a ratio of 4:1) and usually occurs between the ages of 30 and 60 years. The cause is unknown and a

genetic predisposition is not apparent. The patient presents with a painless but persistent, and often

progressive, goiter. Patients are usually euthyroid at presentation but may eventually become

hypothyroid. They may have detectable antithyroid antibody titers and a normal ESR. If obtained, the

24-hour RAIU is often normal or somewhat decreased. Physical examination reveals an exceptionally

firm goiter often described as “woody.” Most commonly, this is a diffuse, bilobar process.

Histologically, the disease is characterized by extensive fibrosis, which may progress to a point of

compression of adjacent structures such as the trachea and esophagus. Riedel thyroiditis is often

accompanied by other equally mysterious focally sclerotic conditions such as retroperitoneal fibrosis,

mediastinal fibrosis, retro-orbital fibrosis, and sclerosing cholangitis.28 Because of its infiltrative nature,

it is important to differentiate Riedel thyroiditis from thyroid carcinoma. FNA is often inadequate and

core-needle or open biopsy may be required. If substantial compression exists, surgery is often required

to relieve these symptoms. Extensive resection is often unsafe or impossible due to infiltration of the

thyroid with the surrounding structures, and wedge resections, especially of the isthmus, may be

effective in relieving tracheal compressive symptoms. Medical therapy, including corticosteroids,

methotrexate, or tamoxifen, may have a positive impact in the chronic setting.29

NODULAR THYROID DISEASE AND GENERAL TREATMENT

CONSIDERATIONS

Nontoxic Multinodular Goiter

From a world health perspective, endemic goiter is still a significant issue. Endemic goiters are caused

by dietary iodine deficiency, which ultimately is also responsible for congenital hypothyroidism

syndrome (historically known as endemic cretinism). Iodine deficiency in a region is addressed over

time by iodination of dietary components (e.g., salt, bread flour, or vegetable oil).

In endemic goiter, T4

levels may be normal or decreased, whereas T3

levels are normal or often

increased. This reflects an adaptive regulatory mechanism by which the thyroid preferentially shifts

production to the more biologically potent T3

. Exogenous thyroxine therapy will induce a decrease in

goiter size in roughly 80% of patients treated. Resection may be indicated for large size, increase in size

while on T4

, or compression of the trachea, esophagus, or superior vena cava.

In most developed countries, the term goiter generically refers to the group of diseases causing

thyroid enlargement in patients not affected by iodine deficiency. In common usage, goiter typically

refers to patients with nodular goiter. Asymptomatic multinodular goiter is common, and unless there is

concern of a malignant nodule, thyroidectomy is not usually indicated. Sometimes, because of the

number of nodules of significant size (>1 cm), repeated FNA during longitudinal observation becomes

impractical and patients may choose thyroidectomy to simplify management. Compressive symptoms

involving the airway or esophagus causing breathing difficulties or dysphagia are an indication for

thyroidectomy, as is a multinodular goiter causing subclinical or obvious thyrotoxicosis (toxic

multinodular goiter). Total thyroidectomy is the procedure of choice because of the significant chance

for recurrent nodular degeneration of the thyroid remnant after subtotal thyroidectomy. If a goiter

develops in a substernal position, thyroidectomy is warranted because of the inability to monitor

continuing growth in the mediastinum. If tracheal compression develops gradually, it may be largely

asymptomatic until a critical point of narrowing is reached, which inhibits passage of air in a relatively

sudden and progressive manner. Because all of the important attachments to the thyroid parenchyma

remain in the neck, even very large substernal goiters can be removed through a cervical incision and

less than 5% will require partial sternotomy.30

Solitary or Dominant Thyroid Nodule

Nodular thyroid disease is clinically appreciated in approximately 4% to 7% in the general population;

however, thyroid nodules are in fact present in up to 60% of patients undergoing autopsy. The majority

of thyroid nodules are benign with around 5% harboring malignancy. The incidence of thyroid cancer

has been increasing with a disproportional increase in small papillary thyroid cancers.31 This increase is

only partially explained by improved surveillance. Appropriately identifying patients with malignancy

that require operation while appropriately avoiding operation for the majority of patients with benign,

asymptomatic nodules can be a challenging task (Algorithm 75-1).

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When assessing a patient with a solitary thyroid nodule, the physician should first determine patient

risk factors that increase the likelihood of malignant disease. A new thyroid nodule that occurs at the

extremes of age is more likely to be malignant than one that occurs in the third through seventh

decades. The risk of a solitary thyroid nodule in a child under 18 being malignant is approximately

22%.32 Patient gender itself does not generally confer risk of malignancy, and the fact that thyroid

cancer occurs in a greater number of women than men is related somewhat to the increased prevalence

of nodular thyroid disease in women.

Many factors apparent on physical examination or imaging can also be used to assess the potential for

malignant disease in the patient with a thyroid nodule. The consideration that nodular disease is

uninodular (e.g., solitary) instead of multinodular has traditionally implied that the former situation is

more concerning for malignancy, however, in the era of thyroid US, this distinction is overemphasized

because at least half of nodules considered solitary by clinical examination are ultimately found to be a

dominant nodule within a multinodular goiter. The characteristics of a nodule assessed by physical

examination (size, firmness, and texture) have a limited ability to predict malignancy, but significant

fixation to surrounding tissues can heighten the level of concern for invasive malignancy. Palpable

lymphadenopathy or ultrasonographically abnormal-appearing lymph nodes in the central or lateral

cervical compartments is certainly concerning for potential malignancy. Although many patients with

benign thyroid disease describe hoarseness or a change in voice, this is often largely subjective and is of

limited concern unless accompanied by objective hoarseness and ipsilateral RLN paralysis confirmed on

laryngoscopic examination. In a patient with a firm thyroid gland in the setting of hypothyroidism,

Hashimoto’s thyroiditis is a common underlying etiology. Patients with rapidly enlarging, firm thyroid

gland with indistinct nodularity should raise concern for thyroid lymphoma or anaplastic thyroid cancer.

A critical question in assessing any patient with a thyroid nodule is whether any history of radiation

exposure exists. At least 90% of radiation-associated thyroid cancers are papillary thyroid cancer.

Typical exposures to radiation in the 1940s and 1950s included external beam irradiation treatment for

acne, tinea capitis, external otitis, recurrent tonsillitis, or neonatal thymic enlargement. In the current

era, excessive diagnostic radiation or high-dose therapeutic irradiation (e.g., treatment of lymphoma or

head and neck malignancies) can contribute to a relevant exposure. There appears to be a linear

relationship between the dose of radiation and the risk for thyroid cancer, with even a higher risk

among those exposed at a young age.33 The typical latent period between exposure and clinically

evident cancer appears to be in the 3- to 8-year range. It is not clear when, if ever, the risk is no longer

present. Another source of radiation exposure to the thyroid gland is nuclear fallout, related to either

atomic weapons or nuclear power plant accidents, such as Chernobyl in 1986. Acute γ-radiation

exposure is likely the main risk factor, but longer-term exposure to diverse radioisotopes of iodine that

secondarily contaminate the regional water and food supplies may also be contributory.

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Algorithm 75-1. Management algorithm for thyroid mass. TFTs, thyroid function tests; US, ultrasound; FNA, fine-needle aspiration;

FLUS, follicular lesion of undetermined significance; AUS, atypia of undetermined significance; RAI, radioactive iodine; MNG,

multinodular goiter.

Another critical question to investigate is whether a family history of thyroid cancer or associated

conditions exists. The key issue is to uncover a family history of medullary thyroid cancer, which

suggests the potential for an inherited syndrome such as familial medullary thyroid carcinoma (FMTC)

or multiple endocrine neoplasia type 2. Papillary thyroid cancer, however, may have a familial

association as well, either independently or, more commonly, associated with Cowden syndrome or

Gardner syndrome (familial adenomatous polyposis).

In most situations, extensive thyroid function testing is not necessary and a TSH is all that is required.

After initial clinical assessment, thyroid nodular disease is often assessed by US. Relevant factors include

the size of the nodule and other sonographic characteristics previously explained. Also important is

whether the nodule is truly solitary or whether there are additional nodules, especially in the

contralateral lobe, which may affect the specific surgical recommendations with regard to

hemithyroidectomy or total thyroidectomy. Symptomatic thyroid cysts may be managed with aspiration

alone, ethanol injection treatment or thyroidectomy.34

The utility of thyroid scintigraphy in patients with normal thyroid function tests is very limited and

should not be routinely used to evaluate thyroid nodules. The only helpful role for radioiodine scan is

with patients with hyperthyroidism to determine if the overproduction of thyroid hormone is due to a

single thyroid nodule (toxic adenoma), multiple thyroid nodules (toxic multinodular goiter), or diffuse

hyperplasia (Graves disease). In the era of US and FNA, the additional diagnostic information provided

by knowing if a nodule is “cold” or “photopenic” is very limited since the indications for FNA lie

primarily in the nodule size, the US appearance, and the patient’s risk factors.

Thyroid Fine-Needle Aspiration Biopsy

FNA is the cornerstone of diagnostic evaluation of a thyroid nodule. Cytologic analysis of FNA samples

can reliably identify colloid nodules, benign nodular hyperplasia, thyroiditis, papillary thyroid

carcinoma (PTC), medullary thyroid carcinoma, and anaplastic thyroid carcinoma. FNA may suggest an

extranodal thyroid lymphoma, but usually more tissue (generally in the form of core-needle biopsy, or

incisional/excisional biopsy) is required for confirmation of the diagnosis and flow cytometry.

Standard disposable needles ranging in size from 23 to 27 gauge and 3- to 10-mL syringes are used for

thyroid or cervical lymph node FNA. After the target nodule is located with US, FNA is performed with

US guidance and multiple passes through the most concerning appearing solid portions of the nodule are

made. An average of three separate biopsy maneuvers per nodule is reasonable practice. The technique

does not rely heavily on aspiration or suction as the name might imply. The ideal sample remains

mostly in the needle hub and barrel before expelling it onto a slide or into a fixative for cytologic

preparation.

4 There are multiple cytologic classification systems used for thyroid FNA with corresponding

recommendations for management. The Bethesda system is one of the more widely used systems which

is outlined in Table 75-1.35 A nondiagnostic FNA lacks the minimum of 6 groupings of thyroid cells

consisting of at least 10 cells per group. The incidence of nondiagnostic biopsies can be reduced with US

guidance and onsite cytopathologic analysis for adequacy of the specimen. The Bethesda system divides

the prior indeterminate category into category III: atypia of undetermined significance/follicular lesion

of undetermined significance and category IV: Follicular neoplasm. There is a recommendation for

repeat FNA for category III results rather than diagnostic thyroidectomy as was typical for previously

defined indeterminate nodules. The use of molecular marker analysis in indeterminate thyroid FNA

specimens is an evolving concept with several tests available which analyze FNA tissue for various

genetic mutations (BRAF, RAS, RET/PTC, and others).36 The prognostic utility of molecular testing

seems most useful when cytopathology is indeterminate (Bethesda categories III and IV) and has limited

added value when cytopathogic analysis is more definitive (Bethesda categories II, V, and VI).

Additionally, when other indications for thyroidectomy exist such as local pressure symptoms, multiple

large nodules, or patient preference, the role of these gene expression profiling tests may be limited and

perhaps needlessly costly.37 FNA classified as follicular lesions or Hürthle cell lesions (Bethesda category

IV) may require at least partial thyroidectomy (e.g., lobectomy) to determine whether it is a follicular

(or Hürthle cell) adenoma or follicular (or Hürthle cell) carcinoma which can be distinguished only by

the demonstration of capsular or vascular invasion on surgical histopathology. FNA should have a false2127

positive rate of 0% to 0.5% and a false-negative rate of 0% to 5%.

DIAGNOSIS

Table 75-1 The Bethesda Classification System for Thyroid FNA Cytology

THYROID MALIGNANCY AND GENERAL TREATMENT

CONSIDERATIONS

Thyroid cancers exhibit a wide spectrum of behavior, from the inconsequential, occult, welldifferentiated thyroid carcinoma to the nearly uniformly fatal undifferentiated anaplastic cancers.

Fortunately, at least 98% of thyroid cancers are well-differentiated and long-term prognosis is excellent.

There has been an increasing incidence of thyroid cancer primarily due to increasing rates of papillary

thyroid cancer with relatively stable rates of other variants.31 The general treatment strategy for

thyroid carcinomas includes surgical resection, staging of disease, appropriate adjuvant treatments, and

secondary screening and follow-up.

Tumor Classification

Thyroid cancers of follicular cell origin are PTC and its variants, follicular thyroid carcinoma and

Hürthle cell carcinoma (HCC). Medullary thyroid cancers are derived from parafollicular (C-cells).

There is a spectrum of dedifferentiation that can occur in PTC ranging from variants such as tall cell or

insular variants. Anaplastic carcinoma represents very dedifferentiated thyroid cancer and carries an

aggressive phenotype and poor prognosis. A number of thyroid cancer classification systems exist. The

American Thyroid Association (ATA), the Armed Forces Institute of Pathology (AFIP), and the World

Health Organization (WHO) all consider papillary thyroid cancers (including classic papillary

carcinoma, mixed papillary–follicular variants, follicular variants, and follicular thyroid carcinomas

[FTC]) as DTC. Still, some disagreement exists about the classification of HCCs or oxyphilic carcinoma

as a subtype of follicular thyroid carcinoma or as its own category. Support for considering HCC as a

subtype of follicular thyroid carcinoma includes the histologic demonstration of the transition of

follicular to Hürthle cells, an intact TSH receptor adenylate cyclase system in Hürthle cells, and the

ability of Hürthle cells to produce thyroglobulin and thus maintain Tg positivity on

immunohistochemical staining.38 Other characteristics, however, such as higher oncogene expression in

HCC than FTC and the general impression that HCC can display a more aggressive clinical course than

FTC cause some to classify HCC tumors outside the FTC family.

Papillary Thyroid Carcinoma

PTC accounts for approximately 85% of thyroid carcinomas. It occurs across a wide spectrum of ages

from childhood to the elderly, with peak incidence in the third and fourth decades of life, and is more

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