATA Grade C)
FNA not indicated if nodule is purely cystic unless FNA is being performed for therapeutic
purposes (ATA Grade E)
ultrasound-guided FNA recommended for(1, 2)
nodules that are not palpable (AACE/AME/ETA Grade A, Level 3; ATA Grade B)
nodules located posteriorly in the thyroid lobe, or predominantly cystic (ATA Grade B)
nodules requiring a repeat FNA due to nondiagnostic cytology results of initial FNA
(ATA Grade A)
sonographically suspicious lymph nodes detected during preoperative staging in
patients having thyroidectomy for malignant cytologic findings on biopsy (if
confirming lymph node malignancy would change management) (ATA Grade B)
efficacy of fine-needle aspiration (FNA) biopsy for detecting thyroid malignancy
FNA may identify 90% of malignant palpable thyroid nodules, but validity of published
data is uncertain (level 2 [mid-level] evidence)
based on systematic review of diagnostic studies with methodologic limitations and
statistical modeling of clinical scenarios
systematic review of 12 diagnostic studies assessing sensitivity of FNA for detecting
thyroid malignancy in palpable thyroid nodules
limited application of reference standard (surgery)
only 8.7% of patients with benign FNA biopsy had surgery
only 1 study had > 25% of patients with negative FNA proceed to surgery
no details of why some patients with negative FNA had surgery and others did not
observed pooled sensitivity about 90% (95% CI 88%-92%)
observed pooled specificity 74% (95% CI 73%-76%)
statistical modeling conducted to estimate risk of malignancy in patients with negative
FNA who did not have surgery
assuming no risk in patients with negative FNA, pooled estimated sensitivity
95%
assuming risk of malignancy in patients with negative FNA was same as in those
with negative FNA who subsequently had surgery, sensitivity 66% (95% CI
65%-68%)
Reference - Ann Surg 2007 Nov;246(5):714, commentary can be found in Ann Surg
2008 Aug;248(2):343 (correction can be found in Ann Surg 2009 Apr;249(4):701)
FNA cytology may detect 56% of medullary thyroid carcinoma lesions (level 2 [mid-
level] evidence)
based on systematic review of diagnostic studies without diagnostic uncertainty
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systematic review of 15 diagnostic studies evaluating FNA cytology for detection of

medullary thyroid carcinoma in 641 histologically confirmed medullary thyroid
carcinoma lesions
FNA cytology had pooled detection rate 56.4% (95% CI 52.6%-60.1%) in analysis of
all studies, results limited by significant heterogeneity
Reference - Clin Endocrinol (Oxf) 2015 Feb;82(2):280
ultrasound-guided core needle biopsy
ultrasound-guided core needle biopsy may give more information in cases where there is a thyroid
neck mass and where FNA cytology had inadequate results (AACE/AME/ETA Grade C, Level 3)(1)
ultrasound-guided core needle biopsy appears to have low sensitivity for malignant lesions of
thyroid gland (level 2 [mid-level] evidence)
based on systematic review of studies with methodologic limitations
systematic review of 16 studies evaluating ultrasound-guided core needle biopsy for detection
of malignant head and neck cancers in 1,267 patients with 1,291 lesions
all studies were level II evidence using Oxford Centre for Evidence-Based Medicine criteria,
no level I studies identified
reference standard was excisional biopsy in all studies
ultrasound-guided core needle biopsy had 68% sensitivity and 100% specificity for detecting
malignancy in pooled analysis of 124 thyroid lesions
Reference - Head Neck 2012 Oct;34(10):1497
Pathology
American Association of Clinical Endocrinologists/Associazione Medici Endocrinologi/European Thyroid

Association classification of cytology from fine-needle aspiration (FNA) biopsy (AACE/AME/ETA Grade
B, Level 3)(1)
benign - negative for malignancy
nondiagnostic - includes inadequate or insufficient cells
follicular lesions
includes all follicular-patterned specimens for which definite cytologic diagnosis of benign or
malignant cannot be made by cytomorphology alone (final diagnosis requires histologic
evaluation), including
adenomatoid hyperplasia
follicular adenoma
follicular neoplasm
Hurthle cell neoplasm
follicular variant of papillary thyroid carcinoma
follicular cytology may also be further subcategorized as follicular lesion/atypia of
undetermined significance, and follicular neoplasm
suspicious - suggests malignancy but does not fulfill the criteria for a definitive diagnosis
malignant (papillary, medullary or anaplastic carcinoma, lymphoma, or metastasis)
findings in medullary thyroid cancer(3)
fine needle aspirate (FNA) cytology
small cells with minimal cytoplasm and abundant stromal amyloid
evidence of calcitonin, chromogranin A, or carcinoembryonic antigen (CEA) on
immunohistochemical staining
gross tumor appearance - whitish-gray, firm to palpation
microscopic appearance
nests of uniform cells with stromal amyloid
parafollicular cell hyperplasia (defined as > 6 parafollicular cells [C-cells] per follicle or > 50
C-cells per low-power field) is precursor lesion
lesions usually unifocal in sporadic medullary thyroid cancer, multifocal and bilateral in
familial medullary thyroid cancer
13/35
cytopathologic and histopathologic evaluations of thyroid nodules appear to have inter- and
intraobserver variability
based on prospective cohort study
776 surgically resected thyroid nodules ≥ 1 cm from 653 patients were assessed for
intraobserver concordance among ≥ 2 central histopathologists who independently read
histopathology slides was calculated
interobserver concordance between diagnoses made by central histopathologists and those
made by local pathologists were calculated
intra- and interobserver concordance for cytopathology was calculated by comparing
diagnoses made by local pathologists with those made by central panel of 3 cytopathologists
concordance on histopathologic distinction between benign and malignant diagnoses was
91% comparing local with central histopathologists
90% comparing 2 central histopathologists
Reference - Ann Intern Med 2013 Sep 3;159(5):325
cytologic and histologic molecular markers
molecular markers such as (BRAF, Ras, RET/PTC, galectin-3) may improve diagnostic accuracy for
patients with indeterminate cytology reports but do not have consistent predictive value for
malignancy and availability limited to specialized centers(1, 2)
use of molecular markers may be considered for patients with indeterminate cytology to help guide
management (ATA Grade C)(2)
for ATA recommendations on perioperative management based on molecular profiling see Thyroid
nodule
gene-expression classifier may help rule out cancer in thyroid nodules with indeterminate
cytology (level 2 [mid-level] evidence)
based on validation cohort study without tests applied to all samples
577 fine-needle aspirates from cytologically indeterminate thyroid nodules > 1 cm were
evaluated using gene-expression classifier
gene-expression classifier consists of 167 genes previously shown to be associated with
benign thyroid nodules
reference standard was blinded histopathological review of specimens from excised lesions
of 328 samples with successful classifier processing
16 samples did not have histological results available
47 samples were excluded for protocol violations
265 samples included in analysis
32% of analyzed nodules were malignant
predictive performance of gene-expression classifier for malignant lesions
sensitivity 92% (95% CI 84%-97%)
specificity 52% (95% CI 44%-59%)
positive predictive value 47% (95% CI 40%-55%)
negative predictive value 93% (95% CI 86%-97%)
Reference - N Engl J Med 2012 Aug 23;367(8):705, editorial can be found in N Engl J Med
2012 Aug 23;367(8):765
DynaMed commentary -- use of this test could help identify low risk patients that do not need
diagnostic hemithyroidectomy, thus avoiding risk of surgery
Other diagnostic testing

genetic testing
American Thyroid Association (ATA) recommendations for rearranged during transfection (RET)
gene analysis(4)
offer germline RET testing to all patients with medullary thyroid carcinoma, primary
calcitonin-producing cell (C-cell) hyperplasia, or multiple endocrine neoplasia type II (MEN
II) (ATA Grade A)
14/35
consider RET testing in patients with intestinal ganglioneuromatosis (ATA Grade B)

initial testing should look for RET mutations in MEN II-specific exons whether single- or
multi-tiered approach to testing is taken (ATA Grade A)
do not use entire RET region sequencing for initial testing (ATA Grade E)
perform analysis of codon M918T on exon 16 and A883F on exon 15 in all patients with
MEN IIb (ATA Grade A)
use entire RET region sequencing when initial exon-specific tests are negative in clinical
setting of MEN II or if discrepancy between genotype and phenotype (ATA Grade B)
codon analysis in asymptomatic carriers of RET proto-oncogene mutation may predict age at
presentation of cancer
based on cohort study
207 asymptomatic patients < 20 years old (from 145 families with RET point mutation in
germ line) who had total thyroidectomy after RET gene confirmation were evaluated
cumulative age-related risk of medullary thyroid carcinoma increased progressively with age,
beginning prior to age 1 year
differences in age at presentation of cancer associated with codon-specific patient groups
Reference - N Engl J Med 2003 Oct 16;349(16):1517 full-text, editorial can be found in N
Engl J Med 2003 Oct 16;349(16):1566, commentary can be found in N Engl J Med 2004 Feb
26;350(9):943, N Engl J Med 2007 Apr 12;356(15):1583
ATA risk stratification(4)
Codon-based Genotype Phenotype Correlation:
ATA Risk Level
ATA Risk Level A ATA Risk Level B ATA Risk Level C
D
768, 790, 791, 804, 609, 611, 618, 620,
Codon 634 918, 883
649, 891 630, 631
MEN II subtype FMTC FMTC/MEN IIa MEN IIa MEN IIb
MTC aggressiveness High Higher Higher Highest
First months of
MTC age of onset Adults 5 years Before age 5 years
life
Abbreviations: ATA, American Thyroid Association; FMTC, familial medullary thyroid
carcinoma; MEN II, multiple endocrine neoplasia type II; MEN IIa, multiple endocrine neoplasia
type IIa; MEN IIb, multiple endocrine neoplasia type IIb; MTC, medullary thyroid carcinoma.
see Multiple endocrine neoplasia type 2A and Multiple endocrine neoplasia type IIb for additional
information
Staging
American Joint Committee on Cancer (AJCC) staging for medullary thyroid cancer, eighth edition
Clinical Staging:
Stage T N M
Stage I T1 N0 M0
Stage II T2-T3 N0 M0
Stage III T1-T3 N1a M0
T1-T3 N1b M0
Stage IVA
T4a Any N M0
Stage IVB T4b Any N M0
Stage IVC Any T Any N M1
definitions of staging abbreviations
primary tumor (T)
TX - primary tumor cannot be assessed
15/35
T0 - no evidence of primary tumor

T1 - tumor ≤ 2 cm in greatest dimension limited to thyroid
T1a - tumor ≤ 1 cm in greatest dimension limited to thyroid
T1b - tumor between > 1 cm and ≤ 2 cm in greatest dimension limited to thyroid
T2 - tumor between > 2 cm and ≤ 4 cm in greatest dimension limited to thyroid
T3 - tumor > 4 cm or with extrathyroidal extension
T3a - tumor ≥ 4 cm in greatest dimesion limited to thyroid
T3b - tumor of any size with gross extrathyroidal extension invading only strap muscles
(sternohyoid, sternothyroid, thyrohyoid or omohyoid muscles)
T4 - advanced disease
T4a - moderately advanced disease; tumor of any size with gross extrathyroidal
extension into nearby tissues of neck, including subcutaneous soft tissue, larynx,
trachea, esophagus, or recurrent laryngeal nerve
T4b - very advanced disease; tumor of any size with extension toward spine or into
nearby large blood vessels, invading prevertebral fascia, or encasing carotid artery or
mediastinal vessels
regional lymph nodes (N)
NX - regional lymph nodes cannot be assesed
N0 - no evidence of locoregional lymph node metastasis
N0a - ≥ 1 cytologically or histologiclly confirmed benign lymph nodes
N0b - no radiologic or clinical evidence of locoregional lymph node metastasis
N1 - metastasis to regional nodes
N1a - metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian,
or upper mediastinal) lymph nodes; can be unilateral or bilateral disease
N1b - metastasis to unilateral, bilateral, or contralateral lateral neck lymph nodes
(levels I, II, III, IV, or V) or retropharyngeal lymph nodes
distant metastasis (M)
M0 - no distant metastasis
M1 - distant metastasis
Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this
information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer
International Publishing.
Management
Management overview
surgery is the main treatment for medullary thyroid cancer (MTC)

thyroidectomy is preferred first-line treatment in most patients with MTC, but recommended
treatments vary by extent of disease
thyroidectomy
American Thyroid Association recommends total thyroidectomy with central neck
dissection for patients without advanced local disease or extensive distant metastases
(ATA Grade B)
National Comprehensive Cancer Network recommends total thyroidectomy for all
patients; bilateral central neck dissection recommended for patients with tumor ≥ 1 cm
or bilateral thyroid disease, and may be considered for patients with tumor < 1 cm and
unilateral thyroid disease
if advanced local disease or distant metastases, consider less aggressive neck surgery to
preserve parathyroid function, speech, and swallowing (ATA Grade C)
if extensive distant metastatic disease, consider palliative neck surgery for pain or tracheal
compromise, but other surgery may be deferred (ATA Grade C)
16/35
before performing surgery for MTC, screen for and (if present) resect pheochromocytoma to avoid
hypertensive crisis (ATA Grade A)
treatment of metastatic, progressive, or unresectable MTC
systemic therapy usually not needed for asymptomatic patients with stable or slowly progressive
small volume metastatic disease; decisions regarding therapy should be made after thorough
discussion with patient (ATA Grade E)
active treatment most often indicated in patients with lesions in critical locations (ATA Grade A),
and may include
tyrosine kinase inhibitors
vandetanib may improve progression-free survival in patients with locally advanced or
metastatic medullary thyroid carcinoma (level 3 [lacking direct] evidence), but
available only through Risk Evaluation and Mitigation Strategy (REMS) program
because of potential cardiac toxicity
cabozantinib may increase progression-free survival in patients with progressive
metastatic medullary thyroid cancer (level 3 [lacking direct] evidence)
surgery for some brain and bone metastases, or for locoregional recurrence in patients with no
distant metastatic disease (ATA Grade B)
external beam radiation therapy for symptomatic or structurally progressive disease not
amenable to surgery (may also be used as adjuvant therapy in patients with increased risk for
locoregional recurrence)
chemotherapy may be considered for selected patients with rapidly progressive disease not
amenable to clinical trials or palliative therapies, but discouraged for routine use in MTC
(ATA Grade E)
radioactive iodine not recommended (ATA Grade E) because MTC cells do not concentrate
RAI
follow-up
after thyroidectomy
provide adequate thyroxine replacement therapy, but thyroid stimulating hormone (TSH)
suppression not needed
oral calcium and vitamin D supplements may reduce risk for symptomatic hypocalcemia after
thyroidectomy (level 2 [mid-level] evidence)
monitor for persistent or recurrent disease with serum calcitonin, carcinoembryonic antigen
(CEA), and imaging as indicated based on clinical and biochemical findings
monitor patients with rearranged during transfection (RET) mutations for pheochromocytoma and
hyperparathyroidism
offer genetic testing and counseling to family members of patients with MTC
screen at-risk family members of patients with clinical MEN II or familial medullary thyroid cancer
but no RET mutation for MTC (with neck ultrasound and serum calcitonin), hyperparathyroidism,
and pheochromocytoma (ATA Grade C)
prophylactic thyroidectomy recommended for all persons with RET mutations, preferably before age 5
years
Medications
American Thyroid Association (ATA) 2009 recommendations(4)

chemotherapy
discourage routine use of chemotherapy for medullary thyroid cancer (MTC) (ATA Grade E),
due to limited efficacy in MTC
do not use standard chemotherapeutic agents as first-line therapy for patients with persistent
or recurrent MTC (ATA Grade D)
chemotherapy may be considered for selected patients with rapidly progressive disease not
amenable to clinical trials or palliative therapies (ATA Grade E)
somatostatin analogs not recommended to control tumor growth (ATA Grade F)
17/35
treatment of MTC-associated symptoms

for diarrhea (ATA Grade C)
antimotility agents - preferred initial therapy
alternative therapies include somatostatin analogs and local debulking therapies
treat cutaneous lichen planus amyloidosis to minimize pruritus (ATA Grade C), options
include
moisturizing lotions and creams
local corticosteroids
systemic antihistamines
capsaicin
phototherapy
medications for metastatic disease
consider vandetanib or cabozantinib if either of (NCCN Evidence category 1)
symptomatic or progressive disease
asymptomatic, not resectable, and structurally progressive disease
decisions regarding therapy should be made after thorough discussion with patient (ATA Grade E)
(see Other management for recommended treatment options)
vandetanib
selective oral rearranged during transfection (RET) tyrosine kinase inhibitor and vascular
endothelial growth factor
FDA approved to treat late-stage (metastatic) medullary thyroid cancer in adults with growing
or symptomatic disease who are ineligible for surgery (FDA Press Release 2011 Apr 7)
available only under restricted distribution program (Risk Evaluation and Mitigation Strategy
[REMS]) due to cardiac toxicity
vandetanib may improve progression-free survival in patients with locally advanced or
metastatic medullary thyroid carcinoma (level 3 [lacking direct] evidence)
based on nonclinical outcome from randomized trial with allocation concealment not
stated
331 patients (mean age 52 years) with locally advanced or metastatic hereditary
medullary thyroid carcinoma randomized to vandetanib 300 mg/day orally vs. placebo
and followed for median 24 months
patients who experienced disease progression were unblinded and could elect
vandetanib treatment
vandetanib associated with improved progression-free survival (hazard ratio 0.46, 95%
CI 0.31-0.69)
comparing vandetanib vs. placebo
objective response in 45% vs. 13% (P < 0.001, NNT 4)
disease control in 87% vs. 71% (P = 0.001, NNT 7)
mortality 13.8% vs. 16% (insufficient data for statistical analysis at median 24
months follow-up)
adverse events including diarrhea, rash, nausea, hypertension, and headache were more
common with vandetanib (no p values reported)
Reference - J Clin Oncol 2012 Jan 10;30(2):134 full-text
vandetanib reported to delay progression of metastatic hereditary medullary thyroid
carcinoma (level 3 [lacking direct] evidence)
based on case series
30 patients with unresectable locally advanced or metastatic hereditary medullary
thyroid carcinoma received initial treatment with vandetanib 300 mg orally once daily
and followed for 10.2 months
22 patients (73%) had disease control (confirmed partial response in 6 patients and
stable disease at ≥ 24 weeks in 16 patients)
adverse events included
diarrhea in 70%
rash in 67%
18/35
fatigue in 63%
nausea in 63%
Reference - J Clin Oncol 2010 Feb 10;28(5):767 full-text
vandetanib reported to induce partial response in children and adolescents with locally
advanced or metastatic hereditary medullary thyroid carcinoma (level 3 [lacking direct]
evidence)
based on case series
16 patients aged 5-18 years with locally advanced or metastatic hereditary medullary
thyroid carcinoma received vandetanib 100 mg/m2 orally once daily in 28-day cycles
for median 27 cycles
vandetanib dose could be increased to 150 mg/m2 daily after 2 cycles if no dose-
limiting toxicity observed
47% had confirmed objective partial response
diarrhea was primary dose-limiting adverse event
Reference - Clin Cancer Res 2013 Aug 1;19(15):4239 full-text
cabozantinib
oral multi-targeted tyrosine kinase inhibitor (inhibits MET, VEGFR2, and RET)
cabozantinib (Cometriq) FDA approved to treat medullary thyroid cancer that has
metastasized (FDA Press Release 2012 Nov 29)
rare adverse effects reported include severe bleeding and gastrointestinal perforation and
fistula formation
cabozantinib may increase progression-free survival in patients with progressive
metastatic medullary thyroid cancer (level 3 [lacking direct] evidence)
based on nonclinical outcome from randomized trial with allocation concealment not
stated
330 patients (median age 55 years) with progressive metastatic medullary thyroid
cancer randomized to cabozantinib 140 mg/day orally vs. placebo until intolerable
toxicity or disease progression
79% had lymph node metastases and 66% had liver metastases, 40% had prior
anticancer therapy
median follow-up 13.9 months
comparing cabozantinib vs. placebo
median progression-free survival (defined as radiographic progression or death)
11.2 months vs. 4 months (p < 0.001)
freedom from progression at 1 year in 47.3% vs. 7.2% (no p value reported)
objective response rate 28% vs. 0% (p < 0.0001)
serious adverse events in 42.1% vs. 22.9% (no p value reported)
mortality 30% vs. 28% (not significant)
no significant difference in overall survival (in interim analysis after 44% of events
required for final analysis)
Reference - J Clin Oncol 2013 Oct 10;31(29):3639, editorial can be found in J Clin
Oncol 2013 Oct 10;31(29):3618
consider enrollment in clinical trials of other small molecule multikinase inhibitors such as
motesanib
sunitinib
sorafenib
Reference - Minerva Endocrinol 2011 Mar;36(1):87
sorafenib associated with partial response or stable disease in about 93% of patients with
medullary thyroid cancer (level 3 [lacking direct] evidence)
based on nonclinical outcome in systematic review without reporting of between-group
comparisons
systematic review of 8 randomized trials or observational studies evaluating sorafenib 400 mg
twice daily in 219 patients with thyroid cancer
52 patients (24%) had medullary thyroid cancer
19/35
partial response in 21.7% (95% CI 0.2%-43.2%)

stable disease in 71.7% (95% CI 49.6%-93.8%)
progressive disease in 6.5% (95% CI 5.3%-7.7%)
Reference - Oncologist 2014 Mar;19(3):251
anti-carcinoembryonic-antigen radioimmunotherapy may improve overall survival in patients
with high-risk metastatic medullary thyroid cancer (MTC) (level 2 [mid-level] evidence)
based on case-control study
29 patients with advanced, progressive MTC received anti-carcinoembryonic antigen/anti-
diethylenetriamine pentaacetic acid-indium bispecific monoclonal antibody, followed 4 days
later by iodine 131 labeled bivalent hapten and compared with 39 matched untreated controls
comparing treated vs. untreated patients
no significant difference in overall survival
median overall survival 110 months vs. 61 months in high-risk patients (defined as
calcitonin doubling time < 2 years) (p < 0.03)
Reference - J Clin Oncol 2006 Apr 10;24(11):1705, editorial can be found in J Clin Oncol
2006 Apr 10;24(11):1653, commentary can be found in J Clin Oncol 2006 Jul 10;24(20):e37
no randomized trials identified evaluating angiogenesis-inhibitors for metastatic thyroid
cancer
based on Cochrane review
Reference - Cochrane Database Syst Rev 2010 Mar 17;(3):CD007958
medications following thyroidectomy
thyroxine(4)
give thyroxine replacement, adjusted to keep thyroid stimulating hormone levels 0.5-2.5
milliunits/L (ATA Grade B)
unlike in differentiated thyroid cancers, thyroid stimulating hormone (TSH) suppression not
needed because MTC is a C-cell tumor, and C-cells are not TSH-dependent
calcium plus vitamin D associated with decreased risk of symptomatic hypocalcemia after
thyroidectomy (level 2 [mid-level] evidence)
based on systematic review of trials with methodologic limitations
systematic review of 9 trials evaluating supplementation with calcium and/or vitamin D in
2,285 patients (mean age 50 years) after thyroidectomy
all trials had ≥ 1 methodologic limitation including
unclear allocation concealment or method of randomization
unclear blinding
small trial size
26.1% had post-thyroidectomy hypocalcemia (definition of hypocalcemia varied between
trials)
compared to no intervention
calcium plus vitamin D associated with reduced risk of symptomatic hypocalcemia in
analysis of 5 trials with 1,084 patients
odds ratio 0.37 (95% CI 0.2-0.67)
NNT 6-15 with symptomatic hypocalcemia in 26% of controls
calcium alone associated with nonsignificant reduction in symptomatic hypocalcemia
(odds ratio 0.51, 95% CI 0.24-1.11) in analysis of 3 trials with 748 patients, results
limited by heterogeneity
no significant differences comparing calcium plus vitamin D to calcium alone in analysis of 4
trials with 687 patients, results limited by heterogeneity
recommendations provided in this systematic review
postoperative oral calcium ≥ 3 g/day should be routinely given to all patients for 2
weeks following thyroid surgery
patients at increased risk of postoperative hypocalcemia should also be treated with
calcitriol 1 mcg/day
Reference - Oncologist 2013;18(5):533 full-text
20/35
teriparatide may reduce rate of hypocalcemia and length of hospital stay in patients at high
risk of hypocalcemia after thyroidectomy (level 2 [mid-level] evidence)
based on small randomized trial without placebo control group
26 patients (mean age 53 years) with intact parathyroid hormone < 10 pg/mL at 4 hours after
thyroidectomy were randomized to teriparatide 20 mcg subcutaneously every 12 hours until
discharge vs. standard clinical care (control)
all patients were prescribed calcium and calcitriol supplements at discharge
comparing teriparatide vs. control
hypocalcemia in 23.1% vs. 84.6% (p = 0.006, NNT 2)
median length of hospital stay 2 days vs. 3 days (p = 0.012)
mean calcium supplementation after 1 month 308 mg/day vs. 1083 mg/day (p = 0.04)
calcium carbonate supplementation discontinued after 1 month in 76.98% vs. 38.4%
(no p value reported)
no serious adverse events reported
Reference - THYPOS trial (J Clin Endocrinol Metab 2016 Nov;101(11):4039)
radioactive iodine
postoperative radioactive iodine not recommended (ATA Grade E)(4) (because it is not
concentrated in MTC)
addition of radioactive iodine to total thyroidectomy does not appear to improve
survival in patients with medullary thyroid cancer (level 2 [mid-level] evidence)
based on retrospective cohort study
293 medullary thyroid cancer patients without distant metastases who had total
thyroidectomy were included
61 patients (23%) also treated with radioactive iodine (RAI)
follow-up duration ranged 7-372 months
disease-specific mortality 9% overall (27 patients)
addition of RAI not associated with improved disease-free survival or disease-specific
survival in multivariate analysis
Reference - Eur J Endocrinol 2013;168(5):779
Surgery and procedures
Thyroidectomy
American Thyroid Association (ATA) 2009 recommendations for patients with known or highly suspected
medullary thyroid carcinoma (MTC)(4)
if present, resect pheochromocytoma before performing surgery for MTC (to avoid hypertensive
crisis) (ATA Grade A)
total thyroidectomy recommended (ATA Grade B)
if no advanced local invasion of primary tumor, no physical or ultrasound evidence of lymph
node metastases, and no evidence of distant metastases - prophylactic central compartment
(level VI) neck dissection
if suspected limited local metastatic disease to regional lymph nodes in central compartment,
no evidence of lateral compartment disease, and no or limited distant metastasis - level VI
compartmental dissection
if suspected limited local metastatic disease to regional lymph nodes in central and lateral
compartments, and no or limited distant metastases - central and lateral (levels II-V) neck
dissection
consider less aggressive neck surgery in patients with advanced local disease or distant metastases
(ATA Grade C)
National Comprehensive Cancer Network recommends total thyroidectomy for patients with MTC
bilateral central neck dissection recommended for patients with tumor > 1 cm or bilateral thyroid
disease
21/35
neck dissection may be considered for patients with tumor < 1 cm and unilateral thyroid disease
Reference - NCCN 2014 Feb from NCCN website (free registration required)
ATA recommends prophylactic total thyroidectomy for all persons with RET (rearranged during
transfection) mutations(4)
complications associated with thyroidectomy and/or neck dissection may include
hypocalcemia (transient or permanent)
recurrent or superior laryngeal nerve injury (transient or permanent)
postoperative bleeding
complications related to general anaesthesia
Reference - Endocr Pract 2011 May-Jun;17(3):456
considerations during thyroid surgery

patients with thyroid disorders have increased risk for anesthesia-related complications which may
affect surgical procedures and postoperative recovery
both general and locoregional anesthesia can be used for thyroidectomy, and there is limited
evidence to support the use of any anesthetic technique over another
perioperative use of antiemetics (such as dexamethasone 8-10 mg IV) help prevent postoperative
nausea and vomiting
intraoperative nerve monitoring with a dual-channel electromyographic endotracheal tube can be
used during thyroid surgery to monitor the laryngeal nerves
despite lack of definitive evidence that laryngeal nerve monitoring prevents nerve injuries, it
may be useful for patients having outpatient thyroidectomy
may help identify recurrent laryngeal nerve complications, but does not appear to prevent
vocal cord injury except potentially in high-risk patients having surgery for cancer
hemostasis
use of LigaSure vessel-sealing device for thyroidectomy may reduce operation time compared
to conventional ligation (level 2 [mid-level] evidence)
harmonic scalpel for hemostasis associated with decreased operation time and blood loss
compared with other hemostatic techniques in patients having thyroid surgery (level 2 [mid-
level] evidence)
using drains in patients having thyroid surgery does not appear to improve outcomes and may
increase length of hospital stay (level 2 [mid-level] evidence)
transoral thyroidectomy is a minimally invasive approach to the thyroid gland that avoids the
physical and psychological effects of postoperative scarring
video-assisted thyroidectomy may reduce risk of early postthyroidectomy voice and swallowing
symptoms (level 2 [mid-level] evidence)
see Thyroid surgery considerations for details
Other surgery and procedures
neck surgery in patients with medullary thyroid cancer (MTC) and advanced local disease or distant
metastases (ATA Grade C)(4)
consider less aggressive neck surgery (than thyroidectomy and with neck dissection) to preserve
parathyroid function, speech, and swallowing in patients with advanced local disease or distant
metastases
perform palliative neck surgery for pain or tracheal compromise in patients with extensive distant
metastatic disease, but otherwise surgery may be deferred
consider surgical resection of isolated or limited brain metastases (ATA Grade C)(4)
alternatives to antimotility agents and somatostatin analogs for treating MTC-associated diarrhea include
(ATA Grade C)(4)
debulking surgery for large tumor deposits
selective artery chemoembolization for large hepatic metastases
surgery for metastatic, progressive, or recurrent disease(4)
22/35
consider re-operative compartmental dissection of image- or biopsy-positive compartments or

observation only in patients with small (< 1 cm), nonthreatening locoregional lymph node
metastases with no distant metastases (ATA Grade C)
consider locoregional surgery for symptomatic and/or progressive locoregional disease > 1 cm (ATA
Grade B)
Radiation therapy
external beam radiation therapy (EBRT)
do not substitute for surgery if neck tumor foci can be resected without excessive morbidity (ATA
Grade E)
postoperative EBRT to neck and mediastinum
may be indicated in patients with gross incomplete resection (ATA Grade B)
consider in patients with (ATA Grade C)
microscopic positive margin(s) with moderate to high volume disease involving central
compartment and ≥ 1 lateral compartment disease or extra-nodal soft-tissue tumor
extension
negative margins with moderate to high volume disease, extra-nodal soft-tissue tumor
extension, and persistently elevated serum calcitonin in absence of distant metastases
do not use to treat persistently elevated serum calcitonin in absence of gross or microscopic
positive margin, or moderate to high volume neck disease with extra-nodal soft tissue
extension (ATA Grade E)
may be indicated for brain or bone metastases not amenable to surgery (ATA Grade C)
Other management
metastatic disease
National Comprehensive Cancer Network (NCCN) recommendations
if asymptomatic disease, consider
resection (if possible) or ablation (NCCN Evidence category 2a)
vandetanib or cabozantinib if not resectable and structurally progressive disease
(NCCN Evidence category 1)
observation (NCCN Evidence category 2a)
if symptomatic or progressive disease, provide best supportive care and consider
vandetanib (NCCN Evidence category 1)
cabozantinib (NCCN Evidence category 1)
other small molecular tyrosine kinase inhibitor (NCCN Evidence category 2a)
dacarbazine-based chemotherapy (NCCN Evidence category 2a)
external beam radiation therapy for focal symptoms (NCCN Evidence category 2a)
bisphosphonates or denosumab for bone metastases (NCCN Evidence category 2a)
palliative resection, abalation, or other regional treatment (NCCN Evidence category
2a)
Reference - NCCN 2014 Feb from NCCN website (free registration required)
American Thyroid Association (ATA) recommendations
systemic therapy usually not needed for asymptomatic patients with stable or slowly
progressive small volume metastatic disease; decisions regarding therapy should be made
after thorough discussion with patient (ATA Grade E)
active treatment (surgery, or alternatively, external beam radiation therapy [EBRT]) most
often indicated in patients with lesions in critical locations (ATA Grade A)
for isolated or limited brain metastases, consider surgical resection (or if not possible,
consider external beam radiation therapy [EBRT]) (ATA Grade C)
for impending or active central nervous system compression urgent treatment includes
glucocorticoid therapy and surgical evaluation (ATA Grade C)
23/35
for impending or active fracture of weight-bearing bone, surgery recommended (ATA

Grade C)
for bone metastases that are painful or clinically significant but not suitable for surgery,
consider EBRT (ATA Grade C)
for symptomatic lesions, consider palliative therapy including surgery (ATA Grade C)
monitor closely for Cushing syndrome and consider treatment (especially bilateral
adrenalectomy) even in setting of widely metastatic medullary thyroid cancer (ATA Grade C)
give high priority to helping patients enroll in well-designed clinical trials (ATA Grade C)
see Metastatic thyroid cancer - American Thyroid Association (ATA) guidelines for details
Consultation and referral
genetic counseling(4)
offer genetic counseling before and after RET (rearranged during transfection) gene testing (ATA
Grade C)
counsel family members who may be affected (ATA Grade C)
notify patient or guardian of risks posed to family members including seriousness of disease,
and forms of treatment and prevention
recommend that patients inform potentially affected family members
offer genetic counseling and testing for family members
involve medical ethics committee of legal system if patient refuses to inform relatives or test
dependents
offer counseling about options of prenatal or preimplantation testing to patients of childbearing age
with RET gene mutation (ATA Grade C)
Follow-up
screen for conditions associated with medullary thyroid cancer(4)

Recommendations for Codon-Based Screening for Patients with MTC:
ATA Risk
ATA Risk Level A ATA Risk Level B ATA Risk Level C
Level D
768, 790, 791, 804 609, 611, 618, 620,
Codons 634 918, 883
649, 891 630, 631
Start at age 20 Start at age 20 Start at age 8 years, Start at age 8
Screening for Pheo
years, periodically years, annually annually years, annually
Start at age 20 Start at age 20 Start at age 8 years,
Screening for HPT NA
years, periodically years, periodically annually
Abbreviations: ATA, American Thyroid Association; HPT, primary hyperparathyroidism; MTC,
medullary thyroid carcinoma; NA, not applicable; Pheo, pheochromocytoma. Reference - Fam
Cancer 2010 Sep;9(3):449
recommended screening tests
for pheochromocytoma - fractionated plasma free metanephrines and normetanephrines, 24-
hour urine metanephrines and normetanephrines, or adrenal imaging (computed tomography
or magnetic resonance imaging)
for hyperparathyroidism - albumin-corrected or ionized calcium
American Thyroid Association 2009 recommendations for post-thyroidectomy care(4)
measure serum calcitonin and carcinoembryonic antigen (CEA) 2-3 months postoperatively (ATA
Grade B)
follow-up based on postoperative calcitonin
if calcitonin undetectable (ATA Grade E)
24/35
begin long-term follow-up with basal calcitonin and physical exam every 6-12 months,
then annually
imaging not required, but consider neck ultrasound to establish baseline
if calcitonin detectable
but < 150 picograms/mL
obtain neck ultrasound (ATA Grade B)
consider additional imaging to establish baseline (ATA Grade C)
and > 150 picograms/mL
obtain neck ultrasound (ATA Grade B)
perform additional imaging to evaluate for distant metastases (ATA Grade B),
including
chest computed tomography (CT)
neck CT
3-phase contrast-enhanced multidetector liver CT or contrast-enhanced
magnetic resonance imaging (MRI)
bone MRI of spine and pelvis
bone scan
if imaging positive
for small (< 1 cm), nonthreatening locoregional lymph node metastases
(ATA Grade C)
with no distant metastases - observe only or perform preoperative
compartmental dissection of image- or biopsy-positive
compartments
with distant metastases - observe only
for symptomatic and/or progressive locoregional disease > 1 cm - consider
locoregional surgery (ATA Grade B)
for symptomatic distant metastases - consider clinical trials and palliative
therapies such as surgery, external beam radiation, percutaneous
interventions, and hepatic embolization (ATA Grade B)
if imaging negative
check basal calcitonin and CEA levels every 6 months to determine doubling
times (ATA Grade B)
repeat basal calcitonin and CEA, plus physical exam at one fourth shortest
doubling time or annually (whichever is shorter) (ATA Grade B)
if CEA rises substantially or calcitonin increases by 20%-100%, obtain neck
ultrasound (ATA Grade C)
if calcitonin > 150 picograms/mL, repeat systemic imaging in addition to neck
ultrasound (ATA Grade C)
additional considerations in patients diagnosed with MTC after hemithyroidectomy (ATA Grade B)
offer additional testing and therapy (including completion thyroidectomy and central lymph
node dissection) if any of
histology shows multicentric tumor, parafollicular cells (C-cell) hyperplasia, extra-
thyroidal extension
positive surgical margin
neck ultrasound suspicious for persistent local disease in contralateral thyroid lobe, or
central or lateral neck compartments
positive RET mutation
family history positive for multiple endocrine neoplasia type II
unifocal intrathyroidal sporadic MTC, no C-cell hyperplasia, negative surgical margin,
and no suspicious neck ultrasound findings with basal calcitonin above reference range
if unifocal intrathyroidal sporadic MTC, no C-cell hyperplasia, negative surgical margin, no
suspicious neck ultrasound findings, and basal calcitonin below upper normal of reference
range > 2 months after surgery, consider additional surgery or follow-up without additional
surgery (ATA Grade B)
25/35
longterm monitoring
in patients with MTC who achieve complete biochemical cure
maintain long-term biochemical monitoring for patients with MTC who achieve
complete biochemical cure (ATA Grade B) including
measure serum calcitonin annually (ATA Grade C)
in patients with persistent MTC or detectable calcitonin postoperatively
monitor with calcitonin and CEA levels, history, and physical exam (ATA Grade C)
frequency of follow-up imaging may depend on relative stability of calcitonin and
CEA, presence or absence of symptoms, and location of known or likely sites of
metastases (ATA Grade C)
stimulated serum calcitonin testing not recommended (ATA Grade D)
after prophylactic thyroidectomy
if no evidence of MTC by testing postoperatively, risk of developing MTC is low and
optimal follow-up uncertain
consider measuring basal serum calcitonin annually (without measuring CEA), and less
frequent testing if no evidence of disease after prolonged follow-up (ATA Grade C)
give adequate thyroxine replacement, adjusted to keep thyroid stimulating hormone levels 0.5-2.5
milliunits/L (ATA Grade B)(4)
Complications and Prognosis

Complications
local extension and compression of neck structures (including respiratory obstruction)(4)

complications from distant metastases (lymph nodes, lung, liver, bone) may include(4)
bronchial obstruction
fracture
spinal cord compression
Cushing syndrome (from tumor secretion of adrenal cortical releasing hormone)
complications associated with thyroidectomy and/or neck dissection may include
hypocalcemia (transient or permanent)
recurrent or superior laryngeal nerve injury (transient or permanent)
postoperative bleeding
complications related to general anaesthesia
Reference - Endocr Pract 2011 May-Jun;17(3):456
Prognosis
10-year survival rates for medullary thyroid cancer (MTC)(4)

Stage I – 100%
Stage II – 93%
Stage III – 71%
Stage IV – 21%
10-year disease-specific survival for MTC about 75%(4)
indicators of worse prognosis include
advanced age(4)
advanced disease stage(4)
associated multiple endocrine neoplasia type IIb(4)
serum and tumor markers
calcitonin doubling time < 2 years
carcinoembryonic antigen doubling time < 2 years
26/35
somatic mutation in RET (rearranged during transfection) oncogene

tumor Cdc25B phosphatase
tumor Ki-67 expression
Reference - Cancer 2010 Feb 15;116(4 Suppl):1118 full-text
decreased and heterogeneous calcitonin immunostaining of tumor (J Clin Endocrinol Metab
1982 Feb;54(2):233)
signs that may indicate tumor dedifferentiation(3, 4)
increasing carcinoembryonic antigen level with stable or decreasing calcitonin
lack of elevation of both carcinoembryonic antigen and calcitonin
postoperative elevated calcitonin levels(3)
mutations in BRAF, RAS, and RET genes each associated with decreased disease-specific survival in
patients with thyroid cancer
based on systematic review without assessment of study quality
systematic review of 25 observational studies evaluating association between genetic mutations and
survival in 5,854 patients with thyroid cancer
14 studies assessed BRAF mutations, 6 studies assessed RAS mutations, 4 studies assessed
RET mutations, and 1 study assessed BRAF and RAS mutations
studies included patients with papillary, anaplastic, medullary, follicular, or poorly
differentiated thyroid cancer
compared to no mutation, decreased disease-specific survival associated with
BRAF mutations (hazard ratio [HR] for death 2.66, 95% CI 1.34-5.27) in analysis of 4 studies
with 2,801 patients
RAS mutations (HR for death 2.9, 95% CI 1.66-5.07) in analysis of 3 studies with 294 patients
RET mutations (HR for death 5.82, 95% CI 2.53-13.38) in analysis of 3 studies with 300
patients
Reference - Thyroid 2015 Jan;25(1):63
older age and higher tumor stage at diagnosis each associated with decreased survival in patients
with medullary thyroid carcinoma
104 patients with medullary thyroid carcinoma or C-cell hyperplasia (mean age at diagnosis 38
years) were followed for mean 8.6 years
estimated cause-specific mortality 10.7% at 5 years, 13.5% at 10 years
mortality independently associated with
higher tumor stage at presentation (p = 0.0013)
age ≥ 45 years at diagnosis (p = 0.027)
in multivariate analysis, mortality not significantly associated with type of medullary thyroid cancer
(sporadic vs. hereditary), extent of thyroidectomy, or gender
Reference - Cancer 2000 Mar 1;88(5):1139
elevated postoperative calcitonin levels associated with increased risk of disease progression in
patients with small medullary thyroid carcinomas
128 patients (mean age 41 years) who had surgery for small medullary thyroid carcinomas (≤ 1.5
cm) were evaluated
calcitonin levels measured at baseline and postoperatively at 3 and 6 months, then yearly after first
surgery
median follow-up 4 years, 25% had follow-up ≥ 10 years
postoperative calcitonin levels ≥ 14.5 pg/mL significantly associated with increased 10-year risk of
disease progression
no significant difference among other tumor size groups
Reference - Eur J Endocrinol 2014 Jul;171(1):117
27/35
Prevention and Screening

Prevention
prophylactic thyroidectomy to prevent medullary thyroid cancer (MTC)

ATA recommends prophylactic total thyroidectomy for all persons with RET (rearranged during
transfection) mutations, with timing based on genotype-specific risk for aggressive MTC(4)
in all patients
perform surgery in experienced tertiary care setting
include level IV compartmental dissection if clinical lymph node metastases, plus
lateral compartmental dissection if biopsy- or imaging-positive lymph nodes identified
prioritize preservation of parathyroid function
in patients with multiple endocrine neoplasia type IIa (MEN IIa) or familial medullary thyroid
cancer (FMTC)
perform prophylactic thyroidectomy before age 5 years in children with codon 634 RET
mutation (ATA Grade A)
in patients with Level A and B MTC risk, prophylactic thyroidectomy may be delayed
beyond age 5 years if all of (ATA Grade B)
normal annual basal and/or stimulated serum calcitonin levels
normal annual neck ultrasound
less aggressive MTC family history
family preference
in patients with Level B MTC risk, consider prophylactic thyroidectomy before age 5
years even if above criteria met (ATA Grade B)
resected or devascularized parathyroid glands should be autografted in neck in patients
with FMTC, and to heterotopic site in patients with MEN IIa
in patients with multiple endocrine neoplasia type IIb (MEN IIb)
for infants < 1 year old
perform prophylactic total thyroidectomy as soon as possible after diagnosis and
during first year of life (ATA Grade B)
prophylactic level VI central compartment neck dissection may not be necessary
in infants with no evidence of extensive disease (ATA Grade E)
for patients > 1 year old
perform prophylactic total thyroidectomy (ATA Grade A)
perform prophylactic central neck dissection without lateral compartment neck
dissection, except in setting of metastasis to these regions (ATA Grade C)
autograft normal parathyroid glands devascularized during surgery into
sternocleidomastoid muscle (ATA Grade C)
ATA Recommendations for Codon-based Timing of Prophylactic Thyroidectomy in Patients
with Multiple Endocrine Neoplasia Type II or Familial Medullary Thyroid Cancer:
ATA Risk Level ATA Risk Level ATA Risk Level ATA Risk Level
A B C D*
768, 790, 791, 609, 611, 618,
Codons 634 918, 883
804, 649, 891 620, 630, 631
When calcitonin
Before age 5 In first year of
Surgery rises or age 5 or At age 5 years
years life
10 years
Abbreviation: ATA, American Thyroid Association. * Multiple endocrine neoplasia type IIb
risk level.
efficacy of prophylactic thyroidectomy in children with MEN IIa
total thyroidectomy at age ≤ 5 years (especially if c634 mutation) may be associated with
decreased recurrence or persistence of MTC (level 2 [mid-level] evidence)
28/35
total thyroidectomy at age < 8 years reported to eliminate persistent or recurrent MTC (level 3
[lacking direct] evidence)
see Multiple endocrine neoplasia type 2A for additional information
Screening
indications for rearranged during transfection (RET) testing(4)

offer RET testing to all people with family history consistent with multiple endocrine neoplasia
(MEN) type II or familial medullary thyroid cancer (FMTC), and at risk for autosomal dominant
inheritance (ATA Grade A)
for MEN IIb, perform testing shortly after birth
for MEN IIa and FMTC, perform testing before age 5 years
Hirschsprung disease (ATA Grade A) (due to association with MEN IIb)
lichen planus amyloidosis (also called cutaneous lichen amyloidosis) or pruritus in central upper
back (ATA Grade C)
screen for medullary thyroid cancer (MTC), and conditions associated with MTC, in at-risk family
members of patients with clinical MEN IIa, MEN IIb, or FMTC but no RET mutation found during entire
gene sequencing (ATA Grade C)(4)
screen every 1-3 years until age 50 years, or 20 years beyond oldest age of diagnosis in family
(whichever is later)
recommended screening tests
for MTC - neck ultrasound and serum calcitonin
for hyperparathyroidism - albumin-corrected or ionized calcium
for pheochromocytoma - plasma free metanephrines and normetanephrines, or 24-hour urine
metanephrines and normetanephrines
in patients with MEN IIa or MEN IIb without MTC, screen for pheochromocytoma and
hyperparathyroidism using same codon-based follow-up surveillance protocol used for patients with MTC
Guidelines and Resources

Guidelines
United States guidelines
National Comprehensive Cancer Network (NCCN) guideline on evaluation and management of medullary
carcinoma can be found at NCCN website (free registration required)
American Thyroid Association (ATA)
ATA revised guideline on management of medullary thyroid carcinoma can be found in Thyroid
2015 Jun;25(6):567 full-text, commentary can be found in Thyroid 2015 Aug;25(8):973, previous
version can be found in Thyroid 2009 Jun;19(6):565
ATA management guideline on medullary thyroid cancer can be found in Thyroid 2009
Jun;19(6):565
ATA critical review on management of recurrent/persistent nodal disease in patients with thyroid
cancer: risks and benefits of surgical intervention versus active surveillance can be found in Thyroid
2015 Jan;25(1):15
ATA statement on preoperative imaging for thyroid cancer surgery can be found in Thyroid 2015
Jan;25(1):3
American Thyroid Association (ATA) statement on surgical application of molecular profiling for
thyroid nodules: current impact on perioperative decision-making can be found in Thyroid 2015
Jul;25(7):760
29/35
American College of Radiology (ACR) Appropriateness Criteria for thyroid carcinoma can be found at
ACR 2013 PDF
American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) clinical practice guideline
on improving voice outcomes after thyroid surgery can be found in Otolaryngol Head Neck Surg 2013
Jun;148(6 Suppl):S1
expert guideline on regional approaches to management of patients with advanced, radioactive iodine-
refractory differentiated thyroid carcinoma can be found in Expert Rev Anticancer Ther 2012
Sep;12(9):1137
United Kingdom guidelines
British Thyroid Association (BTA) guideline on management of thyroid cancer can be found at BTA 2014
Jul PDF
Canadian guidelines
Alberta Health Services (AHS) clinical practice guideline on targeted therapy for locally advanced
unresectable or metastatic medullary thyroid carcinoma can be found at AHS 2012 Nov PDF or at
National Guideline Clearinghouse 2014 Nov 10:48136
Cancer Care Ontario (CCO) evidence-based guideline on radionuclide therapy for neuroendocrine
malignancies can be found at CCO 2011 Aug 15 PDF
European guidelines
Croatian Society for Clinical Cytology (Hrvatsko Društvo za Kliničku Citologiju) guideline on thyroid
cytology can be found in Lijec Vjesn 2012 Jul-Aug;134(7-8):203 [Croatian]
French Society of Otolaryngology and Surgery of the Face and Neck (Société Française d’Oto-Rhino-
Laryngologie et de Chirurgie de la Face et du Cou [SFORL]) practice guidelines on lymph-node
management in adult differentiated thyroid carcinoma can be found in Eur Ann Otorhinolaryngol Head
Neck Dis 2012 Aug;129(4):197
French Endocrinology Society (Société Française d’Endocrinologie [SFE]) guideline on cervical

ultrasound scan and echo-guided techniques in treating differentiated thyroid cancer of vesicular origin
can be found in Ann Endocrinol (Paris) 2011 Jun;72(3):173
Review articles
review can be found in J Surg Oncol 2006 Dec 15;94(8):737

review of management can be found in Minerva Endocrinol 2011 Mar;36(1):87
review of management can be found in Curr Treat Options Oncol 2005 Jul;6(4):347
review of treatment of thyroid cancer can be found in J Thyroid Res 2010 Apr 13;2010:279468 full-text
review of multiple endocrine neoplasia type II can be found in Fam Cancer. 2010 Sep;9(3):449-57
evidence-based approach to management of sporadic medullary thyroid carcinoma can be found in World
J Surg 2007 May;31(5):946
review of management of lymph node metastases in medullary thyroid cancer can be found in J Natl
Compr Canc Netw. 2010 May;8(5):549
review of surgery for lymph node metastases of medullary thyroid carcinoma can be found in Cancer 2016
Feb 1;122(3):358
30/35
review of treatment of lateral neck in sporadic medullary thyroid cancer can be found in Laryngoscope
2010 Jul;120(7):1286
case presentation of medullary thyroid carcinoma with metastases to cervical lymph nodes and liver can
be found in N Engl J Med 2013 Feb 14;368(7):664
MEDLINE search
to search MEDLINE for (Medullary thyroid carcinoma) with targeted search (Clinical Queries), click
therapy, diagnosis, or prognosis
Patient Information
handout on thyroid cancer from American Cancer Society or in Spanish
handout on thyroid cancer from Patient UK
handout on thyroid cancer from Cleveland Clinic
information on thyroid cancer from MacMillan Cancer Support
handout on multiple endocrine neoplasia (MEN) II from MacMillan Cancer Support
handout on thyroid cancer from EBSCO Health Library PDF
ICD Codes
ICD-10 codes
C73 malignant neoplasm of thyroid gland
References
General references used
1. Gharib H, Papini E, Paschke R, et al; AACE/AME/ETA Task Force on Thyroid Nodules. American
Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid
Association Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid
Nodules. Endocr Pract. 2010 May-Jun;16 Suppl 1:1-43 PDF or in J Endocrinol Invest 2010
May;33(5):287
2. Cooper DS, Doherty GM, Haugen BR, et al; American Thyroid Association (ATA) Guidelines
Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. Revised American Thyroid Association
management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009
Nov;19(11):1167-214 full-text, correction can be found in Thyroid 2010 Jun;20(6):674, Thyroid 2010
Aug;20(8):942
3. Chen H, Sippel RS, O'Dorisio MS, Vinik AI, Lloyd RV, Pacak K, North American Neuroendocrine
Tumor Society (NANETS). The North American Neuroendocrine Tumor Society consensus guideline for
the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and
medullary thyroid cancer. Pancreas. 2010 Aug;39(6):775-83 full-text
4. American Thyroid Association Guidelines Task Force; Kloos RT, Eng C, Evans DB, et al. Medullary
thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009
Jun;19(6):565-612
5. Schneider DF, Chen H. New developments in the diagnosis and treatment of thyroid cancer. CA Cancer
J Clin. 2013 Nov-Dec;63(6):374-94
Recommendation grading systems used

31/35
National Comprehensive Cancer Network (NCCN) categories of evidence and consensus

Category 1 - based on high-level evidence, there is uniform NCCN consensus that the intervention
is appropriate
Category 2A - based on lower-level evidence, there is uniform NCCN consensus that the
intervention is appropriate
Category 2B - based on lower-level evidence, there is NCCN consensus that the intervention is
appropriate
Category 3 - based on any level of evidence, there is major NCCN disagreement that the
intervention is appropriate
Reference - NCCN Categories of Evidence and Consensus
American Thyroid Association (ATA) grading system adapted from the United States Preventive Services
Task Force Agency for Healthcare Research and Quality
strength of recommendations
Grade A - strongly recommended based on good evidence that the service or intervention can
improve important health outcomes; evidence includes consistent results from well-designed,
well-conducted studies in representative populations that directly assess effects on health
outcomes
Grade B - recommended based on fair evidence that the service or intervention can improve
important health outcomes; evidence sufficient to determine effects on health outcomes, but
strength of the evidence is limited
Grade C - recommended based on expert opinion
Grade D - recommend against based on expert opinion
Grade E - recommend against based on fair evidence that the service or intervention does not
improve important health outcomes or that harms outweigh benefits
Grade F - strongly recommend against based on good evidence that the service or intervention
does not improve important health outcomes or that harms outweigh benefits
Grade I - recommends neither for nor against because evidence is lacking that the service or
intervention improves important health outcomes, the evidence is of poor quality, or the
evidence is conflicting; balance of benefits and harms cannot be determined
Reference - ATA guideline on management of medullary thyroid cancer (Thyroid 2009
Jun;19(6):565), correction can be found in Thyroid 2009 Nov;19(11):1295, commentary can be
found in Thyroid 2009 Jun;19(6):543, Thyroid 2010 Feb;20(2):233
American Association of Clinical Endocrinologists/Associazione Medici Endocrinologi/European Thyroid

Association (AACE/AME/ETA) grades of recommendation
grades of recommendation
Grade A - ≥ 1 conclusive level 1 publications demonstrating benefit greater than risk
Grade B
no conclusive level 1 publication
≥ 1 conclusive level 2 publications demonstrating benefit greater than risk
Grade C
no conclusive level 1 or 2 publication
≥ 1 conclusive level 3 publications demonstrating benefit greater than risk or no risk at
all or no benefit at all
Grade D
no conclusive level 1, 2, or 3 publication
conclusive level 1, 2, or 3 publication demonstrating risk greater than benefit
levels of evidence
Level 1
well-controlled, generalizable, randomized trials
adequately powered, well-controlled multicenter trials
large meta-analyses with quality ratings
all-or-none evidence
32/35
Level 2
randomized controlled trials with limited body of data
well-conducted prospective cohort studies
well-conducted meta-analyses of cohort studies
Level 3
methodologically flawed randomized clinical trials
observational studies
case series or reports
conflicting evidence with weight of evidence supporting recommendation
Level 4
expert consensus
expert opinion
theory-driven conclusions and unproven claims
Reference - AACE/AME/ETA medical guidelines for diagnosis and management of thyroid nodules
(Endocr Pract 2010 May-Jun;16 Suppl 1:1 PDF or in J Endocrinol Invest 2010 May;33(5):287)
Synthesized Recommendation Grading System for DynaMed Plus

DynaMed systematically monitors clinical evidence to continuously provide a synthesis of the most valid
relevant evidence to support clinical decision-making (see 7-Step Evidence-Based Methodology).
Guideline recommendations summarized in the body of a DynaMed topic are provided with the
recommendation grading system used in the original guideline(s), and allow DynaMed users to quickly see
where guidelines agree and where guidelines differ from each other and from the current evidence.
In DynaMed Plus (DMP), we synthesize the current evidence, current guidelines from leading authorities,
and clinical expertise to provide recommendations to support clinical decision-making in the Overview &
Recommendations section.
We use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to classify
synthesized recommendations as Strong or Weak.
Strong recommendations are used when, based on the available evidence, clinicians (without
conflicts of interest) consistently have a high degree of confidence that the desirable consequences
(health benefits, decreased costs and burdens) outweigh the undesirable consequences (harms, costs,
burdens).
Weak recommendations are used when, based on the available evidence, clinicians believe that
desirable and undesirable consequences are finely balanced, or appreciable uncertainty exists about
the magnitude of expected consequences (benefits and harms). Weak recommendations are used
when clinicians disagree in judgments of relative benefit and harm, or have limited confidence in
their judgments. Weak recommendations are also used when the range of patient values and
preferences suggests that informed patients are likely to make different choices.
DynaMed Plus (DMP) synthesized recommendations (in the Overview & Recommendations section) are
determined with a systematic methodology:
Recommendations are initially drafted by clinical editors (including ≥ 1 with methodological
expertise and ≥ 1 with content domain expertise) aware of the best current evidence for benefits and
harms, and the recommendations from guidelines.
Recommendations are phrased to match the strength of recommendation. Strong recommendations
use "should do" phrasing, or phrasing implying an expectation to perform the recommended action
for most patients. Weak recommendations use "consider" or "suggested" phrasing.
Recommendations are explicitly labeled as Strong recommendations or Weak recommendations
when a qualified group has explicitly deliberated on making such a recommendation. Group
deliberation may occur during guideline development. When group deliberation occurs through
DynaMed-initiated groups:
Clinical questions will be formulated using the PICO (Population, Intervention, Comparison,
Outcome) framework for all outcomes of interest specific to the recommendation to be
developed.
33/35
Systematic searches will be conducted for any clinical questions where systematic searches
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Evidence will be summarized for recommendation panel review including for each outcome,
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significant conflict exists for the recommendation in question.
Panel members will make Strong recommendations if and only if there is consistent
agreement in a high confidence in the likelihood that desirable consequences outweigh
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All steps in this process (including evidence summaries which were shared with the panel,
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Recommendations are verified by ≥ 1 editor with methodological expertise, not involved in
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Recommendations are published only after consensus is established with agreement in phrasing and
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If consensus cannot be reached then the recommendation can be published with a notation of
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DynaMed topics are created and maintained by the DynaMed Editorial Team and Process.
All editorial team members and reviewers have declared that they have no financial or other competing
interests related to this topic, unless otherwise indicated.
DynaMed provides Practice-Changing DynaMed Updates, with support from our partners, McMaster
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Special acknowledgements
Adam M. Brufsky, MD, PhD, FACP (Professor of Medicine and Associate Division Chief of Hematology
and Oncology, University of Pittsburgh School of Medicine; Medical Director, Women's Cancer Center at
Magee-Women's Hospital of University of Pittsburgh Cancer Institute, Co-Director, Comprehensive
Breast Cancer Center; Pennsylvania, United States)
Dr. Brufsky declares relevant financial relationships with Genentech, Celgene, Novartis, Genomic Health,
Agendia, and Biotheranostics (Consultant).
Kim A. Carmichael, MD, FACP (Associate Professor of Medicine, Division of Endocrinology,

Metabolism and Lipid Research, Washington University; Missouri, United States)
Dr. Carmichael declares receiving speaking fees from Merck and Janssen.
34/35
Allen Shaughnessy, PharmD, M Med Ed, FCCP (Professor of Family Medicine and Director of Master
Teacher Fellowship, Tufts University Family Medicine Residency; Cambridge Health Alliance;
Massachusetts, United States)
Dr. Shaughnessy declares no relevant financial conflicts of interest.
Alan Ehrlich, MD (Executive Editor; Associate Professor of Family Medicine, University of

Massachusetts Medical School; Massachusetts, United States)
Dr. Ehrlich declares no relevant financial conflicts of interest.
Jessica Geiger, MD (Fellow of Hematology and Medical Oncology, University of Pittsburgh Medical
Center; Pennsylvania, United States)
How to cite
National Library of Medicine, or "Vancouver style" (International Committee of Medical Journal Editors):
DynaMed Plus [Internet]. Ipswich (MA): EBSCO Information Services. 1995 - . Record No. T113756,
Medullary thyroid cancer; [updated 2018 Nov 30, cited place cited date here]. Available from
https://www.dynamed.com/topics/dmp~AN~T113756. Registration and login required.
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4/3/2019 DynaMed Plus: Medullary thyroid cancer

Medullary thyroid cancer

carcinoma of thyroid gland(4, 5)

medullary carcinoma of thyroid

types of thyroid cancer(4, 5)

Who is most affected

medullary thyroid cancer incidence

Likely risk factors

risk factors for thyroid malignancy include(1, 2)

Etiology and Pathogenesis

20%-25% due to autosomal dominant inheritance of gene mutation(5)

pathogenesis in all forms of medullary thyroid cancer(4)

History and Physical

Chief concern (CC)

common presentations include(4, 5)

History of present illness (HPI)

typical age at onset of medullary thyroid cancer(3)

Past medical history (PMH)

ask about history of radiation exposure

Family history (FH)

ask about family history of

findings suggestive of multiple endocrine neoplasia type IIb include

location, consistency, and size of nodule

suspect in patient with

other thyroid nodules/lesions

thyroid-stimulating hormone (TSH)

Thyroid scintigraphy (radionuclide scanning)

classifies nodules as hot (hyperfunctioning), cold (hypofunctioning), or indeterminate(1)

Biopsy and pathology

fine needle aspiration (FNA) biopsy

nodule < 1 cm with findings on ultrasound suggestive of malignancy

systematic review of 15 diagnostic studies evaluating FNA cytology for detection of

American Association of Clinical Endocrinologists/Associazione Medici Endocrinologi/European Thyroid

Other diagnostic testing

consider RET testing in patients with intestinal ganglioneuromatosis (ATA Grade B)

T0 - no evidence of primary tumor

surgery is the main treatment for medullary thyroid cancer (MTC)

American Thyroid Association (ATA) 2009 recommendations(4)

treatment of MTC-associated symptoms

partial response in 21.7% (95% CI 0.2%-43.2%)

Surgery and procedures

considerations during thyroid surgery

Other surgery and procedures

consider re-operative compartmental dissection of image- or biopsy-positive compartments or

for impending or active fracture of weight-bearing bone, surgery recommended (ATA

Consultation and referral

screen for conditions associated with medullary thyroid cancer(4)

Complications and Prognosis

local extension and compression of neck structures (including respiratory obstruction)(4)

10-year survival rates for medullary thyroid cancer (MTC)(4)

somatic mutation in RET (rearranged during transfection) oncogene

Prevention and Screening

prophylactic thyroidectomy to prevent medullary thyroid cancer (MTC)

indications for rearranged during transfection (RET) testing(4)

Guidelines and Resources

United States guidelines

United Kingdom guidelines

French Endocrinology Society (Société Française d’Endocrinologie [SFE]) guideline on cervical

review can be found in J Surg Oncol 2006 Dec 15;94(8):737

C73 malignant neoplasm of thyroid gland

Recommendation grading systems used

National Comprehensive Cancer Network (NCCN) categories of evidence and consensus

American Association of Clinical Endocrinologists/Associazione Medici Endocrinologi/European Thyroid