Practice Essentials

Thyroid cancers represent approximately 1% of new cancer diagnoses in the United States each
year. Thyroid malignancies are divided into papillary carcinomas (80%), follicular carcinomas
(10%), medullary thyroid carcinomas (5-10%), anaplastic carcinomas (1-2%), primary thyroid
lymphomas (rare), and primary thyroid sarcomas (rare).
Signs and symptoms
Thyroid carcinoma most commonly manifests as a painless, palpable, solitary thyroid nodule.
Patients or clinicians discover most of these nodules during routine palpation of the neck.
Signs and symptoms associated with malignancy in thyroid nodules include the following:
Solitary nodules: Most likely to be malignant in patients older than 60 years and in patients
younger than 30 years
Increased rate of malignancy in males
Nodular growth
Rapid growth: Ominous sign
Usually painless (nontender to palpation); sudden onset of pain more strongly associated with
benign disease (eg, hemorrhage into a benign cyst, subacute viral thyroiditis)
Hard and fixed nodules
Diagnosis
The key to the workup of the solitary thyroid nodule is to differentiate malignant from benign
disease and, thus, to determine which patients require intervention and which patients may be
monitored serially. History taking, physical examination, laboratory evaluation, and fine-needle
aspiration biopsy (FNAB) are the mainstays in the evaluation of thyroid nodules. Imaging studies
can be adjuncts in select cases.
Examination in patients suspected of thyroid cancer includes the following:
Thorough head and neck examination, including thyroid gland and cervical soft tissues
Indirect laryngoscopy
Firm cervical masses are highly suggestive of regional lymph node metastases. Vocal fold
paralysis implies involvement of the recurrent laryngeal nerve.
Procedures
FNAB is the most important diagnostic tool in evaluating thyroid nodules and should be the first
intervention. The following are the 4 possible results from this procedure:
Benign disease
Malignant disease
Indeterminate for diagnosis
Nondiagnostic
Up to 50% of repeated biopsies result in a definitive diagnosis. Patients whose findings are
indeterminate or nondiagnostic despite repeat biopsy can undergo surgery for lobectomy for
tissue diagnosis. Nondiagnostic cases can also be monitored clinically, and radioiodine scans
can be useful for determining the functional status of the nodule, because most hyperfunctioning
nodules are benign.
Laboratory testing
The following laboratory studies may be used to assess patients with suspected thyroid cancer:
Serum thyroid-stimulating hormone concentration: Sensitive for hyperthyroidism/hypothyroidism
and for evaluation of solitary thyroid nodules
Serum calcitonin/pentagastrin-stimulated calcitonin levels: Elevated levels highly suggestive of
medullary thyroid carcinoma
Polymerase chain reaction (PCR) assay for germline mutations in the RET proto-oncogene: For
diagnosis of familial medullary thyroid carcinoma
Imaging studies
The following imaging studies may be used to evaluate patients with suspected thyroid cancer:
Neck ultrasonography: Most common modality to evaluate thyroid disease; however, limited
usefulness for distinguishing between malignant and benign nodules
Thyroid radioiodine imaging: To determine functional status of a nodule but cannot exclude
carcinoma
Neck computed tomography scanning or magnetic resonance imaging (avoid iodinated contrast
agents): To evaluate soft-tissue extension of large or suspicious thyroid masses into the neck,
trachea, or esophagus, and to assess metastases to the cervical lymph nodes; no role in
routine management of solitary thyroid nodules
Management
Malignant diagnoses require surgical intervention. Papillary thyroid carcinoma and medullary
thyroid carcinoma are often positively identified on the basis of FNAB results alone. Cervical
metastases discovered preoperatively or intraoperatively should be removed by means of en
bloc lymphatic dissection of the respective cervical compartment (selective neck dissection) while
sparing the nonlymphatic structures.
Well-differentiated neoplasms
Patients with follicular neoplasm, as determined with FNAB results, should undergo surgery for
thyroid lobectomy for tissue diagnosis. The extent of surgical therapy for well-differentiated
neoplasms is controversial. Primary treatment for papillary and follicular carcinoma is surgical
excision whenever possible. Total thyroidectomy has been the mainstay for treating well-
differentiated thyroid carcinoma. Modifications to total thyroidectomy include subtotal
thyroidectomy to reduce the risk of recurrent laryngeal nerve injury and hypoparathyroidism.
Hrthle cell carcinomas
For patients with Hrthle cell carcinomas based on initial FNAB findings, most surgeons
advocate an aggressive approach with lobectomy and isthmectomy, followed by completion
thyroidectomy with confirmation on final pathologic result. For tumors larger than 5 cm or for
palpable lymphatic metastases, total thyroidectomy (including neck dissection for palpable lymph
nodes) is often performed during the initial operation.
Medullary thyroid carcinomas and familialmedullary thyroid carcinomas
Sporadic medullary thyroid carcinomas and familial medullary thyroid carcinomas are treated
with total thyroidectomy and lymphatic dissection of the anterior compartment of the neck. If the
vasculature of the parathyroid gland is disrupted, autotransplantation of the parathyroid gland
into the sternocleidomastoid muscle or the nondominant forearm is performed. In children with
multiple endocrine neoplasia (MEN) type 2A and MEN 2B syndromes, prophylactic
thyroidectomy and central-compartment lymph-node dissection is performed.
Anaplastic thyroid carcinoma, primary thyroid lymphoma, thyroid sarcoma
Total or subtotal thyroidectomy is performed for anaplastic thyroid carcinoma when the extent of
the tumor permits it. Tracheotomy is needed in cases with airway compromise due to tracheal
invasion.
Stage IE lymphomas may be treated with total thyroidectomy followed by postoperative radiation
therapy. Surgical excision should not be performed if local infiltration into surrounding tissues is
evident. Stage IIE lymphomas are treated with combined chemotherapy and radiation therapy.
Doxorubicin or CHOP (ie, cyclophosphamide, hydroxydaunomycin, Oncovin [vincristine],
prednisone) is the commonly used chemotherapeutic regimen.
The treatment for thyroid sarcomas is total thyroidectomy. Radiation therapy may be used in an
adjunctive setting.
Postsurgical management
After total thyroidectomy, patients undergo radioiodine scanning to detect regional or distant
metastatic disease, followed by radioablation of any residual disease found. In addition, patients
are given thyroid replacement therapy with T4 or triiodothyronine (T3).
In patients with anaplastic thyroid carcinoma, chemotherapy and radiation therapy are typically
administered in combination. Postoperative external-beam irradiation is effective in improving
local control; this may also be used as primary treatment in unresectable cases. Chemotherapy
(most commonly doxorubicin) is added for palliation.
Image library
Algorithm for the management of a solitary thyroid nodule. FNAB = fine needle
aspiration biopsy; US = ultrasonography.
Overview
Thyroid malignancy occurs with relative infrequency in the United States, although benign
thyroid disease is relatively common. Although patients with thyroid cancers generally have
a favorable prognosis compared with that of patients with many other solid tumors, an
estimated 1200 patients died of thyroid cancer in the United States in 1998. Contemporary
treatment of patients with thyroid malignancy requires a multidisciplinary approach involving
an endocrinologist, a thyroid surgeon, a radiologist, and, on occasion, medical and radiation
oncologists.
For excellent patient education resources, visit eMedicineHealth's Thyroid and Metabolism
Center. Also, see eMedicineHealth's patient education article Thyroid Problems.
An image of Hurthle cells can be seen below.
A monomorphous cell population of Hrthle cells arranged in loosely cohesive
clusters and single cells. The cells are polyhedral and have abundant granular cytoplasm with well -defined cell borders.
The nuclei are enlarged and have a central prominent macronucleolus.
Frequency
Thyroid cancers represent approximately 1% of new cancer diagnoses each year.
Approximately 23,500 cases of thyroid cancer are diagnosed yearly in the United States.
The incidence of thyroid malignancies is 3 times higher in women than in men. The
incidence of this disease peaks in the third and fourth decades of life.
Thyroid cancers are divided into papillary carcinomas, follicular carcinomas, medullary
thyroid carcinomas (MTCs), anaplastic carcinomas, primary thyroid lymphomas, and primary
thyroid sarcomas. Papillary carcinoma represents 80% of all thyroid neoplasms. Follicular
carcinoma is the second most common thyroid cancer, accounting for approximately 10% of
cases. MTCs represent 5-10% of neoplasms. Anaplastic carcinomas account for 1-2%.
Primary lymphomas and sarcomas are rare.
Using data on 497 US counties from the National Cancer Institute's Surveillance,
Epidemiolgy, and End Results program, Morris et al found that the tripling of the incidence of
papillary thyroid cancer in the past 3 decades is directly correlated with demographic and
age-based markers of access to health care, suggesting widespread overdiagnosis of the
disease. Supporting this conclusion, rates of mortality from thyroid cancer remained stable
during this period.
[1, 2]

Etiology
Thyroid carcinomas arise from the 2 cell types present in the thyroid gland. The
endodermally derived follicular cell gives rise to papillary, follicular, and probably anaplastic
carcinomas. The neuroendocrine-derived calcitonin-producing C cell gives rise to MTCs.
Thyroid lymphomas arise from intrathyroid lymphoid tissue, whereas sarcomas likely arise
from connective tissue in the thyroid gland.
Radiation exposure significantly increases the risk for thyroid malignancies, particularly
papillary thyroid carcinoma. This finding was observed in children exposed to radiation after
the nuclear bombings in Hiroshima and Nagasaki during World War II. Additional evidence
was gathered after atomic bombs were tested in the Marshall Islands, after the accident at
the Chernobyl nuclear power plant, and in patients who received low-dose radiation therapy
for benign disorders (eg, acne, adenotonsillar hypertrophy). Low-dose radiation exposure
from imaging studies has not been found to have a tumorigenic effect. Radiation targeting
the thyroid gland (eg, iodine-131 ablation of the thyroid) or high-dose external-beam
radiation therapy does not appear to increase the risk of papillary thyroid carcinoma. This is
presumably because cell killing increases with these doses.
Low dietary intake of iodine does not increase the incidence of thyroid cancers overall.
However, populations with low dietary iodine intake have a high proportion of follicular and
anaplastic carcinomas.
Clinical Presentation
History
Thyroid carcinoma most commonly manifests as a painless, palpable, solitary thyroid
nodule. Patients or physicians discover most of these nodules during routine palpation of the
neck. Palpable thyroid nodules are present in approximately 4-7% of the general population,
and most represent benign disease. High-resolution ultrasonography reportedly depicts
thyroid nodules in 19-67% of randomly selected individuals. An estimated 5-10% of solitary
thyroid nodules are malignant. Palpable and nonpalpable nodules of similar size have the
same risk of malignancy.
The patient's age at presentation is important because solitary nodules are most likely to be
malignant in patients older than 60 years and in patients younger than 30 years. In addition,
thyroid nodules are associated with an increased rate of malignancy in male individuals.
Growth of a nodule may suggest malignancy. Rapid growth is an ominous sign.
Malignant thyroid nodules are usually painless. Sudden onset of pain is more strongly
associated with benign disease, such as hemorrhage into a benign cyst or subacute viral
thyroiditis, than with malignancy.
Hoarseness suggests involvement of the recurrent laryngeal nerve and vocal fold paralysis.
Dysphagia may be a sign of impingement of the digestive tract. Heat intolerance and
palpitations suggest autonomously functioning nodules.
Medullary carcinoma can occur as part of multiple endocrine neoplasia (MEN) 2A or 2B
syndrome, as well as familial MTC (FMTC) syndrome. Patients with a family history of
thyroid cancer should be evaluated with vigilance.
Physical examination
Physical examination should include thorough head and neck examination with careful
attention to the thyroid gland and cervical soft tissues, as well as indirect laryngoscopy.
Solitary thyroid nodules can vary from soft to hard. Hard and fixed nodules are more
suggestive of malignancy than supple mobile nodules are. Thyroid carcinoma is usually
nontender to palpation. Firm cervical masses are highly suggestive of regional lymph node
metastases. Vocal fold paralysis implies involvement of the recurrent laryngeal nerve.
Evaluation and Management of the Solitary Thyroid Nodule
The key to the workup of the solitary thyroid nodule is to differentiate malignant from benign
disease and, thus, to determine which patients require intervention and which patients may
be monitored serially. History taking, physical examination, laboratory evaluation, and fine-
needle aspiration biopsy (FNAB) are the mainstays in the evaluation of thyroid nodules.
Imaging studies can be adjuncts in select cases.
Fine-needle aspiration biopsy
FNAB is the most important diagnostic tool in evaluating thyroid nodules and should be the
first intervention. The technique is inexpensive and easy to perform, and it causes few
complications.
To perform FNAB, comfortably position both the patient and the physician. Extend the
patient's neck slightly and palpate the nodule with the nondominant hand. Clean the skin
with alcohol and infiltrate the area with local anesthesia. Place a 21- to 25-gauge needle on
the end of a syringe. Many physicians use trigger-style aspirating handles on the syringe.
Introduce 2 mL of air into the syringe, and place the needle into the skin. Apply negative
pressure to the syringe, and pass the needle through the nodule, which is identified by using
the nondominant hand. After several passes, release the negative pressure, and withdraw
the needle. Use the air remaining in the syringe to expel the specimen from the hub and
needle onto a glass slide or into cytologic solution for a cell block. Fix the slide in alcohol for
Papanicolaou and hematoxylin-eosin staining. Some slides can be air dried and stained with
Romanowsky stain (Diff-Quick).
Successful diagnosis by the cytologist depends on accurate sampling of the nodule and
specimen cellularity. For this reason, several authors recommend performing at least 3
aspirations to ensure adequacy of the specimen and to minimize false-negative results.
Ultrasonographic guidance can help to increase the accuracy of FNAB. Danese et al report
increased false-negative rates with palpation FNAB compared with ultrasonography-guided
FNAB.
The 4 results from FNAB are benign disease, malignant disease, indeterminate for
diagnosis, and nondiagnostic. In their review of several large series, Gharib and Goellner
(1993) found that 69% of FNAB results were benign, 4% were malignant, 10% were
indeterminate, and 17% were nondiagnostic.
[3]
Their false-positive rate was 2.9%, and their
false-negative rate was 5.2%. Sensitivity and specificity were 83% and 92%, respectively.
Results of FNAB determine the next step in managing the thyroid nodule. A definitive
diagnosis is obtained in as many as 50% of repeated biopsies. Patients whose findings are
nondiagnostic despite repeat biopsy can undergo surgery for lobectomy for tissue diagnosis,
or they can be monitored clinically. In these circumstances, radioiodine scans can be useful
for determining the functional status of the nodule, as most hyperfunctioning nodules are
benign.
Indeterminate biopsy findings are labeled suspicious at some institutions. When cellular
material is adequate for evaluation but when malignant and benign disease cannot be
differentiated, biopsy results can be labeled suspicious. Patients with a suspicious diagnosis
should undergo lobectomy for definitive diagnosis.
Malignant diagnoses require surgical intervention. Papillary thyroid carcinoma and MTC are
often positively identified on the basis of FNAB results alone. In patients with these
carcinomas, definitive surgical planning can be undertaken at the outset. However, it is
nearly impossible to distinguish a follicular adenoma from a follicular carcinoma on the basis
of FNAB findings. Patients with follicular neoplasm, as determined with FNAB results, should
undergo surgery for thyroid lobectomy for tissue diagnosis. These patients require complete
thyroidectomy if a malignancy is discovered on review of the pathology. Some controversy
exists regarding the extent of thyroidectomy (total thyroidectomy, subtotal thyroidectomy, or
lobectomy) for a particular pathologic diagnosis. Each pathologic diagnosis and its
corresponding extent of thyroidectomy are discussed below.
Complications of FNAB are few and generally minor. The most common complications are
minor hematoma, ecchymosis, and local discomfort. Clinically significant hematoma and
swelling is exceedingly rare. Inadvertent puncture of the trachea, carotid artery, or jugular
vein usually does not cause clinically significant problems and is managed with the
application of local pressure.
Laboratory evaluation
The serum thyroid-stimulating hormone (TSH) concentration is a highly sensitive measure
for hyperthyroidism or hypothyroidism. A sensitive TSH assay is useful in the evaluation of
solitary thyroid nodules. A low serum TSH value suggests an autonomously functioning
nodule, which typically is benign. However, malignant disease cannot be ruled out on the
basis of low or high TSH levels.
Other thyroid function tests are usually not necessary in the initial workup. Serum
thyroglobulin measurements are not helpful diagnostically because they are elevated in most
benign thyroid conditions.
Elevated serum calcitonin levels are highly suggestive of MTC. Serum calcitonin
measurement, which was once the mainstay in the diagnosis of FMTC, has been replaced
by sensitive polymerase chain reaction (PCR) assays for germline mutations in
the RET proto-oncogene. These mutations are present in patients with MEN 2A, MEN 2B,
and FMTC (see Genetic testing for MEN and FMTC in the Medullary Thyroid Carcinoma
section). However, calcitonin and the more sensitive pentagastrin-stimulated calcitonin are
used as tumor markers to monitor patients who have been treated for MTC. Because of the
low incidence of MTC overall, testing of serum calcitonin is not a cost-effective screening
tool in the primary workup of thyroid nodules.
Imaging procedures
Ultrasonography is the imaging modality most commonly used to evaluate thyroid disease.
This noninvasive study enables accurate evaluation of the thyroid gland. However, the
usefulness of ultrasonography for distinguish between malignant and benign nodules is
limited. Simple cysts found on sonograms are benign, but simple cysts are rarely found.
Cysts are most commonly complex, with at least some solid component that could potentially
harbor malignancy. Microcalcifications noted on sonograms are associated with thyroid
malignancy. Ultrasonography is highly sensitive for thyroid nodules and can depict nodules
only a few millimeters in size.
A sonogram ordered to evaluate a solitary nodule often reveals additional nodules of
questionable clinical significance. The accuracy of FNAB results increases when
sonographic guidance is used. Use of ultrasonography-guided FNAB can be useful for
biopsy of small or difficult-to-palpate thyroid nodules as well as for FNAB of nodules in
children. Ultrasonography can also be useful for accurate measurement of thyroid nodules
that are being monitored serially.
In 2013, researchers at the Mayo Clinic reported that recent dramatic increases in the
diagnosis of low-risk thyroid cancer in the United States are fuelled by the overuse of
ultrasonography.
[4, 5]
The incidence of thyroid cancer in the United States has tripled in the
past 3 decades, from 3.6 per 100,000 in 1973 to 11.6 per 100,000 in 2009, making it one of
the fastest growing diagnoses. The vast majority of the thyroid tumors being detected are
small low-risk papillary thyroid cancers that are unlikely to ever progress enough to cause
symptoms or death. That this represents overdiagnosis is supported by the observation that
the death rate for these cancers has remained stable (0.5 per 100,000 in 1979 and in 2009),
even with the increasing incidence.
[4, 5]

Radioiodine imaging can help in determining the functional status of a nodule. Nonfunctional
nodules do not take up radiolabeled iodine-123 and appear as cold spots in the thyroid (cold
nodules).
[6]
Hyperfunctioning nodules take up radioiodine and appear as hot spots (hot
nodules). Warm nodules appear similar to the surrounding normal thyroid tissue. Hot or
warm nodules were historically thought to be benign; therefore, they did not require further
evaluation for malignancy. However, in a review of 5000 patients undergoing thyroidectomy
regardless of radioimaging findings, Ashcraft and Van Herle (1981) found that 4% of hot
nodules harbored malignancy.
Carcinoma cannot be excluded on the basis of radioiodine scans. Therefore, radioiodine
scans are usually not helpful for the routine evaluation of thyroid nodules. In select
situations, radioiodine studies can be diagnostic adjuncts. When results of repeated FNAB of
a nodule are nondiagnostic, a radioiodine imaging can help in directing management if a hot
nodule is to be monitored clinically.
CT scanning and MRI can be used to evaluate soft-tissue extension of large or suspicious
thyroid masses into the neck, trachea, or esophagus and to assess metastases to the
cervical lymph nodes. These studies do not have a role in the routine management of
solitary thyroid nodules. The use of iodinated contrast agents should be avoided in patients
with possible thyroid carcinoma because they interfere with the postoperative use of
radioactive iodine.
Well-Differentiated Thyroid Carcinoma
Papillary carcinoma
Clinical features
Papillary carcinoma is the most common thyroid malignancy, representing approximately
80%. Papillary carcinoma and follicular carcinoma make up the well-differentiated thyroid
carcinomas. Women develop papillary cancer 3 times more frequently than men do, and the
mean age at presentation is 34-40 years.
Cases can occur familially, either alone or in association with Gardner syndrome (familial
adenomatous polyposis). As noted above, radiation exposure, especially during childhood, is
associated with the development of papillary thyroid carcinoma. Tumors typically appear
after a latency period of about 10-20 years. In addition, an increased incidence of papillary
cancer is hypothesized among patients with Hashimoto thyroiditis (chronic lymphocytic
thyroiditis). Despite this possibility, the rate of malignancy for a given nodule in people with
Hashimoto thyroiditis is similar to that of individuals with a normal gland.
Papillary carcinoma is a slow-growing tumor that arises from the thyroxine (T4)- and
thyroglobulin-producing follicular cells of the thyroid. The cells are TSH sensitive and take up
iodine. They produce thyroglobulin in response to TSH stimulation. This feature has both
diagnostic and therapeutic value for managing residual disease and recurrences after
surgical excision (see Treatment and Prognosis below).
Pathology
On gross pathologic examination, papillary carcinomas are whitish invasive neoplasms with
ill-defined margins. Under microscopy, the tumors are unencapsulated neoplasms that
characteristically grow with papillae consisting of neoplastic epithelium overlying
fibrovascular stalks. Very differentiated tumors can have a complex arborizing pattern.
Nuclei have an empty ground-glass appearance with characteristic nuclear grooves and
pseudoinclusions. Mitoses are rare.
Another histologic feature is the presence of psammoma bodies, which occur in 50% of
papillary carcinomas. Psammoma bodies are calcific concretions that have a circular
laminated appearance. They are found in the stroma of the tumor. In addition, many papillary
carcinomas contain areas that show a follicular growth pattern. However, when the nuclear
features in follicular areas are the same as those in papillary areas, the tumor behaves like a
classic papillary carcinoma and should be designated as such. Papillary carcinoma may be
multicentric, with foci present in both the ipsilateral and contralateral lobes.
Local invasion
Tumors can grow directly through the thyroid capsule to invade surrounding structures.
Growth into the trachea can occur, producing hemoptysis. Extensive involvement can cause
airway obstruction. The recurrent laryngeal nerves can become involved because of their
proximity in the tracheoesophageal groove. Patients present with a hoarse, breathy voice
and, occasionally, dysphagia.
Regional and metastatic disease
Another common feature of papillary carcinoma is its propensity to spread to the cervical
lymph nodes. Clinically evident lymph node metastases are present in approximately one
third of patients at presentation. Microscopic metastases are present in one half. The most
common site of lymph node involvement is in the central compartment (level 6) located
medial to the carotid sheaths on both sides, with extension from the hyoid bone superiorly to
the sternal notch inferiorly. The jugular lymph node chains (levels 2-4) are the next most
common sites of cervical node involvement. Lymph nodes in the posterior triangle of the
neck (level 5) may also develop metastases. This finding has important implications on the
treatment algorithm for patients in this situation (see Treatment and Prognosis below and the
images below).

Algorithm for the management of a solitary thyroid nodule. FNAB = fine needle aspiration biopsy; US = ultrasonography.

Algorithm for the management of malignant thyroid neoplasms. FNAB = fine needle aspiration biopsy; XRT = external-
beam radiation therapy.

Approximately 5-10% of patients develop distant metastases. Distant spread of papillary
carcinoma typically affects the lungs and bone.
Follicular carcinoma
Clinical features
Follicular carcinoma is the second most common thyroid malignancy and represents about
10% of thyroid cancers. Follicular carcinoma represents an increased portion of thyroid
cancers in regions where dietary intake of iodine is low. Similar to papillary carcinoma,
follicular carcinoma occurs 3 times more frequently in women than in men. Patients with
follicular carcinoma are typically older than those with papillary carcinoma at presents. The
mean age range at diagnosis is late in the fourth to sixth decades.
Like papillary carcinomas, follicular carcinomas arise from the follicular cells of the thyroid.
The neoplastic cells are TSH sensitive as well, taking up iodine and producing
thyroglobulina feature that is exploited diagnostically and therapeutically (see
Postoperative radioiodine scanning and ablation below).
Pathology
On gross pathology, the tumors appear as round, encapsulated, light brown neoplasms.
Fibrosis, hemorrhage, and cystic changes are found in the lesions. Under microscopy, the
tumors contain neoplastic follicular cells, which overall can have a solid, trabecular, or
follicular growth pattern (that usually produces microfollicles). The follicular cells in these
tumors do not have characteristic features like papillary carcinoma cells.
Follicular carcinomas are differentiated from benign follicular adenomas by tumor capsule
invasion and/or vascular invasion. For this reason, differentiating follicular adenomas from
follicular carcinomas is extremely difficult with FNAB cytology and frozen section analysis.
The tumors are divided into minimally invasive and widely invasive lesions depending on the
histologic evidence of capsule and vascular invasion. Immunohistochemical staining for
thyroglobulin and cytokeratins is nearly always positive.
Local invasion
Local invasion can occur as it does with papillary carcinoma, with the same presenting
features (see Local invasion for Papillary Carcinoma, above).
Cervical and distant metastases
Unlike papillary carcinoma, cervical metastases from follicular carcinomas are uncommon.
However, the rate of distant metastasis is significantly increased (approximately 20%). Lung
and bone are the most common sites.
Surgical treatment
The extent of surgical therapy for well-differentiated neoplasms is controversial. Primary
treatment for papillary and follicular carcinoma is surgical excision whenever possible. Total
thyroidectomy has been the mainstay for treating well-differentiated thyroid carcinoma. In
this procedure, all apparent thyroid tissue is surgically removed. Major complications in this
procedure are recurrent laryngeal nerve injury and hypoparathyroidism from inadvertent
damage or removal of the parathyroid glands. Complications associated with total
thyroidectomy are discussed in the Technique of Thyroidectomy section below.
After total thyroidectomy, patients undergo radioiodine scanning to detect regional or distant
metastatic disease (see Postoperative radioiodine scanning and ablation below), followed by
radioablation of any residual disease found.
Over the years, modifications to total thyroidectomy have been proposed in an effort to
reduce recurrent laryngeal nerve injury and hypoparathyroidism associated with total
thyroidectomy. Subtotal thyroidectomy has been proffered as an alternative to total
thyroidectomy. With subtotal thyroidectomy, a small portion of gross thyroid tissue opposite
the side of malignancy is left in place to minimize the risk of injuring the recurrent laryngeal
nerve and of inadvertently removing the parathyroid glands on that side. Patients usually
receive postoperative radioiodine treatment in an attempt to ablate the remaining thyroid
tissue.
With improved stratification of patients into prognostic groups (see Prognostic factors below),
some surgeons have proposed thyroid lobectomy with isthmectomy alone as definitive
treatment for patients at low risk for recurrent or metastatic disease. This approach remains
to be substantiated as a feasible alternative to total thyroidectomy.
Using the Surveillance, Epidemiology, and End Results (SEER) database, one study
compared the overall survival (OS) and cause-specific survival (CSS) of 23,605 subjects
with papillary or follicular thyroid cancer treated with local excision, lobectomy, near-total
thyroidectomy, or total thyroidectomy. The 10-year OS and CSS results concluded that total
thyroidectomy resulted in improved survival over other techniques; poorer outcomes were
associated with age, stage T3/T4 disease, positive nodes, and tumor size.
[7]

According to a 2009 study by Asari et al, of 207 patients with follicular thyroid carcinoma, the
127 patients with minimum growth had no lymph node metastases. The authors state that
thyroidectomy is still recommended for all patients with follicular thyroid carcinoma, although
patients with widely invasive disease may need more aggressive surgical treatment. Patients
with minimal disease invasion have an excellent prognosis with limited need for nodal
surgery.
[8]

Management of neck
The neck must be thoroughly examined for lymphatic metastases. Ultrasonography of the
neck with particular attention to the central compartment (level 6) is an effective diagnostic
approach. FNAB of suspicious lymph nodes can be performed. Cervical metastases
discovered preoperatively or intraoperatively should be removed by means of en bloc
lymphatic dissection of the respective cervical compartment (selective neck dissection) while
sparing the nonlymphatic structures. Excision of single nodes, known as berry picking, is
inadequate therapy for metastatic disease. Elective neck dissection (removal of clinically
benign neck lymphatic tissue) in a well-differentiated carcinoma is not indicated because
postoperative radioiodine treatment effectively treats microscopic lymphatic metastases.
Postoperative radioiodine scanning and ablation
Because differentiated thyroid tissue and well-differentiated thyroid carcinomas are TSH
sensitive and because they take up iodine, radioiodine preferentially targets residual normal
or malignant tissue after thyroidectomy. Therefore, radioiodine can be given in diagnostic
doses to detect residual normal or neoplastic tissue in the body and in therapeutic doses to
ablate this tissue. After thyroidectomy, use of radioiodine scanning and ablation has become
commonplace for diagnosing and treating residual thyroid tissue, as well as regional and
distant metastases from well-differentiated thyroid carcinomas. Pretherapeutic iodine-uptake
scanning is controversial because of its cost and because of concerns about
131
I-induced
tumor stunning, which may decrease the effectiveness of radioiodine treatment.
After thyroidectomy, patients are given thyroid replacement therapy with T4 (Synthroid) or
triiodothyronine (T3, Cytomel).
131
I or
123
I scanning is performed when the patient is in a
hypothyroid state (TSH >30-50). Approximately 4-6 weeks after thyroidectomy, hypothyroid
can be induced by discontinuing replacement (T4 for 4 weeks or T3 for 2 weeks) to obtain
high serum TSH levels. A diagnostic dose of
131
I or
123
I is given initially. Whole-body scanning
is performed to detect any tissue taking up radioiodine. If any normal thyroid remnant or
metastatic disease is detected, a therapeutic dose of
131
I is administered to ablate the tissue.
Posttreatment scanning should also be performed because it may reveal metastatic disease
not otherwise noted.
The role of recombinant human TSH (Thyrogen) in remnant ablation continues to evolve.
Thyrogen is approved for postsurgical remnant ablation in Europe but not the United States.
Barbaro et al found equivalent results in postsurgical remnant ablation when they compared
traditional T4 withdrawal with the discontinuation of T4 1 day before TSH stimulation.
Thyrogen stimulation avoids the discomfort of patients having to discontinue thyroid
replacement and is especially useful in those unable to tolerate hypothyroidism or to
generate a high TSH level.
If a treatment dose of
131
I is required, diagnostic thyroid scanning is repeated while the
patient is in the hypothyroid state about 6 months after initial treatment. Again, if the
diagnostic scan is positive, an additional therapeutic dose is given. This process is repeated
until the diagnostic scan is negative.
A promising new development for follow-up thyroid scanning is the use of recombinant
human TSH as opposed to withdrawing T4 to increase autogenous TSH levels. This
approach avoids the discomfort of having to discontinue thyroid replacement therapy for
these scans.
A retrospective analysis of more than 1000 patients with papillary thyroid cancer who
underwent total thyroidectomies found that most patients with low-risk local disease and
some with high-risk T3 tumors who did not receive radioiodine remnant ablation after surgery
had high 5-year recurrence-free survival rates. This suggests that physicians should
carefully consider whether the benefits outweigh the risks associated with radioiodine
remnant ablation when debating the possibility of employing this technique in individual
patients.
[9, 10]

Thyroid suppression
After thyroidectomy and radioiodine ablation, patients with well-differentiated thyroid
carcinoma are maintained on thyroid-suppression suppression. Patients take T4 in daily
doses sufficient to suppress TSH production by the pituitary. Low TSH levels in the
bloodstream reduce tumoral growth rates and reduce recurrence rates of well-differentiated
thyroid carcinomas. The extent to which TSH should be suppressed is controversial. Most
authors recommend reducing TSH levels to 0.1 mU/L. This level provides adequate thyroid
suppression while avoiding deleterious cardiac and bone effects of profound thyroid
suppression.
Follow-up care
Patients are regularly monitored every 6-12 months with serial radioiodine scanning and
serum thyroglobulin measurements after surgery and radioiodine therapy. Thyroglobulin is a
useful marker of tumor recurrence because well-differentiated thyroid cancers synthesize
thyroglobulin. However, it is useful only after total thyroid ablation. Serum thyroglobulin is
measured at the time of follow-up thyroid scanning, during the withdrawal of thyroid hormone
or the administration of recombinant TSH. Serum antithyroglobulin antibodies are measured
in addition to thyroglobulin because their presence invalidates the assay. Thyroglobulin
antibody levels should be obtained with each thyroglobulin measurement. Rising
thyroglobulin level after thyroid ablation suggests recurrence. Ultrasonography of the neck
can also be used to detect regional recurrences.
Pharmacologic therapy
Sorafenib (Nexavar) was approved in November 2013 for differentiated thyroid cancer (DTC)
that is refractory to radioactive iodine treatment. In a study of 417 patients with progressive
radioiodine-refractory DTC, treatment with sorafenib, an orally active inhibitor of VEGFR1-3
and Raf kinases, significantly improved progression-free survival (10.8 months) compared
with placebo (5.8 months).
[11, 12]
Tumor histology was 57% papillary, 25% follicular, and 10%
poorly differentiated. The majority of the patients (96%) had metastatic disease, of which
71% of the target lesions were in the lung, 40% in lymph nodes, and 14% in bone.
At the time of the report, median overall survival had not yet been reached in either study
arm, and 70% of placebo patients had started open-label sorafenib.
[11, 12]
Thus, all reported
responses were partial: 12.2% in the sorafenib group vs 0.5% in the placebo group. The rate
of stable disease for 6 months or longer was 42% in the sorafenib group and 33% in the
placebo group.
Management of recurrence
Recurrences are best treated with surgical excision if the disease is clinically evident and
surgically accessible. Nonlocalized recurrences detected on the basis of elevated
thyroglobulin levels are treated with
131
I. On occasion, recurrent tumors do not concentrate
iodine. Positron emission tomography (PET) may be helpful in localizing disease in such
circumstances. When surgical excision of recurrent disease is not feasible, external-beam
radiation therapy may be useful. Chemotherapy, usually with doxorubicin, is reserved for
tumors that do no respond to other treatments and for palliative care. Response rates of 35-
40% are reported, though complete responses to chemotherapy are rare.
Prognostic factors
The long-term disease-free survival with aggressive treatment and management is nearly
90% overall. A variety of factors are associated with prognosis, as listed below.
Age: The patient's age at diagnosis is one of the most important prognostic features of
well-differentiated thyroid carcinoma. Cancer-related death is most likely to occur if the
patient is >40 years at the time of diagnosis. Recurrences are most common in patients
whose disease is diagnosed when they were < 20 years or >60 years.
Sex: Men are twice as likely as women to die from thyroid cancer.
Size: The size of the primary tumor is related to survival. Patients with primary tumors >4
cm have increased recurrence and cancer-related mortality rates.
Histology: Overall, papillary carcinoma is associated a 30-year cancer-related death rate of
6%. Follicular carcinoma has a 30-year cancer-related death rate of 15%.
Local invasion: Invasion of surrounding tissues outside of thyroid indicates biologic
aggressiveness and significantly worsens the patient's prognosis.
Lymph node metastasis: Lymph node metastasis does not appear to be as important in the
outcome of well-differentiated thyroid carcinomas as in the outcome of most other solid
tumors.
Distant metastasis: Distant metastasis at initial examination is associated with a 68.1-fold
increase in the rate of disease-specific death.
Hrthle Cell Carcinomas
Clinical features
Hrthle cell carcinoma is a rare thyroid malignancy that is often considered a variant of
follicular carcinoma. Also known as oncocytic carcinoma, Hrthle cell carcinoma has unique
biologic features. About 75-100% of the tumor is composed of Hrthle cells, which are also
known as oxyphilic, oncocytic, Askanazy, or large cells. These are large, polygonal follicular
cells that contain abundant granular acidophilic cytoplasm. Hrthle cells can be found in a
variety of benign thyroid conditions, such as Hashimoto thyroiditis, Graves disease, and
multinodular goiter. Benign neoplasms, called Hrthle cell adenomas, that contain more than
75% Hrthle cells can also occur.
Hrthle cell carcinomas account for 2-3% of all thyroid malignancies. They occur more
commonly in women than in men and typically manifest in the fifth decade of life. The clinical
presentation is similar to that of other thyroid malignancies.
Pathology
On pathologic examination, Hrthle cell carcinoma, like follicular carcinoma, is differentiated
from Hrthle cell adenoma by the presence of capsular invasion, vascular invasion, or both.
On gross evaluation, Hrthle cell carcinomas appear brown and solid. Most have an
appreciable capsule. Under microscopy, the tumors have a solid or trabecular growth pattern
of large, granular, polygonal Hrthle cells.
Because malignant tumors are difficult to identify on the basis of cellular elements alone,
Hrthle cell tumors identified on FNAB findings cannot be categorized as malignant or
benign. Therefore, when FNAB results suggest a Hrthle cell neoplasm, a surgically
obtained specimen is required.
Management
Hrthle cell carcinomas behave aggressively. Patients with these lesions are at high risk for
recurrent and metastatic disease. These tumors most often do not take up radioactive
iodine, thereby removing the diagnostic and therapeutic benefits that papillary and follicular
carcinomas have. Most surgeons advocate an aggressive approach to treating these tumors.
Patients with a diagnosis of Hrthle cell neoplasm based on FNAB findings undergo
lobectomy and isthmectomy. If, the final pathologic result confirm Hrthle cell carcinoma,
patients return to surgery for completion thyroidectomy. For tumors >5 cm or for palpable
lymphatic metastases, total thyroidectomy (including neck dissection for palpable lymph
nodes) is often performed during the initial operation.
Prognosis
Patients with Hrthle cell carcinoma should be monitored closely for recurrent and metastatic
disease. The overall 5-year survival rate is 50-60%. Because tumors do not take up iodine
and are not TSH sensitive, thyroid suppression and radioiodine therapy have little value.
External-beam radiation therapy can used to treat metastatic disease. Surgery is the
mainstay of treatment.
Medullary Thyroid Carcinoma
Clinical features
MTCs represent approximately 5% of all thyroid malignancies. A slight female
preponderance is observed. Tumors arise from the parafollicular C cells of the thyroid gland.
C cells are neural-crest derivatives and produce calcitonin. About 75% of MTCs occur
sporadically, and 25% occur familially. Familial cases are commonly multifocal throughout
the thyroid gland, whereas sporadic cases are usually not multifocal.
Patients may present with clinical evidence of MTC, or they may present before MTCs
develop if they are from a family with known FMTC syndrome. New germline mutations can
also occur. Patients with new germline mutations present with MTCs without a positive
family history, but they are at risk for passing on the syndrome.
The FMTC syndromes consist of MEN 2A, MEN 2B, and FMTC. They are inherited in an
autosomal dominant fashion. Children inheriting an FMTC syndrome have a 100% risk of
developing MTC.
MEN 2A (Sipple syndrome) consists of MTC, pheochromocytoma (in 50% of patients), and
hyperparathyroidism (10-20% of patients). MEN 2B consists of MTC, pheochromocytoma (in
50% of patients), marfanoid habitus, and ganglioneuromatosis. FMTC consists of MTC
alone. MTC in MEN 2B has the most aggressive biologic features. In this situation, MTC
usually develops by the age of 10 years, and it has a high propensity for rapid growth and
metastasis. MTC in MEN 2A can appear in the first decade of life, and it almost always
develops by the second decade. MTC in FMTC usually develops during adulthood.
Diagnosis of sporadic cases
Sporadic cases typically manifest with painless solitary thyroid nodules, like other thyroid
malignancies do. Likewise, symptoms of pain, dysphagia, and hoarseness can develop with
local invasion.
Genetic testing for MEN and FMTC
Genetic testing is now the mainstay in the diagnosis of the FMTC syndromes.RET proto-
oncogene mutations (on chromosome arm 10q) have been discovered in each of the MTC
syndromes. The RET proto-oncogene is a receptor tyrosine kinase whose exact function and
role in these syndromes has not been elucidated. Patients with MEN 2A have
germline RET mutations resulting in substitutions of conserved cysteine residues in exons
10 and 11. All patients with MEN 2B have a germline mutation resulting in a threonine-for-
methionine substitution in codon 918 of exon 16. Mutations are described in exons 13 and
14 in patients with FMTC.
Genetic screening with sensitive PCR assays for germline RET mutations is routinely
performed in at-risk patients. Children of parents known to have MEN or FMTC are tested
for RET mutations to guide therapy and future genetic counseling. In addition, patients
presenting with sporadic MTC should undergoRET mutational analysis to rule out new
spontaneous germline mutations, which should prompt the testing of offspring for similar
mutations.
Biochemical testing for MTC
Because MTC cells produce calcitonin, elevated serum calcitonin levels are diagnostic of
MTC. Although routine measurement of serum calcitonin has low yield in managing the
solitary thyroid nodule because of the uncommon nature of MTCs, it is useful in the
surveillance of patients with a history of MTC and in managing familial forms. Stimulating
calcitonin release by using intravenous pentagastrin increases the sensitivity of the test. For
pentagastrin-stimulated calcitonin evaluation, a baseline plasma calcitonin level is
measured, followed by the intravenous administration of pentagastrin 0.5 mg/kg and serial
measurements of calcitonin 1.5 and 5 minutes after injection. Elevated basal or stimulated
calcitonin levels above the normal range for the laboratory strongly suggest MTC.
Plasma calcitonin levels are commonly increased before clinical evidence of MTC appears.
Although this finding was once the mainstay in diagnosing familial forms of MTC, results of
genetic testing have largely supplanted it. Plasma calcitonin testing is now used for the early
detection of MTC in patients already known to be at risk for MTC because of their family
history and genetic results. This level is most commonly used as a tumor marker to identify
residual and metastatic disease after thyroidectomy to treat MTC.
Pathology
On gross examination, MTCs are fairly well circumscribed, though they are unencapsulated.
They are typically tannish pink and often contain yellow granular regions, which represent
focal calcification. Most tumors arise in the middle and upper third of the thyroid lobes,
commensurate with the location of the parafollicular C cells in the thyroid gland. Sporadic
tumors are unilateral, and inherited forms usually involve both thyroid lobes.
MTCs can have a varied microscopic appearance. The tumors typically have a lobular,
trabecular, insular, or sheetlike growth pattern. Some tumors have a fibrotic character.
Malignant cells may appear round, polygonal, or spindle shaped. The cytoplasm is
eosinophilic and finely granular. In the stroma, characteristic deposits of amyloid are
commonly observed. This amyloid has typical green birefringence on Congo red staining,
and this is a feature unique to MTC among thyroid malignancies. Immunohistochemical
stains for calcitonin and carcinoembryonic antigen are microscopically useful for
differentiating MTC from other tumors.
A unique feature to the familial cases of MTC is the finding of C-cell hyperplasia, which can
help in distinguishing familial cases from sporadic ones. C-cell hyperplasia is considered a
precursor to MTC and is usually adjacent to foci of MTC. The finding of C-cell hyperplasia
with MTC should raise the suspicion for familial disease.
Treatment
Both sporadic MTCs and FMTCs are treated with total thyroidectomy and lymphatic
dissection of the anterior compartment of the neck (level VI). If the vasculature of the
parathyroid gland is disrupted, autotransplantation of the parathyroid gland into the
sternocleidomastoid muscle or the nondominant forearm is performed.
Metastasis to the cervical lymph nodes is common in patients with MTC, particularly those
with familial forms with multicentricity and bilaterality of the primary tumor. Lymph node
metastases can occur in more than 50% of patients. Both before and at the time of surgery,
the lateral jugular lymphatics should carefully be palpated for evidence of metastatic
disease. Selective neck dissection (sparing nonlymphatic structures when possible) of levels
II, III, IV, and V is performed when metastases are clinically evident.
Prophylactic thyroidectomy in patients with MEN 2A and MEN 2B
MTC is the most common cause of mortality in patients with MEN 2A and MEN 2B, and
many patients who inherit these syndromes develop MTC in the first decade of life.
Therefore, prophylactic thyroidectomy and central-compartment lymph-node dissection is
being performed in children with these syndromes. Surgery is offered to patients when the
diagnosis is made on the basis of RETmutational analysis. Children with RET mutations
whose parents decline surgery should be monitored with annual measurement of calcitonin
levels. Thyroidectomy is performed when results are abnormal.
Follow-up care
After receiving treatment for MTC, patients are monitored with annual measurement of
serum calcitonin levels for surveillance. Pentagastrin-stimulated calcitonin testing is no
longer widely available. Carcinoembryonic antigen is another tumoral marker associated with
the recurrence of MTC, and it may also be used for surveillance. Patients with elevated
levels of calcitonin or carcinoembryonic antigen are evaluated for recurrent disease. Neck,
abdominal, and pelvic CT or MRI may be used to detect disease if metastasis or recurrence
is suspected. Ultrasonography may be useful to localize cervical disease. In addition,
radionuclide studies and selective venous catheterization with sampling of calcitonin levels
can be performed to localize recurrences. The role of PET is evolving.
Radiation therapy is used in an adjuvant setting at some centers, and it can be used to treat
patients with surgically inoperable recurrences and metastases. Because MTC does not
concentrate iodine, radioiodine therapy has no role in follow-up care or treatment.
A variety of chemotherapeutic regimens have been used to treat metastatic disease. MTC is
relatively insensitive to chemotherapy, though partial responses have been obtained. To
date, the most effective combination is dacarbazine, vincristine, and cyclophosphamide.
Adding doxorubicin to this regimen, some investigators have gained a partial response rate
of about 35%.
Vandetanib (Caprelsa) and cabozantinib (Cometriq) are tyrosine kinase inhibitors approved
by the FDA for progressive, metastatic medullary thyroid cancer. These agents target
various tyrosine kinases including MET, RET, and VEGFR-2.
Prognosis
The overall prognosis for patients with MTC is worse than that of patients with well-
differentiated carcinoma. The reported 10-year survival rate is 65% overall. Young age,
small primary tumor, low stage of disease, and completeness of initial resection improve
survival. Patients with MEN 2B have a prognosis substantially worse than that of patients
with MEN 2A, though the prognosis for both groups has improved with early diagnosis and
intervention.
Anaplastic Carcinoma and Other Thyroid Carcinomas
Anaplastic Thyroid Carcinoma
Clinical features
Anaplastic thyroid carcinoma is one of the least common thyroid carcinomas, accounting for
1.6% of all thyroid cancers. However, it has the most aggressive biologic behavior of all
thyroid malignancies and one of the worst survival rates of all malignancies in general. Like
papillary and follicular carcinomas, anaplastic thyroid carcinomas affect more women than
men, with a female-to-male ratio of about 2-3:1. Patients with anaplastic thyroid carcinomas
present later than those with other thyroid malignancies; the former most typically present in
the sixth or seventh decade of life.
[13]

Anaplastic thyroid carcinoma manifests as a rapidly growing thyroid mass in contrast to well-
differentiated carcinomas, which are comparatively slow growing. Patients commonly
present with associated symptoms due to local invasion. Hoarseness and dyspnea resulting
from the involvement of the recurrent laryngeal nerve and airway occur in as many as 50%
of patients.
Physical examination reveals a firm thyroid mass or masses that are most often larger than 5
cm at presentation. About 30% of patients have vocal cord paralysis, and cervical
metastases are palpable on examination in 40% of patients. At least one half of patients
already have distant metastases at the time of diagnosis. The most common sites of
involvement are the lungs, bones, and brain.
Pathology
On gross examination, anaplastic thyroid carcinoma is a large and invasive tumor. Areas of
focal necrosis and hemorrhage may be present throughout the tumor, giving a highly
variable appearance. The tumor often extends through the capsule of the thyroid gland itself.
Areas of well-differentiated thyroid carcinoma are often found concomitantly, and anaplastic
thyroid carcinoma is believed to arise from a preexisting, well-differentiated thyroid
carcinoma.
On microscopic evaluation, squamoid, spindle cell, and giant cell variants are observed. All 3
histologic variants show high mitotic activity, large foci of necrosis, and notable infiltration.
Immunohistochemical stains are often positive for low-molecular-weight keratins and
occasionally positive for thyroglobulin. Regarding their ultrastructure, the neoplasms have
epithelial features (eg, desmosomes, tight junctions) that are helpful for differentiating them
from sarcomas. Small cell carcinomas, which usually represent lymphomas, may be
confused with anaplastic thyroid carcinoma.
Treatment
The progression of disease is rapid, and most patients die from local airway obstruction or
complications of pulmonary metastases within 1 year despite all treatment efforts. Total or
subtotal thyroidectomy is performed when the extent of the permits it. Neck dissection is
added to manage palpable cervical metastases. Complete excision is often impossible
because many patients present with clinically significant local extension. Tracheal and
laryngeal resection is usually not performed to remove disease because of the poor
prognosis in these circumstances. Tracheotomy is needed in cases with airway compromise
due to tracheal invasion. External-beam irradiation is effective in improving local control. It is
added postoperatively or used as primary treatment in unresectable cases. Chemotherapy is
added for palliation. Doxorubicin is the most commonly used chemotherapeutic agent.
Chemotherapy and radiation therapy typically administered used in combination.
Prognosis
Anaplastic thyroid carcinoma is poorly responsive to multimodality therapy, and median
survival is 8.1 months. Young age, unilateral tumors, small tumors (< 5 cm), no local
invasion of the surrounding tissue, and a lack of cervical metastases are relatively favorable
prognostic indicators. Patients with these features may have slightly prolonged survival.
Long-term survival should prompt a reconsideration of the diagnosis of anaplastic thyroid
carcinoma; the original tumor is usually found to be a variant of MTC or thyroid lymphoma.
Primary Thyroid Lymphoma
Clinical features
Primary lymphomas of the thyroid gland represent approximately 2-5% of all thyroid
malignancies. Most thyroid lymphomas are non-Hodgkin B-cell tumors. The next most
common histologic type is low-grade malignant lymphoma of mucosa-associated lymphoid
tissue (MALT). Hodgkin lymphoma, Burkitt cell lymphoma, and T-cell lymphoma have also
been reported.
The incidence peaks in the sixth decade of life, and most diagnoses are made in patients
aged 50-80 years. Women are more commonly affected than men, with a female-to-male
ratio of 4:1. This tumor is highly associated with chronic lymphocytic thyroiditis (Hashimoto
thyroiditis). Almost all patients with primary thyroid lymphoma have either a clinical history or
histologic evidence of chronic lymphocytic thyroiditis. The risk of primary thyroid lymphoma
increases 70-fold in patients with chronic lymphocytic thyroiditis compared with the general
population.
The most common clinical presentation is an enlarging thyroid mass. Patients may have
clinical or serologic evidence of hypothyroidism. Local extension into the aerodigestive tract
or surrounding tissues may cause dysphagia, dyspnea, or symptoms of pressure in the
neck. Vocal fold paralysis and hoarseness suggest involvement of the recurrent laryngeal
nerve. Regional and distant lymphadenopathy is common.
Diagnosis is based on the patient's clinical presentation with a positive tissue diagnosis.
FNAB may be useful for diagnosing thyroid lymphoma, but it is considered less reliable with
this lesion than with other thyroid malignancies. Lymphoma may be difficult to differentiate
from chronic lymphocytic thyroiditis. Surgical biopsy of the lesion is preferred for diagnosing
thyroid lymphoma. Biopsy enables thorough histochemical and immunohistochemical
analysis to confirm the diagnosis. Tumor cells are positive for leukocyte-common antigen
and for B- or T-cell markers depending on the type of tumor.
Staging of thyroid lymphomas is important for therapeutic and prognostic purposes. Staging
involves CT scanning of the brain, neck, chest, abdomen, and pelvis, as well as bone
marrow biopsy. Most primary thyroid lymphomas are localized to the thyroid gland alone
and, therefore, classified as stage IE (localized to an extranodal site). Involved regional
lymph nodes increase the stage to IIE.
Treatment and prognosis
Stage IE lymphomas may be treated with total thyroidectomy followed by postoperative
radiation therapy. Surgical excision should not be performed if local infiltration into
surrounding tissues is evident. Stage IIE lymphomas are treated with combined
chemotherapy and radiation therapy. Doxorubicin or CHOP (ie, cyclophosphamide,
hydroxydaunomycin, Oncovin [vincristine], prednisone) is the commonly used
chemotherapeutic regimen.
Most thyroid lymphomas are stage IE, which have a 5-year survival rate of up to 85%.
Spread beyond the thyroid gland reduces the 5-year survival rate to about 35%. Lymphomas
at stages higher than this worsen the prognosis.
Sarcoma of the Thyroid Gland
Sarcomas that arise in the thyroid gland are uncommon. They are aggressive tumors that
most likely arise from stromal or vascular tissue in the gland. Malignancies that appear to be
sarcomas should be differentiated from anaplastic thyroid carcinomas, which can appear
sarcomatous.
The treatment for thyroid sarcomas is total thyroidectomy. Radiation therapy may be used in
an adjunctive setting. Most sarcomas are unresponsive to chemotherapy. Recurrence is
common, as it is with sarcomas arising in other sites in the body, and the patient's overall
prognosis is poor.
Technique of Thyroidectomy
Thyroid surgery is performed to diagnose or treat thyroid disease. The extent of surgery
ranges from isthmectomy alone (for small nodules truly localized to the isthmus) to subtotal
thyroidectomy, total thyroidectomy, or extended thyroidectomy. Radioiodine studies
performed after total thyroidectomy usually show residual normal thyroid tissue despite total
thyroidectomy.
Principles of thyroid surgery are accurate execution of the planned excision, avoidance of
injury to the recurrent laryngeal nerve, avoidance of injury to or devascularization of the
parathyroid glands, and meticulous hemostasis.
Indications
Indications for thyroid lobectomy
Biopsy of a solitary thyroid nodule suggestive of malignancy
Management of compressive or cosmetic symptoms due to a multinodular goiter
Management of a well-differentiated thyroid carcinoma in a low-risk patient (This is
controversial.)
Indications for total thyroidectomy
Management of a well-differentiated thyroid malignancy
Management of an MTC
Management of a sarcoma of the thyroid gland
Management of stage IE thyroid lymphoma
Management of an obstructive goiter (Consider subtotal thyroidectomy.)
Preoperative considerations
Vocal fold mobility should always be determined before thyroid surgery. If lobectomy for
biopsy is planned, discuss the potential need for completion thyroidectomy with the patient.
Operative technique
Positioning of the patient is important. Place the patient in a supine position with his or her
neck extended by using a shoulder roll. Plan a horizontal incision in a natural skin crease to
contour the curvature of the neck. The location should overly the thyroid gland, evenly
extending between the anterior aspect of the sternocleidomastoid muscles on both sides.
Elevate skin flaps superiorly and inferiorly in a subplatysmal plane. (Platysma is often absent
in the midline.) Ligate the anterior jugular veins only if they directly limit exposure. Separate
the sternohyoid and sternothyroid muscles in the median raphe, and retract them laterally to
expose the cricoid cartilage and thyroid isthmus.
In the anterior region, dissect the strap muscles off the face of the thyroid lobe (bilaterally for
total thyroidectomy). Supracapsular dissection is continued until the superior pole and its
vascular pedicle are isolated. The superior pole vessels are divided and ligated. The
dissection continues laterally with division of the middle thyroid vein. The thyroid lobe is
gradually medialized. Careful blunt dissection is performed to identify the recurrent laryngeal
nerve in the tracheoesophageal groove.
After the recurrent nerve is identified, carefully follow the nerve superiorly toward the larynx.
The nerve passes closely to the Berry ligament, but its position varies. After the nerve is
thoroughly identified in this region, divide the ligament to release the thyroid gland.
Keep the location of the parathyroid glands in mind during lateral dissection. Avoid disturbing
the gland and vasculature as much as possible. Dissection close to the thyroid capsule
minimizes this risk. If possible, ligate the inferior thyroid artery only after the vessels to the
inferior parathyroid gland branch.
If a parathyroid gland is inadvertently removed, reimplant it in the sternocleidomastoid
muscle or on the volar surface of the forearm after slicing it into small pieces and marking it
with a surgical clip.
During superior dissection, remember the nearby location of the external branch of the
superior laryngeal nerve, which innervates the cricothyroid muscle. Ligation of the superior-
pole vessels tight to the thyroid in this area avoids inadvertent injury to this nerve.
If only lobectomy is planned, divide the thyroid isthmus in the midline. Ligate the final soft-
tissue attachments, and remove and label the lobe. Send it to the pathology laboratory.
When total thyroidectomy is performed, the surgeon may elect not to divide the thyroid
isthmus in the midline, but rather, to perform lateral dissection bilaterally. Identify the
recurrent laryngeal nerves, and manage the inferior and superior vascular pedicles similarly.
Remove the gland in 1 piece, label it, and send it for pathologic analysis.
Irrigate the wound, and achieve meticulous hemostasis. The decision to place a passive or
closed suction drain often depends on the surgeon's judgment. If a drain is used, place it into
the wound and bring it out laterally through the incision or through a separate stab incision.
The present authors have found the routine use of drains unnecessary. Reapproximate the
sternothyroid and sternohyoid, and carefully close the skin in layers.
Postoperative care
If a surgical drain is placed, maintain it until its output has diminished sufficiently, usually on
the first postoperative day. Hypocalcemia may occur in patients who have undergone total
thyroidectomy. Assess for hypocalcemia by inquiring about perioral paraesthesia. In a
patient with hypocalcemia, tapping on preauricular region overlying the trunk of the facial
nerve may cause ipsilateral contraction of the face (Chovstek sign). Measure ionized calcium
postoperatively. Hypocalcemia may require calcium and vitamin D supplementation. Manage
pain with acetaminophen and narcotics as needed.


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