Management of Thyroid Neoplasms

122
122
Management of Thyroid Neoplasms
Faisal I. Ahmad, Mark E. Zafereo, Stephen Y. Lai
KEY POINTS
• The incidence of thyroid cancer is increasing. Although is paramount in the evaluation of the thyroid bed and neck
some of this increase may be attributable to improved in patients with a history of thyroid cancer who present
detection, other factors may also be affecting the biology with new neck masses or increasing thyroglobulin levels.
and incidence of thyroid cancer. • Central compartment (level VI) neck dissection should be
• Women are three times more likely than men to develop considered in patients with high risk papillary thyroid
differentiated thyroid cancers. carcinoma and suspected Hürthle cell carcinoma. Elective
• Exposure to ionizing radiation remains the only lateral neck dissection is not recommended.
well-established environmental risk factor for thyroid • Bilateral central compartment neck dissection should be
cancer. performed in patients with MTC. There is controversy in
• The molecular mechanism underlying thyroid carcinoma regard to the role of elective lateral neck dissection in
is incompletely understood, but rearrangements of RET or MTC, with some centers basing lateral neck dissection on
activation of BRAF play some role in papillary thyroid preoperative calcitonin level, and others advocating against
carcinoma, while RAS family mutations are associated with elective lateral neck dissection for medullary thyroid
follicular thyroid carcinoma. RET mutations are frequently cancer in the absence of radiographically detectable disease
identified in medullary thyroid carcinoma (MTC), with in the lateral neck on high-definition ultrasound.
specific point mutations linked to the aggressiveness of the • In patients with well-differentiated thyroid carcinoma and
disease. cervical metastases, a systematic neck dissection should be
• A rational and systematic approach to the management of performed rather than selective cervical lymph node
a thyroid nodule is necessary to classify benign versus excision or “berry-picking.”
malignant disease appropriately. • The evaluation and management of patients with
• Fine-needle aspiration cytology (FNAC) is the diagnostic anaplastic thyroid cancer is rapidly changing with the
procedure of choice in the evaluation of thyroid nodules. advent of next generation sequencing, tumor mutation
FNAC is generally performed with ultrasound guidance to testing, and targeted systemic therapy directed at specific
improve diagnostic accuracy and yield. tumor mutations.
• Ultrasonography (US) is the most sensitive and specific • Patients with thyroid carcinoma require long-term
diagnostic imaging modality in the evaluation of thyroid follow-up and monitoring. The extent of this workup
nodules. US may also improve the detection of early, depends on the risk classification of each individual
clinically occult cervical lymph node metastasis, thus patient.
altering surgical management of the neck. Additionally, US
Thyroid neoplasms represent almost 95% of all endocrine tumors, Although thyroid cancer is rare, the incidence of thyroid nodules
although they are relatively uncommon and account for approxi- is significantly greater and affects approximately 4% to 7% of the
mately 2.5% of all malignancies. In 2018, the estimated annual US population.8 Although most of these nodules are benign, the
incidence of thyroid cancer in the United States was 53,990 cases, challenge is to identify the 5% or so of patients with a malignant
and approximately 2060 patients (3.8%) were expected to die of lesion. A subset of thyroid cancers is particularly aggressive and
thyroid cancer.1 The incidence of thyroid cancer has been steadily has the potential for devastating morbidity. No reliable indicators
increasing over the past two decades (Fig. 122.1), and thyroid are currently available to determine which patients will develop
cancer has the fastest increasing incidence of all major cancers in aggressive or recurrent disease, although risk categories based
the United States (∼3.1% increase annually).2 The increase in on clinical and pathologic criteria yield important prognostic
incidence is almost completely attributable to papillary thyroid information.
cancer (PTC).3 Globally, incidence rates of thyroid cancer are Most thyroid carcinomas are well-differentiated tumors of
double in high-income countries compared to low-/middle-income follicular cell origin.9,10 These lesions are histologically defined
countries.4 Although some evidence suggests that improved detec- as papillary carcinoma, follicular carcinoma, and Hürthle cell
tion has primarily contributed to the increased incidence, higher carcinoma. A survey of 53,856 patients described the overall
rates of aggressive PTCs are being detected.5,6 More specifically, incidence of thyroid cancer in the United States.10 In this report,
there is an increasing incidence of patients presenting with meta- approximately 79% of cases were papillary carcinoma, 13% were
static disease at the time of diagnosis, suggesting that the true follicular carcinoma, and approximately 3% were Hürthle cell
incidence may be increasing rather than just overdiagnosis of early carcinoma. A small proportion of patients with these lesions (6%)
lesions.7 Additionally, after a period of stability, thyroid cancer– have a family history of thyroid cancer. Medullary thyroid carcinoma
specific mortality has increased during the past 10 to 15 years.3 (MTC), which arises from parafollicular C cells, accounts for about
1869
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CHAPTER 122 Management of Thyroid Neoplasms1869.e1
Abstract Keywords
122
High-definition ultrasound and fine-needle aspiration biopsy are Thyroid
the hallmark of diagnostic evaluation for thyroid neoplasia. Surgery thyroid cancer
remains the mainstay of treatment for the vast majority of thyroid thyroidectomy
cancer. The prognosis for young patients with differentiated thyroid thyroid nodule
cancer is typically excellent, and these patients are often cured
with surgery alone, with the addition of radioactive iodine for
higher risk disease. Patients with extensive extrathyroidal disease
and/or distant metastases may require adjuvant therapies. Medullary
thyroid cancer is usually sporadic, although all patients should
undergo genetic testing for germline RET mutation. The vast
majority of patients with medullary thyroid cancer should undergo
total thyroidectomy and central compartment dissection. Patients
with elevated calcitonin and carcinoembryonic antigen (CEA) after
surgery should undergo distant metastatic work-up, and may
ultimately require systemic therapy. Recent advances have been
made in the molecular genetics of thyroid cancer, particularly in
the understanding of poorly differentiated and anaplastic tumors.
New targeted agents (specifically targeting BRAF and MEK) as
well as immunotherapy have provided new hope of treatment
options for patients with these more aggressive thyroid cancers.
1870 PART VI Head and Neck Surgery and Oncology
Italy10
20 USA11
Age-standardized incidence in Australia12

cases/100,000 per year 15
Hong Kong13
10
New Zealand14
5 UK15
0
1975 1985 1995 2005
Fig. 122.1 Increased incidence of thyroid cancer in women. (Modified from McLeod DS, Sawka AM,
Cooper DS: Controversies in primary treatment of low-risk papillary thyroid cancer, Lancet 381:1046, 2013.)
3% of thyroid carcinomas. Approximately 30% of patients with structure retracts and degenerates into a solid, fibrous stalk;
these lesions have a strong genetic contribution. Anaplastic car- persistence of this tract can lead to the development of a thyroglos-
cinomas, lymphoma, and distant metastases to the thyroid constitute sal duct cyst with variable amounts of associated thyroid tissue.
a small portion of thyroid malignancies. The lateral thyroid primordia arise from the fourth and fifth
The most common presentation of a thyroid cancer is the pharyngeal pouches and descend to join the central component.
development of a thyroid mass or nodule. Assessment of the lesion Parafollicular C cells arise from the neural crest of the fourth
requires a careful history, physical examination, fine-needle aspira- pharyngeal pouch as ultimobranchial bodies and infiltrate the
tion cytology (FNAC), and perhaps imaging studies. With correct upper portion of the thyroid lobes.16 Because of the predictable
diagnosis and management, most patients with well-differentiated fusion of the ultimobranchial bodies to the medial thyroid anlage,
thyroid carcinomas (WDTCs) have an excellent prognosis. The C cells are restricted to a zone deep within the middle to upper
10-year disease-specific mortality rate is less than 7% for PTC third of the lateral lobes.17
and less than 15% for follicular thyroid cancer.10–13 Controversy The thyroid gland is composed of two lateral lobes connected
regarding the treatment of thyroid carcinomas and the extent of by a central isthmus that weighs 15 to 25 g in adults. A thyroid
thyroidectomy to be performed arises because of the indolent lobe usually measures about 4 cm in height, 1.5 cm in width, and
course of most thyroid cancers. Interventions for thyroid cancer 2 cm in depth. The superior pole lies posterior to the sternothyroid
have been difficult to evaluate because of the long follow-up and muscle and lateral to the inferior constrictor muscle and the
the large number of patients needed to determine differences in posterior thyroid lamina. The inferior pole can extend to the level
survival. The morbidity that may accompany any aggressive of the sixth tracheal ring. Approximately 40% of patients have a
intervention needs to be balanced with the generally good prognosis pyramidal lobe that arises from either lobe or the midline isthmus
of patients with thyroid cancer. Professional societies and other and extends superiorly (Fig. 122.2).
groups have established evidence-based clinical practice guidelines The thyroid is enclosed between layers of the deep cervical
for the management of thyroid cancer, but these efforts highlight fascia in the anterior neck. The true thyroid capsule is tightly
the general lack of quality clinical trial data upon which to base adherent to the thyroid gland and continues into the parenchyma
treatment recommendations. to form fibrous septa that separate the parenchyma into lobules.
This chapter begins with a review of the surgical anatomy and The surgical capsule is a thin, filmlike layer of tissue that lies on
embryology of the thyroid gland. After a brief overview of the the true thyroid capsule. Posteriorly, the middle layer of the deep
present understanding of the pathogenetic mechanisms that lead cervical fascia condenses to form the posterior suspensory ligament,
to thyroid cancer, risk factors and staging of thyroid carcinomas or Berry ligament, that connects the lobes of the thyroid to the
are reviewed. An algorithm for the evaluation of a thyroid nodule cricoid cartilage and the first two tracheal rings.
is presented and available diagnostic tools, including the increasing Blood supply to and from the thyroid gland involves two pairs
role of ultrasound examination in the evaluation of the thyroid of arteries, three pairs of veins, and a dense system of connecting
and neck, are reviewed. A review of the different forms of thyroid vessels within the thyroid capsule. The inferior thyroid artery arises
cancer that range from well-differentiated carcinomas to anaplastic as a branch of the thyrocervical trunk (Fig. 122.3). This vessel
and other, less common malignancies is followed by a discussion extends along the anterior scalene muscle and crosses beneath
of surgical management and postoperative adjuvant treatment. the long axis of the common carotid artery to enter the inferior
portion of the thyroid lobe. Although variable in its relation-
ship, the inferior thyroid artery lies anterior to the recurrent
SURGICAL ANATOMY AND EMBRYOLOGY laryngeal nerve (RLN) in approximately 70% of patients.18 The
The thyroid medial anlage derives from the ventral diverticulum inferior thyroid artery is also the primary blood supply for the
of the endoderm from the first and second pharyngeal pouches parathyroid glands.
at the foramen cecum.14,15 The diverticulum descends from the The superior thyroid artery is a branch of the external carotid
base of the tongue to its adult pretracheal position through a artery and courses along the inferior constrictor muscle with the
midline anterior path with the primitive heart and great vessels superior thyroid vein to supply the superior pole of the thyroid.
during weeks 4 to 7 of gestation. The proximal portion of this This vessel lies posterolateral to the external branch of the superior
CHAPTER 122 Management of Thyroid Neoplasms 1871
122
Nonrecurrent
laryngeal n.
Recurrent
laryngeal n.
Parathyroid
glands
Inferior
thyroid a.
B
Recurrent
Fig. 122.2 (A and B) A pyramidal lobe of the thyroid gland may
laryngeal n.
occasionally arise from the isthmus. This portion of the thyroid gland
can be quite variable in size and should be carefully identified and
removed with the surgical specimen. (B, From Lai SY, Weber RS: B
Thyroid cancer. In Ensley JF, Gutkind JS, Jacobs JR, et al., editors:
Fig. 122.3 (A and B) The thyroid gland is intimately associated with
Head and neck cancer: emerging perspectives, San Diego, 2002,
several important adjacent structures. In the lateral view, the gland
Academic Press, p 419.)
has been mobilized medially to show the recurrent laryngeal nerve and
its close relationship to the inferior thyroid artery. This relationship can
vary between sides within a patient. The potential courses of the
nonrecurrent laryngeal nerve are indicated (dashed lines). (From Lai
laryngeal nerve (SLN) as the nerve courses through the fascia SY, Weber RS: Thyroid cancer. In Ensley JF, Gutkind JS, Jacobs JR,
that overlies the cricothyroid muscle. Care should be taken to et al, editors: Head and neck cancer: emerging perspectives, San
ligate this vessel without damaging the SLN. Occasionally, the Diego, 2002, Academic Press, p 420.)
arteria thyroidea ima may arise from the innominate artery, carotid
artery, or aortic arch and may supply the thyroid gland near the
midline.18 Many veins within the thyroid capsule drain into
the superior, middle, and inferior thyroid veins, which lead to the On the right side, the nerve recurs around the fourth arch (sub-
internal jugular or innominate veins. The middle thyroid vein clavian artery), and on the left side, the nerve recurs around the
travels without an arterial complement, and division of this vessel sixth arch (ligamentum arteriosum).
permits adequate rotation of the thyroid lobe to identify the RLN The right RLN leaves the vagus nerve at the base of the neck,
and parathyroid glands. loops around the right subclavian artery, and returns deep to the
The RLN provides motor supply to the larynx and some sensory innominate artery back into the thyroid bed approximately 2 cm
function to the upper trachea and subglottic area. Careful manage- lateral to the trachea (Fig. 122.4). The nerve enters the larynx
ment of thyroid carcinomas requires a thorough knowledge of between the arch of the cricoid cartilage and the inferior cornu of
the course of the RLN (see Fig. 122.3). During development, the the thyroid cartilage. The left RLN leaves the vagus at the level of
inferior laryngeal nerves derive from the sixth branchial arch and the aortic arch and loops around the arch lateral to the obliterated
originate from the vagus nerves under the sixth aortic arch. The ductus arteriosus. The nerve returns to the neck posterior to the
RLN is dragged caudally by the lowest persisting aortic arches. carotid sheath and travels near the tracheoesophageal groove along
a more medial course than the right RLN. The nerve crosses deep to the supraglottis. The external branch extends medially along
to the inferior thyroid artery approximately 70% of the time and the inferior constrictor muscle to enter the cricothyroid muscle.
often branches above the level of the inferior thyroid artery before Along its course, the nerve travels with the superior thyroid
entry into the larynx.19 The RLN travels beneath the inferior fibers artery and vein. The nerve typically diverges from the superior
of the inferior constrictor and behind the cricothyroid articulation thyroid vascular pedicle about 1 cm from the thyroid superior
to enter the larynx. A “nonrecurrent” laryngeal nerve may rarely pole (Fig. 122.7).
occur on the right side and enters from a more lateral course (Fig. Proper management of the parathyroid glands during thyroid
122.5C; see also Fig. 122.3).20 In almost all cases of a nonrecurrent surgery is crucial to avoid hypoparathyroidism. The superior
laryngeal nerve, an aberrant retroesophageal subclavian artery parathyroid glands are derived from the fourth pharyngeal pouch,
(arteria lusoria) or other congenital malformation of the vascular whereas the inferior counterparts originate from the third pha-
rings is present (Fig. 122.6). ryngeal pouch. The parathyroid glands are caramel-colored glands
The SLN arises beneath the nodose ganglion of the upper that weigh 30 to 70 mg. The subtle distinction of tan and yellow
vagus and descends medial to the carotid sheath, dividing into an coloration permits differentiation from adjacent fatty tissue,
internal and external branch about 2 cm above the superior pole although with trauma, the glands can become mahogany in color.
of the thyroid.21 The internal branch travels medially and enters Four parathyroid glands exist in 80% of patients, and at least 10%
through the posterior thyrohyoid membrane to supply sensation of patients have more than four glands.22 The glands are situated
on the undersurface of the thyroid gland in predictable locations.
The superior glands are located at the level of the cricoid cartilage,
usually medial to the intersection of the RLN and the inferior
thyroid artery.22 The inferior glands are more variable in location
than their superior counterparts. These glands may be on the
lateral or posterior surface of the lower pole (Fig. 122.8). In many
patients, the position of the parathyroid glands on one side is
similar to the other side and should be a useful guide.
MOLECULAR BASIS FOR THYROID NEOPLASMS

Numerous genetic and molecular abnormalities have been described
in thyroid neoplasms, and specific genetic alterations of thyroid
carcinoma are summarized in Table 122.1. Similar to other head
and neck cancers, an accumulation of genetic alterations seems
to be required for progression to thyroid carcinoma. The specific
molecular events and their order continue to be defined, and the
current genome sequencing effort by the Cancer Genome Atlas
of PTC should be quite informative.
Alterations noted in the development of thyroid carcinomas
include changes in total cellular DNA content. The loss of
Fig. 122.4 The right vagus nerve (V) can be seen traveling over the chromosomes, or aneuploidy, has been noted in 10% of all papillary
subclavian artery (S). The distal vagus nerve (V*) continues to travel carcinomas but is present in 25% to 50% of all patients who die
inferiorly, while the recurrent laryngeal nerve (RLN) turns superiorly and as a result of these lesions.23 Similarly, the development of follicular
travels deep to the subclavian artery. adenomas is associated with a loss of the short arm of chromosome
A B C
Fig. 122.5 (A) Careful dissection along the lateral portion of the thyroid lobe permits mobilization of the gland
medially. The middle thyroid vein(s) should be carefully identified and ligated. (B) The course of the recurrent
laryngeal nerve along the tracheoesophageal groove is shown intraoperatively. (C) The lateral course of a
nonrecurrent laryngeal nerve has been revealed intraoperatively.
122
A B
Fig. 122.6 (A) Operative case requiring resection of a segment of trachea. A segment of trachea has been
resected between the cricoid (C) and distal trachea (T), with the esophagus (E) in view posteriorly. A
nonrecurrent laryngeal nerve (*) can be seen coming directly off the vagus nerve (V). (B) An axial CT scan of
this same patient shows an aberrant subclavian artery (S) traveling posterior to esophagus.
Fig. 122.7 The external branch of the superior laryngeal nerve,

as noted by the forceps, can been seen traveling towards the
cricothyroid muscle, after inferior reflection of the superior thyroid pole.
Fig. 122.8 Intraoperative view of the superior parathyroid gland (SP),
inferior parathyroid gland (IP), and their relation to the recurrent
laryngeal nerve (*) which is traveling in the tracheoesophageal groove.
11 (11p), and transition to a follicular carcinoma seems to involve
deletions of 3p, 7q, and 22q.24,25 Loss of heterozygosity that involves
multiple chromosomal regions is much more prevalent in follicular kinase A system. Point mutations of the G-protein Ras found in
adenomas and carcinomas than in papillary carcinomas.26 thyroid adenomas and multinodular goiters are believed to be an
Several oncogenes, altered genes that contribute to tumor devel- early mutation in tumor progression.28 Somatic Ras mutations are
opment, have been identified in early thyroid tumor progression. associated with follicular adenomas and, to a lesser extent, with
Mutations in the thyroid-stimulating hormone (TSH) receptor follicular carcinomas. The resultant activation of the phosphati-
and G-protein mutations are found in hyperfunctioning thyroid dylinositol 3′-kinase (PI3K) signal transduction pathway and AKT,
adenomas.27 These changes can lead to the constitutive activation a PI3K-related serine/threonine kinase, also seems to be specific
of cell-signaling pathways, such as the adenylate cyclase–protein to follicular thyroid carcinoma (FTC).29
TABLE 122.1 Incidence of Specific Genetic Alterations Associated With Thyroid Carcinoma
Genetic Alteration PTC FTC PDTC ATC MTC
RET rearrangement 20% Rare
NTRK1 rearrangement 5%–13%
RET mutation Sporadic 30%–50%
MEN-2 95%
BRAF mutation 45% 15% 44%
RAS mutation 10% 40%–50% 44% 20%–60%
PIK3CA mutation Rare Rare Rare 20%
PPARG rearrangement 35% Rare
TP53 Rare Rare 15%–30% 60%–80% Rare
ATC, Anaplastic thyroid carcinoma; FTC, follicular thyroid cancer; MEN-2, multiple endocrine neoplasia type 2; MTC, medullary thyroid carcinoma;
PDTC, poorly differentiated thyroid carcinoma; PTC, papillary thyroid carcinoma.
Other genetic changes have also been associated with certain Presumably, RET gene mutations result in the activation of the
types of thyroid carcinoma. Mutations within the mitogen-activated Ras/JNK/ERK1/2 signaling pathways, which results in further
protein kinase pathway are involved in malignant transformation genomic instability and prevention of entry into the apoptotic
to PTC. Additionally, rearrangements or activation of RET or pathway.42
BRAF protooncogenes, which can also activate mitogen-activated MTC and pheochromocytoma arise from neural crest cells
protein kinase, are often found in PTC.30 Gene rearrangements that contain RET point mutations. These point mutations have
that involve tropomycin receptor kinase A (TRKA) and the gene been well documented in patients with familial MTC and multiple
known as neurotropic tyrosine receptor kinase type 1 (NTRK1), a endocrine neoplasia (MEN) types 2A and 2B.43,44 The aggressiveness
receptor for nerve growth factor, are associated with PTCs. These of the MTC that develops is linked to the specific RET mutation
rearrangements with heterologous sequences generate NTRK1 identified.45 Somatic mutations of RET are also found in approxi-
oncogenes that constitutively activate the tyrosine kinase domain. mately 25% of sporadic MTCs. Many of these are identical to
Mutations in MET/hepatic growth factor have been linked to the codon 918 mutation found as a germline mutation in MEN-2B,
PTC and poorly differentiated thyroid carcinoma (PDTC). Other although other codons are more infrequently involved.46
growth factors such as fibroblast growth factors, epidermal growth Rearrangements of the RET gene by fusion with other genes
factor, and vascular endothelial growth factor and their cognate also create transforming oncogenes. Although more than 10
receptors may have increased expression in thyroid tumors and rearrangements have been described, three oncogene proteins—
can contribute to tumor progression. The transversion point RET/PTC1, RET/PTC2, and RET/PTC3—account for most
mutation T1799A results in the BRAF-V600E mutant protein, of the rearrangements found in PTCs and are more frequently
which is a constitutively active form of this serine/threonine associated with childhood thyroid carcinomas.47 Not all patients
kinase.31 BRAF-V600E is present in approximately 45% of PTCs with papillary carcinomas express an RET/PTC gene, however.48
and in some cases can be associated with poor clinicopathologic Geographic differences are marked, and the gene rearrangement
outcomes, including aggressive pathologic features, increased is strongly associated with radiation exposure. After the Chernobyl
recurrence, loss of radioiodine avidity, and treatment failures.32,33 nuclear disaster, 66% of the PTCs removed from affected patients
Furthermore, this mutation is also found in approximately had RET/PTC1 or RET/PTC3 rearrangements.49 The RET/PTC3
45% of ATCs.34 rearrangement is most commonly associated with a “solid” follicular
Different types of galectin, a carbohydrate-binding protein, variant of PTC, whereas RET/PTC1 is associated more often with
seem to be differentially expressed in papillary and anaplastic the classic or diffuse sclerosing variants.50,51
carcinomas and can be useful in distinguishing benign from
malignant thyroid lesions.35,36 In Cowden disease (familial goiter MOLECULAR DIAGNOSTICS AND
and skin hamartomas), inactivating mutations of the phosphatase
and tensin homologue (PTEN) gene have been identified.37 PTEN TARGETED THERAPIES
may inhibit phosphorylation and kinase activity of AKT1, which The increased understanding of underlying genetic alterations
leads to the development of follicular adenomas and carcinomas.29 related to various subtypes of thyroid carcinoma have led to the
The PAX8/PPARγ γ1 (peroxisome proliferator-activated receptor) development of diagnostic and prognostic assays. Molecular markers
rearrangement seems to be unique to FTC.38 PAX8 is expressed that include galectin-3, cytokeratin, and BRAF have been evaluated
at high levels during thyroid development, and the PAX/PPARγ and may improve the diagnostic accuracy for patients with
γ 1 gene product seems to function as a dominant negative that indeterminate thyroid nodules.52 Combined use of genetic markers
blocks the activation of wild-type PPARγ γ 1. Mutations in the in a gene-expression classifier has been validated in a prospective
tumor-suppressor gene TP53, a transcriptional regulator, seem to multicenter study.53 Furthermore, the BRAF-V600E mutation may
be involved in insular thyroid carcinomas and in the progression assist in risk stratification and may define treatment for patients
from papillary to anaplastic thyroid carcinoma (ATC).39,40 PDTC with PTC and ATC.54,55 Although these tests are becoming com-
has a worse prognosis than WDTC and possesses genetic features mercially available, widespread clinical adoption depends upon
in between WDTC and ATC. further validation.
The role of mutations of the RET oncogene in the development Targeted therapies have focused upon the known oncogenic
of PTC and MTC has been extensively studied.41 Located on signaling pathways, modulators of growth or apoptosis, and
chromosome 10, RET codes for a transmembrane tyrosine kinase angiogenesis inhibitors. A number of phase II studies have dem-
receptor (TRK) that binds glial cell line–derived neurotrophic onstrated promising efficacy for novel small-molecule protein
factor. During embryogenesis, RET protein is normally expressed kinase inhibitors.56–58 Currently, cabozantinib and vandetanib
in the nervous and excretory systems. Abnormalities in RET (medullary thyroid cancer); lenvatinib and sorafenib (differentiated
expression result in developmental defects that include the disrup- thyroid cancer); and combination dabrafenib/trametinib (anaplastic
tion of the enteric nervous system (Hirschsprung disease). thyroid cancer) are the only Food and Drug Administration
(FDA)–approved targeted agents for the treatment of advanced have identified key patient-specific and tumor-specific characteristics
thyroid cancer. Continuing efforts are directed at genetic-based that predict patient outcome. Risk grouping has been used to 122
targeting of disease and restoration of radioiodine avidity. focus aggressive treatment for high-risk patients and to avoid
excessive treatment and its potential complications in patients
with a lower risk for tumor recurrence or tumor-related death.
RISK FACTORS AND ETIOLOGY
Although the specific molecular events related to the development
of thyroid carcinomas remain incompletely defined, several patient
Tumor-Node-Metastasis Classification
and environmental factors have been closely examined. Women The American Joint Commission on Cancer (AJCC) and the
are three times more likely than men to develop differentiated Union Internationale Contre le Cancer (UICC) adopted a tumor-
thyroid cancer and two times more likely to have ATC. The median node-metastasis (TNM) classification system (Table 122.2). This
age at diagnosis is 51 years, with a peak in women at 50 to 54 staging system was recently updated in 2018.68 In this system,
years and in men at 65 to 69 years.2 Epidemiologic studies have patient age at presentation can significantly influence the clinical
not shown a clear association between dietary iodine and thyroid staging of differentiated thyroid carcinomas. The expected 10-year
carcinomas.59 Also, there does not seem to be a simple relationship disease-specific survival for all patients with stage I disease is 98%
between benign goiter and WDTC. Although PTC is not associated to 100%. However, for patients greater than 55 years increasing
with goiter, follicular and ATCs occur more commonly in areas stage portends a worse disease-specific survival, with patients
of endemic goiter. Additionally, two particularly important risk with stage IV disease having less than 50% expected survival
factors—exposure to radiation and a family history of thyroid at 10 years.69,70
cancer—have been studied extensively.
Exposure to ionizing radiation increases patient risk for
the development of thyroid carcinoma.60,61 Ionizing radiation
AMES
exposure is the only established environmental risk factor for In the AMES system, patient age, the presence of metastases,
thyroid cancer.62 Low-dose ionizing radiation treatments (<2000 extent of tumor invasion, and tumor size were used to stratify
cGy) were used in the treatment of enlarged thymus to prevent patients into low-risk and high-risk groups (Table 122.3). Low-risk
sudden crib death, enlarged tonsils and adenoids, acne vulgaris, patients were young (men, <41 years old; women, <51 years old),
hemangioma, ringworm, scrofula, and other conditions. The risk without distant metastases, and all older patients without extra-
increases linearly from 6.5 to 2000 cGy and typically has a latency thyroid papillary carcinoma, without major invasion of the tumor
period that lasts 10 to 30 years. Although higher doses of ion- capsule by follicular carcinoma, or with a primary tumor less than
izing radiation typically lead to the destruction of thyroid tissue, 5 cm in diameter. In a review of 310 patients from 1961 through
patients with Hodgkin disease who receive 4000 cGy also have a 1980, low-risk patients (89%) had a mortality of 1.8% compared
higher incidence of thyroid cancer. Palpable thyroid nodularity with high-risk patients (11%), who had a mortality rate of 46%.
may be present in 17% to 30% of patients exposed to ionizing Recurrence in low-risk patients was 5%, and in high-risk patients,
radiation.63 A patient with a history of radiation exposure who it was 55%.71 In the DAMES system, nuclear DNA content was
presents with a thyroid nodule has a 50% chance of having a added to improve risk stratification for PTC.72
malignancy.64 Of these patients with thyroid cancer, 60% have
cancer within the nodule, and the remaining 40% have cancer in
another area of the thyroid. Thyroid carcinoma tends to be papillary
AGES and MACIS
and is frequently multifocal, and the risk of cervical metastases is In the original AGES system, age at diagnosis, histologic tumor
also higher. grade, extent of disease at presentation, and tumor size were used to
Similarly, patients exposed to radiation from nuclear weapons calculate a prognostic score.73 Because of the infrequent practice of
and accidents have a higher incidence of thyroid cancer. Children tumor grading, a more recent modification of the system eliminated
near the Chernobyl nuclear power facility had a 60-fold increase histologic tumor grade and incorporated metastasis and extent
in thyroid carcinoma after the nuclear accident in 1986.65 Most of resection. The MACIS system accounts for metastasis, age at
of these children were infants at the time of the accident, and diagnosis, completeness of surgical resection, extrathyroid invasion,
many of these cases developed without the typical latency period. and tumor size.74 The MACIS score is calculated as follows:
The thyroid gland seems to be particularly vulnerable to ionizing
radiation in children and yet is relatively insensitive in adults. In 31 ( patient age < 40 years ) or 0.08 × age ( patient age ≥ 40 years )
the life-span study of atomic bomb survivors in Hiroshima and
+ 0.3 × tumor size ( in cm ) + 1 ( if extra thyroidal extension )
Nagasaki, the risk of thyroid cancer was associated with patient
age at the time of the bombings.66 The risk was greatest for + 1 ( if in complete resection ) + 3 ( if distant metastases )
individuals younger than 10 years, and no increased incidence of
thyroid cancer was seen in individuals older than 20 years at the Patients were stratified by their prognostic scores into four
time of exposure. groups with statistically significant differences in 20-year disease-
Finally, familial and genetic contributions need to be fully specific mortality.
evaluated. A patient with a family history of thyroid carcinoma Other risk-classification systems with similar diagnostic criteria
may require specific diagnostic testing. Approximately 6% of have been described.75–77 Although numerous multivariable
patients with PTC have familial disease. PTC occurs with increased prognostic scoring systems have been developed, none is universally
frequency in certain families with breast, ovarian, renal, or central accepted. Additionally, none of these classifications has shown
nervous system malignancies.67 Gardner syndrome (familial colonic clear superiority, and application of these systems to a single
polyposis) and Cowden disease are associated with WDTCs. population has shown incompatible findings compared with the
Patients with a family history of MTC, MEN-2A, or MEN-2B original studies.77,78 These systems do not apply to patients with
warrant evaluation for the RET point mutation. poorly differentiated and more aggressive thyroid carcinomas.
Nevertheless, some general conclusions can be drawn from
these studies regarding the prognosis of patients with WDTCs.
TUMOR STAGING AND CLASSIFICATION Low risk for tumor recurrence and disease-specific mortality is
Numerous staging and classification systems have been devised noted in patients who (1) are younger at diagnosis, (2) have smaller
to stratify patients with thyroid carcinomas. These classifications primary tumors that lack extrathyroid extension or regional/distant
TABLE 122.2 Tumor/Node/Metastasis Staging for Thyroid Cancer

Stage Description
PRIMARY TUMOR (T)
TX Primary tumor cannot be assessed
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 >1 cm but ≤2 cm in greatest dimension, limited to thyroid
T2 Tumor >2 cm and ≤4 cm in greatest dimension, limited to thyroid
T3 Tumor >4 cm limited to the thyroid, or gross extrathyroidal extension invading only strap
muscles
T3a Tumor >4 cm limited to the thyroid
T3b Gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid,
thyrohyoid, or omohyoid muscles) from a tumor of any size
T4 Includes gross extrathyroidal extension beyond the strap muscles
T4a Gross extrathyroidal extension invading subcutaneous soft tissues, larynx, trachea,
esophagus, or recurrent laryngeal nerve from a tumor of any size
T4b Gross extrathyroidal extension invading prevertebral fascia or encasing the carotid artery
or mediastinal vessels from a tumor of any size
REGIONAL LYMPH NODES (N)
NX Regional lymph nodes cannot be assessed
N0 No evidence of locoregional lymph node metastasis
N0a One or more cytologically or histologically 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. This 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)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
Grouping Age <55 Years Age ≥55 Years
PAPILLARY/FOLLICULAR
Stage I Any T, any N M0 T1 N0 M0
T2 N0 M0
Stage II Any T, any N M1 T1 N1 M0
T2 N1 M0
T3a/T3b, any N, M0
Stage III T4a, any N, M0
Stage IVA T4b, any N, M0
Stage IVB Any T, any N, M1
MEDULLARY
Stage I T1 N0 M0
Stage II T2 N0 M0
T3 N0 M0
Stage III T1-T3 N1a M0
Stage IVA T1-3, N1b, M0
T4a, any N, M0
Stage IVB T4b, any N, M0
Stage IVC Any T, any N, M1
ANAPLASTIC
Stage IVA T1-T3a, N0, M0
Stage IVB T1-T3a, N1, M0
T3b, any N, M0
T4, any N, M0
Stage IVC Any T, any N, M1
From the American Joint Committee on Cancer: AJCC cancer staging manual, ed 8, New York, 2018, Springer.
metastases, and (3) have complete gross resection of disease at with a particular form of thyroid carcinoma. More recent manage-
the initial surgery. Delay in treatment negatively affects prognosis; ment guidelines from the American Thyroid Association (ATA)
however, the most significant overall indicator of a poor prognosis have recommended use of the AJCC/UICC staging system for
is distant metastases, especially to bone.11 all patients with differentiated thyroid cancer. Noting that this
Although a single risk-classification strategy is unavailable, these system was developed to predict risk for death, rather than for
criteria should guide physicians to use therapeutic strategies directed recurrence, the ATA guidelines include consensus-based criteria
toward the particular disease and risk for an individual patient, for assessment of risk of recurrence,79 which has been validated
rather than applying a general treatment strategy for all patients in a retrospective analysis (Box 122.1).
TABLE 122.3 Factors Used in Prognostic Classification Systems are carcinoma. With a lifetime incidence of 4% to 7%, the annual
incidence of thyroid nodules in the United States is about 0.1%, 122
TNM AMES AGES MACIS
which is approximately 300,000 new nodules each year.80,81 Most
PATIENT FACTORS of these nodules are benign and do not require removal. With
Age × × × × approximately 37,000 new thyroid cancers each year, about 1 in
Gender × × 20 new thyroid nodules contains carcinoma, however, and approxi-
TUMOR FACTORS mately 1 in 200 nodules is lethal. The challenge in treating patients
Size × × × × with thyroid nodules is to identify patients with malignant lesions
Histologic grade × and to balance the potential morbidity of treatment with the
Histologic type × × * * aggressiveness of the disease.
Extrathyroid spread × × × ×
Lymph node metastasis ×
Distant metastasis × × × × Clinical Assessment: History and
Incomplete resection × Physical Examination
*AGES/MACIS classifications for papillary carcinomas only. Numerous findings should raise suspicion of malignancy in a
AGES, Age at diagnosis, histologic tumor grade, extent of disease at patient presenting with a thyroid nodule. Younger and older patients
presentation, and tumor size; AMES, patient age, metastases, extent are more likely to have a malignant thyroid nodule. Patients younger
of invasion, and tumor size; MACIS, metastasis, age at diagnosis, than 20 years have an approximately 20% to 50% incidence of
completeness of surgical resection, extrathyroid invasion, and tumor
malignancy when presenting with a solitary thyroid nodule.82
size; TNM, tumor/node/metastasis.
Nodular disease is more common in older patients, usually men
older than 40 years and women older than 50 years. Although
children may present with more advanced disease and even cervical
metastases, malignancy in older patients has a considerably worse
BOX 122.1 Risk Stratification for Thyroid Cancer Recurrence prognosis. Men often have more aggressive malignancies than
women, but the overall incidence of thyroid nodules and malignancy
High Risk FTC, extensive vascular invasion is higher in women.
Gross extrathyroidal (≈30%–55%) A family history of thyroid carcinoma should be carefully
extension, incomplete pT4a gross ETE (≈30%–40%) evaluated. Similarly, any history of medullary carcinoma, pheo-
tumor resection, distant pN1 with extranodal extension, >3 chromocytoma, or hyperparathyroidism should raise suspicion
metastases, or lymph LN involved (≈40%) PTC, >1 cm, for the MEN syndromes. Gardner syndrome (polyposis coli) and
node >3 cm TERT mutated ± BRAF mutated Cowden disease also have been associated with WDTCs. As
(≈40%) pN1, any LN >3 cm described previously, a history of previous head and neck radiation
(≈30%) exposure significantly increases the risk of malignancy in patients
PTC, extrathyroidal, BRAF mutated with a thyroid nodule.
(≈10%–40%) PTC, vascular When evaluating the patient, rapid growth of a preexisting or
invasion (≈15%–30%) new thyroid nodule is concerning, although the change may
Clinical N1 (≈20%) represent hemorrhage into a cyst. Throat or neck pain is rarely
pNl, >5 LN involved (≈20%) associated with carcinoma but frequently occurs with hemorrhage
Intermediate Risk
Intrathyroidal PTC, <4 cm, BRAF into a benign nodule. Patients should be carefully questioned
Aggressive histology,
mutated (≈10%) pT3 minor ETE regarding any compressive or invasive symptoms, such as voice
minor extrathyroidal
(≈3%–8%) change, hoarseness, dysphagia, or dyspnea. The clinician should
extension, vascular
pN1, all LN <0.2 cm (≈5%) not rely on these findings alone, however, because unilateral vocal
invasion, or >5 involved
pN1 ≤5 LN involved (≈5%) cord paralysis can be present without voice change or swallowing
lymph nodes (0.2–3 cm)
Intrathyroidal PTC, 2–4 cm (≈5%) difficulties. Although most patients with thyroid cancer are
Multifocal PTMC (≈4%–6%) euthyroid at presentation, symptoms of hyperthyroidism and
pN1 without extranodal extension, hypothyroidism should be explored. Patients with large carcinomas
≤3 LN involved (2%) Minimally that have replaced a significant portion of the normal thyroid
invasive FTC (≈2%–3%) gland may be hypothyroid, and patients with Hashimoto thyroiditis
Intrathyroidal, <4 cm, BRAF wild type may develop lymphoma. Although the history alone cannot
(≈1%–2%) Intrathyroidal unifocal determine the presence of thyroid cancer, important historic features
Low Risk PTMC, BRAF mutated, (≈1%–2%) are associated with thyroid carcinoma and should not be discounted,
Intrathyroidal DTC ≤ 5 LN Intrathyroidal, encapsulated, even if diagnostic tests indicated a benign lesion.
micrometastases FV-PTC (≈1%–2%) The physical examination of a patient with a thyroid nodule
(<0.2 cm) Unifocal PTMC (≈1%–2%) begins with careful palpation of the thyroid to assess the lesion.
The clinician should determine whether the lesion is solitary or
DTC, differentiated thyroid cancer; ETE, extra-thyroidal extension; FTC,
follicular thyroid carcinoma; FV, follicular variant; LN, lymph node; PTC,
the dominant nodule in a multinodular gland, although the risk
papillary thyroid cancer; PTMC, papillary thyroid microcarcinoma; TERT, of carcinoma in either setting is the same.8,64 Asking the patient
telomerase reverse transcriptase. to swallow may assist in the examination because nonthyroid
pathology does not typically elevate with the thyroid during
swallowing. Palpable nodules are typically 1 cm or larger; smaller
nodules can be found incidentally on radiographic studies for
other reasons and can be monitored. Lesions greater than 1 cm
EVALUATION OF A THYROID NODULE in size warrant a complete workup. The firmness of the nodule
The incidence of thyroid nodular disease is quite high, and it may be associated with an increased risk of carcinoma by twofold
spontaneously occurs at a rate of 0.08% per year, starting in early to threefold.83 Nodules greater than 2 cm in diameter and solid
life and extending into the eighth decade.63 Although thyroid lesions have an increased incidence of harboring carcinoma. The
nodules represent a wide spectrum of disease, most are colloid evaluation of larger lesions also requires more caution because
nodules, adenomas, cysts, and focal thyroiditis; only a few (5%) the rate of false-negative results during FNAC also increases.84
Potential substernal extension can be estimated by the relation-

ship of the inferior aspect of the mass to the clavicle. Potential
Diagnostic Studies
thoracic inlet obstruction owing to a substernal goiter can be
assessed with a Pemberton maneuver, in which the patient raises
Laboratory Studies
his or her arms over the head to elicit positive findings of obstruc- Most patients who present with a thyroid nodule are euthyroid.
tion; these include subjective respiratory discomfort or venous The finding of hypothyroidism or hyperthyroidism tends to shift
engorgement that results in facial suffusion. Radiographic studies the workup away from thyroid carcinoma to a functional disorder
are more definitive in determining substernal involvement. of the thyroid gland, such as Hashimoto thyroiditis or a toxic
Further assessment of the patient may reveal the extent of nodule.87 Although many thyroid hormone tests are available, few
involvement of a thyroid lesion. Palpable cervical nodes adjacent are needed in the initial patient evaluation. TSH measurement
to the thyroid nodule increase the suspicion for malignancy, and serves as an excellent screening test, and full thyroid function tests
they may be the only presenting sign of a thyroid carcinoma. can be performed if the TSH level is abnormal.
Adenopathy may be present, however, in a patient affected by Measurement of thyroglobulin (Tg) is generally not performed
Hashimoto thyroiditis, Graves disease, or infection.85,86 Large on initial presentation because it is secreted by normal and
lesions can potentially shift the larynx and trachea within the malignant thyroid tissue; therefore it is not recommended in the
neck. The mobility of the nodule relative to the laryngotracheal ATA guidelines to routinely obtain thyroglobulin levels in the
complex and adjacent neck structures should be evaluated. Malig- setting of a thyroid nodule.79 Levels of thyroglobulin cannot
nant lesions are more likely to be fixed to the trachea, esophagus, differentiate between benign and malignant processes, unless levels
or strap muscles. are extremely high, as in metastatic thyroid cancer. Antithyro-
All patients with a thyroid lesion should have a complete vocal globulin antibodies can also interfere with the assay. Thyroglobulin
cord examination. Extension into the thyroid cartilage and larynx levels may be useful in studying patients who have undergone
may result in a complete vocal cord paralysis that is clinically total thyroidectomy for well-differentiated thyroid cancer.
silent. Laryngoscopy should be performed to assess vocal cord Serum calcitonin levels are not a typical initial test for patients
motion. with a thyroid nodule, unless the patient has a family history of
Despite the importance of the initial clinical assessment, the MTC or MEN-2. If FNAC shows or is suspicious for MTC,
history and physical examination are unreliable in predicting however, calcitonin levels should be obtained. In addition, if the
carcinoma. Many of the clinical signs of malignancy manifest late patient has RET oncogene mutations, the possibility of a coexisting
in the course of disease. Additionally, many of these same findings pheochromocytoma should be evaluated with abdominal magnetic
may be caused by events associated with benign disease (e.g., resonance imaging (MRI) and a 24-hour urine collection to
hemorrhage into a benign nodule). The clinical assessment should measure metanephrines and catecholamines (total and fraction-
provide a justification and a context for the interpretation of ated). The serum calcium level should be measured to exclude
diagnostic studies such as FNAC. Of particular note would be hyperparathyroidism.
any patient and thyroid nodule features that might be concerning
for aggressive carcinoma behavior (Box 122.2).
Fine-Needle Aspiration Cytology
FNAC has become the procedure of choice in the evaluation of
thyroid nodules.79 The findings are highly sensitive and specific,
BOX 122.2 Risk Factors for Aggressive Behavior of although the accuracy of FNAC is related to the skill of the aspirator
Well-Differentiated Thyroid Carcinomas and the experience of the cytopathologist.88 The procedure is
minimally invasive and may be performed quickly with little patient
DEMOGRAPHICS discomfort. In contrast to large-bore needle biopsies, such as the
Age <20 years Tru-cut or Vim-Silverman needle, there are fewer complications.
Men >55 years With the advent of this technique, the number of patients who
Women >55 years require surgery has decreased by 35% to 75%, and the cost in
Male > female managing patients with thyroid nodules has been substantially
History of radiation exposure/therapy reduced.89–91 Also, the yield of malignancies has almost tripled in
Family history of thyroid carcinoma patients who have had thyroid surgery after FNAC.91,92 The accuracy
PHYSICAL EXAMINATION of FNAC diagnosis of papillary carcinoma is 99% with a false-
positive rate of less than 1%.93
Hard, fixed lesion
FNAC should be one of the initial steps in the surgical evaluation
Rapid growth of mass
of a thyroid nodule. Approximately 15% of all aspirates are
Pain
inadequate or nondiagnostic, largely because of the sampling from
Lymphadenopathy
cystic, hemorrhagic, hypervascular, or hypocellular colloid nodules.
Vocal cord paralysis
Repeat aspiration of such a nodule is crucial because a nondiagnostic
Aerodigestive tract compromise
finding should never be interpreted as a negative finding for
Dysphagia
carcinoma. Surgical diagnoses after repeated nondiagnostic aspira-
Stridor
tions revealed malignant nodules in 4% of women and 29% of
HISTOPATHOLOGIC FACTORS (AT INITIAL PRESENTATION) men.94 Nodules that are difficult to localize and nodules that have
Size >4 cm yielded nondiagnostic aspirates on previous attempts may benefit
Extrathyroid spread from ultrasound-guided aspiration. FNAC is increasingly being
Vascular invasion performed with ultrasound guidance to improve diagnostic accuracy
Lymph node metastasis and yield. Cystic nodules with multiple nondiagnostic FNAC
Distant metastasis studies require close observation or surgical excision. Also, surgery
Histologic type should be more strongly considered for a solid nodule that is
Tall cell variant of papillary carcinoma cytologically nondiagnostic.79
Follicular carcinoma Successful FNAC categorizes nodules as benign, malignant,
Hürthle cell carcinoma or suspicious. In 60% to 90% of nodules, FNAC reveals a benign
or “negative” diagnosis. The likelihood of malignancy (false-negative
rate) is 1% to 6%.89,95 The diagnosis of malignancy—particularly bilateral and should include the jugular, submandibular, supracla-
papillary (including follicular variant), medullary, and anaplastic vicular, paratracheal, and suprasternal regions. These studies may 122
carcinomas and lymphomas—can be determined in about 5% of detect cervical nodes that may contain early clinically occult
nodules. The likelihood of a false-positive finding is less than metastatic disease that would not otherwise have been included
5%.89,95 Frequently, false-positive results occur because of difficulties in a surgical dissection.103,104 Characteristics of lymph nodes suspi-
in interpreting cytology in patients with Hashimoto thyroiditis, cious for metastatic deposits include loss of the fatty hilum,
Graves disease, or toxic nodules. A benign cytology is a macrofol- increased vascularity, rounded node configuration, hypoechogenicity
licular lesion or a colloid adenomatous nodule. The remaining of a solid nodule, and microcalcifications.102, 105, 106 US is also useful
“suspicious” samples are composed of lesions that contain abnormal in the evaluation of cervical lymph nodes in patients with a history
follicular epithelium with varying degrees of atypia. This finding of thyroid cancer who present with adenopathy or increasing
needs to be evaluated in the context of patient history and physical thyroglobulin levels. These studies are not useful, however, in the
findings that may be suggestive of malignancy. A complete evaluation of substernal extent of disease or the involvement of
report of the FNAC that details specimen adequacy and pathologic adjacent structures.
findings is crucial, and efforts have been made to standardize this In a patient with multiple thyroid nodules, FNAC should be
information.96,97 This work is represented in the framework for performed in conjunction with a diagnostic US study. Aspiration
the Bethesda System for Reporting Thyroid Cytopathology, which of the largest or “dominant” nodule alone may miss a thyroid
includes six general diagnostic categories associated with an implied malignancy. In the presence of two or more thyroid nodules
cancer risk.98 larger than 1 to 1.5 cm, nodules with a suspicious US appearance
Follicular neoplasms cannot be classified by FNAC alone. The should be aspirated preferentially. If none of the nodules has
presence of hypercellular microfollicular arrays with minimal suspicious US characteristics, and multiple sonographically similar
colloid increases the concern for carcinoma. The differentiation coalescent nodules are present, aspiration of the largest nodule
between follicular adenoma and follicular carcinoma depends on only is reasonable.103
the histologic finding of capsular or vascular invasion, which Currently, there is no role for US in screening asymptomatic
requires evaluation of the entire thyroid nodule. Occasionally, patients for thyroid nodules. Preoperative US evaluation of the
patients with a diagnosis of follicular neoplasm on FNAC have lateral cervical lymph nodes is recommended for all patients with
an iodine-123 (123I) thyroid scan. If the suspicious nodule is “cold,” papillary and Hürthle cell thyroid cancer before initial thyroid-
surgery is indicated. If the nodule is hyperfunctioning compared ectomy because operative management may be altered in 20% of
with the surrounding thyroid, surgery can be avoided. Overall, patients.107 In addition, intraoperative US examination may be
20% of nodules diagnosed as follicular neoplasms by FNAC contain useful in the localization of nonpalpable lesions in the thyroid
thyroid carcinomas.99 Additionally, the finding of atypia of unde- bed or nodal metastases.
termined significance or of a follicular lesion of undetermined Computed tomography (CT) and MRI scans are usually
significance has a lower likelihood of malignancy than a follicular unnecessary in the evaluation of thyroid tumors except for fixed
neoplasm and may be evaluated by repeat FNAC. or substernal lesions. Although these studies are not as effec-
Similarly, Hürthle cell (oxyphilic) neoplasms can be difficult tive as US in the evaluation of thyroid nodules, they are more
to evaluate. The presence of Hürthle cells in an aspirate may reliable in evaluating the relationship of the thyroid lesion to
indicate an underlying Hürthle cell adenoma or carcinoma, but adjacent neck structures, such as the trachea and esophagus. These
these cells can also be present in thyroid disorders, such as studies are useful in determining substernal extension, identify-
multinodular goiter and Hashimoto thyroiditis. Carcinomas can ing cervical and mediastinal adenopathy, and evaluating possible
be found in 20% of nodules identified as follicular and oxyphilic tracheal invasion.108 Anatomic imaging should be obtained when
neoplasms.100 Because of the risk of underlying carcinoma in these visceral compartment invasion is suspected and for localization
cases, surgery is recommended. in patients with nodal disease. Also, CT or MRI can supplement
US, which cannot visualize the regions behind the sternum,
trachea, and esophagus. Caution must be exercised in the use of
Imaging iodine-containing contrast material in patients with multinodular
Ultrasonography (US) is tremendously useful and sensitive. These goiter if a hyperthyroid state is suspected and in patients with
studies detect nonpalpable nodules and differentiate between cystic WDTC. In the latter group, iodinated contrast media precludes
and solid nodules. Ultrasound detection of subcentimeter nodules the use of postoperative radioactive iodine (RAI) therapy for
is valuable because most are nonpalpable and are not detected by 2 to 3 months. Finally, MRI is more accurate than a CT scan
other imaging modalities, even though they may harbor malignant in distinguishing recurrent or persistent thyroid tumor from
disease. In patients with a neck that is difficult to examine (e.g., postoperative fibrosis.
a patient with a history of head and neck irradiation), ultrasonog-
raphy can also clarify findings. These studies provide key baseline
information regarding nodule size and architecture. US is also a
Thyroid Isotope Scanning
noninvasive and inexpensive method for following changes in the Radionuclide scanning with 123I or technetium 99m (99mTc) sestamibi
size of benign nodules. US can identify hemiagenesis and contra- assesses the functional activity of a thyroid nodule and the thyroid
lateral lobe hypertrophy, which may be misdiagnosed as a thyroid gland. Nodules that retain less radioactivity than the surrounding
nodule. The utility of US studies has expanded from detection of thyroid tissue are termed cold, nonfunctioning, or hypofunctional.
thyroid nodules to examination of nodal basins for locoregional These “cold” nodules are thought to have lost functions of fully
staging, intraoperative localization of nonpalpable lesions, and differentiated thyroid tissue and are believed to be at increased
routine follow-up examination of the neck after thyroidectomy. risk of containing carcinoma. In a meta-analysis of patients with
US examinations are being performed in the office by appropriately scanned nodules that were surgically removed, 95% of all nodules
trained surgeons. Additionally, US guidance of FNAC has become were cold.85,86 The incidence of malignancy in cold nodules was
integral to the initial workup and has resulted in improved target 10% to 15% compared with only 4% in “hot” nodules.
selection and diagnostic yield. Technetium 99m scanning only tests iodine transport, but it
A systematic US examination can be extremely valuable in the can be performed in a day and involves less radiation exposure
assessment of a patient with thyroid cancer, including color and than 123I. Cold nodules identified with this test are also cold with
power Doppler examination of the thyroid, specific nodules, and iodine scanning; however, any hot nodules require 123I scanning
lymph nodes.101,102 Examination of the nodal basins should be for confirmation. 123I scanning tests transport and organification
of iodine. This test is more expensive and requires 2 days to (elevated serum TSH level) should be appropriately treated by
complete. Cold lesions can be more difficult to visualize because an endocrinologist, and then FNAC should be performed. Most
of overlying thyroid tissue and glandular asymmetry, although patients are euthyroid (normal serum TSH level), and FNAC should
oblique views during scanning can improve detection. In addition, be performed. US examination can provide valuable diagnostic
99m
Tc does not penetrate the sternum and is not useful in confirming information, especially in the selection of a nodule for biopsy in
substernal extension. a patient with multiple nodules, and it may facilitate FNAC. In a
With the evolution of FNAC, radionuclide scanning is not patient with a thyroid malignancy, evaluation of the nodal basins
routinely performed in the evaluation of a thyroid nodule. More can detect early clinically occult disease and can alter surgical
frequently, cold nodules are detected in patients during evaluation management. Patients with cytologic findings diagnostic or strongly
for hyperthyroid disorders. However, patients who present initially suggestive of malignancy should be referred to a surgeon for
with a thyroid nodule and are found to be hyperthyroid on removal of the lesion.
preliminary thyroid function testing should have radionuclide A diagnosis of follicular neoplasm by FNAC requires surgery
scanning to differentiate between a toxic nodule and Graves disease to determine the presence of follicular adenoma, or papillary or
and a nonfunctioning nodule. Also, after indeterminate FNAC, follicular carcinoma. FNAC suspicious for medullary carcinoma
an 123I thyroid scan should be considered. Surgical treatment should may be subject to immunohistochemical (IHC) techniques to detect
be contemplated if a concordant autonomously functioning nodule calcitonin. Before surgical intervention, a patient with FNAC
is not seen.103 suggestive of medullary carcinoma requires genetic studies and
additional testing (discussed later in the section on MTC). Suspi-
Rational Approach to Management of cious findings on FNAC must be assessed in the context of patient
risk factors in determining the need for surgery. Indeterminate
a Thyroid Nodule cytology may be present in 15% to 30% of FNA specimens and
Numerous diagnostic algorithms have been proposed for the may require repeat FNAC. Lesions reported as atypia or a fol-
evaluation of a thyroid nodule (Fig. 122.9).88,109 Evaluation generally licular lesion of undetermined significance are variably reported
begins with a thorough history and physical examination to identify and have a 5% to 10% risk of malignancy.97 If a nonsurgical
significant risk factors. Surgery may be deemed appropriate based approach is taken, the nodule must be closely monitored, usually
solely on high-risk factors such as age, sex, history of radiation with US. Benign lesions are usually observed and require surgi-
exposure, rapid nodule growth, upper aerodigestive tract symptoms, cal removal only in cases of cosmetic or symptomatic concerns.
and fixation. These nodules must be aspirated again to confirm the diagnosis if
Baseline TSH screening determines the diagnostic course. growth is detected.
Patients with hyperthyroidism (suppressed serum TSH level) Molecular marker testing of indeterminate thyroid FNA
should receive radionuclide scanning to determine the presence specimens can also be used to aid decision making. More specifically,
of a toxic hot nodule, Marine-Lenhart syndrome, or Graves disease the purpose of molecular marker testing is ruling out or ruling
with a concomitant cold nodule.110 A patient with hypothyroidism in thyroid malignancy, based on the presence of certain mutations
in the FNA specimen. As such, an ideal “rule-in” test would have
a good positive predictive value for histopathologically proven
malignancy, while a “rule-out” test would have a high negative
predictive value. Currently, two popular molecular marker testing
Hx/PE panels for indeterminate thyroid lesions are the Afirma Gene
Expression Classifier and ThyroSeq, while ThyGenX/ThyraMIR
and Rosetta GX Reveal have relatively less published clinical data.
Initial workup The Afirma Gene Expression Classifier has a high sensitivity (92%)
TSH FNAC US and negative predictive value (93%), making it a good rule-out
test.79 ThyroSeq also demonstrates a high negative predictive value
(approximately 95%), making it another commonly used rule-out
Carcinoma Follicular Benign Indeterminate test.79 ThyGenX/ThyrMIR has the highest reported positive
neoplasm predictive value (~66%) of the commercially available genetic
molecular tests, and therefore has been used as a rule-in test. The
Surgery TSH TSH Observe Repeat FNAC performance of these commercially available genetic molecular
nl/high low If nodule grows, tests varies between studies and can be largely dependent upon
consider surgery the population studied with associated pre-test probability. The
landscape of molecular genetic testing of thyroid nodules is rapidly
Surgery Radionuclide changing, with frequent updates in clinical performance as
scan companies work to modify and improve the performance of their
commercially available products. Molecular genetic testing of
indeterminate thyroid nodules will continue to remain an area of
Cold Hot intense study in the coming years and use of molecular genetics
in routine clinical decision-making will continue to be defined.
Surgery Evaluate and treat
for thyrotoxicosis REVIEW OF THYROID NEOPLASMS
Fig. 122.9 Algorithm for a rational approach to the evaluation and
management of a thyroid nodule. Surgery is indicated for well-
Thyroid Adenoma
differentiated thyroid carcinoma. Anaplastic carcinoma and lymphoma
require additional workup and assessment to determine treatment.
Clinical Presentation
Ultrasound guidance should be considered for repeat fine-needle A thyroid adenoma is a true benign neoplasm derived from follicular
aspiration cytology (FNAC) after an indeterminate result. Hx/PE, cells. These follicular lesions are occasionally multiple and may
History/physical examination; nl, normal; TSH, thyroid-stimulating arise in the setting of a normal thyroid, nodular goiter, toxic goiter,
hormone; US, ultrasonography. or thyroiditis. They occur most commonly in women older than
30 years. Patients usually present with a solitary, mobile thyroid

nodule. The thyroid mass is often found incidentally on a routine BOX 122.3 World Health Organization Revised Histologic 122
physical examination and is frequently not associated with any Classification of Thyroid Tumors
other signs or symptoms. Sudden hemorrhage into the adenoma
may cause a sudden increase in size and associated pain. I. Epithelial tumors
A. Benign tumors
1. Follicular adenoma
Pathology a. Architectural patterns
The revised histologic classification of thyroid tumors divides i. Normofollicular (simple)
epithelial tumors into the categories of follicular adenoma and ii. Macrofollicular (colloid)
other rare tumors (Box 122.3). Follicular adenomas are the most iii. Microfollicular (fetal)
common benign thyroid lesions. Atypical follicular adenomas may iv. Trabecular and solid (embryonal)
show atypical microscopic features, including excess cellularity, v. Atypical
increased mitotic figures, and necrotic foci. Although most of vi. Noninvasive follicular thyroid neoplasm with
these lesions are benign, they may metastasize even in the absence papillary-like nuclear features
of microinvasion.111 b. Cytologic patterns
On gross examination, thyroid nodules and adenomas are well i. Oxyphilic cell type
circumscribed and are demarcated from adjacent normal thyroid ii. Clear cell type
tissue. The classic adenoma is fleshy and pale, although areas of iii. Mucin-producing cell type
necrosis, hemorrhage, and cystic change may be readily apparent. iv. Signet-ring cell type
Microscopic findings include large and small follicles with abundant v. Atypical
colloid. Cells may be flat, cuboidal, or columnar. The nuclei are 2. Others
small and round with an even chromatin pattern. Mixed populations a. Salivary gland–type tumors
of macrophages and lymphocytes and fibrosis, hemosiderin, and b. Adenolipomas
calcification may be visible. Cystic areas may be present near areas c. Hyalinizing trabecular tumors
of abundant papillae formation. Adenomas that exhibit pseudopapil- B. Malignant tumors
lary structures need to be distinguished from papillary carcinoma. 1. Follicular carcinoma
Oxyphilic (Hürthle) cell adenoma contains mitochondria-rich a. Degree of invasiveness
eosinophilic cells. Thyroglobulin IHC staining can distinguish a i. Minimally invasive (encapsulated)
clear cell adenoma from a parathyroid adenoma and metastasis ii. Widely invasive
from a renal carcinoma. This adenoma also needs to be differenti- b. Variants
ated from the clear cell variant of follicular carcinoma. i. Oxyphilic (Hürthle) cell type
Nodules within a nodular goiter occasionally may be hyper- ii. Clear cell type
functional or “hot.” These lesions are termed autonomously 2. Papillary carcinoma
hyperfunctioning thyroid adenomas and may or may not cause thy- a. Variants
rotoxicosis. These lesions often occur in women, and nodules i. Papillary microcarcinoma
associated with thyrotoxicosis are frequently found in patients ii. Encapsulated variant
older than 40 years. iii. Follicular variant
iv. Diffuse sclerosing variant
v. Oxyphilic (Hürthle) cell type
Management and Prognosis 3. Medullary thyroid cancer
Thyroid nodules determined to be benign require follow-up because a. Variant
of a low false-negative rate (∼5%) with FNAC.112,113 Nodule growth i. Mixed medullary-follicular carcinoma
alone is not an indication of malignancy, but growth is an indication 4. Undifferentiated (anaplastic) carcinoma
for repeat biopsy. The ATA guidelines recommend serial clinical 5. Other carcinomas
examination for easily palpable benign nodules at 6- to 18-month a. Mucinous carcinoma
intervals.103 All other benign nodules should be followed with serial b. Squamous cell carcinoma
US examinations 6 to 18 months after initial FNAC. Patients c. Mucoepidermoid carcinoma
with nodules that remain stable in size may have subsequent II. Nonepithelial tumors
examinations at longer time intervals. Patients with evidence III. Malignant tumors
of nodule growth should have repeat FNAC, preferably with IV. Miscellaneous tumors
US guidance. A. Parathyroid tumors
The surgical evaluation of a thyroid nodule begins with FNAC B. Paragangliomas
that shows a follicular neoplasm. Distinguishing follicular or C. Spindle cell tumors with mucous cysts
Hürthle cell adenoma from carcinoma depends on histopathologic D. Teratomas
analysis after surgical excision. Concern for a potential malignancy V. Secondary tumors
increases with highly cellular findings or pseudopapillary structures VI. Unclassified tumors
on FNAC. The lack of tumor capsule and vascular invasion is VII. Tumorlike lesions
characteristic of a follicular adenoma. A. Hyperplastic goiters
Surgical excision involves a thyroid lobectomy. A unilateral B. Thyroid cysts
partial thyroid lobectomy is no longer an acceptable standard of C. Solid cell nests
care. Patients with a history of radiation to the head and neck, D. Ectopic thyroid tissue
other head and neck cancers, potential high-risk factors, and E. Chronic thyroiditis
comorbidities may benefit from a total thyroidectomy. Risk of F. Riedel thyroiditis
surgical morbidity at the initial surgery must be balanced with G. Amyloid goiter
the potential risks of reoperation. In most patients, thyroid hormone Adapted from Hedinger C, editor: Histological typing of thyroid tumours,
administration is unnecessary when the patient has undergone ed 2, Berlin, 1988, Springer-Verlag.
resection of a single thyroid lobe for a thyroid adenoma.
Autonomously hyperfunctioning thyroid adenomas are usually Most cases of papillary carcinoma occur spontaneously. Of
anatomically and functionally stable. Although most patients do patients with a history of low-dose radiation exposure who develop
not develop thyrotoxicosis, 20% of patients with lesions greater thyroid cancer, the majority develop papillary carcinomas (85%
than 3 cm may develop thyrotoxicosis. Surgery and radioiodine to 90%).121 These lesions also are more common in patients with
therapy can be used to manage these lesions, although many Cowden syndrome (familial goiter and skin hamartomas), Gardner
physicians prefer surgery for patients younger than 40 years. These syndrome (familial colonic polyposis), and familial polyposis. Only
patients may require preoperative medications to control thyrotoxic 6% of papillary carcinomas are associated with familial disease.
symptoms. The lesions are typically removed with a unilateral Papillary microcarcinomas are tumors 1.0 cm or smaller in
thyroid lobectomy, and the remaining thyroid tissue typically size. These lesions are typically nonpalpable and may be incidental
returns to normal function after several months. Ethanol injection findings on unrelated imaging, at the time of thyroid surgery, or
has become increasingly common, especially in Europe, to manage on autopsy examination. Extrathyroid tumors extend to involve
these lesions.114 the thyroid capsule or extend through the thyroid capsule to involve
the surrounding viscera. Based on the AJCC 8th edition TNM
staging, microscopic extrathyroidal extension does not factor into
Thyroid Cyst the T category, while gross extrathyroidal extension to the strap
musculature confers T3b tumor category. A recent study examining
Clinical Presentation over 2300 patients demonstrated that the presence of microscopic
Although a thyroid cyst is not a specific diagnosis, this entity is extrathyroidal extension did not confer worse disease-free survival,
frequently encountered in clinical practice. Approximately 15% locoregional failure, or distant metastatic failure.122 While some
to 25% of all thyroid nodules are cystic or have a cystic compo- studies have suggested that disease-specific survival may be affected
nent.63 The presence of a cyst does not signify a benign lesion by degree of extrathyroidal extension,123–128 several recent large
because papillary carcinomas and parathyroid tumors may manifest single-institutional studies demonstrated no difference in overall
with cystic masses. Papillary carcinoma may be present in 14% or disease-specific survival based on gross strap muscle involvement,
to 32% of all cystic nodules, although most of these lesions are although there was suggestion that gross strap muscle involvement
benign adenomas or colloid nodules.115,116 may increase risk for locoregional recurrence.129,130
Most patients with papillary carcinoma present with a slow-
growing, painless mass in the neck and are often euthyroid. Often,
Pathology the primary lesion is confined to the thyroid gland, although 30%
A thyroid cyst can result from congenital, developmental, or of patients may have clinically evident cervical nodal disease.131,132
neoplastic causes.115 Many cysts result from intranodular ischemia Histologic studies have shown the strong lymphotropic nature of
that causes tissue necrosis and liquefaction. True epithelial-lined papillary carcinoma, which can lead to multifocal disease within
cysts are rare. Occasionally, parathyroid or thyroglossal duct cysts the thyroid and regional lymphatics. Microscopic disease has been
can be mistaken for thyroid nodules. A parathyroid cyst contains identified in the cervical nodes of 50% to 80% of patients and in
high parathyroid hormone levels within the clear fluid, and a the contralateral lobe in 80% of patients with papillary carcinoma
thyroglossal duct cyst contains columnar epithelium. These lesions at the time of surgery.133 The significance of this microscopic
may also be differentiated by US. disease is unclear, however, because clinical recurrences in the
neck and in the contralateral lobe occur in fewer than 10% of
patients.134 The prevalence of microscopic disease largely suggests
Management and Prognosis that most papillary carcinomas have an indolent course that only
When encountered during FNAC, a thyroid cyst should be drained occasionally becomes clinically evident; however, definite predictors
completely. This procedure may prove curative in most simple of the clinical course for papillary carcinoma are not well defined.
cysts, although one or two additional drainage procedures may Advanced disease may be associated with symptoms of local
be required. If a cyst persists after three drainage attempts, or if invasion that include dysphagia, dyspnea, and hoarseness. Occasion-
it reaccumulates quickly, the suspicion for carcinoma should ally, cervical nodal involvement may be more apparent than the
increase. Brown fluid withdrawn from a cyst may represent old thyroid nodule. Distant metastases, especially to the lungs, are
hemorrhage into an adenoma; red fluid is more suspicious for more commonly encountered in children, although less than 5%
carcinoma.83 Clear, colorless fluid may be withdrawn from a of all patients may ultimately develop distant disease.100
parathyroid cyst and can be assessed for parathyroid hormone.117 Thyroid cancer is often suspected in these patients after a
In suspicious cases, the surgeon and patient should consider thorough history and physical examination. The diagnosis is usually
US-guided FNAC to sample a solid component of the lesion or established by FNAC. Thyroid function tests are done routinely
a unilateral thyroid lobectomy to obtain a definitive diagnosis. in the preoperative assessment. Radiographic imaging (CT or
Because of the potential for thyroid carcinoma in cystic lesions, MRI) is selectively performed to define extensive local or substernal
surgical excision for diagnosis is preferable to the injection of disease and to evaluate possible lymph node involvement.
sclerosing agents.
Pathology
Papillary Carcinoma On gross examination, papillary carcinoma is firm, white, and not
encapsulated. The lesion tends to remain flat on sectioning rather
Clinical Presentation than bulging the way normal thyroid tissue or benign nodular
Papillary carcinoma is the most common form of thyroid malig- lesions do. Macroscopic calcifications, necrosis, or cystic changes
nancy and accounts for about 80% of all thyroid cancer.76,118,119 may be readily apparent.135
This lesion typically occurs in patients 30 to 40 years old and is Histologically, these lesions arise from thyroid follicular cells
more common in women, with a female/male ratio of 2 : 1. This and contain papillary structures that consist of a neoplastic epi-
ratio has decreased steadily over the past 40 years as the incidence thelium overlying a true fibrovascular stalk.19 Cells are cuboidal
in men has increased.120 Papillary carcinomas are the predominant with a pale, abundant cytoplasm. Large, crowded nuclei with folded
thyroid malignancy in children (75%). Although children more and grooved nuclear margins may have intranuclear cytoplasmic
commonly present with advanced disease, including cervical and inclusions. Prominent nucleoli account for the “Orphan Annie
distant metastases, their prognosis remains quite favorable. eye” appearance. Laminated calcium densities, psammoma bodies,
are likely the remnants of necrotic calcified neoplastic cells and local recurrence rates and increased pulmonary and cervical
are present in 40% of cases. metastases.40,139 Controversy remains, however, because this 122
Although a follicular component may predominate, lesions with increased local recurrence did not compromise disease survival
any papillary features behave clinically as papillary carcinomas in some studies.71,140
(with the exception of noninvasive follicular neoplasm with After total thyroidectomy, patients may be monitored by fol-
papillary-like nuclear features NIFTP; see below). The designation lowing thyroglobulin levels, which should remain undetectable,
of papillary carcinoma includes mixed papillary follicular carcinoma and by neck US to evaluate the central and lateral cervical compart-
and the follicular variant of papillary carcinoma. A more unfavorable ments. Increase in thyroglobulin levels raises suspicions for disease
prognosis is associated with certain histologic forms of papillary recurrence and requires appropriate screening. Approximately 12%
carcinoma, including diffuse sclerosing and tall cell variants.19,136 of patients with papillary carcinoma are not cured by initial treat-
The tall cell variant is characterized by well-formed papillae covered ment, which leads to a prolonged clinical course.141 Recurrent
by cells that are twice as tall as they are wide. The rarer columnar disease may occur after many years and can involve the thyroid
cell variant is characterized by the presence of prominent nuclear bed (5% to 6%), regional lymphatics (8% to 9%), or distant sites
stratification.19 (4% to 11%).142 Successful treatment of recurrence varies by site
Papillary carcinomas have a strong tendency for lymphatic of involvement and by the patient’s initial risk classification.
spread within the thyroid and to local lymph nodes in the Generally, lymph node metastases do not seem to have an
paratracheal and cervical regions. The tendency for intraglan- impact on overall survival in most patients with low- and
dular spread may lead to the multifocal disease often present intermediate-risk disease.142–144 Lymph node micrometastases
in patients. Discrete lesions may be due to de novo formation, (<1 cm) typically have no impact on survival, but may potentially
however, especially in patients previously exposed to ionizing increase locoregional recurrence risk.145 Additionally, overall lymph
radiation.137 node density (the ratio of positive lymph nodes to total number
Local invasion occurs in 10% to 20% of these tumors and of lymph nodes excised) has been suggested to be a predictor of
leads to involvement of the overlying strap muscles, laryngeal and outcomes in PTC, with patients with a density of ≤ 0.19 having
tracheal framework, RLNs, pharynx, and esophagus. This extension a 10-year disease specific survival of 98% compared to only 90%
may evolve from the primary lesion or from extracapsular extension for those with a density greater than 0.19.146 Cervical recurrences
of metastatic nodes. Angioinvasion is a clear harbinger of increased occur in 20% of patients with low-risk disease and in 59% of
risk for recurrence and worse prognosis.76 A coexisting lymphocytic patients with high-risk disease.71,147 The continuing debate regarding
thyroiditis has been correlated with decreased recurrence and extent of lymphadenectomy at the time of thyroidectomy reflects
better overall prognosis. a shift in focus from overall survival to recurrence-free survival.
The vast majority of locoregional recurrences can be salvaged
with surgery, although local recurrences necessarily indicate that
Management and Prognosis patients require reoperation in the thyroid bed. In a recent series
Most patients with papillary carcinoma do well regardless of of 85 patients with recurrent central neck disease, salvage surgery
treatment. Prolonged survival, even with recurrent disease, has resulted in a regional control rate of 94% and a disease-specific
led to controversy regarding the extent of thyroidectomy for survival rate of 100% with a median follow-up of 44 months.148
patients with WDTC (see the section titled “Extent of Surgery” Studies examining lateral neck recurrence have shown similar
under “Surgical Management and Technique”). A balance must results, with patients undergoing true salvage lateral neck surgery
be achieved between an effective surgical treatment for these demonstrating 98% lateral neck regional control and 91% disease-
malignancies and the potential morbidity of this surgery. Numerous specific survival at 10 years.149
studies have attempted to categorize patients by their risk factors Because microscopic cervical disease does not generally affect
and to justify more aggressive surgical intervention for high-risk disease-specific survival, management of cervical metastasis tends
patients (see the section on tumor staging and classification). The to be conservative.145 There is no role for elective lateral neck
National Comprehensive Cancer Network (NCCN) Clinical dissection when there is absence of disease on high-definition
Practice Guidelines in Oncology and the ATA provide specific ultrasound, especially considering the effectiveness of radioiodine
recommendations for evaluation and management of WDTC.79,138 therapy in ablating microscopic disease.134 The ATA management
Incidental micropapillary thyroid carcinoma is usually identified guidelines recommend central compartment (level VI) neck dis-
in a thyroid specimen removed for other reasons. Unilateral thyroid section for ultrasonographically apparent central nodal disease or
lobectomy and isthmectomy is usually sufficient surgical treatment, gross nodal disease discovered at the time of thyroid surgery.79
unless angioinvasion or tumor at the margins of the resection is Prophylactic (elective) central lymph node dissection may be
present. These patients can be treated with thyroid hormone to considered for patients with PTC without clinical evidence of
suppress TSH, and they can be closely followed up with US. In lymph node metastases for advanced primary tumors (T3/T4) or
patients with a small, encapsulated PTC (<1 cm in diameter), a clinically involved lateral neck nodes.79 However, the influence of
thyroid lobectomy is sufficient. elective central lymph node dissection on outcome of these patients
When patients present with biopsy-proven disease or indications remains unclear, although elective removal may potentially decrease
of disease in both lobes, total thyroidectomy is generally the nodal recurrence and the need for reoperation. It has been suggested
procedure of choice. Additionally, patients stratified into high-risk that individual surgeons who perform prophylactic central compart-
categories in any of the classification schemes previously described ment dissection must evaluate their number of central compartment
(see the section on tumor staging and classification) may benefit dissections needed to prevent one recurrence (number needed to
from a more extensive surgical procedure that includes paratracheal treat), with a concomitant awareness of their individual number
lymph node dissection. Removal of all thyroid tissue allows thyroid of central compartment dissections per related complication
hormone suppression therapy and radioiodine ablation of any (number needed to harm).150
potential remaining microscopic disease. In patients with palpable or visible neck disease, a comprehensive
Multifocal disease is present in 80% of patients in some neck dissection (levels II through Vb) should be performed, as
reports.132,136 This percentage may represent de novo multicentric opposed to selective cervical lymph node excision, or “berry-
tumor formation or intraglandular metastasis. The prevalence of picking.” Level Vb lymph nodes are commonly involved with
multifocal disease lends credence to the argument for more differentiated thyroid cancer, and these lymph nodes can be removed
complete surgical removal of the thyroid gland in patients with from under the sternocleidomastoid muscle contiguous with level
PTC. Patients who underwent partial thyroidectomy had higher IV nodes, without a formal level V dissection. Although level
I is seldom involved, metastatic disease is frequently noted on is dependent on both nuclear features as well as overall architecture.
histologic examination of nodal levels II through V.151 In addi- Nikiforov et al. developed specific diagnostic criteria for diagnosing
tion, because the incidence of contralateral subclinical metastasis NIFTP.161 These criteria include encapsulation or a clear demarca-
is less than 20%, elective treatment of the contralateral neck tion from adjacent thyroid issues; a follicular growth pattern with
is not advocated. less than 1% papillae, no psammoma bodies, less than 30% solid/
The presence of distant metastasis is associated with a worse trabecular/insular growth pattern; nuclear features of PTC (enlarge-
prognosis, and approximately 5% of patients with PTC develop ment, elongation, irregular contours, grooves, pseudoinclusions,
distant metastasis at some point during their disease course.100 chromatin clearing); and the absence of vascular/capsular invasion,
Most commonly, the lungs are involved, although bone sites and tumor necrosis, and high mitotic activity. Although this neoplasm
the central nervous system may also be affected. is thought to occur due to clonal proliferation, the genetic altera-
In nearly every study, patient age at the time of diagnosis is tions for NIFTP are not well-defined and are not included in the
an important prognostic variable.11,152,153 Older patients with current diagnostic criteria. NIFTP has been associated with
papillary carcinoma, especially those older than 55 years, have a approximately 40% rate of RAS mutations.165,166 However, the
worse prognosis. Extrathyroid invasion seems to be more common rate of BRAF mutations in non-encapsulated FVPTC ranges
in older patients. The prognosis for men younger than 40 years between 26% and 50%, compared to 0% for NIFTP.165,167 This
is comparable to that of women of the same age. Overall survival data suggests that genetically NIFTP may be distinct from both
is worse for men, however, and their risk of death from PTC may classical PTC and non-encapsulated FVPTC.164
be twice as great.71,152
Children fare better with this disease. Among patients younger
than 15 years, 90% show cervical metastasis at some time during
Management and Prognosis
their disease course,154 and 20% of children may present with In a 2009 study from Memorial Sloan Kettering, Ghossein
pulmonary metastases.155 Neither cervical nor pulmonary metastases demonstrated no recurrences or metastases after 11 years in 42
seem to impact survival. Perhaps these differences relate to biologic patients with EFVPTC.168 Several recent studies, after its reclas-
differences in the disease process between age groups. sification to NIFTP, have also demonstrated no evidence of disease
Finally, the tall cell variant of PTC is different from other recurrence or metastases after surgery alone with a median
forms of this disease. A review of patients with tall cell variant follow-up greater than 10 years.161,169 Since NIFTP is not considered
papillary carcinoma showed a more aggressive natural history in a malignancy, it can be adequately treated with a thyroid lobectomy,
all age groups and a worse prognosis.156 without the need for completion thyroidectomy, central neck
dissection, or postoperative radioactive iodine therapy. Although
Noninvasive Follicular Neoplasm With NIFTP and EFVPTC were previously treated similarly to PTC,
more conservative treatment is now recommended due to its
Papillary-Like Nuclear Features indolent nature and low risk of recurrence/metastases.
The follicular variant of papillary thyroid carcinoma (FVPTC)
Follicular Carcinoma
was first recognized in the 1970s as a tumor that consists of
neoplastic follicles rather than papillae, with follicular cells showing
nuclear features of PTC.157,158 FVPTC has two main subtypes: Follicular carcinomas represent approximately 10% of thyroid
non-encapsulated (infiltrative) and encapsulated.158 While the malignancies. The mean age of presentation is 50 years, compared
non-encapsulated subtype behaves like a carcinoma and invades with a mean age of 35 years in patients with papillary carcinoma.
into the surrounding thyroid parenchyma, the encapsulated subtype Women more commonly have this lesion, with a female/male
behaves as an indolent tumor with nonexistent metastatic potential ratio of 3 : 1.170 These lesions occur more frequently in iodine-
and recurrence rates. The encapsulated subtype has also increased deficient areas, especially areas of endemic goiter.7 Follicular
in incidence over the last few decades, and now comprises carcinomas have been correlated with pregnancy and with certain
10% to 20% of all thyroid cancer diagnoses in the United States human leukocyte antigen (HLA) subtypes (DR1, DRw, and DR7).
and Europe.159,160 Also, a rare form of familial follicular carcinoma is reported in
As such, this encapsulated subtype deserves special mention patients with dyshormonogenesis. The overall incidence of follicular
due to its highly indolent behavior and the risk of overtreatment. carcinoma in decreasing in the United States.
In 2016, Nikiforov et al. reclassified the encapsulated follicular Patients usually present with a solitary thyroid nodule, although
variant of papillary thyroid carcinoma (EFVPTC) as NIFTP, to some patients may have a history of longstanding goiter and recent
reflect its lack of invasion and indolent nature.161 NIFTPs present rapid increase in nodule size. These lesions are typically painless,
clinically similar to other thyroid neoplasms, and are often detected but hemorrhage into the nodule may cause pain. Cervical
on physical examination with palpation of a nodule, or found lymphadenopathy is uncommon at initial presentation, although
incidentally on unrelated imaging studies. Larger tumors can also distant metastases are more frequently encountered than with
be symptomatic due to mass effect on surrounding structures. papillary carcinomas. In rare cases (1%), the follicular carcinoma
Detection with FNA is difficult as capsular invasion cannot be may be hyperfunctioning, in which case the patient presents with
assessed, and NIFTP shares nuclear features with PTC and fol- signs and symptoms of thyrotoxicosis.
licular architecture with follicular neoplasms.162 Consequently, Other than characterization of a follicular neoplasm, a definitive
FNA has a 29% false-positive rate and 9% to 58% true predictive preoperative diagnosis is usually impossible by FNAC. Differentia-
value for detecting NIFTP for follicular variant tumors.163 tion between follicular adenoma and follicular carcinoma requires
an evaluation of the thyroid capsule for invasion or identification
of vascular invasion. Typically, about 20% of thyroid nodules that
Pathology show follicular neoplasm cytology contain carcinoma.
On gross examination, NIFTP presents as a solid well-circumscribed In contrast to papillary carcinoma, FTCs are less likely to
neoplasm with a thin capsule and a clear demarcation between metastasize via lymphatic pathways (found in <10% of patients).108
the neoplasm and the surrounding thyroid tissue. The tumor is More commonly, follicular carcinomas spread through local
typically paler than surrounding tissues and rarely demonstrates extension and hematogenous spread. Often, the presence of cervical
necrosis and hemorrhage.164 Histopathological diagnosis of NIFTP lymph node disease indicates significant local disease and visceral
invasion.120,171 Distant metastasis is also more common in follicular for detection and ablation of metastatic disease, although more
cancers than in papillary cancers, especially at presentation.172,173 aggressive surgical intervention may not improve survival because 122
A pathologic bone fracture may be the initial presentation invasiveness already indicates the increased likelihood of distant
of follicular carcinoma. Other common sites include liver, lung, metastasis. Neck dissection is performed if cervical lymphadenopathy
and brain. is present. When cervical disease is present, consultation with the
pathologist is warranted because the patient may have a follicular
variant of PTC. Elective neck dissections are unwarranted because
Pathology nodal involvement is unlikely.15
FTC tends to manifest as solitary, encapsulated lesions. Cytologic The recurrence rate after initial management is approximately
analysis of follicular neoplasms reveals small follicular arrays or 30%.177 Recurrence is related to the degree of invasiveness of the
solid sheets of cells.19 The follicular structures have lumens that initial lesion, not the extent of initial thyroid surgery. Minimally
do not contain colloid, and the overall architectural pattern invasive disease behaves similarly to follicular adenoma and is
depends on the degree of tumor differentiation. Increased cel- typically cured with conservative surgical procedures (thyroid
lularity may increase the suspicion for carcinoma, but cytology lobectomy).178 Recurrence of minimally invasive follicular carcinoma
alone is insufficient to distinguish between a follicular adenoma is approximately 1%. Invasive follicular carcinomas have higher
and carcinoma. distant metastasis rates (10% to 20%) comparted to papillary
Histologic findings are necessary to distinguish benign and carcinomas,179 and the prognosis for patients with follicular car-
malignant lesions. Malignant lesions are differentiated by the cinoma relates largely to this distant metastasis risk. Distant
identification of capsular invasion and potential microvascular metastasis risk is higher, and survival outcomes lower, particularly
invasion of vessels along the tumor capsule.111,174 Complete capsular in patients with capsular invasion and angioinvasion.180 Overall
evaluation must be performed. Frozen-section analysis is often 5-year survival is 90%, and it decreases to 84% at 10 years.181 The
inadequate, and definitive diagnosis requires complete assessment presence of distant metastasis diminishes 5-year survival to 82%.182
of permanent sections. Factors that worsen prognosis include age older than 50 years at
The degree of capsular invasion is important for patient presentation, tumors greater than 4 cm in size, higher tumor grade,
prognosis. Follicular carcinomas can be divided into two broad marked vascular invasion, extrathyroid extension, and distant
categories: minimally invasive tumors show evidence of invasion metastasis at the time of diagnosis.15
into, but not through, the tumor capsule at one or more sites, and The prognosis for patients with follicular carcinoma has typically
these lesions do not exhibit small-vessel invasion; frankly invasive been reported to be worse than for patients with papillary carci-
tumors show invasion through the tumor and often exhibit vascular noma. However, some reports that matched age, sex, and stage at
invasion.175 Tumor infiltration and invasion may be apparent at time of diagnosis suggest that patients with papillary and follicular
surgery, with tumor present in the middle thyroid or jugular veins. carcinomas have similar survival patterns.11,13 The poor prognosis
Many other factors have been investigated as means to dif- of patients with follicular carcinoma may be related to the increased
ferentiate between adenomas and carcinomas. To date, no molecular number of patients who present at an older age and at a more
markers have been clinically useful. DNA ploidy varies in adenomas advanced disease stage, and the increased rate of distant metastases
and carcinomas with considerable overlap.176 Aneuploid follicular among FTCs. Also, in contrast to papillary carcinoma, patients
carcinomas are noted to behave in a more aggressive manner. who develop locoregionally recurrent follicular carcinoma have
decreased overall survival.183
Patients diagnosed with a follicular lesion by FNAC may have a
Hürthle Cell Tumor
thyroid lobectomy with isthmectomy performed. Another option
for these patients is short-term observation with follow-up
ultrasound, as only approximately 15% of patients with an FNAC According to the World Health Organization classification, Hürthle
diagnosis of follicular lesion will ultimately have thyroid cancer. cell tumor is a subtype of follicular cell neoplasm. Hürthle cell
The pyramidal lobe, if present, should be included in the thyroid tumor nodules can be found in patients with Hashimoto thyroiditis
lobectomy and isthmusectomy resection. As described previously, or Graves disease or within a nodular goiter. These tumors are
cytologic findings alone cannot differentiate between follicular derived from oxyphilic cells of the thyroid gland. Although the
adenoma and follicular carcinoma. Intraoperative frozen-section precise function of these cells is unknown, Hürthle cells express
analysis is not helpful because of the incomplete assessment of TSH receptors and produce thyroglobulin.
the tumor capsule. Frozen sections should be analyzed, however, Hürthle cell neoplasms are typically diagnosed by FNAC, and
if there is gross suspicion of metastatic central compartment approximately 20% of these lesions are malignant. Similar to
lymphadenopathy. A total thyroidectomy is often performed if follicular lesions, histologic criteria are required to diagnose
carcinoma is identified in a lymph node. carcinomas. Hürthle cell carcinomas represent approximately 3%
Total thyroidectomy may be preferred in older patients of all thyroid malignancies. The mean age of presentation for
with a nodule greater than 4 cm in size diagnosed by FNAC as patients with Hürthle cell carcinoma may be older than that for
follicular neoplasm. In these patients, the risk of carcinoma is follicular carcinoma.99,184 Hürthle cell carcinomas tend to behave
approximately 50%.139 Additional factors that may favor a total more aggressively than papillary and follicular carcinomas, and
thyroidectomy as the initial surgical procedure include a family they are often multifocal and bilateral at presentation. These
history of thyroid carcinoma, history of radiation exposure, and malignancies also are more likely to metastasize to cervical nodes
patient preference.79 and distant sites.185
A diagnosis of follicular carcinoma after a thyroid lobectomy
may necessitate a completion thyroidectomy, especially in the
presence of angioinvasion. Patients with minimally invasive follicular
Pathology
cancer have a very good prognosis, and the initial thyroid lobectomy FNAC of Hürthle cell tumors typically show hypercellularity and
is generally sufficient treatment. Invasiveness of follicular carcinoma the presence of eosinophilic cells. These neoplasms are character-
correlates directly with decreased survival, however. In patients ized by sheets of eosinophilic cells packed with mitochondria.
with invasive follicular carcinomas, many surgeons tend toward Cytologic differentiation between adenoma and malignant tumor
completion and total thyroidectomy to permit radioiodine scanning by FNAC is extremely difficult. Benign colloid thyroid nodules
can be associated with Hürthle cell changes, although clinicians Patients with MEN-2B have a Marfanoid body habitus and may
should be aware that Hürthle cell changes in benign nodules are have MTC, pheochromocytoma, or mucosal neuromas. Although
not associated with Hürthle cell tumors. Histologic findings of penetrance for MTC approaches 100% in these patients, expression
capsular or vascular invasion confirm the presence of Hürthle of other features varies.193,195
cell carcinoma. FNAC diagnosis of MTC is confirmed by elevated serum
calcitonin. All patients with MTC should have testing for mutation
of the RET protooncogene. Genetic screening has replaced provoca-
Management and Prognosis tive pentagastrin-stimulation testing. Careful screening for
The clinical approach to Hürthle cell tumors is similar to that hereditary diseases is also necessary when a patient is diagnosed
for follicular neoplasms. With Hürthle cell adenoma, resection with MTC. Hyperparathyroidism can be assessed by serum calcium
of the affected lobe and isthmus is sufficient. Invasive findings levels and appropriate imaging studies. Patients should also be
for Hürthle neoplasms on formal pathology generally warrant screened for the presence of a pheochromocytoma with 24-hour
a total or completion thyroidectomy. Hürthle cell carcinomas urinary levels for catecholamines and metanephrines, and they
tend to be more aggressive than other follicular carcinomas, should undergo abdominal MRI. An undiagnosed pheochromo-
and they are less amenable to radioiodine therapy because of cytoma could lead to an intraoperative hypertensive crisis and
their decreased tendency to take up radiolabeled iodine. Because death. Additionally, the detection of any hereditary form of MTC
locoregional nodal metastases may occur, careful examination for in a patient should lead to family screening. Affected family
local disease extension or adjacent cervical lymphadenopathy should members can often be identified and treated at earlier stages of
be performed. disease with improved survival.196,197
Postoperative management should include TSH suppression
and thyroglobulin monitoring and periodic US evaluation of the
central and lateral cervical compartments. A 99mTc scan may be
Pathology
useful for detecting persistent local or metastatic disease. A 123I MTC originates from parafollicular C cells of neuroectodermal
scan and ablation can be performed to remove any residual normal origin.198 The cells descend to join the thyroid gland proper and
thyroid tissue to allow for better surveillance. This therapy is are concentrated mainly in the lateral portions of the superior
unlikely to be effective in tumor ablation, however, because few poles. Most MTC lesions are located in the middle and upper
Hürthle cell carcinomas (∼10%) take up radioiodine.186 thyroid poles. In patients with hereditary forms of MTC, the
Overall, survival rates for Hürthle cell carcinoma are significantly disease is often multifocal. Grossly, the tumor is solid and firm
worse than for follicular thyroid cancer. The number of patients and has a gray cut surface. The lesion is nonencapsulated but well
who die of Hürthle cell carcinoma is greater than the number circumscribed.
who die of papillary or follicular carcinoma.187 Additionally, Hürthle These lesions are composed of sheets of infiltrating neoplastic
cell carcinoma is associated with the highest incidence of distant cells that are heterogeneous in shape and size. The cells are sepa-
metastases among the WDTCs.188 rated by collagen, amyloid, and dense irregular calcification. The
amyloid deposits are likely polymerized calcitonin and are virtually
pathognomonic for MTC, although not all MTCs contain
Medullary Thyroid Carcinoma amyloid.199 More aggressive tumors typically have increased mitotic
figures, nuclear pleomorphism, and areas of necrosis. IHC for
Clinical Presentation calcitonin and CEA are useful diagnostic studies.
MTCs are a distinct category of disease and represent approximately
3% of all thyroid carcinomas. These malignancies arise from
parafollicular C cells and may secrete calcitonin, CEA, histamini-
dases, prostaglandins, and serotonin. Measurement of secreted Specific guidelines were recently published by the ATA regarding
calcitonin is useful for the diagnosis of MTC and for postsurgical the management of MTC.200 Preoperative workup includes
surveillance for residual and recurrent disease. measurement of calcitonin and serum CEA. Patients with germline
MTC shows an intermediate behavior between WDTCs and RET mutations should be screened for pheochromocytoma
anaplastic carcinomas, and there is significant variation in the (MEN-2A and -2B) and hyperparathyroidism (MEN-2A). CT
biologic behavior of these tumors, with some tumors demonstrating scan of the chest and mediastinum and ultrasound examination
a very indolent course, and others presenting with progressive of the neck are recommended.
distant disease. Women and men are equally affected by MTCs.189 Total thyroidectomy is the treatment of choice in patients with
Patients usually present with a neck mass associated with palpable MTC because the lesions have a high incidence of multicentricity
cervical lymphadenopathy (≤20%).190 Local pain is more common and an aggressive disease course. Patients with familial MTC or
in these patients and indicates the presence of local invasion, MEN-2 should have the entire gland removed, even in the absence
which may be associated with dysphagia, dyspnea, or dysphonia. of a palpable mass.
MTC may manifest along with PTC because related mutations Because of the frequent involvement of cervical nodes, initial
in RET are present in both diseases. Although MTC spreads initially surgical management should include bilateral central compartment
to cervical nodes, distant metastases may be found in the neck dissection. The superior mediastinal lymph nodes (level VII)
mediastinum, liver, lung, and bone and are present in 50% of should be routinely removed as well. When palpable lateral cervical
patients at diagnosis.191 nodes are present, treatment that includes an ipsilateral or bilateral
Most MTCs (70%) are spontaneous unifocal lesions in patients comprehensive neck dissection (levels II through V) should be
50 to 60 years old without an associated endocrinopathy.190 The considered. When central compartment lymph node metastases
remaining 30% of cases that affect younger patients are familial. are present, elective ipsilateral lateral neck dissection may be
These hereditary MTCs are inherited as autosomal-dominant considered because nodal metastases can be present in more than
traits with nearly 100% penetrance. MTC in these patients is 60% of these patients.138,201,202 In patients with MTC and no US
preceded by multifocal C-cell hyperplasia and leads to disease that evidence of neck metastases, the ATA recommends that a lateral
is multicentric and bilateral in 90% of cases.192,193 Familial MTC is neck dissection may be considered based on calcitonin levels.
not associated with any other endocrine pathology. Two forms of Ipsilateral and contralateral lateral neck dissections may be
MEN syndrome are associated with MTC. Patients with MEN-2A considered when calcitonin levels are greater than 20 pg/mL and
exhibit MTC, pheochromocytoma, and hyperparathyroidism.192,194 200 pg/mL, respectively.203 Recent data, however, suggests this
may result in overtreatment of the lateral neck. In a recent study involvement at the time of presentation, and more than 50% have
from MD Anderson, Zafereo et al. found no difference in biochemi- systemic metastases.214 122
cal cure, locoregional disease control, or survival between patients
undergoing elective lateral neck dissection for MTC, and patients
with observation of the lateral neck in the absence of disease on
Pathology
high-definition ultrasound. This study suggests a role for observa- In the case of ATC, the gross specimen shows areas of necrosis
tion of the lateral neck in patients with MTC with negative and macroscopic invasion of surrounding tissues, often with lymph
preoperative high-definition ultrasound, regardless of preoperative node involvement. Microscopically, sheets of cells with marked
calcitonin level.204 heterogeneity are present. Spindle, polygonal, and giant multinucle-
Potentially associated conditions, such as hyperparathyroidism ated cells are present with occasional foci of differentiated cells.
and pheochromocytoma, must be carefully evaluated and, if neces- These cells do not produce thyroglobulin, transport iodine, or
sary, must be treated before thyroidectomy. A pheochromocytoma express thyroid hormone receptors.211 These findings can often
may need to be removed before treatment of the thyroid lesion. be established on FNAC, although a formal biopsy is occasionally
Alternatively, preoperative treatment with α-adrenergic blockade necessary to exclude a diagnosis of lymphoma.
(phenoxybenzamine) or α-methyltyrosine is necessary to avoid a The development of ATC is thought to be a multistep dedif-
hypertensive crisis during surgery. In the presence of hypercalcemia, ferentiation process that develops after a series of genetic aber-
the parathyroid glands need to be identified during thyroidectomy. rations.215 BRAF and RAS mutations are considered to be early
If the parathyroid glands are abnormal, they should be removed. event mutations and are seen in approximately 40% and 30% of
Otherwise, they should be adequately marked to facilitate future these tumors, respectively. TP53 mutations also occur in approxi-
identification, especially in patients with MEN-2A. mately 50% of tumors and are thought to represent a late genetic
Children with any of the genetic disorders that lead to MTC event.216–218 Although routine molecular testing of ATC has not
need to be treated aggressively. Typically, a total thyroidectomy yet been recommended in guidelines, certain mutations (such as
should be performed prior to 5 years of age for MEN-2A and BRAF V600E) are actionable with targeted therapies, and therefore
prior to the first year of life for MEN-2B.79 Removal of the thyroid recent studies have recommended molecular testing of all anaplastic
gland should prevent development of MTC in these patients and thyroid cancer patients.215
will improve survival. However, MTC has been diagnosed in
MEN-2B patients as young as 7 months.205
After surgery, patients require close follow-up and monitoring
of serum calcitonin and CEA levels. Calcitonin is more sensitive Management of anaplastic carcinoma is extremely difficult and
for detecting persistent or recurrent disease, but CEA levels seem requires a multidisciplinary approach. Advanced care planning
to be predictive for survival.202 Increasing or persistent calcitonin and surrogate decision-making issues must be clearly discussed.
levels should increase suspicion for residual or recurrent disease. Rapid and accurate assessment of the disease burden is critical
Localization studies should be performed to identify potential due to the often very short tumor doubling time.219,220 Surgical
sites of disease involvement. Tumor debulking for metastatic disease resection may be considered if locoregional disease can be resected
or local recurrence can decrease symptoms of flushing and diarrhea grossly. Consensus-based guidelines for the management of patients
and may reduce the risk of death from recurrent central neck with ATC provide recommendations regarding disease resection
disease.191,206 MTCs do not respond to radioiodine therapy or and do not support tumor debulking given the lack of benefit for
TSH suppression therapy, however, because of their parafollicular local control or survival.221 Retrospective evaluation of various
C-cell origin.197 External-beam radiation therapy (EBRT) has been treatment strategies identified a subset of patients who have had
controversial for patients with positive tumor margins or unresect- long-term survival.10,106,222,223 Independent prognostic variables
able tumor, and no effective chemotherapy regimen has been include resectability of local disease, absence of distant metastasis
found. Targeted therapies, including cabozantinib and vandetanib, at diagnosis, and adjuvant treatment with radiation therapy.
are approved for use in the setting of advanced recurrent Additionally, many long-term survivors had small areas of anaplastic
disease,207–209 and newer RET-specific inhibitors are being studied foci within well-differentiated carcinoma.
in current clinical trials. The appropriateness of tracheostomy for ATC patients remains
Prognosis for patients with MTC is directly related to disease controversial. Although tracheostomy clearly overcomes acute
stage. The overall 10-year survival rate is 61% to 75%, but this airway distress, questions have been raised regarding potential
decreases to 45% if cervical nodes are involved.197,210 The best prolongation of suffering.224,225 Nutritional support should be
outcome is for patients with familial MTC, then MEN-2A, sporadic addressed because dysphagia is very common at presentation, but
disease, and MEN-2B. potential airway issues that may occur with sedation must be
recognized prior to gastrostomy placement. Traditionally, median
survival for ATC was only 2 to 6 months.212,226
Anaplastic Carcinoma However, recent advances in next generation sequencing of
ATC with rapid tumor mutation testing and potential treatment
Clinical Presentation with targeted therapy, particularly for those with BRAF mutation,
ATC is one of the most aggressive malignancies, and few patients have changed the landscape of treatment for anaplastic thyroid
have historically survived 6 months beyond initial presentation.81,211 cancer.215 A contemporary study from MD Anderson demonstrated
These lesions represent approximately 1% of all thyroid carcino- that patients with localized disease who undergo surgical resection,
mas,212 and they typically occur in older patients; presentation external beam radiation therapy, and systemic chemotherapy can
before 50 years is extremely rare. Women are more commonly achieve a median overall survival of 22 months, compared to 6.5
affected than men, with a ratio of 3 : 2, and 80% of these malignan- months for those with unresectable disease that received only
cies may occur with a coexisting carcinoma and may represent radiation and chemotherapy.223 Recently, the FDA approved the
transformation of a well-differentiated thyroid cancer.211,213 use of dabrafenib plus trametinib for the treatment of locally
Patients typically present with a rapidly enlarging neck mass, advanced or metastatic BRAF-positive ATC. This combination
accompanied by pain, dysphonia, dysphagia, and dyspnea. Often of BRAF and MEK inhibitors has demonstrated a 69% response
the mass is quite large and is fixed to the tracheolaryngeal rate (complete or partial) in 15 patients.227 Clinical trials are
framework, which results in vocal cord paralysis and tracheal available for various chemotherapeutic agents (e.g., taxanes) and
compression. More than 60% have lateral neck lymph node targeted therapeutic agents, and this is an area of active research
interest.215,228 Additionally, recent studies have shown promise with Typically, the history and physical examination identify
addition of immunotherapy regimens to other targeted therapy, the source of the metastasis. FNAC is performed for definitive
and even the possibility of neoadjuvant targeted therapy and diagnosis. Thyroidectomy may be considered for palliation,
immunotherapy prior to surgical resection and postoperative especially when the primary lesion is very slow growing (e.g.,
chemoradiation.229 renal cell carcinoma).238
Other Forms of Thyroid Cancer Squamous Cell Carcinoma

Squamous cell carcinoma of the thyroid is very rare and represents
Insular Thyroid Carcinoma a fraction of 1% of thyroid cancers.239 Older patients are most
Insular carcinoma was named for the clusters of cells that contain commonly affected, and the disease can progress rapidly with local
small follicles resembling pancreatic islet cells.230 These tumors invasion and metastasis. During the workup, metastasis from another
are very rare and manifest as an independent lesion or concomitantly site within the upper aerodigestive tract needs to be excluded.
with papillary or FTCs. These cells stain with thyroglobulin Early detection and aggressive surgical treatment seems to represent
antibodies but not for calcitonin. Typically, capsular and vascular the best option for palliation and cure. As with other squamous
invasion is present at the time of diagnosis, and angioinvasion is cell carcinomas of the head and neck, adjuvant radiation therapy
a hallmark of insular thyroid carcinoma. is generally indicated, although it is not well characterized.240
These lesions are much more aggressive than follicular and
papillary carcinomas, with associated increased recurrence and
decreased survival.231 On the other hand, focal insular carcinoma
SURGICAL MANAGEMENT AND TECHNIQUE
located within follicular or PTC may not adversely affect recurrence
and survival. Many insular thyroid carcinomas are able to con-
Approach to the Thyroid Gland
centrate radioiodine. Before any thyroid surgery, any voice changes or previous neck
surgery should prompt assessment of vocal cord mobility by indirect
mirror or flexible fiberoptic laryngoscopy. Although many patients
Lymphoma with thyroid carcinomas are euthyroid, necessary medical therapy
Primary thyroid lymphoma is unusual and represents less than should be instituted for patients with thyrotoxicosis or hypothyroid-
1% of all thyroid malignancies.232 Women are more commonly ism to avoid intraoperative metabolic derangements, such as
affected at a ratio of 3 : 1, and lymphoma typically manifests in hypertensive crisis. Details of this management are beyond the
patients older than 50 years. Patients may present with symptoms scope of this chapter, but management should include consultation
similar to anaplastic carcinoma, although the rapidly enlarging with an endocrinologist.
mass is often painless. Symptoms may also include regional The patient should be positioned supine on the operating table
adenopathy, dysphagia, and vocal cord paralysis caused by RLN with an inflatable pillow or shoulder roll and adequate head support
invasion. Many affected patients are clinically hypothyroid or are to permit neck extension for optimal exposure. A symmetric
already receiving thyroid replacement therapy for conditions such transverse incision along a skin crease approximately 1 cm below
as Hashimoto disease.233 Non-Hodgkin B-cell type lymphoma the cricoid cartilage is made through the platysma. The length
is most common, although Hodgkin disease and plasmacytomas of the incision depends on the size of the thyroid gland. Larger
occur.234 Thyroid lymphoma can arise as part of a generalized incisions are necessary for patients with short, thick necks; difficulty
lymphomatous condition because many of these patients have with neck extension; or a low-lying thyroid gland. Subplatysmal
Hashimoto disease. A current hypothesis as to why this occurs is skin flaps are raised superiorly to the level of the thyroid cartilage
chronic antigenic lymphocyte stimulation that results in lymphocyte notch and inferiorly to the clavicle.
transformation. Exposure of the thyroid gland is obtained through a midline
A definite diagnosis needs to be made and frequently can be vertical incision through the superficial layer of the deep cervical
established by FNAC. Occasionally, a needle-core or open cervical fascia between the sternohyoid and sternothyroid muscles. The
lymph node biopsy may be necessary. Because of the rare incidence strap muscles are separated, and dissection proceeds laterally along
of primary thyroid lymphoma, a comprehensive survey must be the thyroid capsule until the ansa cervicalis is noted at the lateral
done to exclude the presence of lymphoma at other sites. edge of the sternohyoid muscle/medial aspect of the internal jugular
Patients typically respond rapidly to chemotherapy, especially vein. Rarely, the strap muscles must be divided to gain access to
with a combination of cyclophosphamide, hydroxydaunomycin, a large thyroid lobe or tumor. This division should be done high
vincristine, and prednisone (CHOP).235,236 Combined radiation on the muscle to preserve innervation from the ansa hypoglossal
and chemotherapy regimens have also been developed and have nerve. The strap muscles may be reapproximated before skin
been promising. Thyroidectomy and nodal resection may be closure. Any evidence of frank invasion of thyroid carcinoma into
considered to alleviate symptoms of airway obstruction in patients the strap muscles should result in an en bloc resection of the
who do not respond rapidly to treatment, but surgical options are section of the affected muscle with the thyroid lobe.
not primary treatment modalities. Through careful dissection, the thyroid lobe is swept antero-
The prognosis depends on the histologic grade of the tumor medially to the tracheolaryngeal framework (see Fig. 122.5A).
and the presence of extrathyroid disease. Overall, 5-year survival The middle thyroid vein should be identified, and division of this
is about 50%. Intrathyroid disease survival is 85% and decreases vessel improves lateral exposure. The cricoid and trachea should
to 40% for patients with extrathyroid disease. be identified in the midline, and continued mobilization is achieved
by sweeping dorsally all tissue along the posterolateral border of
the thyroid lobe. Meticulous hemostasis should be maintained to
Metastatic Carcinoma facilitate identification of the SLN, RLN, and parathyroid glands.
The thyroid is a rare site for metastases from other cancers. The pedicle along the superior thyroid pole is identified early
Metastasis can occur, however, from primary lesions in the kidney, by retracting the thyroid inferomedially. This maneuver exposes
breast, lung, and skin (i.e., melanoma). The most common metastatic Joll’s triangle, which is bounded by the trachea, superior thyroid
tumor to the thyroid is from a hypernephroma. Also, approximately vessels, and the constrictor muscles of the pharynx. Dissection
1% of bronchogenic carcinomas metastasize to the thyroid, but should be carried out close to the thyroid capsule to avoid possible
these account for 20% of all metastases to the thyroid.237 injury to the external branch of the SLN. Frequently, the external
branch of the SLN that supplies the cricothyroid muscle can be Ischemic parathyroids should be evaluated prior to surgical closure
visualized, and nerve monitoring can also be employed to assist to confirm viability. Parathyroids situated anteriorly on the thyroid 122
with identification of the SLN, particularly to ensure that the gland may require autotransplantation. When central compartment
nerve is not injured while dividing the superior thyroid pedicle. nodal dissection is performed, the inferior parathyroid gland may
The superior pole vessels should be individually identified and have to be autotransplanted if the blood supply to this gland
isolated for ligation close to the thyroid lobe. At this point, the cannot be pedicled inferiorly or laterally with the lymph node
tissues posterolateral to the superior pole can be swept away from dissection. If there is doubt in regard to the identity of a parathyroid
the lobe in a posteromedial direction. gland, frozen section biopsy of a tiny piece of the gland should
Identification of the RLN is often achieved through an infero- be performed. The parathyroid glands can be minced into pieces
lateral approach in a space defined by Loré and colleagues241 as 1 mm3 and reimplanted in the ipsilateral sternocleidomastoid
the retrolaryngeal node triangle. This triangle is bounded by the muscle.
trachea medially, the carotid sheath laterally, and the undersurface When the lobe is mobilized, and key structures are identified,
of the retracted inferior thyroid pole superiorly. Careful dissection the isthmus can be transected close to the contralateral side (if
in this area parallel to the course of the RLN should safely identify a lobectomy is being performed). Any pyramidal lobe should be
the nerve (see Fig. 122.5B). A thyroid goiter or unusually large removed in continuity with the thyroid lobe and isthmus when
thyroid mass can potentially displace the nerve. In these cases, present. For a total thyroidectomy, the same procedure is repeated
the RLN can become fixed to and splay across the undersurface on the contralateral side, with the entire specimen often maintained
of the enlarged thyroid lobe. Great care must be taken in these en bloc with a total thyroidectomy procedure. The decision to
situations, and identification of the nerve may require a superior proceed to excision of the opposite thyroid lobe may depend on
approach, identifying the RLN at its entry into the larynx. the findings of the initial thyroid lobectomy. After removal of
When identified, the RLN should be followed to its laryngeal the thyroid specimen, hemostasis is verified, and most routine
entry at the level of the cricoid cartilage, passing under or through thyroid lobectomies and total thyroidectomies do not require
the Berry ligament and entering the larynx deep to the inferior a drain. Strap muscles are closed along the midline to prevent
constrictor muscle. The nerve may divide into multiple branches tracheal adhesion to the skin. The platysma is reapproximated
before entering the larynx.242 The most difficult portion of the with absorbable sutures, and the skin is closed with a running
operation is typically the dissection where the recurrent nerve subcuticular suture.
passes immediately under or through Berry’s ligament. The RLN
is in close proximity to the thyroid, tethered down by the ligament.
Bleeding can occur at this site and should be controlled by gentle
Approach to the Central Neck
pressure before identification of the nerve to avoid injury. A small The central neck includes lymph nodes in level VI and superior
portion of thyroid tissue may be embedded with the ligament and mediastinal nodes (previously referred to as level VII). Level VI
can account for a remnant of thyroid tissue left after total thy- lymph nodes are within a space bounded by the hyoid (superior),
roidectomy. Although controversy exists regarding routine use of sternal notch (inferior), carotid artery (lateral), sternothyroid muscle
intraoperative RLN monitoring, most high-volume thyroid (anterior), and prevertebral fascia (posterior). The prelaryngeal
surgeons currently routinely use RLN monitoring.243 Nerve (Delphian) nodes are typically visualized during resection of the
monitoring may be useful if nerve identification or handling or pyramidal lobe and may be removed during the thyroidectomy.
both are anticipated to be more difficult.244–246 Examples of such During this dissection, the fascia over the cricothyroid muscle
situations include extensive extrathyroidal disease, bulky paratra- should be preserved. Pretracheal dissection begins at the lower
cheal node disease, and particularly reoperative cases in the thyroid margin of the isthmus and removes the lymph node–bearing
bed or central compartment. fibrofatty soft tissue from the front face of the trachea inferiorly
Blood vessels are best ligated and divided on the thyroid capsule to the level of the innominate artery. This dissection may be
to reduce the risk of parathyroid devascularization (Fig. 122.10). performed in conjunction with the right paratracheal dissection,
especially at the lower extent, to facilitate identification of the
innominate artery. Additionally, great care must be exercised not
to extend this procedure laterally from the front face of the trachea
to avoid potential injury to the RLN. Often the pretracheal lymph
nodes are excised en bloc with an ipsilateral or bilateral paratracheal
dissection.
Paratracheal dissection encompasses a region that extends
from the lower margin of the cricoid cartilage to the innominate
artery crossing the trachea. The medial boundary on each side
is the trachea, and the carotid artery is the lateral boundary. The
common carotid artery is identified and dissected along the entire
extent of the paratracheal space. This facilitates identification of
the great vessels in the superior mediastinum. The nodes in the
paratracheal region are intimately associated with the RLN, which
must be clearly dissected and visualized during this procedure. In
reoperative cases, the RLN may be more easily identified inferiorly
in previously undissected areas, particularly in the low paratracheal
area. Given the course of the RLN on each side of the neck, there
are differences to the surgical approach. In the right neck, the
RLN travels from lateral to medial in the paratracheal region to
divide the space. A more ventral location of the innominate artery
relative to the aortic arch also creates a more ventral course for
Fig. 122.10 A parathyroid gland is shown in close proximity to the the right RLN, which results in dorsal tissue space where lymph
recurrent laryngeal nerve. Close dissection and ligation of vessels nodes may reside; thus complete nerve dissection and transposition
along the thyroid capsule ensure that the vascular supply to the is more commonly required in the right paratracheal space. In the
parathyroid glands remains intact. left neck, the RLN ascends along the boundary of the paratracheal
region within the tracheoesophageal groove. In either case, the are greater than 20 pg/mL and 200 pg/mL, respectively.203 This
goal should be to complete the dissection with minimal nerve may result in overtreatment, however, and recent data suggests
manipulation. Many superior mediastinal lymph nodes are accessible that observation may be an option as well.204
transcervically, although invasive mediastinal disease or mediastinal
disease at the level of the aortic arch or lower may require access
with a sternotomy or manubriectomy for adequate exposure and
Intrathoracic Goiter
removal. Less than 1% of patients may have a thyroid gland that is partially
The inferior parathyroid glands are more at risk than the or completely intrathoracic.249,250 In most of these patients, the
superior parathyroid glands during this dissection. The superior intrathoracic goiter can be removed via a collar incision in the
parathyroid glands are typically at the level of the cricoid cartilage neck without resorting to a sternotomy. The vascular supply,
and can be preserved. The inferior parathyroid glands should be typically originating in the neck, is identified, ligated, and divided.
identified and preserved when possible, but if their vascular pedicle Gentle blunt finger dissection typically can free loose fascial
cannot be preserved with the paratracheal dissection, they should attachments and facilitate mobilization of the sternal component
be autotransplanted. of the goiter into the neck. Division of the isthmus may facilitate
mobilization of the substernal goiter from beneath the sternum.
Large sutures can be placed deeply into the goiter to facilitate
Special Surgical Situations traction and blunt dissection to permit delivery of the thyroid
through the neck.
Management of Regional Lymphatics Patients with substernal goiters who have had previous thyroid
Management of the neck in patients with WDTCs is typically operations, some patients with invasive malignant tumors, and
conservative. Cervical node disease is rare in follicular carcinomas patients with no thyroid tissue in the neck may require a median
but is more common in papillary carcinomas. There is generally sternotomy. Occasionally, the substernal goiter may simply be too
no role for elective neck dissection in cases of follicular carcinoma. large to deliver through a cervical incision. In these cases, the
The ATA management guidelines recommend central compartment thyroidectomy is usually performed in collaboration with a thoracic
(level VI) neck dissection for patients with clinically involved central surgeon.
neck in well-differentiated thyroid cancer.79 If disease is present
by palpation or visible inspection, patients should have a concurrent
central compartment lymph node dissection with total thyroid-
Recurrent Laryngeal Nerve Invasion
ectomy or completion thyroid lobectomy. Surgical situations that necessitate sacrifice of the RLN are
Because of the higher frequency of microscopic tumor spread uncommon. If preoperative vocal cord paralysis is present, and
in MTCs and their lack of radioiodine uptake, elective bilateral carcinoma invasion is seen intraoperatively, the nerve may be
central compartment lymph node dissection is recommended. sacrificed (Fig. 122.11). More commonly, the RLN should be
Central compartment dissection should include the Delphian dissected free of gross extrathyroidal soft tissue disease, accepting
nodes, paratracheal lymphatics, and lymph nodes of the upper the possibility of microscopic disease along the nerve (Fig. 122.12).
mediastinum. The RLN, inferior thyroid artery, and parathyroid Among patients with WDTCs, no survival difference has been
glands should be identified, and the lymphatics should be removed found between patients with RLN sacrifice and patients treated
en bloc from the level of the cricoid to the innominate artery. postoperatively with radioiodine for gross disease left on the
When performing bilateral central compartment dissection, nerve.236 When the RLN is resected, immediate reinnervation
preservation of the parathyroid glands can be difficult. Attempts should be performed if feasible either by primary repair, nerve
should be made in the dissection, especially contralateral to the graft, or ansa cervicalis transfer (Fig. 122.13).
thyroid lesion, to identify and preserve the ascending branch of Sacrifice of the RLN requires the exclusion of nerve infiltration
the inferior thyroid artery that supplies the superior parathyroid by benign disease processes. Graves disease, Hashimoto thyroiditis,
gland. If the vascular supply to the parathyroid gland is compro- and Reidel thyroiditis can involve the RLN with or without vocal
mised, a tiny biopsy specimen of the gland should be obtained to cord paralysis. Benign processes can cause stretch injuries to the
confirm the presence of parathyroid tissue, and the gland may be RLN that resolve with surgical removal of the mass. Finally,
placed into a pocket in the sternocleidomastoid muscle. The gland lymphomas can involve the RLN, but treatment is rarely surgical
should be minced into 1-mm or smaller pieces. and should not involve excision of the nerve.
When palpable lateral cervical nodes are present, and metastatic
disease is confirmed by FNAC, a selective neck dissection, including
levels II through V, should be performed. Level VB lymph nodes
Extended Surgical Resection
can be removed contiguous with level 4 nodes, pulling them Surgical treatment of thyroid carcinomas should include removal
medially under the sternocleidomastoid muscle, while level VA of all gross disease. Fixation to the thyroid cartilage or trachea
nodes are rarely involved with differentiated or medullary thyroid may require partial-thickness or full-thickness removal of those
cancer. The submandibular and submental nodes (level I) are rarely structures (Fig. 122.14). Thyroid cartilage lamina can be removed
involved and should be dissected only when there is clinically without major morbidity, if the internal thyroid perichondrium
positive disease in this region.133,247 Cervical involvement is fre- is left intact. The trachea can be partially resected and repaired
quently ipsilateral to the primary thyroid lesion.240 to permit en bloc tumor removal. Traditional literature cites that
In patients with MTC, lymph node metastasis occurs in 81% primary anastomosis can be performed for resections that involve
of cases.248 Retrospective analysis revealed a 10-year survival rate 4 to 5 tracheal rings, although larger tracheal resections can be
of 67% for patients with MTC treated with neck dissection versus performed in select circumstances.251 Additionally, tracheal shaving
43% for patients who were not treated with neck dissection.201 can be performed, leaving the internal mucosa intact. Isolated
Palpable cervical disease necessitates central compartment and full-thickness defects can be repaired with composite mucosal-
comprehensive neck dissection. In patients with clinically negative cartilage grafts from the nasal septum. In patients with more
neck disease, surgical treatment should include total thyroidectomy extensive skeletal involvement, a partial laryngectomy may be
and central compartment dissection, and possible elective neck required, and has shown improvements in survival.252, 253 Total
dissection. The ATA recommends that lateral neck dissections can laryngectomy should be performed in only the most extreme cases
be considered based on calcitonin levels; ipsilateral and contralateral of extensive intraluminal invasion, substantial cricoid involvement,
lateral neck dissections should be considered when calcitonin levels and/or bilateral RLN dysfunction, typically in association with
122
A B
Fig. 122.11 (A) Intraoperative photograph demonstrating encasement of the recurrent laryngeal nerve (*) with
tumor. If the vocal cord has some mobility preoperatively, attempt can be made to dissect the nerve through
tumor. (B) In this particular case, the nerve can be visualized grossly invaded with tumor (enlarged and
discolored nerve), requiring nerve sacrifice. Attempt should be made to re-anastomose the proximal and distal
segments of the nerve, and if this not possible, the ansa cervicalis nerve can be anastomosed to the distal
end of the recurrent laryngeal nerve as it enters the cricothyroid joint.
A B C
Fig. 122.12 (A) Residual/recurrent thyroid disease at the cricothyroid joint is often intimately associated with
the recurrent laryngeal nerve. In this revision central compartment dissection, the left recurrent laryngeal nerve
(*) can be seen partially encased with tumor at the cricothyroid joint. (B and C) demonstrate stepwise
microdissection and mobilization of the recurrent laryngeal nerve from tumor, with preservation of nerve
integrity.
A B C
Fig. 122.13 (A) Large thyroid tumor with encasement and gross involvement of the left recurrent laryngeal
nerve, nerve stimulator. (B) Following tumor resection, the distal stump (forceps) of the recurrent laryngeal
nerve has been preserved for ansa cervicalis to recurrent laryngeal nerve anastomosis. (C) Ansa cervicalis (A)
to recurrent laryngeal nerve (*) anastomosis.
parathyroidectomy or anterior cervical spinal fusion, may have involved

the thyroid bed.
Reoperative surgery has been associated with a higher incidence
of complications than initial thyroid surgery. Scarring and fibrosis
from prior surgery may cause difficulty in identifying tissue planes,
which results in an increased risk of injury to the RLN. Potential
injury or devascularization of the parathyroid glands on one side
of the neck creates increased concern for preservation of the glands
on the contralateral side. Older series reported a high incidence
of complications in reoperative surgery.134,254 More recent reports
indicate, however, that the risk of permanent hypoparathyroidism
or RLN injury is less than 2%.255–258
Although reoperative thyroid surgery cannot be completely
avoided, steps may be taken to minimize the need for reoperation.
Before the initial surgery, preoperative preparation should include
a thorough evaluation for thyroid mass fixation or RLN palsy or
paralysis. In these patients, preoperative imaging and potential
coordination with other surgeons help to prevent unexpected
intraoperative findings. Finally, US evaluation of the thyroid bed
and lateral neck provides essential preoperative assessment of the
extent of disease and facilitates surgical planning. Even in patients
with palpable lymph node recurrences, US evaluation of the lateral
and central compartments may change the extent of the surgical
procedure in 40% of patients undergoing reoperative surgery.107
A
The minimum adequate surgical treatment for a thyroid nodule
is a thyroid lobectomy and isthmectomy. A unilateral subtotal
thyroidectomy may encompass a suspected thyroid nodule but
can leave residual disease behind. En bloc resection of the thyroid
lobe can be performed safely and often eliminates the need to
return to the original surgical bed for reexploration.
Typically, reoperation should be performed within 3 to 4 days
of the initial operation, if definitive pathology is available, or after
3 months. Healing and inflammation during the early and late
time points are typically manageable for reoperation. No control
studies to date have addressed the issue of the degree of inflam-
mation in the neck encountered during repeat surgery.
Before reoperation, the vocal cords should be visualized to
identify any potential RLN injury. Imaging studies can be useful
in cases of disease recurrence to identify local invasion or cervical
disease and potential involvement of the RLN or parathyroid
glands. During surgery, the RLN should be followed from previ-
ously undissected territory in the low paratracheal area into the
B surgical bed. The surgeon should be familiar with numerous
Fig. 122.14 (A) Lateral view of the neck shows a large, compressive techniques to identify the RLN. A lateral approach from the medial
thyroid mass. (B) Axial computed tomography scan reveals extensive border of the sternocleidomastoid, a low anterior neck approach,
local invasion by the thyroid lesion that involves the thyroid cartilage, and a medial approach to the superior pole of the thyroid have
larynx, and esophagus. been described.257 Intraoperative monitoring of the RLN can be
very helpful, and an electrophysiologic nerve stimulator can facilitate
and confirm nerve identification. Visualization of the RLN is
crucial, and the use of loop magnification may be helpful to identify
particularly aggressive histopathology. Pharyngeal and esophageal the RLN and parathyroid glands.
local invasion typically requires resection of the immediate area Because of the difficulties associated with permanent hypo-
and primary closure (Fig. 122.15). Typically thyroid tumors invade parathyroidism, preservation of the parathyroid glands is crucial
the esophageal muscularis, but not the lumen of the esophagus, in reoperative surgery. Prior surgery may have disrupted the normal
and careful resection of the esophageal muscularis allows extirpation anatomic locations of the gland or may have created scarring that
of this disease. However, in rare cases, especially in patients present- makes gland localization difficult. During revision central compart-
ing with significant preoperative dysphagia, more extensive and ment dissection when the thyroid gland has been removed, superior
full-thickness involvement may require myofascial/myocutaneous parathyroid glands (if present) should be generally left in situ in
pedicled or free flap reconstruction. the scar tissue posterior to the superior aspect of the RLN. Inferior
glands are more variable in location and may be more difficult to
preserve in situ, but should be autotransplanted if their blood
Reoperative Thyroid Surgery supply cannot be preserved with removal of the central compart-
Reoperative thyroid surgery may be required in various clinical ment lymph nodes. The surgical specimen needs to be inspected
situations. A patient may have had a previous thyroid lobectomy carefully, and biopsy specimens of potential parathyroid tissue
and may require a completion thyroidectomy. Recurrence of should be obtained. The combination of parathyroid preservation
disease may require reexploration of the thyroid bed or dissec- in situ and autotransplantation of devascularized parathyroid tissue
tion of the cervical lymph nodes, including the central compart- significantly reduces the risk of permanent hypoparathyroidism.259
ment (level VI). In addition, previous neck surgery, such as a Parathyroid tissue that has been reimplanted functions even when
122
A B
C D
Fig. 122.15 (A) Axial computed tomography scan shows a large, locally invasive thyroid mass. (B) The large
thyroid mass has been dissected free from adjacent structures but involves the esophagus. (C) Resection
of the thyroid mass required excision of a portion of the esophagus. The esophagus was closed primarily.
(D) Postoperative barium swallow study showed that the esophagus was intact, and the patient was able to
tolerate a regular diet. (From Lai SY, Weber RS: Thyroid cancer. In Ensley JF, Gutkind JS, Jacobs JR, et al,
editors: Head and neck cancer: emerging perspectives, San Diego, 2002, Academic Press, p 424.)
other parathyroid glands have been left intact and in the absence minimum amount of thyroid removed should be a lobectomy and
of hypocalcemia.259 isthmectomy. In the past, some surgeons have advocated a near-total
Intraoperative US may be useful for the resection of radiographi- thyroidectomy that preserves the posterior portion of the gland
cally identified, nonpalpable lesions within the thyroid bed or on one side to avoid injury to the RLN and at least one parathyroid
nodal basins. The technique may be particularly helpful in patients gland, but this is not acceptable in contemporary management of
who have had EBRT or for lesions that are smaller than 2 cm, thyroid carcinomas. A total thyroidectomy involves the complete
locally invasive, or adherent to the airway. US can be performed removal of both thyroid lobes, although 123I scans may reveal 2%
through the strap muscles in an open wound, and a needle can to 5% residual tissue.262
be placed in the target lesion as a guide. The general trend in surgical practice and guidelines is for
less aggressive thyroid surgery, with thyroid lobectomies now more
commonly performed for differentiated thyroid cancers less than
Extent of Surgery 4 cm.79 Proponents of a more conservative surgical approach suggest
Surgery is the primary modality for treatment of thyroid carcinomas. that thyroid lobectomy and isthmectomy is sufficient treatment
Although well-differentiated thyroid cancers can be extremely for most patients (>80%). These patients would be categorized
aggressive and lethal, most patients have prolonged survival even as low risk in the different classification schemes (see the section
with residual or recurrent disease. Controversy exists regarding on tumor staging and classification). Thyroid lobectomy and
the extent of surgery to be performed in patients with well- isthmectomy are simpler to perform and are less time-consuming
differentiated carcinomas. The primary goals of surgical treatment than a total thyroidectomy. The overall risk of morbidity from
should be to eradicate primary disease, to reduce the incidence RLN, SLN, and parathyroid gland injury is less. Finally, compared
of local or distant recurrence, and to facilitate the treatment of with total thyroidectomy, this conservative approach does not
metastases. These oncologic goals should be achieved with minimal adversely affect prognosis and survival.
morbidity. Furthermore, recent studies have demonstrated that Numerous studies support the conservative approach. In the
active surveillance may be an option in patients with micropapillary AGES classification, low-risk patients with papillary carcinoma
carcinomas.260,261 had the same 2% 25-year mortality rate regardless of whether
The large body of literature regarding thyroid carcinoma and they were treated with thyroid lobectomy or total thyroidectomy.73
its treatment has created a wide variety of terms for describing A study by Shah and associates76 based risk classifications on the
the extent of thyroid tissue removal. Most surgeons agree that a AJCC staging system. No difference in 20-year survival was reported
subtotal excision of a thyroid nodule is unacceptable, and that the based on surgical treatment for patients with intrathyroid tumors
of less than 4 cm; however, patients treated with total thyroidectomy progress. Ultimately, the primary goal of thyroid surgery
had an increased risk of complications. should remain the effective eradication of thyroid cancer with
Although survival differences are not found, several studies minimal morbidity.
report an increased incidence of local recurrence in patients treated
with only a thyroid lobectomy.263,264 Some controversy exists Evolution of Surgical Techniques
regarding the relationship of local recurrence to disease survival,
especially with papillary carcinomas.153,258 Finally, patients catego- for Thyroidectomy
rized as high risk in these classification systems are treated with Over the past decade, surgical approaches have been developed
total thyroidectomy and radioiodine ablation therapy. to permit thyroid surgery through smaller incisions.268,269 Some
A more aggressive surgical approach favors total thyroidectomy of these approaches advance to the thyroid bed from remote
in most cases and lobectomy for small, single lesions. Proponents incisions in the axilla or chest.270,271 In addition to improved
of this approach favor total thyroidectomy as a better oncologic cosmesis, proponents of these approaches advocate superior
operation. Removal of the entire thyroid gland encompasses visualization of critical structures, such as the SLN, through the
potential extracapsular extension and multicentric lesions. Morbidity use of endoscopic instruments (Fig. 122.16). Implementation of
of this procedure is low with good technique and an experienced these approaches must be cautious, with an emphasis on providing
surgeon.256 Several studies showed improved survival and decreased equal or improved operative outcomes relative to traditional open
local or distant recurrence.132,143,265 Cautionary studies also show approaches.272,273
the risk of aggressive disease even in patients determined to be The evolution of robotic surgery technology has been relatively
low-risk in the various classification schemes.266,267 rapid. The da Vinci Surgical System (Intuitive Surgical, Sunnyvale,
Postoperative thyroglobulin levels are more valid with removal CA) provides a number of features that have been capitalized
of all normal thyroid tissue. Total thyroidectomy also facilitates upon in the development of novel surgical approaches to the
the use of postoperative diagnostic scans to evaluate for metastases thyroid gland, including true three-dimensional visualization, highly
and recurrence. Diagnostic radioiodine uptake should ideally be articulated EndoWrist capability, and motion scaling. Transaxillary
1% or less after total thyroidectomy. Subsequent radioiodine thyroidectomy was developed to avoid a cervical incision.274
treatment does not need to be used to ablate excess normal tissue Additionally, a breast incision approach has been developed as has
and can be concentrated on the removal of residual carcinoma a robotic facelift thyroidectomy.275,276 Natural orifice techniques
and distant metastases. are currently under development and include a transoral endoscopic
Controversy surrounding the extent of surgery will continue thyroidectomy that is being adopted for robotic instrumenta-
to persist because no uniform set of characteristics can be used tion.277,278 Given the relatively early stage of development and
to classify the aggressiveness of WDTCs. Results of treatment continuing accrual of clinical data, the overall level of adoption
will also continue to differ among institutions and surgeons. of these techniques is difficult to determine. Clearly, these tech-
Nevertheless, initial surgery should address gross disease in the niques have extensive equipment and training requirements.
thyroid and neck nodes. The extent of the surgery should be guided Continued research is necessary to determine the benefits of these
by the patient’s risk factors, operative findings, and intraoperative techniques relative to cost and potential complications.
RLN
SLN
Parathyroid
glands
A B
Fig. 122.16 (A and B) The magnification provided through a 5-mm 30-degree endoscope provides excellent
intraoperative visualization of the superior laryngeal nerve (SLN) and the recurrent laryngeal nerve (RLN) and
parathyroid glands. (From Lai SY, Walvekar RR, Ferris RL: Minimally invasive video-assisted thyroidectomy:
expanded indications and oncologic completeness, Head Neck 30:1403–1407, 2008.)
compartment dissections when cervical disease is present rather

Special Treatment Situations than simple node plucking.290 Care should be taken to identify 122
and preserve the blood supply to the parathyroid glands. Indications
Children for lateral neck dissection (levels II through Vb) are similar to
In children, nodular thyroid disease is uncommon, with an incidence adult patients.
of 0.2% to 1.8%.279 Thyroid nodules in children are more likely Although children and adolescents commonly present with
than in adults to be malignant. Most neck masses that occur in more advanced disease than adults, their prognosis remains excel-
children are due to congenital or inflammatory causes. Malignant lent. In several series, young patients have a 10-year survival near
neck masses may be due to lymphoproliferative disorders, sarcomas, 100% and a 2- to 5-year survival rate near 90%.293 Relapse is
or thyroid carcinomas. Less than 6% of pediatric neck tumors most common in the cervical lymphatics, and it is more common
are thyroid malignancies,280 and approximately 10% of all thyroid in children than in adults. Recurrence seems to be more common
carcinomas occur in patients younger than 21 years.281 in younger patients and in those with papillary histology.294 Cervical
Most children with thyroid neoplasms present with an disease can be surgically excised, and pulmonary recurrence is
asymptomatic mass within either the thyroid or the lateral neck. responsive to radioiodine therapy.292
The lesions are often asymptomatic and are frequently noted by
a parent or pediatrician during a routine physical examination. A
complete history should include special attention to family history
Pregnancy
and radiation exposure. The physical examination should carefully Because thyroid neoplasms occur more commonly in women and
evaluate potential fixation of the thyroid gland to surrounding often during their childbearing years, physicians occasionally need
neck structures. Vocal cord mobility should be documented. The to manage this disease in pregnant women. The incidence of
central compartment and lateral neck should also be carefully thyroid nodules during pregnancy has been reported as 2% to
palpated. Lymph node metastases are present in more than 50% 10%.295,296 Management of these patients must protect the well-
of children with differentiated thyroid cancer,282 and local extension being of the mother and the fetus and must minimize the risks
reported in 18%. In addition, 15% of patients have distant of preterm labor or abortion. A crucial principle in thyroid nodule
metastasis, frequently identified with postoperative radioiodine management during pregnancy and breastfeeding is the absolute
scan.283,284 A chest radiograph may be normal or may show a fine contraindication for the use of RAI.297
interstitial reticular pattern, which can be mistaken for miliary During pregnancy, the thyroid gland physiology is markedly
tuberculosis. Children with extensive pulmonary thyroid metastases altered. The gland can increase significantly in size because of a
may present with dyspnea on exertion. relative iodine insufficiency and hormonal changes.298,299 These
The diagnostic workup in children should include FNAC and physiologic and hormonal changes may increase the incidence
US. An uncooperative child may require sedation and US guidance of thyroid nodules or cause the enlargement of existing thyroid
for FNAC. Because an advanced stage of disease is common in nodules.
children at initial presentation, US provides valuable information The presence of any discrete thyroid nodule should be evaluated
regarding the size and consistency of the thyroid mass. US examina- by FNAC.300 Some authors argue that a pregnant patient beyond
tion also can identify potential regional involvement of the 20 weeks of gestation should have FNAC deferred until after the
paratracheal or cervical lymphatics. pregnancy to reduce patient anxiety.296,301 These authors argue
Although the most common cause of a solitary thyroid nodule that treatment would likely occur after pregnancy, and they advocate
in children is a follicular adenoma (69%), malignancies are found FNAC only when the nodule shows continued growth or other
in 16% to 25% of nodules.285,286 The most common malignant suspicious features. Other authors advocate FNAC at any stage
histologic type is papillary carcinoma, which is present in more of pregnancy.297
than 80% of cases. In contrast to thyroid carcinoma in adults, US may be used for initial assessment and continued moni-
papillary carcinomas are usually follicular in pattern, and tall cell toring. Ultrasound evaluation is effective for the evaluation of
and columnar cell variants do not occur in children.287,288 A diffuse thyroid and cervical involvement. CT scans during pregnancy
sclerosing variant can also be seen in children and can be more are not recommended, although MRI, if necessary, may be
biologically aggressive. Hürthle cell carcinomas may manifest with performed safely.
multiple lesions and a papillary architecture as a familial syn- When FNAC is benign or indeterminate, US can be used to
drome.289 MTCs constitute about 10% of pediatric thyroid car- monitor the nodule for possible growth during pregnancy. If FNAC
cinomas, and all family members need to be carefully evaluated is suspicious or shows thyroid carcinoma, surgery can generally
for possible familial MTC or MEN syndromes. be safely postponed until after delivery, even in cases where women
Management of a child with thyroid carcinoma must balance present with cervical metastases or the diagnosis is early in
the potential morbidity associated with treatment against the low pregnancy, given the general indolent nature of the vast majority
probability that the patient will die of the disease. The ATA has of well differentiated thyroid cancer.302 Even most medullary thyroid
specific guidelines for the management of thyroid nodules and cancers demonstrate a rather indolent natural history of growth,
differentiated thyroid cancer in children.290 The primary goal and generally do not warrant surgery during pregnancy. Surgery
of surgery is to remove gross disease completely at the primary can be considered during the second trimester if there is substantial
and regional metastatic sites. A total thyroidectomy is more growth documented ultrasonographically during pregnancy,
often recommended, due to the increased incidence of bilateral although this is very rarely necessary.79 Pregnant patients undergo-
and multifocal disease.281,282,290–292 Multifocal disease is present ing thyroid or parathyroid surgery during pregnancy have been
in 10% to 30% of patients. In addition, a total thyroidectomy demonstrated to have increased perioperative complications
allows the use of serum thyroglobulin to monitor disease recur- compared to nonpregnant controls, which included maternal-fetal
rence and facilitates the use of radioiodine to identify and treat complications (e.g., fetal distress, cesarean section).303 Additionally,
distant metastases. there is generally no difference in prognosis of pregnant patients
Children often present with cervical nodal metastases that with a thyroid carcinoma diagnosed early in gestation who defer
require therapeutic lymphadenectomy. In patients with nodal surgery until after labor.304 Aggressive thyroid histopathology (e.g.,
disease, the paratracheal and pretracheal lymph nodes are involved poorly differentiated or anaplastic thyroid cancers) that grows
in 90% of cases.41 The metastatic deposits are frequently compres- rapidly and/or invades adjacent cervical structures is extremely
sive, rather than infiltrative, with respect to adjacent neck structures. rare in women of child-bearing age. In such a rare circumstance,
As with adults, children should have comprehensive central if surgery is considered, it should be done during the second
trimester after thorough discussion among the patient, obstetrician- Vocal cord function should be evaluated and documented by indirect
gynecologist, endocrinologist, and surgeon. laryngoscopy or flexible fiberoptic laryngoscopy, especially in
patients who have had previous surgery.
Unilateral RLN injury leads to a vocal cord in the paramedian
Complications position, and the voice may be breathy, lack volume, and fatigue
Mortality rates in thyroid surgery are extremely low, and serious easily. Concurrent injury of the SLN results in a more laterally
complications occur in less than 2% of all thyroid cases.15 Complica- positioned vocal cord and worsens voice quality and glottic
tions can typically be divided into nonmetabolic and metabolic competence.308 Occasionally, patients may have difficulty with
complications. Of particular concern are injury to the RLN and aspiration and pneumonia.307
hypoparathyroidism. Postoperative infections are very unusual Bilateral RLN injury may manifest very dramatically. Immediate
because of the abundant blood supply in the thyroid bed. The postoperative stridor and dyspnea may require immediate reintuba-
prevention of scar widening or hypertrophy depends on proper tion and a possible tracheostomy. Occasionally, bilateral RLN
placement of the incision, which can often be hidden within existing injury may not be immediately noticeable, and patients may adapt
skin creases; to avoid the increased skin tension over the sternal to the reduced airway. Over time, the vocal cords move to the
notch, the incision should not be placed too low in the neck. midline and compromise the airway.
Pneumothorax is very rare and is often associated with extended Identification and careful dissection along the course of the
procedures that involve subclavicular dissection. Chylous fistulas RLN decreases the incidence of permanent injury. The surgeon
may occur more often on the left side but are usually self-limiting should also be aware of the possibility of a nonrecurrent nerve,
when wound drainage is adequate. which is almost always on the right side and associated with a
retroesophageal subclavian artery. If the nerve is transected during
surgery, microsurgical repair of the nerve is recommended. Although
Bleeding Complications the repair is unlikely to restore normal function, reanastomosis
Hemorrhage is uncommon when surgery is performed with of the RLN may maintain some vocal cord tone and decrease
meticulous hemostasis. Bleeding may occur, however, because of the extent of vocal cord atrophy.309 Some surgeons advocate
an undetected coagulopathy or a technical mishap. Significant anastomosis of the ansa hypoglossal nerve to the distal end of the
hemorrhage in the immediate postoperative period can lead to severed RLN to prevent laryngeal synkinesis and possible vocal
life-threatening airway compression. A rapidly expanding hematoma cord hyperadduction.310,311
requires immediate opening of the surgical incision and evacuation Comprehensive management of vocal cord injury is beyond
of blood. Airway control can be established, and the patient can the scope of this chapter. In most cases, RLN injury is detected
be returned to the operating room for complete exploration to postoperatively. Management is supportive. Return of normal vocal
identify bleeding sites. A wound seroma may occur, especially cord function generally occurs within 12 months after temporary
after the removal of a large goiter. If a fluid collection is present, RLN injury occurs, and speech therapy can be valuable. Serial
simple needle aspiration should manage the problem and prevent examinations should document a potential return of function or
the risk of infection. compensation by the contralateral vocal cord. In patients with
continued vocal incompetence or aspiration, treatment directed
toward vocal cord medialization may consist of vocal cord injection,
Superior Laryngeal Nerve Injury thyroplasty, or arytenoid medialization. In cases of bilateral RLN
Injury to the external branch of the SLN may be as high as 25% injury, management is directed at improving the airway, while not
in thyroid surgery, but the exact frequency is unknown. While completely sacrificing voice quality, and it may involve arytenoi-
disturbance of SLN function may be temporary and mild, many dectomy or transverse cordotomy.
SLN injuries are unrecognized yet still cause some permanent
voice morbidity. Injury to the SLN alters function of the crico-
thyroid muscle, which normally serves to lengthen and tense the
Hypocalcemia
vocal cords. Patients may have difficulty shouting, and singers Transient symptomatic hypocalcemia after total thyroidectomy
find difficulty with pitch variation, especially in the higher frequen- occurs in approximately 7% to 25% of cases, but permanent
cies. The external branch of the SLN may not be visualized with hypocalcemia is less common (0.4% to 13.8%).312,313 The risk of
every thyroid surgery, as it often lies deep to the inferior constrictor hypoparathyroidism is related to the size and degree of invasion
muscle, but nevertheless the relationship of the SLN to the superior of the tumor, the pathology, and the extent of the procedure, as
pole vessels should be appreciated and respected during thyroid well as surgeon experience.73,314 Changes in serum calcium levels
surgery. Adequate exposure of the superior thyroid pole and close are often transient and may not always be related to parathyroid
ligation of the individual vessels on the thyroid capsule may prevent gland trauma or vascular compromise.
SLN injury, as well as the use of nerve monitoring. Voice therapy Parathyroid autotransplantation may be considered when the
may help patients to compensate in cases of SLN injury. risk of postoperative hypocalcemia is increased.315,316 These situ-
ations may include thyroid carcinoma that requires total thyroid-
ectomy with central neck dissection, en bloc resections that require
Recurrent Laryngeal Nerve Injury removal of the parathyroid glands, and reoperation after previous
Injury to the RLN has a much greater impact and is more noticeable thyroid or parathyroid surgery. Autotransplantation is commonly
than SLN injury. The incidence of permanent RLN paralysis is performed in the sternocleidomastoid muscle, although various
approximately 1% to 2% with thyroid surgery.143,305,306 Temporary locations, including the brachioradialis muscle of the nondominant
dysfunction occurs in at least 2% to 5% of patients,241 but the forearm, have been used.317
incidence of temporary neuropraxia (often related to heat, stretch, Transient hypocalcemia is often related to variations in serum
or traction injury) is likely underestimated by many thyroid protein binding caused by perioperative alterations in acid-base
surgeons. Incidence of temporary and permanent injury may be status, hemodilution, and albumin concentration. These changes
elevated in some revision procedures. RLN injury is also more do not produce hypocalcemic symptoms. Sudden changes in levels
common in thyroidectomy with neck dissection, although this of ionized serum calcium can result in perioral and distal extremity
may reflect more advanced disease states.307 Disease-specific risk paresthesias, however. As calcium levels continue to decline, patients
factors for permanent nerve damage include recurrent thyroid may experience tetany, bronchospasm, mental status changes,
carcinoma, substernal goiter, and various thyroiditis conditions. seizures, laryngospasm, and cardiac arrhythmias. Chvostek sign
and Trousseau sign may develop with increased neuromuscular cancer depend upon higher risk features, such as concerning
irritability as serum calcium levels decrease to less than 8 mg/dL. histologic subtypes (e.g., tall cell, columnar, insular, and PDTCs), 122
Typically, serum calcium levels are measured in the immediate the presence of intrathryoid vascular invasion, and gross or
postoperative period and the next morning for patients with a microscopic multifocal disease. In the absence of high-risk features,
total or completion thyroidectomy. Patients should have a stable RAI ablation is not recommended for patients with unifocal or
or increasing serum calcium level prior to discharge from the multifocal cancer when the lesions are smaller than 1 cm.
hospital. Patients who undergo a thyroid lobectomy do not usually Elevated TSH levels are necessary to enhance uptake of iodine
require serum calcium monitoring. Findings that should be wor- by thyroid cancer cells. A TSH level greater than 30 mU/L is
risome for hypoparathyroidism include hypocalcemia, hyperphos- associated with increased radioiodine uptake in tumors.325 Patients
phatemia, and metabolic alkalosis. PTH levels may also be measured are taken off thyroid hormone suppression therapy for 3 to 4
to predict potential hypocalcemia.318 Often there can be a lag weeks before scanning and are placed on a low-iodine diet.79
period of 24 to 36 hours before serum calcium starts to drop after Additionally, the administration of exogenous recombinant human
surgery, underscoring the importance of checking PTH in patients TSH has proved safe and effective for stimulating radioiodine
for whom there is concern for potential hypoparathyroidism prior uptake and for detecting serum thyroglobulin in patients undergoing
to discharge home from the hospital. evaluation for thyroid cancer persistence and recurrence.326,327
Treatment for hypocalcemia is typically initiated if the patient Whole-body diagnostic scans stage the patient and determine
is symptomatic or serum calcium levels decrease to less than 7.5 mg/ the need and potential benefit of radioiodine therapy. A phenom-
dL. In these patients, cardiac monitoring may be warranted. Patients enon termed stunning may occur, however, when scanning doses
should receive 10 mL of 10% calcium gluconate and 5% dextrose of 131I induce follicular cell damage. Poor uptake by thyroid remnant
in water intravenously, titrated to symptom resolution, and sub- and metastases of subsequent therapeutic 131I doses reduces the
sequent serum calcium level tests should be obtained. Oral calcium potential benefits of this therapy.328 Pretreatment scans are now
supplementation should begin with 2 to 3 g of calcium carbonate performed with small doses of 131I (2 to 3 mCi) or 123I. The physical
per day. Calcitriol (1,25-dihydroxycholecalciferol) also should be properties of 123I permit better image quality and decrease possible
initiated. Assuming parathyroid glands have been preserved and/ stunning of functioning thyroid cells by the 131I β-particle emis-
or autotransplanted, the vast majority of hypoparathyroidism is sion329; this permits the maximal benefit of 131I in ablation after
transitory, recovering in the first two weeks following surgery, the diagnostic procedure.330
with slow titration off oral calcium and/or calcitriol as outpatient. After the diagnostic scan, therapeutic ablative doses of 131I can
Adjustments in supplemental calcium and vitamin D may be done be given. Typically, 30 mCi of 131I is given for uncomplicated cases
in consultation with an endocrinologist. with only thyroid bed uptake.331,332 Current guidelines recommend
using the minimum activity necessary to achieve successful thyroid
remnant ablation, particularly for low-risk patients.103 Patients
POSTOPERATIVE MANAGEMENT AND with distant metastases may receive 100 to 150 mCi.333,334 Doses
SPECIAL CONSIDERATIONS greater than 200 mCi have not been shown to be more effective
in most cases.
Thyroid Hormone Replacement and No clear evidence exists regarding the superiority of 131I delivery
by empiric fixed amounts, quantitative tumor dosimetry, or blood/
Thyroid-Stimulating Hormone Suppression Therapy body dosimetry.335 Currently there are data available that dem-
After total or completion thyroidectomy, exogenous supplementa- onstrates recombinant human TSH–mediated 131I therapy is as
tion of thyroid hormone is necessary to prevent symptomatic effective as high-dose radioiodine, with a lower rate of adverse
hypothyroidism.11,95 To counteract potential trophic effects of TSH events.331 Posttreatment scans are typically performed within one
that could facilitate recurrence or progression of WDTCs, long- week after RAI therapy to visualize potential metastases.
term supplementation with levothyroxine is monitored to suppress Diverse alternatives and protocols exist regarding the use of
TSH to below-normal levels (<0.1 mU/L in high- and intermediate- radioiodine therapy. Surgeons who favor total thyroidectomy for
risk patients and 0.1 to 0.5 mU/L in low-risk patients).86 Patients most thyroid carcinomas argue that removal of normal tissue
who receive suppressive therapy have a lower recurrence rate and enhances radioiodine ablation therapy. Proponents of more
improved survival.319,320 conservative treatment suggest that radioiodine therapy can be
In the immediate postoperative period, patients may be given used to remove even a remaining thyroid lobe before whole-body
liothyronine sodium, which has a shorter half-life than levothyroxine scanning for residual tumor or metastases. Current ATA guidelines
and decreases the waiting period before radioiodine body scanning; recommend against the use of RAI ablation instead of completion
it may also allow ablative therapy to be performed. thyroidectomy.79 Continued work in this area is aimed at improving
patient outcomes and decreasing disease recurrence.
Radioactive Iodine Treatment
Radiolabeled iodine has been used for more than 40 years to
External-Beam Radiotherapy and Chemotherapy
ablate normal thyroid tissue and to treat residual tumor and Because of the effectiveness of surgery and radioiodine treatment
metastases.321 The 131I isotope emits β-particles that penetrate and for most thyroid carcinomas, EBRT and systemic therapy are
destroy tissue within a 2-mm zone. Patients classified as high risk rarely indicated. The indications for locoregional EBRT and
with PTC and many patients with follicular carcinoma are con- traditional cytotoxic chemotherapy among patients with well
sidered for treatment.172 When administered as part of the initial differentiated and medullary thyroid cancers are becoming increas-
therapy, postoperative 131I treatment contributes to decreased ingly rare in an era of targeted systemic therapy based on tumor
recurrence and disease-specific mortality.322–324 genetic mutations. Postoperative adjuvant EBRT likely improves
Current ATA treatment guidelines recommend RAI ablation local control in select cases of aggressive histopathology (e.g.,
for all patients with gross extrathyroid extension of the tumor or poorly differentiated or anaplastic thyroid cancers) or extrathyroidal
known distant metastases regardless of tumor size.79 RAI can be disease invasive of the esophagus or laryngotrachea. The effect
considered for patients with a primary tumor greater than 4 cm of EBRT on survival is uncertain, however.336,337 EBRT is also
in size, tumors with microscopic extrathyroidal extension, and commonly employed as palliative therapy in patients with distant
regional metastases. RAI treatment decisions for these patients metastasis of thyroid origin, particularly those involving bone.240
with intermediate to high risk of recurrence or death from thyroid In a study examining the effect of adding EBRT to RAI for patients
with T4a disease with esophageal or laryngotracheal invasion, groups.79 Increasing serum thyroglobulin levels are highly sensitive
patients receiving both modalities demonstrated an improvement (97%) and specific (100%) for thyroid cancer recurrence.347 Eleva-
in 5-year disease-free survival (57% vs. 43%) and lower locoregional tion of thyroglobulin levels warrants further evaluation, typically
failure (3% vs. 34%).220 When contemplating the option of beginning with high-definition ultrasound of the neck. Depending
postoperative EBRT, it should always be considered that EBRT on risk classification, additional follow-up procedures vary. The
may eliminate the option for future surgery, and therefore should ATA guidelines recommend measurement of serum thyroglobulin
generally be reserved for patients for whom further thyroid/neck and a cervical ultrasound examination in low-risk patients approxi-
surgery will not be possible, or would create significant morbidity mately 12 months after initial treatment with surgery and
(e.g., total laryngectomy). radioiodine ablation.79 In intermediate-risk and high-risk patients,
Based on improved understanding of the biologic basis for cervical ultrasound examination and serum thyroglobulin measure-
thyroid cancer development and progression, numerous novel ments are recommended every 6 to 12 months. The follow-up
targeted-therapy agents, including kinase and angiogenesis inhibi- management paradigm has moved away from diagnostic whole-body
tors, have been approved by the FDA.57,338–344 Through recent radioiodine scans.
trials with targeted therapies, the FDA has approved two kinase Patients with MTCs require serial measurements of calcitonin
inhibitors, sorafenib and lenvatinib, for use in advanced stage and CEA. Suspected recurrences may also be detected with a
differentiated thyroid cancer, cabozatinib and vandetanib for MTC, pentagastrin stimulation test. If serum calcitonin and CEA are rising,
and a combination of dabrafenib/trametinib for ATC.119,209,227,228,339,344 neck imaging and distant metastatic work-up may be indicated.
FOLLOW-UP MANAGEMENT SUMMARY

Patients treated for thyroid carcinomas require long-term follow-up High-definition ultrasound and fine-needle aspiration biopsy are
and monitoring. Approximately 25% of patients with differentiated the hallmark of diagnostic evaluation for thyroid neoplasia. Surgery
thyroid carcinomas experience tumor recurrence, and 66% of remains the mainstay of treatment for the vast majority of thyroid
these recurrences occur within the first decade after initial treat- cancer. The prognosis for young patients with differentiated thyroid
ment.11 Various staging systems for thyroid cancer, including the cancer is typically excellent, and these patients are often cured
AJCC/IUCC system, were developed to predict risk for death, with surgery alone, with the addition of RAI for higher risk disease.
not to predict recurrence.103,345,346 After initial surgery and remnant Patients with extensive extrathyroidal disease and/or distant
ablation, low-risk patients have no local or distant metastases and metastases may require adjuvant therapies.
have complete resection of all macroscopic tumor with no locore- Medullary thyroid cancer is usually sporadic, although all
gional tumor invasion, no aggressive histology, no vascular invasion, patients should undergo genetic testing for germline RET mutation.
and no 131I uptake outside the thyroid bed in the first posttreatment The vast majority of patients with medullary thyroid cancer should
whole-body radioiodine scan. Intermediate-risk patients have minor undergo total thyroidectomy and central compartment dissection.
extrathyroidal extension, aggressive histology, or vascular invasion. Patients with elevated calcitonin and CEA after surgery should
High-risk patients have gross extrathyroidal extension, incomplete undergo distant metastatic work-up, and may ultimately require
tumor resection, distant metastases, or radioiodine uptake beyond systemic therapy.
the thyroid bed on the posttreatment scan done after thyroid Recent advances have been made in the molecular genetics of
remnant ablation. thyroid cancer, particularly in the understanding of poorly dif-
In addition to regular physical examination, thyroid hormone ferentiated and anaplastic tumors. New targeted agents (specifically
and TSH levels are monitored, with higher risk patients recom- targeting BRAF and MEK) as well as immunotherapy have provided
mended for varying periods and degrees of thyroid hormone new hope of treatment options for patients with these more
suppression. Thyroglobulin levels should be closely monitored. aggressive thyroid cancers.
Levels should be monitored at least annually for the first several
years, and more frequently for patients that fall in higher risk For a complete list of references, visit ExpertConsult.com.
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Management of Thyroid Neoplasms

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Management of Thyroid Neoplasms

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122

Age-standardized incidence in Australia12

MOLECULAR BASIS FOR THYROID NEOPLASMS

Fig. 122.7 The external branch of the superior laryngeal nerve,

TABLE 122.2 Tumor/Node/Metastasis Staging for Thyroid Cancer

Potential substernal extension can be estimated by the relation-

30 years. Patients usually present with a solitary, mobile thyroid

Other Forms of Thyroid Cancer Squamous Cell Carcinoma

parathyroidectomy or anterior cervical spinal fusion, may have involved

compartment dissections when cervical disease is present rather

FOLLOW-UP MANAGEMENT SUMMARY

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