2947Thyroid Nodular Disease and Thyroid Cancer CHAPTER 385

Clinical Manifestations Most patients with nontoxic MNG are

asymptomatic and euthyroid. MNG typically develops over many

years and is detected on routine physical examination, when an individual notices an enlargement in the neck, or as an incidental finding

on imaging. If the goiter is large enough, it can ultimately lead to

compressive symptoms including difficulty swallowing, respiratory

distress (tracheal compression), or plethora (venous congestion), but

these symptoms are uncommon. Symptomatic MNGs are usually

extraordinarily large and/or develop fibrotic areas that cause compression. Sudden pain in an MNG is usually caused by hemorrhage

into a nodule. Hoarseness, reflecting laryngeal nerve involvement may

suggest malignancy but more commonly is due to others causes such

as gastroesophageal reflux.

Diagnosis On examination, thyroid architecture is distorted, and

multiple nodules of varying size can be appreciated. Because many

nodules are deeply embedded in thyroid tissue or reside in posterior

or substernal locations, it is not possible to palpate all nodules. Pemberton’s sign, characterized by facial suffusion when the patient’s arms

are elevated above the head, suggests that the goiter has increased

pressure in the thoracic inlet. A TSH level should be measured to

exclude subclinical hyper- or hypothyroidism, but thyroid function is

usually normal. Tracheal deviation is common, but compression must

usually exceed 70% of the tracheal diameter before there is significant

airway compromise. Pulmonary function testing can be used to assess

the functional effects of compression, which characteristically causes

inspiratory stridor. CT or MRI can be used to evaluate the anatomy of

the goiter and the extent of substernal extension or tracheal narrowing.

A barium swallow may reveal the extent of esophageal compression.

The risk of malignancy in MNG is similar to that in solitary nodules.

Ultrasonography should be used to identify which nodules should

be biopsied based on a combination of size and sonographic pattern

(Fig. 385-1) (Chap. 382). For nodules with more suspicious sonographic patterns (e.g., hypoechoic solid nodules with infiltrative borders), biopsy is recommended at a lower size cutoff than those with less

suspicious imaging features (Figs. 385-1 and 385-2).

TREATMENT

Nontoxic Multinodular Goiter

Most nontoxic MNGs can be managed conservatively. T4

 suppression is rarely effective for reducing goiter size and introduces the

risk of subclinical or overt thyrotoxicosis, particularly if there is

underlying autonomy or if it develops during treatment. Contrast

agents and other iodine-containing substances should be avoided

because of the risk of inducing the Jod-Basedow effect, characterized

by enhanced thyroid hormone production by autonomous nodules.

Radioiodine has been used when surgery is contraindicated in areas

where large nodular goiters are more prevalent (e.g., some areas of

Europe and Brazil) because it can decrease MNG volume and may

selectively ablate regions of autonomy. Dosage of 131I depends on

the size of the goiter and radioiodine uptake but is usually about

3.7 MBq (0.1 mCi) per gram of tissue, corrected for uptake

COMPOSITION

(Choose 1)

Cystic or almost 0 points

completely cystic

Spongiform 0 points

Mixed cystic 1 point

and solid

Solid or almost 2 points

completely solid

ECHOGENICITY

(Choose 1)

Anechoic 0 points

Hyperechoic or 1 point

isoechoic

Hypoechoic 2 points

Very hypoechoic 3 points

0 Points 2 Points 3 Points 4 to 6 Points 7 Points or More

TR1

Benign

No FNA

TR2

Not Suspicious

No FNA

TR3

Mildly Suspicious

FNA if ≥ 2.5 cm

Follow if ≥ 1.5 cm

TR4

Moderately Suspicious

FNA if ≥ 1.5 cm

Follow if ≥ 1 cm

TR5

Highly Suspicious

FNA if ≥ 1 cm

Follow if ≥ 0.5 cm*

ACR TI-RADS

COMPOSITION ECHOGENICITY SHAPE MARGIN ECHOGENIC FOCI

Spongiform: Composed

predominantly (>50%) of small cystic

spaces. Do not add further points

for other categories.

Mixed cystic and solid: Assign

points for predominant solid

component.

Assign 2 points if composition

cannot be determined because of

calcification.

Anechoic: Applies to cystic or

almost completely cystic nodules.

Hyperechoic/isoechoic/hypoechoic:

Compared to adjacent parenchyma.

Very hypoechoic: More hypoechoic

than strap muscles.

Assign 1 point if echogenicity cannot

be determined.

Taller-than-wide: Should be

assessed on a transverse image

with measurements parallel to

sound beam for height and

perpendicular to sound beam for

width.

This can usually be assessed by

visual inspection.

Lobulated: Protrusions into adjacent

tissue.

Irregular: Jagged, spiculated, or

sharp angles.

Extrathyroidal extension: Obvious

invasion = malignancy.

Assign 0 points if margin cannot be

determined.

Large comet-tail artifacts:

V-shaped, >1 mm, in cystic

components.

Macrocalcifications: Cause

acoustic shadowing.

Peripheral: Complete or incomplete

along margin.

Punctate echogenic foci: May have

small comet-tail artifacts.

Add Points From All Categories to Determine TI-RADS Level

*Refer to discussion of papillary microcarcinomas for 5-9 mm TR5 nodules.

SHAPE

(Choose 1)

Wider-than-tall 0 points

Taller-than-wide 3 points

MARGIN

(Choose 1)

Smooth 0 points

Ill-defined 0 points

Lobulated or 2 points

irregular

Extra-thyroidal 3 points

extension

ECHOGENIC FOCI

(Choose All That Apply)

None or large 0 points

comet-tail artifacts

Macrocalcifications 1 point

Peripheral (rim) 2 points

calcifications

Punctate echogenic 3 points

foci

FIGURE 385-1 American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS). TI-RADS is a five-tiered system categorizing the sonographic

appearance of thyroid nodules based on increased risk for malignancy. For each level (TR1–5), there are recommendations for both fine-needle aspiration (FNA) minimum

size cutoffs and follow-up. (Reproduced with permission from FN Tessler et al: ACR Thyroid Imaging, Reporting and Data System (TI-RADS): White Paper of the ACR TI-RADS

Committee. J Am Coll Radiol 14:587, 2017.)

2948 PART 12 Endocrinology and Metabolism

FIGURE 385-2 Sonographic patterns of thyroid nodules. A. High suspicion

ultrasound pattern for thyroid malignancy ACR TI-RADS TR5 (hypoechoic solid

nodule with irregular borders and punctate echogenic foci). B. Very low suspicion

ultrasound pattern for thyroid malignancy ACR TI-RADS TR1 (spongiform nodule

with microcystic areas comprising >50% of nodule volume). ACR TI-RADS, American

College of Radiology Thyroid Imaging Reporting and Data System.

A

B

(typical dose 370–1070 MBq [10–29 mCi]). Repeat treatment may

be needed, and effectiveness may be increased by concurrent

administration of low-dose recombinant TSH (0.1 mg IM). It

is possible to achieve a 40–50% reduction in goiter size in most

patients. Earlier concerns about radiation-induced thyroid swelling

and tracheal compression have diminished, as studies have shown

this complication to be rare. When acute compression occurs,

glucocorticoid treatment or surgery may be needed. Radiationinduced hypothyroidism is less common than after treatment for

Graves’ disease. However, posttreatment autoimmune thyrotoxicosis may occur in up to 5% of patients treated for nontoxic MNG.

Surgery remains highly effective but is not without risk, particularly

in older patients with underlying cardiopulmonary disease.

■ TOXIC MULTINODULAR GOITER

The pathogenesis of toxic MNG appears to be similar to that of nontoxic MNG; the major difference is the presence of functional autonomy in toxic MNG. The molecular basis for autonomy in toxic MNG

remains unknown. As in nontoxic goiters, many nodules are polyclonal, whereas others are monoclonal and vary in their clonal origins.

Genetic abnormalities known to confer functional autonomy, such as

activating TSH-R or GS

α mutations (see below), are not usually found

in the autonomous regions of toxic MNG goiter.

In addition to features of goiter, the clinical presentation of toxic

MNG includes subclinical or mild overt hyperthyroidism. The patient

is usually elderly and may present with atrial fibrillation or palpitations,

tachycardia, nervousness, tremor, or weight loss. Recent exposure to

iodine, from contrast dyes or other sources, may precipitate or exacerbate thyrotoxicosis. The TSH level is low. The uncombined T4

 level

may be normal or minimally increased; T3

 is often elevated to a greater

degree than T4

. Thyroid scan shows heterogeneous uptake with multiple regions of increased and decreased uptake; 24-h uptake of radioiodine may not be increased but is usually in the upper normal range.

Prior to definitive treatment of the hyperthyroidism, ultrasound

imaging should be performed to assess the presence of discrete nodules

corresponding to areas of decreased uptake (“cold” nodules). If present,

fine-needle aspiration (FNA) may be indicated based on sonographic

patterns and size cutoffs (see “Approach to the Patient with Thyroid

Nodules”). The cytology results, if indeterminate or suspicious, may

direct the therapy to surgery.

TREATMENT

Toxic Multinodular Goiter

Antithyroid drugs normalize thyroid function and are particularly

useful in the elderly or ill patients with limited life span. In contrast

to Graves’ disease, spontaneous remission does not occur and so

treatment is long term. Radioiodine is generally the treatment of

choice; it treats areas of autonomy as well as decreasing the mass

of the goiter by ablating the functioning nodules. Sometimes, however, a degree of autonomy may persist, presumably because multiple autonomous regions may emerge after others are treated, and

further radioiodine treatment may be necessary. Surgery provides

definitive treatment of underlying thyrotoxicosis as well as goiter.

Patients should be rendered euthyroid using an antithyroid drug

before operation.

■ HYPERFUNCTIONING SOLITARY NODULE

A solitary, autonomously functioning thyroid nodule is referred to as

toxic adenoma. The pathogenesis of this disorder has been unraveled

by demonstrating the functional effects of mutations that stimulate

the TSH-R signaling pathway. Most patients with solitary hyperfunctioning nodules have acquired somatic, activating mutations in the

TSH-R (Fig. 385-3). These mutations, located primarily in the receptor

transmembrane domain, induce constitutive receptor coupling to GS

α,

increasing cyclic adenosine monophosphate (AMP) levels and leading

to enhanced thyroid follicular cell proliferation and function. Less commonly, somatic mutations are identified in GS

α. These mutations, which

are similar to those seen in McCune-Albright syndrome (Chap. 412) or

in a subset of somatotrope adenomas (Chap. 380), impair guanosine

triphosphate (GTP) hydrolysis, causing constitutive activation of the

cyclic AMP signaling pathway. In most series, activating mutations in

either the TSH-R or the GS

α subunit genes are identified in >90% of

patients with solitary hyperfunctioning nodules.

Thyrotoxicosis is usually mild and is generally only detected when a

nodule is >3 cm. The disorder is suggested by a subnormal TSH level;

the presence of the thyroid nodule, often large enough to be palpable;

and the absence of clinical features suggestive of Graves’ disease or

other causes of thyrotoxicosis. A thyroid scan provides a definitive

diagnostic test, demonstrating focal uptake in the hyperfunctioning

nodule and diminished uptake in the remainder of the gland, as activity

of the normal thyroid is suppressed.

TREATMENT

Hyperfunctioning Solitary Nodule

Radioiodine ablation is usually the treatment of choice. Because

normal thyroid function is suppressed, 131I is concentrated in the

hyperfunctioning nodule with minimal uptake and damage to

2949Thyroid Nodular Disease and Thyroid Cancer CHAPTER 385

normal thyroid tissue. Relatively large radioiodine doses (e.g., 370–

1110 MBq [10–29.9 mCi] 131I) have been shown to correct thyrotoxicosis in ~75% of patients within 3 months. Hypothyroidism occurs

in <10% of those patients over the next 5 years. Surgical resection is

also effective and is usually limited to lobectomy, thereby preserving thyroid function and minimizing risk of hypoparathyroidism

or damage to the recurrent laryngeal nerves. Medical therapy using

antithyroid drugs and beta blockers can normalize thyroid function

but is not an optimal long-term treatment. Using ultrasound guidance, percutaneous radiofrequency ablation has been used successfully in some centers to ablate hyperfunctioning nodules, and this

technique has also been used to reduce the size of nonfunctioning

thyroid nodules.

BENIGN LESIONS

The various types of benign thyroid nodules are listed in Table 385-1.

Benign nodules may be hyperplastic and reflect a combination of both

macro- and microfollicular architecture or they may be neoplastic,

encapsulated adenomas that generally have a more monotonous

microfollicular pattern. If the adenoma is composed of oncocytic follicular cells arranged in a follicular pattern, this is termed Hürthle cell

adenoma. Hyperplastic nodules generally appear as mixed cystic/solid

or spongiform lesions on ultrasound. The definition of spongiform

requires the presence of microcystic areas comprising >50% of the

nodule volume, with the concept that this microcystic sonographic

pattern recapitulates the histology of macrofollicles containing colloid

(Fig. 385-2B). However, the majority of solid nodules (whether hypo-,

iso-, or hyperechoic) are also benign. FNA, usually performed with

ultrasound guidance, is the diagnostic procedure of choice to evaluate

thyroid nodules (see the “Approach to the Patient with Thyroid Nodules” section). Pure thyroid cysts, <1% of all thyroid growths, consist

of colloid and are benign as well. Cysts frequently recur, even after

repeated aspiration, and may require surgical excision if they are large.

Ethanol ablation to sclerose the cyst has been used successfully for

patients who are symptomatic.

TSH suppression with LT4 therapy does not decrease thyroid nodule

size in iodine-sufficient populations. However, if there is relative iodine

deficiency, both iodine and LT4 therapy have been demonstrated to

decrease nodule volume. If LT4 is administered in this situation, the

TSH should be maintained at or just below the lower limit of normal,

but not frankly suppressed. If the nodule has not decreased in size after

6–12 months of therapy, treatment should be discontinued because

little benefit is likely to accrue from long-term treatment; the risk of

iatrogenic subclinical thyrotoxicosis should also be considered.

THYROID CANCER

Thyroid carcinoma is the most common malignancy of the endocrine

system. Malignant tumors derived from the follicular epithelium are

classified according to histologic features. Differentiated tumors, such

as papillary thyroid cancer (PTC) or follicular thyroid cancer (FTC), are

often curable, and the prognosis is good for patients identified with earlystage disease. In contrast, anaplastic thyroid cancer (ATC) is aggressive,

responds poorly to treatment, and is associated with a bleak prognosis.

Over the past 30 years, the incidence of thyroid cancer has increased

from 4.9 to >15 cases per 100,000 individuals in the United States.

However, disease-specific mortality has only minimally increased.

The increased incidence is predominantly attributable to small T1

papillary cancer tumors (<2 cm) and has led experts to consider that

thyroid cancer is being overdiagnosed, suggesting that cancers are

being detected that would otherwise be unlikely to harm a patient.

The concept of cancer overdiagnosis is predicated upon the presence

of a disease reservoir (the autopsy prevalence of PTC is ~25%), activities leading to disease detection (increased diagnostic imaging with

incidental detection of nodules), and a mismatch in the directional

rate between diagnosis and mortality (thyroid cancer disease-specific

mortality not changed in 40 years). Similar trends have been observed

worldwide, especially in countries with a higher proportion of privately financed health care, leading to increased resource utilization

including imaging. The 20-year disease-specific mortality for low-risk

TABLE 385-1 Classification of Thyroid Growths

Benign

Hyperplasia

Colloid nodule

Follicular epithelial cell adenomas

Conventional

Oncocytic (Hürthle cell)

Malignant Approximate Prevalence, %

Follicular epithelial cell

Papillary carcinomas 80–85

 Classic variant

 Follicular variant

 Diffuse sclerosing variant

 Tall cell, columnar cell variants

Follicular carcinomas 5–12

 Conventional

 Oncocytic (Hürthle cell)

Poorly differentiated carcinomas 3–5

 Anaplastic (undifferentiated)

carcinomas

1

C-cell origin (calcitonin-producing)

Medullary thyroid cancer <10

 Sporadic

 Familial

 MEN 2

Other malignancies

Lymphomas 1

Metastases

 Breast, melanoma, lung, kidney

Others

Abbreviation: MEN, multiple endocrine neoplasia.

Transmembrane

domains

Activating mutations

4 7 5 6

Cell growth, differentiation

Hormone synthesis

GSα

AC

cyclic AMP

TSH-R

Extracellular domain

FIGURE 385-3 Activating mutations of the thyroid-stimulating hormone receptor

(TSH-R). Mutations (*) that activate TSH-R reside mainly in transmembrane 5 and

intracellular loop 3, although mutations have occurred in a variety of different

locations. The effect of these mutations is to induce conformational changes that

mimic TSH binding, thereby leading to coupling to stimulatory G protein (GSα) and

activation of adenylate cyclase (AC), an enzyme that generates cyclic AMP.

2950 PART 12 Endocrinology and Metabolism

thyroid cancer is 1%. Fortunately, epidemiologic data in the United

States document a decrease in new thyroid cancer diagnoses (62,450

cases in 2015 and 52,070 cases in 2019), and this trend correlates with

the implementation of evidence-based guidelines that recommend

higher size thresholds for nodule FNA.

Current trends in thyroid cancer care focus on (1) avoiding overdiagnosis by limiting FNA by sonographic risk stratification with

size cutoffs; (2) limiting surgery, radioiodine, and subsequent surveillance for low-risk tumors; and (3) identifying patients at higher recurrence risk for more aggressive treatment and monitoring. Prognosis is

worse in older persons (>65 years). Thyroid cancer is twice as common

in women as men, but male gender is associated with a worse prognosis. Additional important risk factors include a history of childhood

(before age 18) head or neck irradiation, evidence for local tumor fixation or gross metastatic involvement of lymph nodes, and the presence

of distant metastases (Table 385-2).

Several unique features of thyroid cancer facilitate its management:

(1) thyroid nodules are amenable to biopsy by FNA; (2) iodine radioisotopes can be used to diagnose (123I and 131I) and potentially treat

(131I) differentiated thyroid cancer, reflecting the unique uptake of this

anion by the thyroid gland; and (3) serum markers allow the detection

of residual or recurrent disease, including the use of Tg levels for PTC

and FTC and calcitonin for medullary thyroid cancer (MTC).

■ CLASSIFICATION

Thyroid neoplasms can arise in each of the cell types that populate the

gland, including thyroid follicular cells, calcitonin-producing C cells,

lymphocytes, and stromal and vascular elements, as well as metastases

from other sites (Table 385-1). The American Joint Committee on Cancer (AJCC) staging system using the tumor, node, metastasis (TNM)

classification is most commonly used (Table 385-3).

■ PATHOGENESIS AND GENETIC BASIS

Radiation Early studies of the pathogenesis of thyroid cancer

focused on the role of external radiation, which predisposes to

chromosomal breaks, leading to genetic rearrangements and loss of

tumor-suppressor genes. External radiation of the mediastinum, face,

head, and neck region was administered in the past to treat an array of

conditions, including acne and enlargement of the thymus, tonsils, and

adenoids. Radiation exposure increases the risk of benign and malignant thyroid nodules, is associated with multicentric cancers, and shifts

the incidence of thyroid cancer to an earlier age group. Radiation from

nuclear fallout also increases the risk of thyroid cancer. Children seem

more predisposed to the effects of radiation than adults.

TSH and Growth Factors Many differentiated thyroid cancers

express TSH receptors and, therefore, remain responsive to TSH.

Higher serum TSH levels, even within normal range, are associated

with increased thyroid cancer risk in patients with thyroid nodules.

These observations provide the rationale for T4

 suppression of TSH in

patients with thyroid cancer. Residual expression of TSH receptors also

allows TSH-stimulated uptake of 131I therapy (see below).

Oncogenes and Tumor-Suppressor Genes Thyroid cancers are

monoclonal in origin, consistent with the idea that they originate as a

TABLE 385-2 Risk Factors for Thyroid Carcinoma in Patients with

Thyroid Nodule from History and Physical Examination

History of head and neck irradiation

before the age of 18, including mantle

radiation for Hodgkin’s disease and

brain radiation for childhood leukemia

or other cranial malignancies

Exposure to ionizing radiation from

fallout in childhood or adolescence

Age <20 or >65 years

Rapidly enlarging neck mass

Male gender

Family history of papillary thyroid

cancer in two or more first-degree

relatives, MEN 2, or other genetic

syndromes associated with thyroid

malignancy (e.g., Cowden’s syndrome,

familial adenomatous polyposis,

Carney complex, PTEN [phosphatase

and tensin homolog] hamartoma tumor)

Vocal cord paralysis, hoarse voice

Nodule fixed to adjacent structures

Lateral cervical lymphadenopathy

(ipsilateral to the nodule)

Abbreviation: MEN, multiple endocrine neoplasia.

TABLE 385-3 Definitions of AJCC TNM

Definition of Primary Tumor (T)

Papillary, Follicular, Poorly Differentiated, Hürthle Cell and Anaplastic Thyroid

Carcinoma

T Category T Criteria

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1 Tumor ≤2 cm in greatest dimension limited to the thyroid

T1a Tumor ≤1 cm in greatest dimension limited to the thyroid

T1b Tumor >1 cm but ≤2 cm in greatest dimension limited to the thyroid

T2 Tumor >2 cm but ≤4 cm in greatest dimension limited to the 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

Note: All categories may be subdivided: (s) solitary tumor and (m) multifocal

tumor (the largest tumor determines the classification).

Definition of Regional Lymph Node (N)

N Category N Criteria

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

Definition of Distant Metastasis (M)

M Category M Criteria

M0 No distant metastasis

M1 Distant metastasis

MX Distant metastasis cannot be assessed

Source: Used with permission of the American College of Surgeons, Chicago, Illinois.

The original source for this information is the AJCC Cancer Staging System (2020).

consequence of mutations that confer a growth advantage to a single

cell. In addition to increased rates of proliferation, some thyroid cancers

exhibit impaired apoptosis and features that enhance invasion, angiogenesis, and metastasis. Thyroid neoplasms have been analyzed for a variety

of genetic alterations, but without clear evidence of an ordered acquisition

of somatic mutations as they progress from the benign to the malignant

state. On the other hand, certain mutations, such as RET/PTC and PAX8-PPARγ1 rearrangements, are relatively specific for thyroid neoplasia.

As described above, activating mutations of the TSH-R and the GS

α

subunit are associated with autonomously functioning nodules. Although

these mutations induce thyroid cell growth, this type of nodule is almost

always benign, likely because they drive differentiation pathways.

Activation of the RET-RAS-BRAF signaling pathway is seen in up

to 70% of PTCs, although the types of mutations are heterogeneous. A

variety of rearrangements involving the RET gene on chromosome 10

bring this receptor tyrosine kinase under the control of other promoters, leading to receptor overexpression. RET rearrangements occur in

20–40% of PTCs in different series and were observed with increased

2951Thyroid Nodular Disease and Thyroid Cancer CHAPTER 385

frequency in tumors developing after the Chernobyl radiation accident.

Rearrangements in PTC have also occurred for another tyrosine kinase

gene, TRK1, which is located on chromosome 1. To date, the identification of PTC with RET or TRK1 rearrangements has not proven useful

for predicting prognosis or treatment responses. BRAF V600E mutations

appear to be the most common genetic alteration in PTC. These mutations activate the kinase, which stimulates the mitogen-activated protein kinase (MAPK) cascade. RAS mutations, which also stimulate the

MAPK cascade, are found in ~20–30% of thyroid neoplasms (NRAS >

HRAS > KRAS), including both PTC follicular variant and FTC. Of note,

simultaneous RET, BRAF, and RAS mutations rarely occur in the same

tumor, suggesting that activation of the MAPK cascade is critical for

tumor development, independent of the step that initiates the cascade.

RAS mutations also occur in FTCs. In addition, a rearrangement of

the thyroid developmental transcription factor PAX8 with the nuclear

receptor PPARγ is identified in a significant fraction of FTCs. Overall,

~70% of follicular cancers have mutations or genetic rearrangements.

Loss of heterozygosity of 3p or 11q, consistent with deletions of tumorsuppressor genes, is also common in FTCs.

Most of the mutations seen in differentiated thyroid cancers have

also been detected in ATCs. TERT promoter mutations occur in <10%

of differentiated PTCs but are more common in ATC. BRAF mutations

are seen in up to 50% of ATCs. Mutations in CTNNB1, which encodes

β-catenin, occur in about two-thirds of ATCs, but not in PTC or FTC.

Mutations of the tumor-suppressor P53 also play an important role in the

development of ATC. Because P53 plays a role in cell-cycle surveillance,

DNA repair, and apoptosis, its loss may contribute to the rapid acquisition of genetic instability as well as poor treatment responses (Chap. 72).

The role of molecular diagnostics in the clinical management of

thyroid cancer is under investigation. In principle, analyses of specific

mutations might aid in classification, prognosis, or choice of treatment.

Although BRAF V600E mutations are associated with loss of iodine

uptake by tumor cells. As discussed below, trials of multikinase pathway inhibitors are ongoing as a means to restore iodine uptake and

enhance sensitivity to radioiodine treatment. Higher recurrence rates

have been variably reported in patients with BRAF-positive PTC, but

the impact on survival rates is unclear.

MTC, when associated with multiple endocrine neoplasia (MEN) type

2, harbors an inherited mutation of the RET gene. Unlike the rearrangements of RET seen in PTC, the mutations in MEN 2 are point mutations

that induce constitutive activity of the tyrosine kinase (Chap. 388).

MTC is preceded by hyperplasia of the C cells, raising the likelihood

that as-yet-unidentified “second hits” lead to cellular transformation. A

subset of sporadic MTC contains somatic mutations that activate RET.

■ WELL-DIFFERENTIATED THYROID CANCER

Papillary PTC is the most common type of thyroid cancer, accounting for 80–85% of well-differentiated thyroid malignancies. Microscopic PTC is present in up to 25% of thyroid glands at autopsy, but

most of these lesions are very small (several millimeters) and are not

clinically significant. Characteristic cytologic features of PTC help

make the diagnosis by FNA or after surgical resection; these include,

large, clear nuclei with powdery chromatin (described as an “orphan

Annie eye” appearance) with nuclear grooves and prominent nucleoli.

The histologic finding of these cells arranged in either papillary structures or follicles distinguishes the classic and follicular variants of PTC,

respectively. There are several subtypes of papillary thyroid cancer. The

more differentiated classic and follicular variants are likely to have an

indolent course in the absence of angioinvasion or metastatic adenopathy. The aggressive variants (tall cell, columnar cell, hobnail, poorly

differentiated) require more intensive therapy and closer follow-up.

Recently, a subtype previously known as the encapsulated PTC follicular variant, without capsular or angioinvasion, is no longer considered

malignant and has been renamed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).

PTC may be multifocal and invade locally within the thyroid gland

as well as through the thyroid capsule and into adjacent structures

in the neck. It has a propensity to spread via the lymphatic system

but can metastasize hematogenously as well, particularly to bone and

lung. Because of the relatively slow growth of the tumor, a significant

burden of pulmonary metastases may accumulate, sometimes with

remarkably few symptoms. The prognostic implication of lymph node

spread depends on the volume of metastatic disease. Micrometastases,

defined as <2 mm of cancer in a lymph node, do not affect prognosis.

However, gross metastatic involvement of multiple 2- to 3-cm lymph

nodes indicates a 25–30% chance of recurrence and may increase

mortality in older patients. The staging of PTC by the TNM system

is outlined in Table 385-3. Most papillary cancers are identified in the

early stages (>95% stages I or II) and have an excellent prognosis, with

survival curves similar to expected survival (Fig. 385-4). Mortality is

markedly increased in stage IV disease, especially in the presence of

distant metastases (stage IVB), but this group comprises only about 1%

of patients. The treatment of PTC is described below.

Follicular The incidence of FTC varies widely in different parts of

the world; it is more common in iodine-deficient regions. Currently,

FTC accounts for only about 5% of all thyroid cancers diagnosed in the

United States. FTC is difficult to diagnose by FNA because the distinction between benign and malignant follicular neoplasms requires histology because the nuclear features of follicular adenomas and carcinomas

do not differ. Rather, follicular carcinoma is diagnosed by the presence

of capsular and/or vascular invasion. Follicular carcinomas with only

capsular invasion have a very low risk of metastasis, and lobectomy

alone suffices. Angioinvasive FTC is more aggressive and may metastasize to bone, lung, and the central nervous system. Mortality rates associated with angioinvasive FTC are less favorable than for PTC, in part

because a larger proportion of patients present with stage IV disease.

Poor prognostic features include distant metastases, age >55 years, primary tumor size >4 cm, and the presence of marked vascular invasion.

TREATMENT

Surgery for Well-Differentiated Thyroid Cancer

All well-differentiated thyroid cancers >1 cm (T1b or larger) should

be surgically excised, although active surveillance is an option for

small intrathyroidal micropapillary thyroid cancers (T1a) without

metastases. In addition to removing the primary lesion, surgery

allows accurate histologic diagnosis and staging. Because there is

no compelling evidence that bilateral thyroid surgery improves

survival, the initial surgical procedure may be either a unilateral

(lobectomy) or bilateral (near-total thyroidectomy) procedure for

patients with intrathyroidal cancers >1 cm and <4 cm (T1b and

T2  tumors) in the absence of metastatic disease and after a careful sonographic evaluation for metastatic cervical adenopathy. For

patients at high risk for recurrence, bilateral surgery allows administration of radioiodine for remnant ablation and potential treatment

p <0.001

Stage = I

Stage = II

Stage = III

Stage = IV

0

0.0

1.0

0.8

0.6

0.4

Disease-specific survival probability 0.2

12 24 36 48 60

Time from diagnosis (months)

72 84 96 108 120 132

FIGURE 385-4 Unadjusted disease-specific survival curves for patients with papillary

thyroid cancer in the AJCC/UICC 8th edition TNM staging system. (Reproduced with

permission from LN Pontius et al: Projecting survival in papillary thyroid cancer: A

comparison of the seventh and eighth editions of the American Joint Commission on

Cancer/Union for International Cancer Control staging systems in two contemporary

national patient cohorts. Thyroid 27:1408, 2017.)

2952 PART 12 Endocrinology and Metabolism

of iodine-avid metastases, if indicated, as well as for monitoring of

serum Tg levels. Therefore, near-total thyroidectomy is appropriate for tumors >4 cm or in the presence of metastases or clinical

evidence of extrathyroidal invasion. In addition, for patients found

to have a high-risk tumor after lobectomy based upon aggressive

pathology features (e.g., vascular invasion or a less differentiated

subtype), completion surgery should be performed. Surgical complication rates are acceptably low if the surgeon is highly experienced

in the procedure. Preoperative sonography should be performed

in all patients to assess the central and lateral cervical lymph node

compartments for suspicious adenopathy, which if present, should

undergo FNA and be removed, as indicated, at surgery.

TSH SUPPRESSION THERAPY

Because most tumors are still TSH-responsive, LT4 suppression of

TSH is a mainstay of thyroid cancer treatment. Although TSH suppression clearly provides therapeutic benefit, there are no prospective

studies that define the optimal level of TSH suppression. The degree of

TSH suppression should be individualized based on a patient’s risk of

recurrence. It should be adjusted over time as surveillance blood tests

and imaging confirm absence of disease or, alternatively, indicate possible residual/recurrent cancer. For patients at low risk of recurrence,

TSH should be maintained in the lower normal limit (0.5–2.0 mIU/L).

For patients either at intermediate or high risk of recurrence, TSH

levels should be kept to 0.1–0.5 mIU/L and <0.1 mIU/L, respectively,

if there are no strong contraindications to mild thyrotoxicosis. TSH

should be <0.1 mIU/L for those with known metastatic disease.

RADIOIODINE TREATMENT

After near-total thyroidectomy, <1 g of thyroid tissue remains in

the thyroid bed. Postsurgical radioablation of the remnant thyroid

eliminates residual normal thyroid, facilitating the use of Tg determinations. In addition, well-differentiated thyroid cancer often

incorporates radioiodine, although less efficiently than normal

thyroid follicular cells. Radioiodine uptake is determined primarily by expression of the NIS and is stimulated by TSH, requiring

expression of the TSH-R. The retention time for radioactivity is

influenced by the extent to which the tumor retains differentiated

functions such as iodide trapping and organification. Consequently,

for patients at higher risk of recurrence and for those with known

distant metastatic disease, 131I therapy may provide an adjuvant role

and potentially treat residual tumor cells.

Indications Not all patients benefit from radioiodine therapy.

Neither recurrence nor survival rates are improved in stage I patients

with T1 tumors (≤2 cm) confined to the thyroid. No benefit has

been demonstrated for larger (>2 cm but <4 cm) low-risk tumors.

However, in higher risk patients (larger tumors, more aggressive

variants of papillary cancer, tumor vascular invasion, extrathyroidal

invasion, presence of large-volume lymph node metastases), radioiodine reduces recurrence and may increase survival for older patients.

131I Thyroid Ablation and Treatment As noted above, the decision

to use 131I for thyroid ablation should be coordinated with the surgical approach, because radioablation is much more effective when

there is minimal remaining normal thyroid tissue. Radioiodine is

administered after iodine depletion (patient follows a low-iodine

diet for 1–2 weeks) and in the presence of elevated serum TSH

levels to stimulate uptake of the isotope into both the remnant

and potentially any residual tumor. To achieve high serum TSH

levels, there are two approaches. A patient may be withdrawn from

thyroid hormone so that endogenous TSH is secreted and, ideally, the serum TSH level is >25 mIU/L at the time of 131I therapy.

A typical strategy is to treat the patient for several weeks postoperatively with liothyronine (25 μg qd or bid), followed by thyroid hormone withdrawal for 2 weeks. Alternatively, recombinant human

TSH (rhTSH) is administered as two daily consecutive injections

(0.9 mg) with administration of 131I 24 h after the second injection.

The patient can continue to take LT4 and remains euthyroid. Both

approaches have equal success in achieving remnant ablation.

A pretreatment scanning dose of 131I (usually 111 MBq [3 mCi])

or 123I (74 MBq [2 mCi]) can reveal the amount of residual

tissue and provides guidance about the dose needed to accomplish

ablation. However, because of concerns about radioactive “stunning” that impairs subsequent treatment, there is a trend to avoid

pretreatment scanning with 131I and use either 123I or proceed directly

to ablation, unless there is suspicion that the amount of residual tissue will alter therapy or that there is distant metastatic disease. In

the United States, outpatient doses of up to 6475 MBq (175 mCi)

can be given at most centers. The administered dose depends on

the indication for therapy, with lower doses of 1100 MBq (30 mCi)

given for remnant ablation but higher doses of up to 5500 MBq

(150 mCi) reserved for use as adjuvant therapy when residual disease is suspected or present. Whole-body scanning (WBS) following radioiodine treatment is used to confirm the 131I uptake in the

remnant and to identify possible metastatic disease.

Surveillance Testing Serum thyroglobulin is a sensitive marker of

residual/recurrent thyroid cancer after ablation of the residual postsurgical thyroid tissue. Current Tg assays have functional sensitivities as low as 0.1 ng/mL, as opposed to older assays with functional

sensitivities of 1–2 ng/mL, reducing the number of patients with

truly undetectable serum Tg levels. Because the vast majority of PTC

recurrences are in cervical lymph nodes, a neck ultrasound should

be performed about 6 months after thyroid ablation; ultrasound has

been shown to be more sensitive than WBS in this scenario.

In low-risk patients who have no clinical evidence of residual

disease after ablation, negative cervical sonography, and a basal Tg

<0.2 ng/mL on LT4, the risk of structural recurrence is <3% at 5 years,

and the frequency of follow-up testing can be decreased to annual

TSH and Tg testing, with only periodic ultrasound examination.

The use of WBS is reserved for patients with known iodine-avid

metastases or those with elevated serum thyroglobulin levels and

negative imaging with ultrasound, chest CT, neck cross-sectional

imaging, and positron emission tomography (PET) CT who may

require additional 131I therapy.

In addition to radioiodine, external beam radiotherapy is also

used to treat gross residual neck disease or specific metastatic

lesions, particularly when they cause bone pain or threaten neurologic injury (e.g., vertebral metastases).

New Potential Therapies Kinase inhibitors target pathways

known to be active in thyroid cancer, including the RAS, BRAF,

RET, EGFR, VEGFR, and angiogenesis pathways. Treatment has

been shown to stabilize progressive metastatic disease that is refractory to radioiodine therapy, although only one study has demonstrated improved survival. Given the significant associated toxicities

and the need for ongoing therapy, patient selection is critical to

limit systemic therapy to those with significant morbidity risk. The

American Thyroid Association guidelines recommend active surveillance for asymptomatic patients with metastatic tumors between

1 and 2  cm and then intervention as the rate of tumor growth

increases. In addition, based on genetic analyses of metastases,

mutation-selective kinase inhibitors are now being used. Ongoing

trials are also exploring whether differentiation protocols, targeting

the MAPK pathway, might enhance radioiodine uptake and efficacy.

■ ANAPLASTIC AND OTHER FORMS OF

THYROID CANCER

Anaplastic Thyroid Cancer As noted above, ATC is a poorly

differentiated and aggressive cancer. The prognosis is poor, and most

patients die within 6 months of diagnosis. Because of the undifferentiated state of these tumors, the uptake of radioiodine is usually

negligible, but it can be used therapeutically if there is residual uptake.

Chemotherapy has been attempted with multiple agents, including

anthracyclines and paclitaxel, but it is usually ineffective. External beam

radiation therapy can be attempted and continued if tumors are responsive. Both multitargeted and mutation-directed kinase inhibitors are in

clinical trials and may prolong survival by a few months.

Thyroid Lymphoma Lymphoma in the thyroid gland often arises

in the background of Hashimoto’s thyroiditis. A rapidly expanding

thyroid mass suggests the possibility of this diagnosis. Diffuse large-cell

2953Thyroid Nodular Disease and Thyroid Cancer CHAPTER 385

Evaluate and Rx

for hyperthyroidism

Atypia or follicular lesion

of undetermined

significance (AUS/FLUS)

Repeat US-guided

FNA or consider

molecular testing

Nondiagnostic Repeat US-guided FNA Nondiagnostic

Malignant

Suspicious for PTC

Follicular neoplasm Consider molecular testing Surgery if indicated

Surgery if indicated

Surgery

Benign Follow

Close follow-up or surgery

Diagnostic US with

LN assessment Nodule not functioning Radionuclide scanning

Hyperfunctioning nodule

Results of FNA cytology

History, physical

examination, TSH

Normal or high TSH Low TSH

Bethesda System Cytology Reporting

EVALUATION OF THYROID NODULES

DETECTED BY PALPATION OR IMAGING

Nodule(s) detected on US

Do FNA based upon

US imaging features and size

FIGURE 385-5 Approach to the patient with a thyroid nodule. See text and references for details. FNA, fine-needle aspiration; LN, lymph node; PTC, papillary thyroid cancer;

Rx, therapy; TSH, thyroid-stimulating hormone; US, ultrasound.

lymphoma is the most common type in the thyroid. Biopsies reveal

sheets of lymphoid cells that can be difficult to distinguish from smallcell lung cancer or ATC. These tumors are often highly sensitive to

external radiation. Surgical resection should be avoided as initial therapy

because it may spread disease that is otherwise localized to the thyroid. If

staging indicates disease outside of the thyroid, treatment should follow

guidelines used for other forms of lymphoma (Chap. 108).

■ MEDULLARY THYROID CARCINOMA

MTC can be sporadic or familial and accounts for ~5% of thyroid cancers. There are three familial forms of MTC: MEN 2A, MEN 2B, and

familial MTC without other features of MEN (Chap. 388). In general,

MTC is more aggressive in MEN 2B than in MEN 2A, and familial

MTC is more aggressive than sporadic MTC. Elevated serum calcitonin provides a marker of residual or recurrent disease. All patients with

MTC should be tested for RET mutations, because genetic counseling

and testing of family members can be offered to those individuals who

test positive for mutations.

The management of MTC is primarily surgical. Prior to surgery,

pheochromocytoma should be excluded in all patients with a RET

mutation. Unlike tumors derived from thyroid follicular cells, these

tumors do not take up radioiodine. External radiation treatment and

targeted kinase inhibitors may provide palliation in patients with

advanced disease (Chap. 388).

APPROACH TO THE PATIENT

Thyroid Nodules

Palpable thyroid nodules are found in ~5% of adults, but the prevalence varies considerably worldwide. Given this high prevalence

rate, practitioners may identify thyroid nodules on physical examination. However, the increased usage of diagnostic medical imaging

(e.g., carotid ultrasound, cervical spine MRI) has led to an increased

frequency of incidental nodule detection, accounting for the majority of patients currently presenting for nodule evaluation. The main

goal of this evaluation is to identify, in a cost-effective manner, the

small subgroup of individuals with malignant lesions that have the

potential to be clinically significant.

Nodules are more common in iodine-deficient areas, in women,

and with aging. Most palpable nodules are >1 cm in diameter, but

the ability to feel a nodule is influenced by its location within the

gland (superficial vs deeply embedded), the anatomy of the patient’s

neck, and the experience of the examiner. More sensitive methods

of detection, such as CT, thyroid ultrasound, and pathologic studies,

reveal thyroid nodules in up to 50% of glands in individuals aged

>50 years. The presence of these thyroid incidentalomas has led to

much debate about how to detect nodules and which nodules to

investigate further.

An approach to the evaluation of thyroid nodules detected by

either palpation or imaging is outlined in Fig. 385-5. Most patients

with thyroid nodules have normal thyroid function tests. Nonetheless, thyroid function should be assessed by measuring a TSH

level, which may be suppressed by one or more autonomously

functioning nodules. If the TSH is suppressed, a radionuclide scan

is indicated to determine if the identified nodule is “hot,” as lesions

with increased uptake are almost never malignant and FNA is

unnecessary. Otherwise, the next step in evaluation is performance

of a thyroid ultrasound for three reasons: (1) For nodules detected

on physical examination, ultrasound will confirm if the palpable

nodule is indeed a nodule. About 15% of “palpable” nodules are

2954 PART 12 Endocrinology and Metabolism

not confirmed on imaging, and therefore no further evaluation is

required. (2) Ultrasound will assess if there are additional nonpalpable nodules for which FNA may be recommended based on

imaging features and size. (3) Ultrasound will characterize the

imaging pattern of the nodule, which, combined with the nodule’s

size, facilitates decision-making about FNA. There are several validated risk stratification systems (RSS) for sonographic imaging of

thyroid nodules (American College of Radiology [ACR] Thyroid

Imaging Reporting and Data System [TI-RADS], American Thyroid

Association, European Thyroid Association [EU-TIRADS], among

others). These demonstrate consistent risk estimates for thyroid

cancer based on certain sonographic patterns. All provide size cutoff

recommendations for nodule FNA based on sonographic patterns,

with lower size cutoffs for nodules with more suspicious ultrasound

patterns, but the specific size cutoff criteria differ among the RSS.

Not surprisingly, the RSSs with lower size cutoffs have higher sensitivity and lower specificity for thyroid cancer diagnosis than those

with higher cutoffs. Nevertheless, all have been shown to reduce

unnecessary FNAs by at least 45%, in part due to the recommendation not to perform FNA for spongiform nodules. ACR TI-RADS

is currently the most widely used RSS in the United States, and

nodules are classified from TR1 to TR5 (Fig. 385-1).

For example, a spongiform nodule (TR1) has a <3% chance

of cancer, and observation rather than FNA is generally recommended by all RSSs, whereas 10–20% of solid hypoechoic nodules

with smooth borders (TR4) are malignant and FNA is recommended at size cutoffs ranging from 1–1.5 cm. All the RSSs recommend FNA at 1 cm for the highest suspicion pattern nodule, TR5

(Figs. 385-1 and 385-2). Given what is known about the prevalence

and generally indolent behavior of small thyroid cancers <1 cm,

none of the RSSs recommend FNA for any nodule <1 cm unless

metastatic cervical lymph nodes are present.

FNA biopsy, ideally performed with ultrasound guidance, is the

best diagnostic test when performed by physicians familiar with

the procedure and when the results are interpreted by experienced

cytopathologists. The technique is particularly useful for detecting

PTC. However, the distinction between benign and malignant follicular patterned lesions is often not possible using cytology alone

because of the absence of characteristic nuclear features in follicular

carcinoma. Using the current ultrasound RSS for FNA decisionmaking, FNA biopsies yield the following spectrum of cytology

diagnoses: 55–60% benign, 5% malignant or suspicious for malignancy, 5–7% nondiagnostic or yielding insufficient material for

diagnosis, and 25–30% indeterminate. The Bethesda System is now

widely used to provide more uniform terminology for reporting

thyroid nodule FNA cytology results. This six-tiered classification

system with the respective estimated malignancy rates is shown in

Table 385-4. Importantly, because NIFTP can only be diagnosed

by surgical pathology, NIFTP is included in the malignancy estimates. Specifically, the Bethesda System subcategorized cytology

specimens previously labeled as indeterminate into three categories: atypia or follicular lesion of undetermined significance (AUS/

FLUS), follicular neoplasm, and suspicious for malignancy.

Cytology results indicative of malignancy generally mandate surgery, after performing preoperative sonography to evaluate the cervical lymph nodes. Nondiagnostic cytology specimens most often

result from cystic lesions but may also occur in fibrous long-standing

nodules or very vascular nodules where a longer needle dwell time

may result in a hemorrhagic specimen. Ultrasound-guided FNA is

indicated when a repeat FNA is necessary. Repeat FNA will yield a

diagnostic cytology in ~50% of cases. Given the low false-negative

rate of a benign cytology (<3%), benign nodules with a low suspicion sonographic pattern (TR2, TR3) can be followed. Those with

more worrisome ultrasound features, especially TR5 nodules, should

undergo repeat FNA because of a higher likelihood of a missed

malignancy. The use of LT4 to suppress serum TSH is not effective in

shrinking nodules in iodine-replete populations, and therefore, LT4

suppression should not be used. The three indeterminate cytology

classifications introduced by the Bethesda System are associated

with different risks of malignancy (Table 385-4). For nodules with

suspicious for malignancy cytology, surgery is recommended after

ultrasound assessment of cervical lymph nodes. Options to be discussed with the patient include lobectomy versus total thyroidectomy.

On the other hand, the majority of nodules with AUS/FLUS and

follicular neoplasm cytology results are benign; the range of malignancy (ROM) varies from 10 to 40%. The traditional approach for

these patients is diagnostic lobectomy for histopathologic diagnosis.

Therefore, many patients undergo surgery for benign nodules. Over

the past decade, the uncertainty about the ROM for indeterminate

cytology nodules has been the driver for the development of molecular testing, which can better differentiate benign from malignant

nodules. Based on results from next-generation sequencing, which

includes point mutations, small insertions/deletions, and gene

fusions, as well as results from microRNA analyses and gene expression, the current validated and commercially available molecular

tests combine these techniques with the following two goals: (1) risk

stratification of thyroid nodules based on a positive result; and (2)

reduction in cancer risk to an acceptable level for nonsurgical surveillance based on a negative result. Assuming a 25–30% ROM for

nodules with indeterminate cytology, the negative predictive values

for the currently validated molecular tests are >95%.

The evaluation of a thyroid nodule is stressful for most patients.

They are concerned about the possibility of thyroid cancer, whether

verbalized or not. It is constructive, therefore, to review the diagnostic approach and to reassure patients when no malignancy is

found. When a suspicious lesion or thyroid cancer is identified, the

generally favorable prognosis and available treatment options can

be reassuring.

■ FURTHER READING

Cibas ES et al: The 2017 Bethesda system for reporting thyroid cytopathology. Thyroid 27:1341, 2017.

Davies L, Hoang J: Thyroid cancer in the USA: Current trends and

outstanding questions. Lancet Diab Endocrinol 9:11, 2021.

Dunn LA et al: Vemurafenib redifferentiation of BRAF mutant, RAIrefractory thyroid cancers. J Clin Endocrinol Metab 104:1417, 2019.

Durante C et al: The diagnosis and management of thyroid nodules:

A review. JAMA 319:914, 2018.

Fagin JA, Wells SA: Biologic and clinical perspectives on thyroid

cancer. N Engl J Med 375:1054, 2016.

Haugen BR et al: 2015 American Thyroid Association management

guidelines for adult patients with thyroid nodules and differentiated

thyroid cancer. Thyroid 26:1, 2016.

Tessler FN et al: ACR Thyroid Imaging Reporting and Data System

(TI-RADS): White paper of the ACR TI-RADS committee. J Am Coll

Radiol 14:587, 2017.

Tuttle RM et al: Updated American Joint Committee and

Cancer/Tumor-Node-Metastasis Staging System for differentiated

and anaplastic thyroid cancer (eighth edition): What changed and

why? Thyroid 27:751, 2017.

TABLE 385-4 Bethesda Classification for Thyroid Cytology Version 2

DIAGNOSTIC CATEGORY

RISK OF MALIGNANCY

(INCLUDING NIFTP)

 I. Nondiagnostic or unsatisfactory 5–10%

 II. Benign 0–3%

III. Atypia or follicular lesion of unknown

significance (AUS/FLUS)

~10–30%

IV. Follicular neoplasm 25–40%

V. Suspicious for malignancy 50–75%

VI. Malignant 97–99%

Abbreviation: NIFTP, noninvasive follicular thyroid neoplasm with papillary-like

nuclear features.

2955 Disorders of the Adrenal Cortex CHAPTER 386

The adrenal cortex produces three classes of corticosteroid hormones:

glucocorticoids (e.g., cortisol), mineralocorticoids (e.g., aldosterone), and adrenal androgen precursors (e.g., dehydroepiandrosterone

[DHEA]) (Fig. 386-1). Glucocorticoids and mineralocorticoids act

through specific nuclear receptors, regulating aspects of the physiologic stress response as well as blood pressure and electrolyte homeostasis. Adrenal androgen precursors are converted in the gonads and

peripheral target cells to sex steroids that act via nuclear androgen and

estrogen receptors.

386 Disorders of the

Adrenal Cortex

Wiebke Arlt

Disorders of the adrenal cortex are characterized by deficiency

or excess of one or several of the three major corticosteroid classes.

Hormone deficiency can be caused by inherited glandular or enzymatic disorders or by destruction of the pituitary or adrenal gland by

autoimmune disorders, infection, infarction, or iatrogenic events such

as surgery or hormonal suppression. Hormone excess is usually the

result of neoplasia, leading to increased production of adrenocorticotropic hormone (ACTH) by the pituitary or neuroendocrine ectopic

ACTH-producing cells or increased production of glucocorticoids,

mineralocorticoids, or adrenal androgen precursors by adrenal nodules. Adrenal nodules are increasingly identified incidentally during

cross-sectional imaging of chest or abdomen performed for other

reasons.

■ ADRENAL ANATOMY AND DEVELOPMENT

The normal adrenal glands weigh 6–11 g each. They are located above

the kidneys and have their own blood supply. Arterial blood flows

CH3

HO

H3C

H3C

H3C

H3C

H H

H

OH OH

H

HO

H3C

H3C

H

HO

H3C CH3

H3C

O

H H

H

HO

H3C

H3C

H

O

CH3

O

O

H3C

H3C

H H

H

CH3

O

O

H3C

H3C

H H

H

O

O

O

H3C

H3C

H H

H

CH3

O

OH

O

H3C

H3C

H H

H

OH

O

OH

O

H3C

H3C

H H

H

O

OH

OH

O

H3C HO

H3C

H H

HO

O

HO

H3C

H H

H

O

OH HO

O

CHO

H3C

H H

H

O

OH HO

H

OH

O

O OH

O

H3C

H3C

H H

H

OH

O

H

H

H

H

H3C

H3C

H

O

H

H

O

CH3

CH3

H

OH

H

H

O

H3C

H3C

H

OH

H

H

H

Pregnenolone

Cholesterol

Glucocorticoids

Mineralocorticoid Mineralocorticoids

precursors

Glucocorticoid

precursors

Progesterone

HSD17B SRD5A

HSD11B1

HSD11B2

17-hydroxypregnenolone

17-hydroxyprogesterone

(17OHP)

11-

Deoxycortisol Cortisol

Androstenedione

Testosterone 5-Dihydrotestosterone

Deoxycorticosterone

Corticosterone

18OH-Corticosterone

Aldosterone

Cortisone

DHEA

DHEAS

CYP11A1

ADX

HSD3B2

HSD3B2

HSD3B2

CYP21A2

POR

CYP17A1

POR

CYP17A1

POR

CYP17A1

POR

SULT2A1

PAPSS2

CYP17A1

POR

CYP11B2

ADX

CYP11B1

ADX

CYP11B2

ADX

CYP11B1

ADX

H6PDH

CYP21A2

POR

CYP11B2

ADX

CH3

CH3

O

H H

H

O

S

O

O OAdrenal androgen

precursors

Androgens

11-hydroxyandrostenedione

11-ketoandrostenedione

11-ketotestosterone

AKR1C3

HSD11B1 HSD17B2/4

HSD11B2

H6PDH

CYP11B1

ADX

O

H

O

H

H

HO

O

H

O

H

H

O

O

H

OH

H

H

O

FIGURE 386-1 Adrenal steroidogenesis. ADX, adrenodoxin; AKR1C3, aldo-keto reductase 1C3; CYP11A1, side chain cleavage enzyme; CYP11B1, 11β-hydroxylase;

CYP11B2, aldosterone synthase; CYP17A1, 17α-hydroxylase/17,20 lyase; CYP21A2, 21-hydroxylase; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone

sulfate; H6PDH, hexose-6-phosphate dehydrogenase; HSD11B1, 11β-hydroxysteroid dehydrogenase type 1; HSD11B2, 11β-hydroxysteroid dehydrogenase type 2; HSD17B,

17β-hydroxysteroid dehydrogenase; HSD3B2, 3β-hydroxysteroid dehydrogenase type 2; PAPSS2, PAPS synthase type 2; POR, P450 oxidoreductase; SRD5A, 5α-reductase;

SULT2A1, DHEA sulfotransferase.

2956 PART 12 Endocrinology and Metabolism

–

–

+

+

Hypothalamus

Circadian

rhythm

Stressors

(physical, emotional, including

fever, hypoglycemia, hypotension)

Anterior

pituitary

Adrenal cortex

CRH

Neurotransmitters

Circulating

cortisol

ACTH

FIGURE 386-2 Regulation of the hypothalamic-pituitary-adrenal (HPA) axis. ACTH,

adrenocorticotropic hormone; CRH, corticotropin-releasing hormone.

300

400

500

600

0

100

200

22 23 24 123456 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Clock time

Cortisol (nmol/L)

Nadir: 0015 h

MESOR: 5.25 µg/dL (145 nmol/L)

Acrophase: 0830 h

FIGURE 386-3 Physiologic cortisol circadian rhythm. Circulating cortisol concentrations (geometrical

mean ± standard deviation values and fitted cosinor) drop under the rhythm-adjusted mean (MESOR) in the

early evening hours, with nadir levels around midnight and a rise in the early morning hours; peak levels

are observed ~8:30 a.m. (acrophase). (Reproduced with permission from M Debono et al: Modified-release

hydrocortisone to provide circadian cortisol profiles. J Clin Endocrinol Metab 94:1548, 2009.)

initially to the subcapsular region and then meanders from the outer

cortical zona glomerulosa through the intermediate zona fasciculata to

the inner zona reticularis and eventually to the adrenal medulla. The

right suprarenal vein drains directly into the vena cava, while the left

suprarenal vein drains into the left renal vein.

During early embryonic development, the adrenals originate from

the urogenital ridge and then separate from

gonads and kidneys at about the sixth week of

gestation. Concordant with the time of sexual

differentiation (seventh to ninth week of gestation,

Chap. 390), the adrenal cortex starts to produce

cortisol and the adrenal sex steroid precursor

DHEA. The orphan nuclear receptors SF1 (steroidogenic factor 1; encoded by the gene NR5A1)

and DAX1 (dosage-sensitive sex reversal gene 1;

encoded by the gene NR0B1), among others, play

a crucial role during this period of development,

as they regulate a multitude of adrenal genes

involved in steroidogenesis.

■ REGULATORY CONTROL OF

STEROIDOGENESIS

Production of glucocorticoids and adrenal

androgens is under the control of the hypothalamic-pituitary-adrenal (HPA) axis, whereas

mineralocorticoids are regulated by the

renin-angiotensin-aldosterone (RAA) system.

Glucocorticoid synthesis is under inhibitory

feedback control by the hypothalamus and the

pituitary (Fig. 386-2). Hypothalamic release of

corticotropin-releasing hormone (CRH) occurs

in response to endogenous or exogenous stress. CRH stimulates

the cleavage of the 241–amino acid polypeptide proopiomelanocortin (POMC) by pituitary-specific prohormone convertase 1 (PC1),

yielding the 39–amino acid peptide ACTH. ACTH is released by the

corticotrope cells of the anterior pituitary and acts as the pivotal regulator of adrenal cortisol synthesis, with additional short-term effects

on mineralocorticoid and adrenal androgen synthesis. The release

of CRH, and subsequently ACTH, occurs in a pulsatile fashion that

follows a circadian rhythm under the control of the hypothalamus,

specifically its suprachiasmatic nucleus (SCN), with additional regulation by a complex network of cell-specific clock genes. Reflecting

the pattern of ACTH secretion, adrenal cortisol secretion exhibits a

distinct circadian rhythm, starting to rise in the early morning hours

prior to awakening, with peak levels in the morning and low levels in

the evening (Fig. 386-3).

Diagnostic tests assessing the HPA axis make use of the fact that it

is regulated by negative feedback. Glucocorticoid excess is diagnosed

by employing a dexamethasone suppression test. Dexamethasone, a

potent synthetic glucocorticoid, suppresses CRH/ACTH by binding

hypothalamic-pituitary glucocorticoid receptors (GRs) and, therefore,

results in downregulation of endogenous cortisol synthesis. Various

versions of the dexamethasone suppression test are described in detail

in Chap. 380. If cortisol production is autonomous (e.g., adrenal nodule), ACTH is already suppressed, and dexamethasone has little additional effect. If cortisol production is driven by an ACTH-producing

pituitary adenoma, dexamethasone suppression is ineffective at low

doses but usually induces suppression at high doses. If cortisol production is driven by an ectopic source of ACTH, the tumors are usually

resistant to dexamethasone suppression. Thus, the dexamethasone

suppression test is useful to establish the diagnosis of Cushing’s syndrome and assist with the differential diagnosis of cortisol excess.

Conversely, to assess glucocorticoid deficiency, ACTH stimulation

of cortisol production is used. The ACTH peptide contains 39 amino

acids, but the first 24 are sufficient to elicit a physiologic response. The

standard ACTH stimulation test involves administration of cosyntropin

(ACTH 1-24), 0.25 mg IM or IV, and collection of blood samples at 0,

30, and 60 min for cortisol. A normal response is defined as a cortisol

level >15–20 μg/dL (>400–550 nmol/L) 30–60 min after cosyntropin

stimulation, with the precise cutoff dependent on the assay used. A

low-dose (1 μg cosyntropin IV) version of this test has been advocated;

however, it has no superior diagnostic value and is more cumbersome

to carry out. Alternatively, an insulin tolerance test (ITT) can be used

to assess adrenal function. It involves injection of insulin to induce

hypoglycemia, which represents a strong stress signal that triggers