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8 October 2013

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Thyroid Cancer
Annu. Rev. Med. 2014.65. Downloaded from www.annualreviews.org
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Tobias Carling and Robert Udelsman

Department of Surgery, Yale University School of Medicine, New Haven,
Connecticut 06510; email: Tobias.carling@yale.edu, Robert.udelsman@yale.edu

Annu. Rev. Med. 2014. 65:13.113.13

The Annual Review of Medicine is online at
med.annualreviews.org
This articles doi:
10.1146/annurev-med-061512-105739
c 2014 by Annual Reviews.
Copyright 
All rights reserved

Keywords
surgery, lymph node dissection, radioactive iodine, targeted therapy,
molecular diagnostics

Abstract
Thyroid cancer is rapidly increasing in incidence, but the mortality
rate remains at. Debate has arisen over the need to detect or treat
most thyroid cancers early, given their favorable natural history. The
appropriate extent of surgery for thyroid cancer is also controversial:
some researchers advocate partial and others total thyroidectomy; some
advocate prophylactic central cervical lymph node dissection, whereas
others only rarely recommend lymphadenectomy. Although radioactive
iodine is effective, its appropriate use and dosage remain controversial.
In addition, molecular analysis of thyroid cancer is frequently used for
diagnostic purposes involving preoperative ne-needle biopsy specimens as well as to dene targetable pathways altered in the disease to
guide clinical trials of drug therapy for advanced thyroid cancers.

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INTRODUCTION

tively indolent nature and excellent long-term

survival associated with thyroid malignancies.
Radiation exposure to the thyroid gland in
childhood, age, female sex, and family history
are risk factors that increase the incidence of
well-differentiated thyroid cancer. Exposure of
radiation to the thyroid may occur either from
external sources or from ingestion of radioactive material. Within the rst decade after the
Chernobyl accident, some regions of Belarus
showed a 100-fold increase in thyroid cancer in
individuals below the age of 15 at the time of
exposure (4), reecting the importance of age
at exposure in the development of radiationassociated thyroid cancer (5).
Epidemiological studies have demonstrated
a four- to ten-fold increased risk of welldifferentiated thyroid cancer in rst-degree
relatives of subjects with this neoplasia (6).
In contrast to the well-described molecular pathology associated withMTC, the
molecular and clinical genetics of follicular
cellderived thyroid cancer are less clear.
Well-differentiated thyroid cancer can both be
inherited in an autosomal dominant fashion as
the main feature in some syndromes and have
an increased incidence in other tumor susceptibility syndromes (7). Table 1 summarizes
the most common known genetic alterations
identied in nonfamilial thyroid cancer derived
from follicular cells.

The normal thyroid gland is composed histologically of two main parenchymal cell types.
Follicular cells line the colloid follicles, concentrate iodine, and produce thyroid hormones.
These cells give rise to both well-differentiated
cancers (i.e., papillary and follicular) and
anaplastic thyroid cancer. The second cell
type, the C or parafollicular cell, produces the
hormone calcitonin and is the cell of origin for
medullary thyroid carcinoma (MTC).

Epidemiology and Pathogenesis

The diagnosis of thyroid cancer, specically
papillary thyroid cancer (PTC), has increased
rapidly, with a 240% increased incidence over
the past three decades (1). Although the majority of newly diagnosed thyroid cancers are
small PTCs, increased incidences have been
exhibited for all sizes and stages of PTC in both
genders and in all ethnic groups (2). PTC is the
most common endocrine malignancy, accounting for 96.0% of total new endocrine cancers
and 66.8% of deaths due to endocrine cancers
(3). Per cancer statistics, 60,200 new cases
of thyroid cancer will be diagnosed in 2013,
with 1,850 deaths due to the disease (3). The
discrepancy between the total number of cases
of thyroid cancer and deaths reects the rela-

Table 1 Summary of most common currently known genetic alterations identified in nonfamilial thyroid cancer derived
from follicular cellsa
Intermediate/poorly
Genetic alteration

Well-differentiated thyroid cancer

PTC

differentiated
thyroid cancer

Anaplastic thyroid cancer

FTC

RET/PTC rearrangement

1325%

0%

013%

0%

BRAF mutation

2969%

0%

013%

012%

NTRK1 rearrangement

513%

Unknown

Unknown

Unknown

RAS mutation

021%

4053%

1827%

2060%

PPARG rearrangement

0%

2563%

0%

0%

CTNNB1 mutation

0%

0%

025%

66%

TP53 mutation

05%

09%

1738%

6788%

Abbreviations: BRAF, B-type Raf kinase; CTNNB1, -catenin; FTC, follicular thyroid carcinoma; NTRK1, neurotrophic tyrosine kinase receptor,
type 1; PPARG, peroxisome-proliferator-activated-receptor-; PTC, papillary thyroid cancer; RET, rearranged in transformation.

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Diagnosis and Pathology

The vast majority of thyroid cancers present
as thyroid nodules detected by the patient, by
the clinician via physical examination, or with
imaging of the neck for other disorders. A minority of thyroid nodules are malignant. There
is a 510% chance of malignancy in thyroid
nodules detected in the general population, but
men and patients at the extremes of age are at
higher risk (5). A history of a rapid increase
in size, dyspnea, dysphagia, or hoarseness, or
the development of Horners syndrome, albeit
not specic for malignancy, are worrisome ndings. A family history of thyroid cancer should
prompt an extended investigation. On examination of the neck, the rmness, lack of mobility,
and large size of the nodule(s); adherence to surrounding structures; and the presence of lymphadenopathy are important clues indicating an
increased probability of carcinoma. However,
these features lack specicity for malignancy.
Once a patient is referred to a thyroid surgeon, routine indirect or direct laryngoscopy is
important, not only in the preoperative evaluation, but also in the assessment of a thyroid nodule. Vocal cord paralysis is generally
associated with advanced thyroid malignancy.
Thyroid function testing, including serum
thyroid-stimulating hormone (TSH) measurement, should be performed to identify underlying thyroid dysfunction but not to differentiate
benign from malignant nodules (5). However,
a suppressed TSH level in the setting of a dominant thyroid nodule is highly suggestive of an
autonomously functioning nodule. These hot
nodules should not undergo ne-needle aspiration (FNA), as they are rarely malignant and
the FNA ndings are often misleading (5). A
serum calcitonin level should be determined in
patients with a thyroid nodule when either sporadic or familial MTC is suspected (8).
High-resolution ultrasonography is a useful
adjunct to the clinical examination for assessing
thyroid nodules, detecting multiple nodules not
discerned by palpation, assisting in the performance of a FNA, and evaluating for the presence of suspicious cervical lymph nodes. Ul-

trasonography can identify whether a lesion is

cystic or solid, and the vast majority of purely
cystic thyroid lesions are benign. The accuracy
of cytologic diagnosis using FNA ranges from
70% to 97% and is highly dependent on the skill
of both the individual performing the biopsy
and the cytopathologist interpreting it (5). If an
adequate sample is obtained, 70% are classied as benign, 4.0% as malignant, and 10% as
suspicious or indeterminate, and 17% demonstrate an insufcient sample (9). The malignant
potential of follicular neoplasms can rarely be
determined by cytologic evaluation; thus, the
biopsies from such lesions are generally classied as suspicious or indeterminate, and most
come to surgical resection. The cells from follicular adenomas and follicular carcinomas appear cytologically identical; only by identifying capsular or vascular invasion on histologic
specimens can cancer be diagnosed. Specimens
with predominantly Hurthle
cells are treated in

the same fashion; however, extensive Hurthle

cell changes can be seen in Hashimotos thyroiditis. Malignancy is found in approximately

2030% of follicular and Hurthle
cell nodules

that are classied as indeterminate by FNA

analysis.
A variety of molecular markers have been
assessed in FNA specimens in an attempt
to develop more discriminating cytologic
subclassications to improve the yield of
malignancy found at surgery. BRAF (B-type
Raf kinase) mutational analysis and, to a lesser
extent, analysis of RET/PTC (rearranged
in transformation/papillary thyroid carcinoma) rearrangement and RAS mutations
have recently been extensively evaluated
in cytological specimens (10, 11). At select
institutions, analysis of such biomarkers in
FNA samples has become routine to improve
the accuracy of the preoperative diagnosis (12).
Recently, initial data based on the use of a
gene expression panel to further characterize
thyroid nodules with an indeterminate FNA
were presented (13). Further validation of the
role of mRNA expression levels play in aiding
physicians in the diagnosis of thyroid nodules is
needed.
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Papillary thyroid cancer constitutes approximately 8085% of malignant epithelial thyroid

tumors in developed countries where sufcient
iodine is present in the diet. Microscopically,
papillary carcinomas are characterized by the
presence of papillae, but some variants contain
no papillary areas, are totally follicular in pattern, and are classied as the follicular variant.
Biologically, all these tumors, independent of
their degree of follicular pattern, show similar
clinical characteristics. Papillary carcinoma has
a propensity to invade lymphatic spaces and,
therefore, leads to microscopic multimodal lesions in the gland as well as a high incidence
of regional lymph node metastases. The latter
may be the presenting symptom of a thyroid
papillary carcinoma because the primary tumor
is very small in some cases. Papillary thyroid
carcinomas of less than 1 cm are often referred
to as microcarcinomas.
True follicular thyroid carcinoma (FTC) is
an unusual tumor comprising approximately 5
10% of thyroid malignancies in nonendemic
goiter areas of the world (14). Prior to the introduction of iodinated salt, follicular carcinoma
was much more frequently diagnosed. In contrast to the overall indolent behavior of the classical well-differentiated thyroid carcinomas,
subtypes of these tumors have been identied
as being more aggressive and thus have been
labeled thyroid cancers with intermediate differentiation. These tumors comprise approximately 1015% of all thyroid cancers (15). They
include Hurthle
cell (oncocytic, oxyphilic) car
cinomas as well as variants of PTC such as the
tall cell variant, columnar cell variant, diffuse
sclerosing variant, and insular carcinoma.

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Natural History and Prognosis

In general, well-differentiated thyroid cancer is
one of the least morbid solid carcinomas, with
patients showing favorable long-term survival.
However, a small proportion of patients with
PTC and a slightly larger proportion of patients
with FTC die from disease-related causes. As
opposed to other solid neoplasms, one major
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Carling

tases appear not to have a strong correlation

with overall survival in most series, but they do
consistently correlate to local recurrence (16).
At presentation, approximately two-thirds
of patients have gross disease localized to the
thyroid. The median size of tumors is between
2.0 cm and 2.5 cm in most large series (17, 18).
Patients with papillary carcinomas smaller than
1.0 cm are considered to have minimal or occult PTC (papillary microcarcinoma). In North
American studies, the incidence of occult papillary tumors ranges between 0.5% and 14.0%,
with a greater proportional incidence in older
age groups. In Japan, a majority of such occult
microcarcinomas are unlikely to lead to clinically signicant disease (19). For this reason,
standard practice is not to investigate or submit
to biopsy nodules that are small (<10 mm), except in the setting of familial thyroid carcinoma,
a history of neck irradiation, or otherwise concerning sonographic features (5).
Regional lymph node metastases are present
at the time of primary diagnosis in 2090%
of patients with PTC and to a lesser extent
in other histiotypes (15). The wide range depends not only on the actual pathological stage
of the tumor, but also on which diagnostic
modalities are employed to assess the potential metastases. Factors associated with lymph
node metastasis in PTC patients include tumor
size, extracapsular invasion, and multifocality.
Micrometastases are common. However, there
is a lack of distinction between macro- and micrometastatic disease in the scientic literature
as well as in tumor staging, complicating the estimation of the true incidence of micro- versus
macrometastatic spread. Comprehensive preoperative cervical ultrasonography is the standard of care in evaluating both central and lateral lymph nodes for metastases. It identies
cervical adenopathy in 2031% of cases (20).
A small minority of patients have distant
metastatic hematogenous disease at the time
of diagnosis. In a large series, 1% to 2% of
PTC patients and 2% to 5% of FTC patients
had metastases outside the neck or mediastinum
at the time of diagnosis (18). Having distant
metastases at the time of presentation is a strong

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predictor of a poor outcome, as 4390% of

these patients die secondary to their thyroid
malignancy (18).
In the overall population with PTC, there is
a 90% to 95% long-term survival and a 70% to
80% long-term survival for patients with follicular cancers. The 20% of patients who develop recurrent disease include a majority with
local cervical recurrences either in their lymph
nodes or the thyroid bed, and a minority of
patients demonstrate distant metastases to the
lung, bone, and liver (21). Apart from their
role as clinical indicators of prognosis, several
molecular genetic alterations have been studied
as putative predictive markers in thyroid cancer. Genes encoding effectors in the mitogenactivated protein kinase (MAPK) pathway have
been of particular interest. Mutations in one
such gene, BRAF, are associated in some, but
not all, studies with an increased likelihood of
extrathyroidal extension, lymph node metastasis, recurrence, and mortality (22, 23).

TREATMENT OF
DIFFERENTIATED
THYROID CARCINOMA
Surgery
The key decisions in the surgical management
of thyroid cancer are whom to operate on
and how extensive a resection to perform. If
a high-quality FNA specimen is diagnostic
of malignancy, a denitive procedure can
be performed in the absence of intraoperative frozen section analysis. A randomized
controlled trial demonstrated a very limited
role of frozen section analysis for the vast
majority of patients with follicular neoplasms
(24). Thus, the recommended approach in this
group of patients is to excise the thyroid lobe
harboring the nodule and to wait for denitive
pathologic analyses on parafn-embedded
tissue. If the lesion turns out to be a follicular
carcinoma, a completion thyroidectomy is
generally performed during a second operation
to remove the contralateral thyroid lobe (25).

A long-standing controversy among endocrine surgeons has existed regarding the extent of surgical resection for well-differentiated
thyroid cancer. The completeness of surgical
resection is associated with lower recurrence
and improved survival; thus, most surgeons advocate total thyroidectomy over thyroid lobectomy (26). The increased risk of performing a
total thyroidectomy versus a lesser resection is
related to the theoretical risk of increased morbidity including iatrogenic hypoparathyroidism
and recurrent nerve injury. Virtually all experienced surgeons should be able to perform total
thyroidectomies with a rate of recurrent nerve
injuries of less than 1%, with the long-term risk
of hypoparathyroidism of 24% (27). Note,
however, that surgeon experience is strongly
related to lower complication rates, especially
in total thyroidectomy and when operating on
patients with malignant versus benign disease
(28). We advocate more aggressive treatment
(i.e., total thyroidectomy) for the vast majority
of patients with well-differentiated thyroid
carcinoma.
For patients with extrathyroidal extension,
en bloc resection of invaded structures should
be performed when possible. If the tumor is
in the anterior thyroid, resection of the overlying strap muscles causes no symptoms postoperatively. For posterior tumors, the margins
are either the trachea or esophagus. For the
majority of well-differentiated thyroid cancers,
tracheal or esophageal resections are not indicated. However, for gross involvement of either
of these structures, resection with reconstruction may be appropriate (29).
Large-scale population-based studies have
shown that regional lymph node metastases
among patients with thyroid cancer impact both
local recurrence and cause-specic mortality
(30). The recent American Thyroid Association guidelines suggest prophylactic centralcompartment neck dissection (ipsilateral or
bilateral) may be performed in patients with
PTC with clinically uninvolved central neck
lymph nodes, especially for advanced primary
tumors (5, 31). The arguments for and against
prophylactic central lymph node dissection in
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Table 2 Summary of arguments for and against prophylactic central lymph node dissection in
well-differentiated thyroid carcinoma

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For

Against

Presence of lymph node metastasis has a negative

effect on patient outcome

May lead to higher rates of hypoparathyroidism

Presence of lymph node metastasis in the central

neck cannot reliably be identied preoperatively or
at operation

May lead to higher rates of recurrent laryngeal

nerve injury

Improves accuracy in staging

Absence of level I data indicating lower recurrence

and mortality rates

Decreases postoperative thyroglobulin levels

Majority of thyroidectomies in the United States is

performed by low-volume surgeons

Can be performed as safely as total thyroidectomy

alone, at least in experienced hands
Leads to avoidance of reoperations in the central
neck, which are associated with increased morbidity
May lead to lower recurrence rates and mortality
rates

well-differentiated thyroid carcinoma are

outlined in Table 2. Given the low rates of
both newly identied structural disease and
morbidity after surgery for PTC, prohibitively
large sample sizes would be required to obtain
sufcient statistical power to demonstrate
signicant differences in outcomes between
patients with and those without prophylactic
central neck dissection. Thus, an adequately
powered randomized prospective controlled
trial of prophylactic central lymph node
dissection is not feasible (27).
Gross lateral cervical metastatic disease is
treated by modied radical neck dissection, preserving the internal jugular vein, sternocleidomastoid muscle, and the accessory nerve, which
results in excellent local control and minimal
morbidity. The lymph nodes typically involved
are the level VI (central compartment) lymph
nodes; the level II, III, and IV nodes along the
internal jugular vein corresponding to the upper, mid, and lower neck; and the level V nodes
(posterior neck) (Figure 1a,b). If positive (on
preoperative FNA or intraoperative frozen section analysis) for metastatic cancer, these lymph
node areas should be completely dissected
(32).

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Radioiodine Therapy
Postoperative radioiodine ablation is often used
in patients with well-differentiated thyroid
cancer. The lack of well-designed, randomized
controlled studies and the low probability
that any large multicenter treatment studies
will ever come to fruition force the clinician
to rely on retrospective studies, surveys of
practice habits, and guidelines (5). The goals of
treatment are to destroy any residual thyroid
tissue, to prevent locoregional recurrence
and to facilitate long-term surveillance with
whole-body iodine scans and/or stimulated
thyroglobulin measurements. Several large
retrospective studies demonstrate reductions
in both recurrence and cause-specic mortality
after 131 I ablation (5, 33). However, other large
studies have failed to show such a relationship,
especially in low-risk patients (33). In studies
showing a benet with 131 I ablation, patients
with larger tumors (>1.5 cm), multifocality,
residual disease, and nodal metastasis seem to
benet from the treatment. Thus, the recent
American Thyroid Association guidelines recommend radioiodine ablation for patients with
stage III and stage IV disease; all patients with
stage II disease younger than 45 years; most

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IIB

IB

IIA

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VA

VB

IA

External branch
of superior
laryngeal nerve

Hyoid bone
Common
carotid
artery

III
VI

Superior horn
of thymus

IV

VI

VII

VII
Thymus

Recurrent
laryngeal nerve

Figure 1
The thyroid gland and lymphatic node basins. (a) Schematic representation of the lymphatic node basins of the
neck. The lateral neck lymph node compartments (levels IIV) and the central neck compartment (level VI).
(b) Schematic illustration of the anatomical borders of the central neck compartment (level VI). The superior
margin is at the level of the hyoid bone, the inferior margin is at the level of the brachiocephalic vessels,
and the lateral margins are at the medial aspect of the common carotid arteries. The central neck (level VI)
contains the precricoid (Delphian), pretracheal, paratracheal, and perithyroidal nodes, including those along
the recurrent laryngeal nerves and the external branch of the superior laryngeal nerve. The parathyroid
glands are also normally located in the central neck. Reprinted with permission from Reference 34.

patients older than 45 years; and selected patients with stage I disease, especially those with
larger tumors (>1.5 cm), multifocality, residual
disease, nodal metastasis, vascular invasion,
and intermediately differentiated histology (5).
The dosing of 131 I for ablation is controversial. Low-dose ablation with less than 30 mCi is
often administered on an outpatient basis. This
approach should be reserved for low-risk young
patients who may benet from an overall lower
radiation exposure and who accept the fact that
several low radioiodine doses may be necessary
before successful ablation. Higher ablative
doses ranging from 100 to 200 mCi should be
used preferentially for older high-risk patients,
particularly those with an incomplete resection
of the primary tumor, an invasive primary
tumor, tumors of intermediate differentiation,
or metastases. Dosimetry can be employed

with the goal of deriving the dose of 131 I that

will deliver no more than 200 cGy to the
blood, with no more than 120 mCi retained at
48 h or 80 mCi in the presence of pulmonary
metastases. Recently, two studies showed that
low-dose radioactive iodine ablation is likely
sufcient for the vast majority of patients with
low-risk differentiated thyroid cancer (34,
35).
To optimize uptake by both normal residual
thyroid and thyroid cancer, the traditional
practice has been to render patients hypothyroid with a goal of increasing their serum
levels of TSH. To accomplish this, thyroid
replacement after thyroidectomy is often
performed by administering triiodothyronine
(T3 ), which has a much shorter half-life than
that of thyroxine (T4 ), and discontinuing it two
weeks before treatment. In response to this
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hypothyroid state, TSH must achieve levels of

greater than 30 mU/L to obtain optimal uptake
of radioiodine. It is also recommended that a
serum thyroglobulin level be obtained during
this period of hypothyroid state. A low-iodine
diet is recommended 1 to 2 weeks before scanning and/or ablative 131 I therapy to enhance
the uptake and retention of radioiodine (5).
Alternatively, imaging and treatment employing TSH stimulation with recombinant human
TSH to detect and treat residual normal thyroid
tissue as well as thyroid cancer are now being
performed with increased frequency. The latter
technique avoids inducing hypothyroidism.
Most but not all studies have demonstrated
a role for TSH suppression therapy in the management of thyroid cancer after therapy. A recent meta-analysis supported the efcacy of
TSH suppression in preventing adverse clinical effects (36). However, such a benet has not
been substantiated in low-risk patients. Thus,
high-risk patients should be maintained with
a serum TSH level below 0.1 mU/L, whereas
TSH levels at or slightly below the normal
range (i.e., 0.10.5 mU/L) seem appropriate for
low-risk patients. There is a weak, but dosedependent, relationship between 131 I therapy
and the development of second malignancies,
such as bone and soft tissue tumors, colorectal
cancer, salivary tumors, and leukemia (37, 38).

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Management of Local Recurrence

and Distant Metastasis
Metastases discovered during surveillance are
likely to be manifestations of persistent disease
that survived 131 I therapy and thus are rarely
curable by additional 131 I treatment. However,
a reduction of the tumor burden with additional
treatment may offer survival and/or palliative
benets. Preferred treatments, in hierarchical
order, are surgical excision of locoregional disease in potentially curable patients, 131 I therapy, external beam radiotherapy (EBRT), close
surveillance in asymptomatic patients, and experimental clinical trials (5).
Patients with nodal locoregional recurrence
in the neck should undergo modied radical
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neck dissection and/or central compartment

(level VI) neck dissection, depending on
the location of the recurrence. In select
patients, with tumor invasion into the aerodigestive tract, more aggressive surgery may
be warranted (29). For regional lymph node
metastasis not amenable to surgical therapy,
or distant metastasis detected via whole-body
iodine scan, 131 I therapy is usually employed,
especially in lesions that are radioiodine avid.
Similar to the discussion of initial treatment,
no consensus exists with regard to dosing of
131
I, although most authors use a high dose
ranging between 150 and 300 mCi. Pulmonary
metastases are frequently detected exclusively
on radioiodine scanning and tend to respond
to 131 I treatment. Treatment can be performed
every 612 months as long as the disease
continues to respond. However, pulmonary
brosis may limit further 131 I treatment (39).
Complete surgical resection of isolated symptomatic bone metastases and 131 I treatment for
radioiodine-avid widespread disease have both
been associated with increased palliation and
survival, and they are recommended especially
in younger patients (39). A combination of
treatments may be considered for symptomatic
bone lesions when surgery or 131 I treatment
is not possible or effective (5). Similarly,
complete surgical resection of CNS metastasis
seems to be the most efcacious treatment,
whereas EBRT may be considered in patients
who are not candidates for surgery.

Role of External Beam Radiotherapy,

Chemotherapy, and Biologic
Therapies
The role of EBRT and chemotherapy in
thyroid cancer is limited. EBRT should be
considered in patients with unresectable gross
residual cervical disease; painful bone metastases; and metastases in critical locations not
amenable to surgery that would likely result in
fracture, neurological, or compressive symptoms (such as metastases in the CNS, vertebral
bodies, selected mediastinal lymph nodes, and
pelvis). The single chemotherapeutic agent

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most commonly used for thyroid cancer is

doxorubicin (Adriamycin) with partial response
rates of 30% and up to 45% in some series.
Combination therapy with Adriamycin and
cisplatin has produced disappointing results
that were no better than single-agent trials,
and the toxicity was worse. For surgically unresectable local disease that has not responded
to radioiodine, the best treatment may be a
combination of hyperfractionated radiation
treatments plus Adriamycin. Response rates of
more than 80% have been reported using this
regimen, but even in this situation, complete
responses are rare and limited in duration (5).
The management of patients with welldifferentiated thyroid cancers that progress
despite current therapies presents a great challenge. During the past decade, biologic discoveries have sparked trials testing novel biologically targeted therapies for advanced thyroid
carcinomas, and several novel agents are currently being tested in vitro and in clinical studies
(40). Most clinical trials so far have focused on
various tyrosine kinase inhibitors (TKIs), and
more work is needed to clarify which patients
with differentiated thyroid cancer may benet
most from TKI treatment (41, 42).

with the usual size of 23 cm for welldifferentiated thyroid cancer. Invasion into the
trachea, larynx, or recurrent laryngeal nerve
leads to obstructive symptoms, hemopthysis,
dysphagea, and hoarseness, which are often
present at diagnosis (43).
The majority of patients with ATC present
with unresectable primary tumors that encase
or grossly invade vital structures such as the
trachea, larynx, esophagus, recurrent nerve,
or common carotid artery. Surgical resection
should always be considered. However, the role
of the surgeon for most patients with ATC is to
establish a clear histologic diagnosis, stage the
patient, protect the airway, and engage medical and radiation oncology to consider palliative
protocols (44).
The median survival in most series is under 5 months from the time of diagnosis. The
majority of patients die as a result of local recurrence, although distant metastases may occur,
primarily in lung, bone, and liver. External radiation has been used with limited success to treat
locally recurrent ATC. Adriamycin is the single most effective chemotherapeutic for ATC,
and Adriamycin plus platinum is more effective
than is Adriamycin alone.

POORLY DIFFERENTIATED
THYROID CARCINOMA

MEDULLARY THYROID
CARCINOMA

Anaplastic thyroid carcinoma (ATC) is one

of the most aggressive and difcult human
malignancies to treat and is one of the most
lethal. The association of ATC with welldifferentiated thyroid carcinoma suggests two
features of the biology of this tumor. First,
ATC may arise via the dedifferentiation of prior
well-differentiated thyroid cancer. Second, the
aggressive growth pattern of this anaplastic tumor may replace all previous evidence of a welldifferentiated tumor. Also, the close association
between ATC and well-differentiated thyroid
cancer suggests that the risk factors are similar.
Patients usually present with a palpable
mass that is rapidly increasing in size. The
median tumor size in patients with ATC is
89 cm, with a range of 320 cm as compared

MTC constitutes 312% of most institutional

series of thyroid cancers (14). Sporadic or nonfamilial MTC accounts for 6070% of cases,
with three distinct familial syndromes accounting for the remainder. MTC is the most prominent clinical diagnosis in multiple endocrine
neoplasia (MEN) 2A and MEN 2B. In 1986,
familial MTC in the absence of the associated
features of MEN 2A or MEN 2B was described.
Appreciation of this syndrome has shifted the
diagnosis percentage of sporadic MTC as a
function of the total number of cases from 80%
to 60% and even lower in some series. In addition to the presence or absence of associated
endocrine abnormalities, each of these familial
forms of MTC has a unique natural history and
prognosis (45).
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The clinical symptoms at the time of

presentation vary. Patients with familial MTC
who are identied by screening with stimulation tests or with molecular analysis (detection
of RET gene mutation) are usually identied
before the development of macroscopic disease. Before the availability of genetic testing
for familial MTC, basal and stimulated serum
calcitonin levels were used to screen patients.
Sequential calcitonin and carcinoembryonic
antigen (CEA) measurements are still important as tumor markers for surveillance of
patients with MTC (8).
For patients with sporadic MTC who are not
identied by biochemical or genetic screening,
the appropriate operation in most cases is a total thyroidectomy with central node dissection
and usually an ipsilateral modied radical neck
dissection. Total thyroidectomy is indicated in
the sporadic setting because a small proportion
of lesions may be bilateral and because it may
not be clear at the time of operation whether
a patient is an index case of familial disease or
the disorder is a true sporadic case. Because all
familial syndromes have a high propensity for
bilateral tumors, total extracapsular thyroidectomy is always indicated. Combined with thyroid resection, a central lymph node dissection
should generally be performed. In addition, owing to the high incidence of ipsilateral nodal
metastasis at presentation, formal modied radical neck dissection is ideally combined with the
initial exploration (8).
The incidence of positive lymph nodes
correlates with the size of the primary lesion
at the time of diagnosis. For lesions smaller
than 1 cm, there is an 11% incidence of
nodal disease, whereas 60% of patients with
tumors larger than 2 cm will have positive
cervical lymph nodes (45). The incidence of
distant metastases at the time of diagnosis
varies with the clinical setting. Patients with
familial non-MEN MTC tend to have a less
aggressive clinical course, and 2% of these
patients present with distant metastases. Unfortunately, patients with sporadic disease are
often explored without a clear diagnosis and/or
by surgeons without experience in managing

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this malignancy. FNA specimens suggestive of

MTC should be stained for calcitonin, which
if positive is highly suggestive of MTC. In
addition, a serum calcitonin and CEA levels in
this setting are almost always elevated, thereby
conrming the diagnosis. It is important to
screen for catecholamine excess prior to surgical exploration, as a patient with apparently
sporadic MTC may in fact have a familial
syndrome with an occult pheochromocytoma.
The outcome of treatment of patients with
sporadic MTC has improved. Recent studies
show a 5-year survival between 80% and 90%
and 10-year survival between 70% and 80%
for combined series of familial and sporadic
MTC (46). The natural history and prognosis for the various subtypes of MTC correlate
with described genetic changes. The introduction of genetic testing and prophylactic surgery
has improved the prognosis in cases of familial
disease. Because different mutations in the RET
gene are associated with variable disease aggressiveness, more recent research has attempted to
correlate a certain mutation (genotype) with the
patients clinical course (phenotype) to provide
genotype-specic recommendations for treatment (47). Thus, individuals with RET gene
mutations associated with MEN 2A and familial MTC are advised to undergo prophylactic
thyroidectomy at age ve to six years, whereas
affected individuals in kindreds with MEN 2B
should undergo thyroidectomy during infancy
owing to the aggressiveness and earlier age at
onset of MTC in these patients (45). Patients
with inherited MTC may be stratied into three
RET gene mutation risk groups, and with increased knowledge of genotype-phenotype correlations, more individualized management (especially timing of prophylactic thyroidectomy)
can be used in the treatment of familial variants
of MTC (8).
For patients with metastatic MTC, surgical resection may still offer the best chance of
survival as well as long-term palliation (8). In
the setting of persistent hypercalcitonemia and
negative imaging studies, remedial surgery with
formal neck dissection is often indicated. However, prior to such an operation, practitioners

Udelsman

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should perform a laparoscopic evaluation of the

liver to rule out supercial hepatic metastases
(45). If present, the enthusiasm for remedial
neck dissection, especially in an asymptomatic
patient, is markedly reduced (8).
The results of MTC treatment with EBRT
or chemotherapeutic agents are disappointing.
The initial proof of concept of TKI treatment
for metastatic MTC was achieved when vandetanib became the rst drug approved in the
United States for treatment of the disease and
the phase III data of vandetanib treatment in
MTC was recently published (48, 49).

FUTURE DIRECTIONS
Owing to the overall excellent prognosis and
low morbidity of treatment of the vast majority
of patients with thyroid cancer, large-scale
randomized controlled trails proving improved
efcacy have been unfeasible. Thus, a number of management strategies, such as the

extent of initial surgery, need for radioactive iodine ablation, etc., remain somewhat
controversial. However, there have been a
number of advancements including enhanced
molecular diagnostic tools for FNA diagnosis, improved surgical outcomes, and novel
biological treatments for MTC. The greatest
challenges in thyroid cancer management are
in patients with advanced disease such as those
with well-differentiated thyroid cancer that
progress despite current therapies and those
with advanced MTC and ATC. With novel
genetic and genomic technologies, studying the
molecular pathogenesis of thyroid cancer will
likely aid researchers in identifying genes and
pathways involved early in cancer development.
Such knowledge will provide critical insights
for prevention, improved diagnosis, and classication. On a long-term scale, deciphering
the molecular pathogenesis of thyroid cancer
will be essential for individualized medical and
surgical treatment of these patients.

DISCLOSURE STATEMENT
The authors are not aware of any afliations, memberships, funding, or nancial holdings that
might be perceived as affecting the objectivity of this review.

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