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case records of the massachusetts general hospital
From the Departments of Medicine
(L.J.W., D.S.R.) and Pathology (P.M.S.),
Massachusetts General Hospital; the De-
partments of Otology and Laryngology
(G.W.R.) and Radiology (M.E.C.), Massa-
chusetts Eye and Ear Infirmary; and the
Departments of Medicine (L.J.W., D.S.R.),
Surgery (G.W.R.), Radiology (M.E.C.), and
Pathology (P.M.S.), Harvard Medical
School — all in Boston.
N Engl J Med 2013;368:664-73.
DOI: 10.1056/NEJMcpc1210080
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of m e dic i n e
Founded by Richard C. Cabot
Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor Emily K. McDonald, Assistant Editor
Case 5-2013: A 52-Year-Old Woman
with a Mass in the Thyroid
Lori J. Wirth, M.D., Douglas S. Ross, M.D., Gregory W. Randolph, M.D.,
Mary Elizabeth Cunnane, M.D., and Peter M. Sadow, M.D., Ph.D.
PR E SEN TAT ION OF C A SE
A 52-year-old woman was seen in the thyroid clinic at this hospital because of a
mass in the neck.
The patient had been well until 2.5 months before presentation, when she noted
a mass in the right side of her neck and felt a lump in her throat when swallowing.
She was seen by her primary care physician. She had a history of myxomatous
mitral valve with regurgitation, cardiac arrhythmias (atrial premature complexes
and ventricular premature contractions), ovarian cysts, and anxiety; she had had a
total hysterectomy and right salpingo-oophorectomy for uterine fibroids. She drank
alcohol in moderation and did not smoke or use illicit drugs. Medications included
atenolol, lisinopril, fluoxetine, calcium carbonate, a multivitamin, and amoxicillin
before dental work. She had no known allergies. She was married, had no children,
and worked in an office. Her father had hypothyroidism, an aunt had a goiter, and
a sister had an unspecified thyroid problem; her other siblings were healthy.
On examination, the blood pressure was 128/74 mm Hg, the pulse 66 beats per
minute, the weight 66.7 kg, and the height 165.1 cm. A nodule was palpable in
the thyroid on the right side; there was no palpable lymphadenopathy. A grade
2/6 systolic murmur was heard at the apex. The remainder of the examination was
normal.
The blood level of thyrotropin was 1.74 μU per milliliter (reference range, 0.40 to
5.00). Ultrasonography of the thyroid gland revealed a heterogeneous, hypoechoic
nodule (42 mm by 32 mm by 26 mm) in the midpole of the right lobe. The nodule
had lobulated margins, scattered central calcification, and mild central blood flow.
A solid, hypoechoic nodule (24 mm by 19 mm by 34 mm), posterior and inferior
to the first nodule, contained several foci of punctate calcifications. An enlarged
lymph node in the lower cervical region (level 4) on the right side of the neck had
abnormal internal architecture and contained microcalcifications.
The patient was referred to the thyroid clinic at this hospital. She reported a mild
cough productive of yellow phlegm, occasional palpitations, and a timbre of her
voice that was lower than usual, which she attributed to a recent upper respira-
tory infection. She had no history of radiation to the head or neck. Vital signs were
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 case records of the massachusetts gener al hospital
normal. A firm mass (40 mm in greatest dimen-
sion) and a smaller nodule (inferoposterior to
the first) were palpated in the right lobe of the
thyroid. A single palpable lymph node was near-
by. The remainder of the examination was nor-
mal. Ultrasonography of the thyroid performed
in the clinic revealed two solid, heterogeneous
thyroid nodules with irregular borders in the
right lobe, calcifications in the larger nodule, and
cervical lymphadenopathy, including a node ad-
jacent to the larger nodule.
A diagnostic procedure was performed.
DIFFER EN T I A L DI AGNOSIS
Dr. Douglas S. Ross: All the discussants are aware of
the diagnosis in this case. This 52-year-old wom-
an had had a lump in her neck for 2 months. May
we review the imaging studies?
Dr. Mary Elizabeth Cunnane: Ultrasonography
performed for the evaluation of a neck mass
revealed a 4-cm nodule in the right lobe of the
thyroid that was hypoechoic, with lobulated bor-
ders and microcalcification (Fig. 1A). Inferior to
this mass was a second lesion, thought to be
another large thyroid nodule. Lateral to the ca-
rotid artery was a lymph node at level 4 on the
right side, which was enlarged and hyperechoic,
suggesting metastatic involvement (Fig. 1B). This
was one of multiple abnormal lymph nodes at
this site.
Computed tomography (CT) performed after
the administration of contrast material revealed
the nodule in the right lobe of the thyroid, but
what appeared on ultrasonography to be a sec-
ond thyroid nodule was recognized on CT as a
markedly enlarged node in the central neck that
deeply infiltrated the tracheoesophageal groove
and could not be separated from either the tra-
chea or the esophagus (Fig. 1C). There was no
evidence of tracheal invasion. Multiple abnormal-
appearing nodes in the lateral neck were again
seen, but in addition, an enlarged retropharyn-
geal node on the right side was identified on the
CT scan (Fig. 1D).
Evaluation of a thyroid nodule
and lymphadenopathy
Dr. Ross: Imaging studies showed that this patient
had thyroid nodules and cervical lymphadenopa-
thy. The most likely diagnosis is papillary thyroid
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cancer with nodal metastases. Follicular thyroid
cancer spreads hematogenously, and cervical-node
metastases are uncommon, except in the oxyphil-
cell (Hürthle-cell) variant. Medullary thyroid can-
cer is also commonly associated with nodal me-
tastases, but fewer than 4% of thyroid cancers
are medullary. Poorly differentiated thyroid can-
cer is also possible. Anaplastic thyroid cancer and
primary thyroid lymphoma are unlikely, since
they usually manifest as rapidly growing neck
masses; lymphoma is markedly hypoechoic. Two
uncommon possibilities are tumors that are met-
astatic to the thyroid and a reactive or lympho-
proliferative disorder associated, frequently inci-
dentally, with adenomatous goiter or Hashimoto’s
thyroiditis.
Serum thyrotropin is measured to assess the
functionality of a thyroid mass. When the thyro-
tropin level is subnormal, radionuclide scanning
with 123I is performed to determine whether the
nodule is autonomously secreting thyroid hor-
mone. Hyperfunctioning nodules are almost
never malignant, and fine-needle aspiration is
not required. In addition, the serum level of thy-
rotropin correlates directly with the risk of can-
cer.1 This patient had a normal thyrotropin level,
and scintigraphy was not performed; however,
the suspicious ultrasonographic findings indi-
cated the need for a tissue diagnosis regardless.
Whether this patient’s serum calcitonin level
should be assessed for the detection of medul-
lary carcinoma before surgery is controversial.
Levels of calcitonin greater than 100 pg per mil-
liliter (reference range, <8) are highly predictive
of medullary thyroid cancer2; however, levels
from 20 through 100 pg per milliliter may occur
in patients with other disorders, such as renal
insufficiency, hypergastrinemia (e.g., omeprazole
use), hypercalcemia, neuroendocrine tumors, in-
flammation, and possibly Hashimoto’s thyroid-
itis.3 The administration of pentagastrin, which
stimulates secretion of calcitonin by tumors but
does not stimulate secretion in other conditions,
can be used to confirm the abnormal levels of
calcitonin and to select patients for surgery 4;
however, in the United States, pentagastrin is not
available and evaluation of elevated basal calci-
tonin levels under 100 pg per milliliter is diffi-
cult. In 2006, European guidelines recommended
calcitonin screening,5 but the American Thyroid
Association (ATA) guidelines in 2009 did not
665
 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

C D

Figure 1. Imaging of the Neck and Thyroid.

An ultrasonographic image of the right lobe of the thyroid (Panel A) reveals a large nodule that is hypoechoic and
has lobulated borders (arrows) and small foci of hyperechogenicity representing calcification. An ultrasonographic
image in the sagittal view (Panel B) at level 4 of the right lateral neck shows an enlarged, hypoechoic lymph node.
This node contains a focus of microcalcification (arrow) and has abnormal internal architecture and blood flow. A
CT scan of the neck obtained after the administration of contrast material (Panel C) reveals an enlarged, irregular
lymph node in the central neck, extending deeply into the tracheoesophageal groove. There is no clear plane of sep-
aration between this mass and the posterior trachea or the right lateral esophagus (arrow). An enlarged lymph node
is seen in the right retropharyngeal space (Panel D, arrow).

recommend for or against it.6 The 2010 sum-
mary of recommendations from European and
American societies7 suggests that calcitonin
screening should be considered before perform-
ing thyroidectomy for nodular goiter. Calcium
infusions also stimulate calcitonin release by
tumors, and a small study suggests that this will
provide a useful alternative to pentagastrin.8
When validated, this approach may lead to the
acceptance of calcitonin screening in the United
States. The calcitonin level was not measured in
this patient before surgery.
Fine-needle aspiration biopsy of one or more
of this patient’s thyroid nodules and perhaps a
lymph node was the next appropriate test for
determining the diagnosis. Since her clinical
presentation was consistent with papillary cancer
with cervical-node metastases, I did not think
that the surgeon would require cytologic proof
of nodal involvement to proceed with a lateral

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 case records of the massachusetts gener al hospital

node dissection, and fine-needle aspiration bi- greatest dimension) that was infiltrating the
opsy was performed on only the thyroid nodules. tracheoesophageal groove, and it allowed for the
prediction of invasion of the recurrent laryngeal
PATHOL O GIC A L DISCUSSION nerve.
Laryngeal examination is important both be-
Dr. Peter M. Sadow: The patient underwent fine- fore and after thyroid surgery.9 Vocal-cord palsy
needle aspiration biopsy of two nodules discov- may be present preoperatively with invasive dis-
ered by ultrasound examination — a lobulated, ease, but it may be asymptomatic. The presence
calcified mass (4.2 cm) in the midpole of the of vocal-cord palsy greatly influences the man-
right lobe, and a solid nodule (2.4 cm), inferolat- agement of the contralateral lobe of the thy-
eral to the larger mass. The specimens were clin- roid.17 Laryngeal examination is also advised
ically designated as “highly suspicious for papil- preoperatively because management of the re-
lary carcinoma.” Specimens from the two lesions current laryngeal nerve, when found to be invad-
(Fig. 2A) showed cells that had variably sized and ed at surgery, requires knowledge of the nerve’s
mostly round nuclei with areas of clearing, focal preoperative function.18
irregularity, and coarse chromatin. There were Since it was likely that the right recurrent la-
scattered stripped nuclei and cells with varying ryngeal nerve in this patient would have to be
amounts of cytoplasm and cometlike cytoplas- sacrificed, a plan was configured preoperatively
mic tails. The cytopathological diagnosis was with the endocrinology service for radioactive
papillary thyroid carcinoma. iodine ablation of the left lobe of the thyroid,
obviating the need for dissection of the remain-
DISCUSSION OF M A NAGEMEN T ing functional recurrent laryngeal nerve, which
carries the inherent risk of bilateral vocal-cord
Surgical management of thyroid cancer paralysis and possible tracheotomy.19,20 At sur-
Dr. Gregory W. Randolph: The surgical goal for this gery, invasive disease was identified, requiring
patient with presumed papillary thyroid cancer is resection of the right strap muscles, a 3-cm sec-
to resect all gross disease in the thyroid and in tion of the right recurrent laryngeal nerve, and
macroscopically involved cervical nodal beds. the muscular coat of the upper cervical esopha-
Lymph-node involvement is common and in- gus on the right side (Fig. 3).
creases locoregional recurrence but has a mini- Approximately 10 to 15% of patients with
mal effect on survival.6,9 A distinction should be thyroid cancer present with such extrathyroidal
made between small-volume microscopic nodal extension. Nearly 50% of patients with invasive
disease, which occurs in up to 80% of cases of disease have involvement of the recurrent laryn-
papillary thyroid cancer and is not associated geal nerve.18 In this patient, intraoperative elec-
with an increased risk of recurrence, and clini- trophysiological monitoring of the recurrent la-
cally apparent macroscopic nodes, such as were ryngeal nerve was helpful in identifying the
seen in this patient, which occur in 35% of cases nerve both above and below the area of nerve
of papillary thyroid cancer and are associated invasion. Segmental defects of the recurrent la-
with an increased risk of nodal recurrence.10-14 ryngeal nerve are well treated by anastomosis of
Compartment-oriented dissection targeting mac- the ansa cervicalis nerve to the distal recurrent
roscopic nodal disease has replaced more isolat- laryngeal nerve (Fig. 3), which was performed in
ed nodal resection, termed “berry picking.” this patient and has been shown to improve the
Macroscopic nodal disease in this patient was postoperative vocal outcome.21
preoperatively mapped with the use of ultraso-
nography and CT. CT is used to evaluate the PATHOL O GIC A L DISCUSSION
central neck, retropharyngeal, and mediastinal
lymph nodes; owing to the use of iodinated con- Dr. Sadow: The specimen from the surgically re-
trast material, a short delay is necessary before sected right lobe of the thyroid with central soft
postoperative radioactive iodine treatment is tissue weighed 59 g. Most of the lobe (7.0 of
begun.15,16 In this case, CT provided apprecia- 8.1 cm) was occupied by a firm, white, lobular
tion of the central nodal mass (6.5 cm in the mass (Fig. 2C). Histologic sections revealed a

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

C D

Fat

E F
T

Figure 2. Pathological Appearance of Tumor Specimens.

Liquid-based cytologic preparations of the primary thyroid lesion (Panel A, Papanicolaou stain) and liver metastasis
(Panel B, Papanicolaou stain) show similar morphologic features, with asymmetric nuclei and cometlike cytoplasmic
tails. A gross image of the excised and bisected right lobe of the thyroid (Panel C) shows replacement of the majority
of the lobe by white nodular tumor, with a scant, uninvolved brown rim. Histologic images of the primary tumor
(Panels D and E, hematoxylin and eosin) highlight nested tumor (T) adjacent to normal thyroid follicles (N), as well
as lymphovascular invasion (asterisk) and involvement of perithyroidal fat. The classic salt-and-pepper appearance
(rounded or cleared-out nuclei with coarse chromatin) of neuroendocrine lesions is seen in the insets. A lymph
node metastasis (Panel F, hematoxylin and eosin) shows intranodal tumor confinement and nested architecture,
features that are similar to those of the primary tumor.

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 case records of the massachusetts gener al hospital

A Preoperative anatomy, right lateral side

B Postoperative anatomy, right lateral side

Thyroid Cricoid
cartilage cartilage
Recurrent
laryngeal
nerve

Vagus Thyroid
nerve Ansa Recurrent
cervicalis Ansa cervicalis laryngeal nerve
nerve nerve,
redirected Trachea

Internal
jugular vein Internal Esophagus
Common Thyroid tumor
carotid artery invasion jugular vein Common carotid artery

COLOR FIGURE
Figure 3. Surgical Approach to Locally Advanced Thyroid Cancer.
Draft 6 1/15/13
A side view of the thyroid and paratracheal region shows invasion of the recurrent laryngeal Author
nerve (Panel
Wirth
A). The recur-
rent laryngeal nerve is closely related to the posterolateral aspect of the two thyroid lobes.FigTherefore,
# 3 extrathyroidal
thyroid cancer that extends posteriorly can directly invade the recurrent laryngeal nerve and Titlecause vocal paralysis.
Surgical management of thyroid cancer that infiltrates the recurrent laryngeal nerve involves ME
segmental
Hastings
resection
of the nerve. The postresection thyroid bed (Panel B) shows anastomosis of the ansa cervicalisDE nerve
Harris to the distal
recurrent laryngeal nerve, which provides ongoing neural tone to the affected hemilarynx,Artistpreventing
Knoper vocal-cord
muscular atrophy, and has been shown to improve postoperative vocal outcomes. AUTHOR PLEASE NOTE:
Figure has been redrawn and type has been reset
Please check carefully

Issue date 02/14/13

nested, cellular lesion, devoid of colloid, infiltrat-
ing the lobe, with focal extrathyroidal extension
(Fig. 2D) and lymphovascular invasion (Fig. 2E).
There was no evidence of follicle formation or
involvement, and cells had rounded or cleared-
out nuclei with coarse chromatin, the so-called
salt-and-pepper pattern of neuroendocrine le-
sions. Metastases were seen in 6 of 30 perithyroi-
dal lymph nodes (Fig. 2F) and lymph nodes in
the right lateral neck, with the largest metastatic
focus measuring 1.9 cm. Tumor cells stained for
thyroid transcription factor 1, calcitonin, and
carcinoembryonic antigen (CEA). Staining with
Congo red was negative for amyloid. The find-
ings were diagnostic of medullary thyroid carci-
noma. One month later, a biopsy specimen from
the largest of multiple liver lesions (2.8 cm in the
greatest dimension) revealed metastatic carcino-
ma (Fig. 2B).
The preoperative clinical impression in this
case was papillary thyroid carcinoma, most likely
because of the intralesional calcification and
lymph-node involvement. Although the preoper-
ative fine-needle aspiration biopsy specimens
were diagnostic of carcinoma, they were misin-
terpreted as papillary carcinoma.22,23 Evaluation
of cytologic preparations can be challenging for
several reasons, including specimen cellularity,
obfuscation by blood, and the diverse morpho-
logic features of the lesions. Cytologic features
of medullary thyroid carcinoma include cells with
spindled, plasmacytoid, or cometlike projections
of cytoplasm; naked nuclei may also be seen.
Nuclei are generally round but vary in size (endo-
crine-related nuclear atypia), with coarse chro-
matin.24 These features are distinct from those
of papillary carcinomas, which include nuclear
enlargement, pleomorphism, grooves, and intra-
nuclear pseudoinclusions25; papillary fronds are
often noted on cytologic smears. On rare occa-
sions, cytomorphologic and architectural overlap
occurs between medullary thyroid carcinoma and
follicular thyroid lesions.26
DISCUSSION OF M A NAGEMEN T
Surgical management of medullary
carcinoma of the thyroid
Dr. Randolph: Total thyroidectomy, for potential
multifocal disease, and central neck dissection,

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 The n e w e ng l a n d j o u r na l
given the high rate of regional nodal involve-
ment, are recommended for patients with medul-
lary thyroid carcinoma, after pheochromocyto-
ma has been ruled out.6 Clinically apparent
nodes are resected with compartmental dissec-
tion,6 which may be recommended even to pa-
tients with known preoperative distant metasta-
sis, to palliate the neck symptoms, treat pain,
and maintain a safe airway. This patient had
clinically apparent nodal disease; such patients
often have occult distant metastases, and even
aggressive nodal surgery may not cure the dis-
ease.27 This patient had had a surgical approach
tailored to papillary carcinoma, which most like-
ly was also appropriate for the ultimately diag-
nosed medullary carcinoma.
Endocrine management of medullary
thyroid cancer
Dr. Ross: Twenty percent of cases of medullary
thyroid cancer are familial or associated with
multiple endocrine neoplasia type 2 (MEN-2),
which is a consideration in this patient. Germline
mutations in RET that lead to ligand-independent
activation have been reported in patients with
MEN-2A, MEN-2B, and familial medullary thy-
roid carcinoma.28-33 If the diagnosis is known
preoperatively, either measurements of plasma
metanephrine levels or 24-hour urine studies of
metanephrines and catecholamines are used to
screen for pheochromocytoma. The convenience
and high negative predictive value of normal plas-
ma metanephrine levels make this a useful first
test.34 A positive test for hyperparathyroidism
can be addressed at the time of thyroidectomy.
The levels of calcitonin and CEA are propor-
tional to tumor burden and differentiation.
Knowledge of preoperative levels is useful when
assessing the persistence of markers after thy-
roidectomy. Since this patient was thought to
have papillary thyroid cancer, the measurement
of calcitonin, CEA, and plasma metanephrine
levels and assessment of parathyroid function
were not performed preoperatively. In retrospect,
preoperative measurement of the calcitonin level
would have helped guide surgery and the subse-
quent treatment of this patient.
Postoperative management included reassess-
ment of parathyroid function, thyroid hormone–
replacement therapy, remeasurement of calcito-
nin and CEA levels, and imaging studies. Since
it takes several weeks for calcitonin and espe-
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of m e dic i n e
cially CEA levels to reach their nadir postopera-
tively, the ATA guidelines on medullary thyroid
cancer suggest measurement of tumor markers
2 to 3 months after surgery.35 Patients with an
undetectable calcitonin level have a 3% risk of
recurrent disease and do not require imaging,
although a baseline ultrasonographic image can
be obtained. If the calcitonin level is less than
150 pg per milliliter, monitoring with ultraso-
nography of the neck is sufficient; higher levels
of calcitonin, such as those in this patient, re-
quire comprehensive imaging to assess distant
hepatic, pulmonary, and osseous metastases.35
In this patient, screening for germline RET
mutations was negative. If it had been positive,
screening of family members would be essential.
Medical Oncologic Management
of Medullary Thyroid Cancer
Dr. Lori J. Wirth: This 52-year-old, otherwise healthy
woman had a stage T4aN1b sporadic medullary
thyroid cancer. Four weeks postoperatively, the
calcitonin level was 281 pg per milliliter (refer-
ence range, <8) and the CEA level 13.1 ng per
milliliter (reference range, <3.4). Postoperatively,
combined 18F-fluorodeoxyglucose (FDG) positron-
emission tomography (PET) and CT revealed en-
larged FDG-avid retropharyngeal and mediastinal
lymph nodes and multiple FDG-avid liver lesions.
As compared with CT of the neck 2 months ear-
lier, the nodal disease had progressed. Baseline
imaging studies of the liver were not available, so
we could not evaluate for progression in the liver.
To rule out another cancer and to confirm the
presence of incurable metastatic disease, a fine-
needle aspiration biopsy specimen of the liver
was obtained, which was positive.
Prognosis of medullary thyroid cancer
The first question we considered was, “What is
this patient’s prognosis?” When calcitonin and
CEA levels normalize after surgery, the progno-
sis is excellent. The prognosis is less favorable for
patients, such as this one, with involved cervical
nodes, persistently elevated calcitonin and CEA
levels, and distant metastases at diagnosis. None-
theless, the 10-year survival rate among patients
with distant metastasis was 48% in one large ret-
rospective series.36 Some patients survive only a
few years, but other patients, even those with dis-
tant metastases, can survive for decades. Thus,
the challenge is to differentiate between patients
 case records of the massachusetts gener al hospital
who will live with medullary thyroid cancer for
many years and those who will die soon from
their disease and who are most in need of sys-
temic therapy.
The kinetics of calcitonin and CEA are even
more informative than the levels themselves in
predicting this patient’s prognosis.32,37-39 A meta-
analysis shows that the 10-year survival rate
among patients with a calcitonin doubling time
of less than 1 year is 18%, as compared with
95% with a doubling time of more than 1 year.40
CEA doubling times are similarly informative.
We did not have this patient’s calcitonin and CEA
doubling times at our initial visit, but the levels
of both tumor markers were unexpectedly low
for a patient with metastatic disease, in which
the calcitonin level is often in the thousands and
the CEA level in the hundreds.27,41,42 Dedifferen-
tiated medullary thyroid cancer, in which the
CEA level increases out of proportion to the cal-
citonin level, is thought to herald a more fulmi-
nant course.37,43-45 Another pattern thought to
carry a poor prognosis is low levels of both cal-
citonin and CEA. Thus, we were concerned that
this patient, with disease that had shown pro-
gression on imaging studies over a 2-month
period and unexpectedly low calcitonin and CEA
levels, could get into trouble soon, rather than
live with indolent disease for many years.
Our next question was, “Does this asymp-
tomatic patient need treatment now, or is watch-
ful waiting more appropriate?” There is no po-
tentially curative treatment available and no
evidence that early treatment is better than ini-
tiating treatment later. Any systemic treatment
will have side effects and affect quality of life. If
a patient is expected to do well for years, watch-
ful waiting is often preferred. For this patient,
however, initiation of treatment was indicated.
Targeted therapy for medullary thyroid
cancer
The last question, then, was, “What is the best
systemic approach to treatment of metastatic
medullary thyroid carcinoma?” Until recently,
only cytotoxic chemotherapy was available. How-
ever, studies of chemotherapy such as dacarba-
zine, fluorouracil, and doxorubicin are primarily
small, single-center trials showing limited activ-
ity, with response rates ranging from 10 to
20%.46 When responses are seen, they are gener-
ally short-lived.
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There is emerging interest in targeted therapy
for medullary thyroid cancer, which could be the
best option for this patient. The target that has
received the most attention is RET, a receptor
tyrosine kinase that is expressed in neural crest–
derived tissues, including parafollicular (C) cells;
RET is mutated not only in familial medullary
thyroid cancer but also in 20 to 50% of the tu-
mors in sporadic medullary thyroid cancer.47,48
Vandetanib is one of several tyrosine kinase in-
hibitors with anti-RET activity.49,50 A large, phase
3 trial involving patients with either sporadic or
inherited medullary thyroid cancer showed im-
provement in progression-free survival in patients
receiving vandetanib as compared with those
receiving placebo (30 months vs. 19 months);
almost half the patients had a response, and the
median duration of the responses was more than
2 years.51 Testing for somatic RET mutations is
currently not commercially available, but in this
study, responses were seen both in patients with
the mutation and in those without the mutation.
The most common adverse events were diarrhea,
rash, nausea, hypertension, fatigue, headache,
anorexia, and acne; prolongation of the QTc in-
terval was less common but potentially life-
threatening. Thus, vandetanib is clearly effica-
cious in the treatment of medullary thyroid
cancer, but the side effects cannot be down-
played when considering treatment for an as-
ymptomatic patient such as this one, in the ab-
sence of aggressive disease.
In this patient, who needed treatment despite
the absence of symptoms, we started vandetanib
shortly after examination of a liver-biopsy speci-
men confirmed metastatic disease. The drug was
held after week 4, when the QTc interval ex-
ceeded 500 msec, and was resumed at a reduced
dose when the QTc interval fell below 450 msec.
The patient has had mild diarrhea, an acneiform
rash, and fatigue. She is undergoing monthly
clinical, electrocardiographic, and electrolyte
monitoring and bimonthly restaging according
to measurements of tumor markers and imaging
studies. During the first 2 months of treatment,
calcitonin and CEA levels dropped by 87% and
51%, respectively, and a restaging PET-CT study
showed a decrease in FDG avidity, although
only the dominant liver lesion had decreased in
size. All other lesions were stable. The patient
has continued to receive vandetanib; after
8 months of treatment, imaging revealed stable
671
 The n e w e ng l a n d j o u r na l of m e dic i n e

disease, but the serum calcitonin level had begun A NAT OMIC A L DI AGNOSIS
to rise.
For this patient, options for treatment of dis- Medullary thyroid carcinoma, metastatic to cer-
ease progression may become available in the vical lymph nodes and the liver.
future, since clinical trials have shown activity This case was presented at the Cancer Center Grand Rounds.
Dr. Dror Michaelson assisted with the organization of the con-
of other tyrosine kinase inhibitors in medullary ference.
thyroid cancer, in particular cabozantinib, which Dr. Wirth reports receiving consulting fees from Bayer, Boeh-
targets hepatocyte growth factor receptor (MET), ringer Ingelheim, Acceleron, and Exelexis; Dr. Ross, receiving
consulting fees from Genzyme and Novo Nordisk; and Dr. Ran-
vascular endothelial growth factor receptor 2, and dolph, providing expert testimony on behalf of patients or health
RET.52,53 As a result, cabozantinib may become care providers in medicolegal cases involving surgery. No other
potential conflict of interest relevant to this article was reported.
another treatment option for patients like this Disclosure forms provided by the authors are available with
one who have this orphan disease. the full text of this article at NEJM.org.

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