CHAPTER 24 The Endocrine System

frequent causes of SIADH are the secretion of ectopic

ADH by malignant neoplasms (particularly small-cell
carcinoma of the lung), drugs that increase ADH secre-
tion, and a variety of central nervous system disorders,
including infections and trauma. The clinical manifesta-
tions of SIADH are dominated by hyponatremia, cere-
bral edema, and resultant neurologic dysfunction.
Although total body water is increased, blood volume
remains normal, and peripheral edema does not
develop.

Hypothalamic Suprasellar Tumors

Neoplasms in this location may induce hypofunction or
hyperfunction of the anterior pituitary, diabetes insipi-
dus, or combinations of these manifestations. The most
commonly implicated tumors are gliomas (sometimes
Figure 24-7 Adamantinomatous craniopharyngioma, demonstrating charac-
arising in the chiasm; Chapter 28) and craniopharyngiomas.
teristic compact, lamellar "wet" keratin (right half of photomicrograph) and
The craniopharyngioma is thought to arise from vestigial cords of squamous epithelium with peripheral palisading on the left. (Courtesy
remnants of Rathke pouch. These slow-growing tumors Dr. Charles Eberhart, Department of Pathology, Johns Hopkins University,
account for 1% to 5% of intracranial tumors. A small minor- Baltimore, Md .)
ity of these lesions occurs within the sella, but most are
suprasellar, with or without intrasellar extension. A
bimodal age distribution is observed, with one peak in
childhood (5 to 15 years) and a second peak in adults 65
years or older. Patients usually come to attention because
of headaches and visual disturbances, while children "reticulum" that becomes more prominent in the internal layers.
sometimes present with growth retardation due to pitu- "Palisading" of the squamous epithelium is frequently observed
itary hypofunction and GH deficiency. Abnormalities of at the periphery. Compact, lamellar keratin formation ("wet
the WNT signaling pathway, including activating mutations keratin") is a diagnostic feature of this tumor (Fig. 24-7). As
of the gene encoding ~-catenin, have been reported in mentioned earlier, dystrophic calcification is a frequent
craniopharyngiomas. finding. Additional features include cyst formation, fibrosis, and
chronic inflammation. The cysts of adamantinomatous cranio-
pharyngiomas often contain a cholesterol-rich, thick brownish-
yellow fluid that has been compared to "machine oil." These
tumors extend fingerlets of epithelium into adjacent brain, where
Craniopharyngiomas average 3 to 4 em in diameter; they they elicit a brisk glial reaction.
may be encapsulated and solid, but more commonly they are Papillary craniopharyngiomas contain both solid sheets and
cystic and sometimes multiloculated . They often encroach on papillae lined by well-differentiated squamous epithelium. These
the optic chiasm or cranial nerves, and not infrequently they tumors usually lack keratin, calcification, and cysts. The squa-
bulge into the floor of the third ventricle and base of the brain. mous cells of the solid sections of the tumor lack the peripheral
Two distinct histologic variants are recognized: adamantino- palisading and do not typically generate a spongy reticulum in
matous craniopharyngioma (most often observed in children) the internal layers.
and papillary craniopharyngioma (most often observed in Patients with craniopharyngiomas, especially those less than
adults). The adamantinomatous type frequently contains radio- 5 em in diameter, have an excellent recurrence-free and overall
logically demonstrable calcifications; the papillary variant calci- survival. Larger lesions are more invasive but this does not
fies only rarely. impact on the prognosis. Malignant transformation of cranio-
Adamantinomatous craniopharyngioma consists of nests or pharyngiomas into squamous carcinomas is exceptionally rare
cords of stratified squamous epithelium embedded in a spongy and usually occurs after irradiation.

THYROID GLAND
The thyroid gland, usually located below and anterior thyroglobulin. In response to hypothalamic factors, TSH
to the larynx, consists of two bulky lateral lobes connected (thyrotropin) is released by thyrotrophs in the anterior pitu-
by a relatively thin isthmus. The thyroid is divided by itary into the circulation. The binding of TSH to its receptor
thin fibrous septae into lobules composed of about 20 on the thyroid follicular epithelium results in activation of
to 40 evenly dispersed follicles, lined by a cuboidal to the receptor, allowing it to associate with a Gs protein (Fig.
low columnar epithelium, and filled with PAS-positive 24-8). Activation of the G protein stimulates downstream
 Thyroid gland

hormone has diverse cellular effects, including the

stimulation of carbohydrate and lipid catabolism and
protein synthesis in a wide range of cells. The net result is
an increase in the basal metabolic rate. In addition, thyroid
hormone has a critical role in brain development in the
fetus and neonate (see later).
The function of the thyroid gland can be inhibited by a
TRH variety of chemical agents, collectively referred to as goi-
trogens. Because they suppress T3 and T4 synthesis, the level
of TSH increases, and subsequent hyperplastic enlarge-
ment of the gland (goiter) follows. The antithyroid agent
propylthiouracil inhibits the oxidation of iodide and thus
blocks the production of thyroid hormones; parentheti-
cally, propylthiouracil also inhibits the peripheral deiodin-
ation of circulating T4 into T3, thus ameliorating symptoms
of thyroid hormone excess (see later). Iodide, when given
in large doses to individuals with thyroid hyperfunction,
also blocks the release of thyroid hormones by inhibiting
the proteolysis of thyroglobulin. Thus, thyroid hormone is
synthesized and incorporated into colloid, but it is not
released into the blood.
The thyroid gland follicles also contain a population of
parafollicular cells, or C cells, which synthesize and secrete
the hormone calcitonin. This hormone promotes the absorp-
tion of calcium by the skeletal system and inhibits the
resorption of bone by osteoclasts.
Diseases of the thyroid include conditions associated
Gene expression on with excessive release of thyroid hormones (hyperthyroid-
Figure 24-8 Homeostasis in the hypothalamus-pituitary-thyroid axis and ism), thyroid hormone deficiency (hypothyroidism), and
mechanism of action of thyroid hormones. Secretion of thyroid hormones (T3 mass lesions of the thyroid. We will first consider the clini-
and T4) is controlled by trophic factors secreted by both the hypothalamus cal consequences of disturbed thyroid function, and then
and the anterior pituitary. Decreased levels of T3 and T. stimulate the release turn to the disorders that generate these problems.
of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyroid-
stimulating hormone (TSH) from the anterior pituitary, causing T3 and T. levels
to rise. Elevated T3 and T. levels, in turn, feed back to suppress the secretion
of both TRH and TSH. TSH binds to the TSH receptor on the thyroid follicular Hyperthyroidism
epithelium, which causes activation of G proteins, and cAMP-mediated syn-
thesis and release of thyroid hormones (T3 and T4). In the periphery, T3 and Thyrotoxicosis is a hypermetabolic state caused by ele-
T4 interact with the thyroid hormone receptor (TR) to form a hormone- vated circulating levels of free T 3 and T4 • Because it is
receptor complex that translocates to the nucleus and binds to so-called caused most commonly by hyperfunction of the thyroid
thyroid response elements (TREs) on target genes to initiate transcription. gland, it is often referred to as hyperthyroidism. However,
in certain conditions the oversupply is related to either
excessive release of preformed thyroid hormone (e.g., in
events that result in an increase in intracellular cAMP thyroiditis) or to an extrathyroidal source, rather than
levels, which stimulates thyroid growth and thyroid hyperfunction of the gland (Table 24-3). Thus, strictly
hormone synthesis and release via cAMP-dependent speaking, hyperthyroidism is only one (albeit the most
protein kinases. common) cause of thyrotoxicosis. The terms primary and
Thyroid follicular epithelial cells convert thyroglobulin secondary hyperthyroidism are sometimes used to designate
into thyroxine (TJ and lesser amounts of triiodothyronine hyperthyroidism arising from an intrinsic thyroid abnor-
(T3). T4 and T3 are released into the systemic circulation, mality and that arising from processes outside of the
where most of these peptides are reversibly bound to cir- thyroid, such as a TSH-secreting pituitary tumor, respec-
culating plasma proteins, such as thyroxine-binding globu- tively. With this caveat, we follow the common practice of
lin and transthyretin. The binding proteins act as a buffer using the terms thyrotoxicosis and hyperthyroidism inter-
that maintains the serum unbound ("free") T3 and T4 con- changeably. The three most common causes of thyrotoxi-
centrations within narrow limits, while ensuring that the cosis are associated with hyperfunction of the gland and
hormones are readily available to the tissues. In the periph- include the following:
ery, the majority of free T4 is deiodinated to T3; the latter
binds to thyroid hormone nuclear receptors in target cells • Diffuse hyperplasia of the thyroid associated with Graves
with tenfold greater affinity than does T4 and has propor- disease (approximately 85% of cases)
tionately greater activity. Binding of thyroid hormone to • Hyperfunctional multinodular goiter
its nuclear thyroid hormone receptor (TR) results in the • Hyperfunctional thyroid adenoma
assembly of a multiprotein hormone-receptor complex
on thyroid hormone response elements (TREs) in target Clinical Course. The clinical manifestations of hyperthy-
genes, up regulating their transcription (Fig. 24-8). Thyroid roidism are protean and include changes referable to the
 CHAPTER 24 The Endocrine System

Table 24-3 Disorders Associated with Thyrotoxicosis ophthalmopathy associated with proptosis occurs only in
Associated with Hyperthyroidism Graves disease (see later).
• The skeletal system is also affected. Thyroid hormone
Primary
stimulates bone resorption, increasing porosity of corti-
Diffuse hyperplasia (Graves disease) cal bone and reducing the volume of trabecular bone.
Hyperfunctioning ("toxic") multinodular goiter
Hyperfunctioning ("toxic") adenoma
The net effect is osteoporosis and an increased risk of
Iodine-induced hyperthyroidism fractures in patients with chronic hyperthyroidism.
Neonatal thyrotoxicosis associated with maternal Graves disease Other findings include atrophy of skeletal muscle, with
fatty infiltration and focal interstitial lymphocytic infil-
Secondary
trates; minimal liver enlargement due to fatty changes
TSH-secreting pituitary adenoma (rare)* in the hepatocytes; and generalized lymphoid hyperpla-
Not Associated with Hyperthyroidism sia and lymphadenopathy in patients with Graves
Granulomatous (de Quervain) thyroiditis (painfu~ disease.
Subacute lymphocytic thyroiditis (painless) • Thyroid storm refers to the abrupt onset of severe hyper-
Struma ovarii (ovarian teratoma with ectopic thyroid) thyroidism. This condition occurs most commonly in
Factitious thyrotoxicosis (exogenous thyroxine intake) patients with underlying Graves disease and probably
·Associated with increased thyroid-stimulating hormone (TSH); all other causes of thyrotoxicosis results from an acute elevation in catecholamine levels,
associated with decreased TSH. as might be encountered during infection, surgery, ces-
sation of antithyroid medication, or any form of stress.
Patients are often febrile and present with tachycardia
out of proportion to the fever. Thyroid storm is a medical
emergency. A significant number of untreated patients
hypermetabolic state induced by excess thyroid hormone and die of cardiac arrhythmias.
to overactivity of the sympathetic nervous system (i.e., an • Apathetic hyperthyroidism refers to thyrotoxicosis occur-
increase in the ~-adrenergic "tone") . ring in older adults, in whom advanced age and various
• Excessive levels of thyroid hormone result in an increase co-morbidities may blunt the features of thyroid
in the basal metabolic rate. The skin of thyrotoxic patients hormone excess that typically bring younger patients to
tends to be soft, warm, and flushed because of increased attention. The diagnosis of thyrotoxicosis in these indi-
blood flow and peripheral vasodilation, adaptations viduals is often made during laboratory work-up for
that serve to increase heat loss. Heat intolerance is unexplained weight loss or worsening cardiovascular
common. Sweating is increased because of higher disease.
levels of calorigenesis. Heightened catabolic metabo- A diagnosis of hyperthyroidism is made using both
lism results in weight loss despite increased appetite. clinical and laboratory findings. The measurement of
• Cardiac manifestations are among the earliest and most con- serum TSH concentration is the most useful single
sistent features. Individuals with hyperthyroidism can screening test for hyperthyroidism, because its levels are
have elevated cardiac contractility and cardiac output, decreased even at the earliest stages, when the disease
in response to increased peripheral oxygen require- may still be subclinical. A low TSH value is usually con-
ments. Tachycardia, palpitations, and cardiomegaly are firmed with measurement of free T4, which is predictably
common. Arrhythmias, particularly atrial fibrillation, increased. In occasional patients, hyperthyroidism results
occur frequently and are more common in older
patients. Congestive heart failure may develop, espe-
cially in older patients with preexisting cardiac disease.
Myocardial changes, such as focal lymphocytic and
eosinophilic infiltrates, mild fibrosis, myofibril fatty
change, and an increase in size and number of mito-
chondria, have been described. Some individuals with
thyrotoxicosis develop reversible left ventricular dysfunc-
tion and "low-output" heart failure, so-called thyrotoxic
or hyperthyroid cardiomyopathy.
• Overactivity of the sympathetic nervous system produces
tremor, hyperactivity, emotional lability, anxiety, inabil-
ity to concentrate, and insomnia. Proximal muscle
weakness and decreased muscle mass are common
(thyroid myopathy). In the gastrointestinal system, sympa-
thetic hyperstimulation of the gut results in hypermotil-
ity, diarrhea, and malabsorption.
• Ocular changes often call attention to hyperthyroidism.
A wide, staring gaze and lid lag are present because of
Figure 24-9 A person with hyperthyroidism. A wide-eyed, staring gaze,
sympathetic overstimulation of the superior tarsal caused by overactivity of the sympathetic nervous system, is one of the
muscle (also known as Muller's muscle), which functions features of this disorder. In Graves disease, one of the most important causes
alongside the levator palpebrae superioris muscle to of hyperthyroidism, accumulation of loose connective tissue behind the eye-
raise the upper eyelid (Fig. 24-9). However, true thyroid balls, also adds to the protuberant appearance of the eyes.
 Thyroid gland

predominantly from increased circulating levels of T3 ("T3 Table 24-4 Causes of Hypothyroidism
toxicosis"). In these cases, free T4 levels may be decreased, Primary
and direct measurement of serum T3 may be useful. In rare
Genetic defects in thyroid development (PAXB, FOXE1, TSH receptor
cases of pituitary-associated (secondary) hyperthyroidism, mutations) (rare)
TSH levels are either normal or raised. Determining TSH Thyroid hormone resistance syndrome (THRB mutations) (rare)
levels after the injection of thyrotropin-releasing hormone Postablative
(TRH stimulation test) is used in the evaluation of cases of Surgery, radioiodine therapy, or external irradiation
suspected h yperthyroidism with equivocal changes in the Autoimmune hypothyroidism
baseline serum TSH level. A normal rise in TSH after Hashimoto thyroiditis*
administration of TRH excludes secondary hyperthyroid- Iodine deficiency*
Drugs (lithium, iodides, p-aminosalicylic acid)*
ism. Once the diagnosis of thyrotoxicosis has been con- Congenital biosynthetic defect (dyshormonogenetic goiter) (rare) *
firmed by a combination of TSH assays and free thyroid
hormone levels, measurement of radioactive iodine uptake Secondary (Central)
by the thyroid gland can help to determine the etiology. Pituitary failure (rare)
For example, there may be diffusely increased uptake in Hypothalamic failure (rare)
the whole gland (Graves disease), increased uptake in a "Associated with enlargement of thyroid ("goitrous hypothyroidism"). Hashimoto thyroiditis and
solitary nodule (toxic adenoma), or decreased uptake postablative hypothyroidism account for the majority of cases of hypothyroidism in developed
countries. FOXE1, forkhead box E1; PAXB, paired box 8; THRB, thyroid hormone receptor ~·
(thyroiditis) .
The therapeutic options for hyperthyroidism include
several medications, each with a different mechanism of
action. Typically, these include a ~-blocker to control
symptoms induced by increased adrenergic tone, a thion- parenchyma (thyroid agenesis), or the gland may be greatly
amide to block new hormone synthesis, an iodine solution reduced in size (thyroid hypoplasia) due to germline muta-
to block the release of thyroid hormone, and agents that tions in genes responsible for thyroid development
inhibit peripheral conversion of T4 to T3 . Radioiodine, (Table 24-4).
which is incorporated into thyroid tissues, resulting in
ablation of thyroid function over a period of 6 to 18 weeks, Autoimmune hypothyroidism. Autoimmune hypothy-
may also be used. roidism is the most common cause of hypothyroidism in
iodine-sufficient areas of the world. The vast majority of
cases of autoimmune hypothyroidism are due to Hashimoto
Hypothyroidism thyroiditis. Circulating autoantibodies, including anti-
microsomal, antithyroid peroxidase, and anti thyroglobulin anti-
Hypothyroidism is a condition caused by a structural or bodies, are found in this disorder, and the thyroid is
functional derangement that interferes with the produc- typically enlarged (goitrous). Autoimmune hypothyroid-
tion of thyroid hormone. Hypothyroidism is a fairly ism can occur in isolation or in conjunction with autoim-
common disorder. By some estimates the population prev- mune polyendocrine syndrome (APS), types 1 and 2 (see
alence of overt hypothyroidism is 0.3 %, while subclinical discussion in "Adrenal Glands").
hypothyroidism can be found in greater than 4%. The prev-
alence increases with age, and it is nearly tenfold more Iatrogenic hypothyroidism. This can be caused by either
common in women than in men. It can result from a defect surgical or radiation-induced ablation. A large resection of the
anywhere in the hypothalamic-pituitary-thyroid axis. As gland (total thyroidectomy) for the treatment of hyperthy-
in the case of hyperthyroidism, this disorder is divided into roidism or a primary neoplasm can lead to hypothyroid-
primary and secondary forms, depending on whether the ism. The gland may also be ablated by radiation, whether
hypothyroidism arises from an intrinsic abnormality in the in the form of radioiodine administered for the treatment
thyroid itself, or occurs as a result of pituitary and hypo- of hyperthyroidism, or exogenous irradiation, such as
thalamic disease (Table 24-4). Primary hypothyroidism external radiation therapy to the neck. Drugs given inten-
accounts for the vast majority of cases, and may be accom- tionally to decrease thyroid secretion (e.g., methimazole
panied by an enlargement in the size of the thyroid gland and propylthiouracil) can also cause acquired hypothy-
(goiter). roidism, as can agents used to treat nonthyroid conditions
Primary hypothyroidism can be congenital, autoim- (e.g., lithium, p-aminosalicylic acid).
mune, or iatrogenic. Secondary (or central) hypothyroidism is caused by
deficiencies of TSH or, far more uncommonly, TRH. Any
Congenital hypothyroidism. Worldwide, congenital hy- of the causes of hypopituitarism (for example, pituitary
pothyroidism is most often the result of endemic iodine tumor, postpartum pituitary necrosis, trauma, and nonpi-
deficiency in the diet (see later). Other rare forms of con- tuitary tumors), or of hypothalamic damage from tumors,
genital hypothyroidism include inborn errors of thyroid me- trauma, radiation therapy, or infiltrative diseases can cause
tabolism (dyshormonogenetic goiter), wherein any one of the central hypothyroidism.
multiple steps leading to thyroid hormone synthesis may
be defective, such as (1) iodide transport into thyrocytes, Cretinism
(2) " organification" of iodine (binding of iodine to tyrosine
residues of the storage protein, thyroglobulin), and (3) io- Cretinism refers to hypothyroidism that develops in
dotyrosine coupling to form hormonally active T3 and T4 . infancy or early childhood. The term cretin was de-
In rare instances there may be complete absence of thyroid rived from the French chretien, meaning "Christian" or
 C H A P T E R 24 The Endocrine System

"Christlike," and was applied to these unfortunates because nature of symptoms. Patients with unexplained increases
they were considered to be so mentally retarded as to be in body weight or hypercholesterolemia should be assessed
incapable of sinning. In the past this disorder occurred for potential hypothyroidism. Measurement of the serum
fairly commonly in regions of the world where dietary TSH level is the most sensitive screening test for this
iodine deficiency is endemic, such as the Himalayas, inland disorder. The TSH level is increased in primary hypothy-
China, Africa, and other mountainous areas. It is now roidism as a result of a loss of feedback inhibition of TRH
much less prevalent as a result of the widespread supple- and TSH production by the hypothalamus and pituitary,
mentation of foods with iodine. On rare occasions, cretin- respectively. The TSH level is not increased in persons with
ism may also result from genetic defects that interfere with hypothyroidism due to primary hypothalamic or pituitary
the biosynthesis of thyroid hormone (dyshormonogenetic disease. T4 levels are decreased in individuals with hypo-
goiter, see earlier). thyroidism of any origin.
Clinical features of cretinism include impaired develop-
ment of the skeletal system and central nervous system,
manifested by severe mental retardation, short stature, Thyroiditis
coarse facial features, a protruding tongue, and umbilical
hernia. The severity of the mental impairment seems to be Thyroiditis, or inflammation of the thyroid gland, encom-
related to the time at which thyroid deficiency occurs in passes a diverse group of disorders characterized by some
utero. Normally, maternal T3 and T4 cross the placenta and form of thyroid inflammation.
are critical for fetal brain development. If there is maternal Although multiple entities exist under the diagnostic
thyroid deficiency before the development of the fetal umbrella of "thyroiditis," this discussion focuses on the
thyroid gland, mental retardation is severe. In contrast, three most common and clinically significant subtypes: (1)
maternal thyroid hormone deficiency later in pregnancy, Hashimoto thyroiditis, (2) granulomatous (de Quervain)
after the fetal thyroid has become functional, does not thyroiditis, and (3) subacute lymphocytic thyroiditis.
affect normal brain development.
Hashimoto Thyroiditis
Myxedema
Hashimoto thyroiditis is an autoimmune disease that
The term myxedema is applied to hypothyroidism devel- results in destruction of the thyroid gland and gradual
oping in the older child or adult. Myxedema was first and progressive thyroid failure. It is the most common
linked with thyroid dysfunction in 1873 by Sir William cause of hypothyroidism in areas of the world where
Gull in an article addressing the development of a "cretin- iodine levels are sufficient. The name is derived from the
oid state" in adults. The clinical manifestations vary with 1912 report by Hashimoto describing patients with goiter
the age of onset of the deficiency. Older children show and intense lymphocytic infiltration of the thyroid (struma
signs and symptoms intermediate between those of the lymphomatosa) . It is most prevalent between 45 and 65 years
cretin and those of the adult with hypothyroidism. In the of age and is more common in women than in men, with
adult the condition appears insidiously and may take years a female predominance of 10:1 to 20:1. It can also occur in
before arousing clinical suspicion. children and is a major cause of nonendemic goiter in the
Myxedema is marked by a slowing of physical and pediatric population.
mental activity. The initial symptoms include generalized
fatigue, apathy, and mental sluggishness, which may Pathogenesis. Hashimoto thyroiditis is caused by a
mimic depression. Speech and intellectual functions are breakdown in self-tolerance to thyroid autoantigens. This
slowed. Patients with myxedema are listless, cold intoler- is exemplified by the presence of circulating autoantibod-
ant, and frequently overweight. Decreased sympathetic ies against thyroglobulin and thyroid peroxidase in the
activity results in constipation and decreased sweating. vast majority of Hashimoto patients. The inciting events
The skin is cool and pale because of decreased blood flow . have not been elucidated, but possibilities include abnor-
Reduced cardiac output probably contributes to shortness malities of regulatory T cells (Tregs), or exposure of nor-
of breath and decreased exercise capacity, two frequent mally sequestered thyroid antigens (Chapter 6). Similar
complaints. Thyroid hormones regulate the transcription to other autoimmune diseases, Hashimoto thyroiditis
of several sarcolemmal genes, such as calcium ATPases has a strong genetic component. Increased susceptibility to
and the ~ adrenergic receptor, and lowered expression of Hashimoto thyroiditis is associated with polymorphisms
these genes results in a decrease in cardiac output. In addi- in immune regulation-associated genes, including cytotoxic
tion, hypothyroidism promotes an atherogenic profile-an T lymphocyte-associated antigen-4 (CTLA4) and protein
increase in total cholesterol and low-density lipoprotein tyrosine phosphatase-22 (PTPN22), both of which code for
(LDL) levels-that probably contributes to the increased regulators ofT-cell responses. Susceptibility to other auto-
cardiovascular mortality in this disease. Histologically, immune diseases, such as type 1 diabetes (see later), is also
there is an accumulation of matrix substances, such as gly- associated with polymorphisms in both CTLA4 and
cosarninoglycans and hyaluronic acid, in skin, subcutane- PTPN22 .
ous tissue, and a number of visceral sites. This results in Induction of thyroid autoimmunity is accompanied by
nonpitting edema, a broadening and coarsening of facial a progressive depletion of thyroid epithelial cells by apop-
features, enlargement of the tongue, and deepening of tosis and replacement of the thyroid parenchyma by mono-
the voice. nuclear cell infiltration and fibrosis. Multiple immunologic
Laboratory evaluation plays a vital role in the diagnosis mechanisms may contribute to thyroid cell death, includ-
of suspected hypothyroidism because of the nonspecific ing (Fig. 24-10):
 Thyroid gland

Thyroid ~
epithelium l_l_l_l__L_j
~
Breakdown in self tolerance and
induction of thyroid autoimmunity

~! ~
CDB+
cytotoxic
CD4+
T 1 cell
H
(IJ
T-cell y-IFN I
Fas • +
Fas

Antibody-dependent
cell-mediated cytotoxicity

Figure 24-10 Pathogenesis of Hashimoto thyroiditis. Breakdown of peripheral tolerance to thyroid autoantigens, results in progressive autoimmune destruction
of thyroid cells by infiltrating cytotoxic T cells, locally released cytokines, or by antibody-dependent cytotoxicity.

• CDS+ cytotoxic T cell-mediated cell death: CDS+ cytotoxic Clinical Course. Hashimoto thyroiditis most often comes
T cells may destroy thyroid follicular cells. to clinical attention as painless enlargement of the thyroid,
• Cytokine-mediated cell death: Activation of CD4+ T cells usually associated with some degree of hypothyroidism, in
leads to the production of inflammatory cytokines such a middle-aged woman. The enlargement of the gland is
as interferon-y in the thyroid gland, with resultant usually symmetric and diffuse, but in some cases it may be
recruitment and activation of macrophages and damage sufficiently localized to raise the suspicion of a neoplasm.
to follicles. In the usual case, hypothyroidism develops gradually. In
• A less likely mechanism involves binding of antithyroid some patients, however, it may be preceded by transient
antibodies (antithyroglobulin, and antithyroid peroxi- thyrotoxicosis caused by disruption of thyroid follicles,
dase antibodies) followed by antibody-dependent cell- leading to release of thyroid hormones ("hashitoxicosis").
mediated cytotoxicity (Chapter 6). During this phase, free T4 and T3 levels are elevated, TSH
is diminished, and radioactive iodine uptake is decreased.
As hypothyroidism supervenes, T4 and T3 levels fall,
accompanied by a compensatory increase in TSH.
Individuals with Hashimoto thyroiditis are at increased
risk for developing other autoimmune diseases, both
MORPHOLOGY
The thyroid is often diffusely enlarged, although more localized
enlargement may be seen in some cases. The capsule is intact ,
and the gland is well demarcated from adjacent structures. The
cut surface is pale , yellow-tan , firm , and somewhat nodular.
There is extensive infiltration of the parenchyma by a mono-
nuclear inflammatory infiltrate containing small lympho-
cytes, plasma cells, and well-developed germinal centers (Fig.
24-11 ). The thyroid follicles are atrophic and are lined in many
areas by epithelial cells distinguished by the presence of abun-
dant eosinophilic, granular cytoplasm, termed Hurthle cells.
This is a metaplastic response of the normally low cuboidal
follicular epithelium to ongoing injury. In fine-needle aspiration
biopsy samples, the presence of Hi.lrthle cells in conjunction
with a heterogeneous population of lymphocytes is character-
istic of Hashimoto thyroiditis. In "classic" Hashimoto thyroiditis,
interstitial connective tissue is increased and may be abundant.
Unlike Reidel thyroiditis (see later), the fibrosis does not extend Figure 24-11 Hashimoto thyroiditis. The thyroid parenchyma contains a
beyond the capsule of the gland. dense lymphocytic infiltrate with germinal centers. Residual thyroid follicles
lined by deeply eosinophilic Hurthle cells are also seen.
 C H A PT E R 24 The Endocrine System

endocrine (type 1 diabetes, autoimmune adrenalitis) and

nonendocrine (systemic lupus erythematosus, myasthenia
gravis, and Sjogren syndrome; Chapter 6). They are also at
increased risk for the development of extranodal marginal
zone B-celllymphomas within the thyroid gland (Chapter
13). The relationship between Hashimoto disease and
thyroid epithelial cancers remains controversial, with some
morphologic and molecular studies suggesting a predispo-
sition to papillary carcinomas.

Subacute Lymphocytic (Painless) Thyroiditis

Subacute lymphocytic thyroiditis, which is also referred to as
painless thyroiditis, usually comes to clinical attention
because of mild hyperthyroidism, goitrous enlargement of
the gland, or both. Although it can occur at any age, it is
most often seen in middle-aged adults and is more common Figure 24-12 Granulomatous thyroiditis. The thyroid parenchyma contains a
in women. A disease process resembling painless thyroid- chronic inflammatory infiltrate with a multinucleate giant cell (above left) and
a colloid follicle (bottom right}.
itis can occur during the postpartum period in up to 5% of
women (postpartum thyroiditis). Painless and postpartum
thyroiditides are variants of autoimmune thyroiditis. Most thyroid follicular cells. In contrast to autoimmune thyroid
of the patients have circulating antithyroid peroxidase disease, the immune response is virus-initiated and not
antibodies or a family history of other autoimmune disor- self-perpetuating, so the process is limited.
ders. As many as a third of cases can evolve into overt
hypothyroidism over time, and the thyroid histology may
resemble Hashimoto thyroiditis.
The gland may be unilaterally or bilaterally enlarged and firm,
with an intact capsule that may adhere to surrounding struc-
tures. On cut section, the involved areas are firm and yellow-
Except for possible mild symmetric enlargement, the thyroid
white and stand out from the more rubbery, normal brown
appears grossly normal. Microscopic examination reveals lym-
thyroid substance. Histologic changes are patchy and depend
phocytic infiltration with large germinal centers within the thyroid
on the stage of the disease. Early in the active inflammatory
parenchyma and patchy disruption and collapse of thyroid
phase, scattered follicles may be disrupted and replaced by
follicles. Unlike Hashimoto thyroiditis, however, fibrosis and
neutrophils forming microabscesses. Later, more characteristic
Hi.lrthle cell metaplasia are not prominent.
features appear in the form of aggregates of lymphocytes,
activated macrophages, and plasma cells associated with col-
Clinical Course. Affected individuals may present with a lapsed and damaged thyroid follicles. Multinucleate giant
painless goiter, transient overt hyperthyroidism, or both. cells enclose naked pools or fragments of colloid (Fig. 24-12),
Some patients transition from hyperthyroidism to hypo- hence the designation granulomatous thyroiditis. In later
thyroidism before recovery. As stated, as many as a third stages of the disease a chronic inflammatory infiltrate and fibro-
of affected individuals eventually progress to overt hypo- sis may replace the foci of injury. Different histologic stages are
thyroidism over a 10-year period. sometimes found in the same gland, suggesting waves of
destruction over a period of time.
Granulomatous Thyroiditis
Granulomatous thyroiditis (also called De Quervain thyroid- Clinical Course. Granulomatous thyroiditis is the most
itis) occurs much less frequently than does Hashimoto common cause of thyroid pain. There is a variable enlarge-
disease. The disorder is most common between the ages of ment of the thyroid. Inflammation of the thyroid and
40 and 50 and, like other forms of thyroiditis, affects women hyperthyroidism are transient, usually diminishing in 2 to
considerably more often than men (4:1). 6 weeks, even if the patient is not treated. Nearly all patients
have high serum T4 and T3 levels and low serum TSH levels
Pathogenesis. Granulomatous thyroiditis is believed to be during this phase. However, unlike in hyperthyroid states
triggered by a viral infection. The majority of patients have such as Graves disease, radioactive iodine uptake is dimin-
a history of an upper respiratory infection just before the ished. After recovery, generally in 6 to 8 weeks, normal
onset of thyroiditis. The disease has a seasonal incidence, thyroid function returns.
with occurrences peaking in the summer, and clusters of
cases have been reported in association with coxsackievi- Other, less common forms of thyroiditis include Riedel
rus, mumps, measles, adenovirus, and other viral infec- thyroiditis, a rare disorder characterized by extensive fibro-
tions. Although the pathogenesis of the disease is unclear, sis involving the thyroid and contiguous neck structures.
one model suggests that it results from a viral infection that The presence of a hard and fixed thyroid mass clinically
leads to exposure to a viral or thyroid antigen secondary simulates a thyroid carcinoma. It may be associated
to virus-induced host tissue damage. This antigen stimu- with fibrosis in other sites in the body, such as the retro-
lates cytotoxic T lymphocytes, which then damage peritoneum, and appears to be another manifestation of a
 Thyroid gland

systemic autoimmune IgG4-related disease, which is asso- autoimmune thyroid disorders, and not surprisingly share
ciated with fibrosis and tissue infiltration by plasma cells many underlying features . For example, as with Hashimoto
producing IgG4 (Chapter 6). thyroiditis, genetic factors are important in the etiology

ill KEY CONCEPTS

of Graves disease. The concordance rate in monozygotic
twins is 30% to 40 %, compared with less than 5% among
dizygotic twins, and like Hashimoto thyroiditis, genetic
Thyroiditis susceptibility is linked to polymorphisms in immune-
• Hashimoto thyroiditis is the most common cause of hypo- function genes like CTLA4 and PTPN22 and the HLA-DR3
thyroidism in regions where dietary iodine levels are allele.
sufficient. Autoimmunity also plays a role in the development
• Hashimoto thyroiditis is an autoimmune thyroiditis charac- of the infiltrative ophthalmopathy that is characteristic of
terized by progressive destruction of thyroid parenchyma, Graves disease. In Graves ophthalmopathy, the protrusion
Hurthle cell change, and mononuclear (lymphoplasma- of the eyeball (exopthalmos) is associated with increased
cytic) infiltrates, with germinal centers and with or without volume of the retroorbital connective tissues and extraocu-
extensive fibrosis . lar muscles, for several reasons. These include (1) marked
• Subacute lymphocytic thyroiditis often occurs after a preg- infiltration of the retroorbital space by mononuclear cells,
nancy (postpartum thyroiditis), typically is painless, and is predominantly T cells; (2) inflammation with edema and
characterized by lymphocytic inflammation in the thyroid. swelling of extraocular muscles; (3) accumulation of extra-
It is also a type of autoimmune thyroiditis. cellular matrix components, specifically hydrophilic gly-
• Granulomatous (de Quervain) thyroiditis is a self-limited cosaminoglycans such as hyaluronic acid and chondroitin
disease, probably secondary to a viral infection, and is sulfate; and (4) increased numbers of adipocytes (fatty
characterized by pain and the presence of a granuloma- infiltration). These changes displace the eyeball forward
tous inflammation in the thyroid . and can interfere with the function of the extraocular
muscles. Studies performed in animal models suggest
that orbital preadipocyte fibroblasts, which express the
TSH receptor, appear to stimulate the autoimmune reac-
Graves Disease tion. Activated CD4+ helper T cells secrete cytokines that
stimulate fibroblast proliferation and synthesis of extra-
Graves disease is the most common cause of endogenous cellular matrix proteins (glycosaminoglycans), leading to
hyperthyroidism. Graves reported in 1835 his observa- progressive infiltration of the retroorbital space and
tions of a disease characterized by "violent and long con- ophthalmopathy.
tinued palpitations in females" associated with enlargement
of the thyroid gland. The disease is characterized by a triad
of clinical findings :
• Hyperthyroidism associated with diffuse enlargement of
the gland The thyroid gland is usually symmetrically enlarged due to
• Infiltrative ophthalmopathy with resultant exophthalmos diffuse hypertrophy and hyperplasia of thyroid follicular epi-
• Localized, infiltrative dermopathy, sometimes called pre- thelial cells (Fig. 24-13A). Increases in weight to over 80 gm are
tibial myxedema, which is present in a minority of patients not uncommon. On cut section, the parenchyma has a soft,
meaty appearance resembling muscle. Histologically, the fol-
Graves disease has a peak incidence between 20 and 40
licular epithelial cells in untreated cases are tall and more
years of age. Women are affected as much as 10 times more
crowded than usual. This crowding often results in the forma-
frequently than men. This disorder is said to affect 1.5% to
tion of small papillae, which project into the follicular lumen and
2 % of women in the United States.
encroach on the colloid, sometimes filling the follicles (Fig .
24-138). Such papillae lack fibrovascular cores, in contrast to
Pathogenesis. Graves disease is an autoimmune disorder
those of papillary carcinoma (see later). The colloid within the
characterized by the production of autoantibodies against
follicular lumen is pale, with scalloped margins. Lymphoid infil-
multiple thyroid proteins, most importantly the TSH
trates, consisting predominantly ofT cells, along with scattered
receptor. A variety of antibodies that can either stimulate
B cells and mature plasma cells, are present throughout the
or block the TSH receptor are detected in the circulation.
interstitium. Germinal centers are common.
The most common antibody subtype, known as thyroid-
Preoperative therapy alters the morphology of the thyroid in
stimulating immunoglobulin (TSI), is observed in approxi-
Graves disease. Administration of iodine causes involution of
mately 90 % of patients with Graves disease. In contrast to
the epithelium and the accumulation of colloid by blocking
antibodies reactive with thyroglobulin and thyroid peroxi-
thyroglobulin secretion. Treatment with the antithyroid drug pro-
dase, TSI is almost never observed in other autoimmune
pylthiouracil exaggerates the epithelial hypertrophy and hyper-
diseases of the thyroid. TSI binds to the TSH receptor and
plasia by stimulating TSH secretion.
mimics its actions, stimulating adenyl cyclase and increas-
Changes in extrathyroidal tissue include lymphoid hyperpla-
ing the release of thyroid hormones. As stated, some
sia, especially enlargement of the thymus in younger patients.
patients also have TSH receptor blocking antibodies in the
The heart may be hypertrophied, and ischemic changes may
circulation, and in a minority of patients these may lead to
be present, particularly in patients with preexisting coronary
hypothyroidism.
artery disease. In patients with ophthalmopathy, the tissues of
Graves disease (hyperthyroidism) and Hashimoto thy-
the orbit are edematous because of the presence of hydrophilic
roiditis (hypothyroidism) represent two extremes of
 CHAPTER 24 The Endocrine System

Figure 24-13 Graves disease. A, There is diffuse symmetric enlargement of the gland and a beefy deep red parenchyma. Compare w ith gross photograph of
multinodular goiter in Figure 24-15. B, Diffusely hyperplastic thyroid in a case of Graves disease. The follicles are lined by tall, columnar epithelium. The crowded,
enlarged epithelial cells project into the lumens of the follicles. These cells actively resorb the colloid in the centers of the follicles, resulting in the scalloped
appearance of the edges of the colloid. (A, Reproduced with permission from Lloyd RV, et al (eds): Atlas of Nontumor Pathology: Endocrine Diseases.
Washington, DC, American Registry of Pathology, 2002.)

propylthiouracil), radioiodine ablation, and thyroidec-

mucopolysaccharides. In addition , there is infiltration by lym-
tomy. Surgery is used mostly in patients who have large
phocytes and fibrosis. Orbital muscles are edematous initially
goiters that are compressing surrounding structures.
but may undergo fibrosis late in the course of the disease. The
dermopathy, if present, is characterized by thickening of the
dermis due to deposition of glycosaminoglycans and lympho- KEY CONCEPTS
cyte infiltration. Graves Disease
• Graves disease, the most common cause of endogenous
Clinical Course. The clinical findings in Graves disease hyperthyroidism, is characterized by the triad of thyrotoxi-
include some changes associated with thyrotoxicosis and cosis, ophthalmopathy, and dermopathy.
others associated uniquely with Graves disease, such as • Graves disease is an autoimmune disorder caused by acti-
diffuse hyperplasia of the thyroid, ophthalmopathy, and der- vation of thyroid epithelial cells by autoantibodies to the
mopathy. The degree of thyrotoxicosis varies from case to TSH receptor that mimic TSH action (thyroid-stimulating
case and is sometimes less conspicuous than other mani- immunoglobulins).
festations of the disease. Diffuse enlargement of the thyroid • The thyroid in Graves disease is characterized by diffuse
is present in all cases. The thyroid enlargement may be hypertrophy and hyperplasia of follicles and lymphoid infil-
accompanied by increased flow of blood through the trates; glycosaminoglycan deposition and lymphoid infil-
hyperactive gland, often producing an audible "bruit." trates are responsible for the ophthalmopathy and
Sympathetic overactivity produces a characteristic wide, dermopathy.
staring gaze and lid lag. The ophthalmopathy of Graves • Laboratory features include elevations in serum free T3 and
disease results in abnormal protrusion of the eyeball T4 and decreased serum TSH.
(exophthalmos). The extraocular muscles are often weak.
The exophthalmos may persist or progress despite success-
ful treatment of the thyrotoxicosis, sometimes resulting in
corneal injury. The infiltrative dermopathy, or pretibial Diffuse and Multinodular Goiters
myxedema, is most common in the skin overlying the shins,
where it presents as scaly thickening and induration. The Enlargement of the thyroid, or goiter is caused by
basis of such localization is not clear, and it is present only impaired synthesis of thyroid hormone, which is most
in a minority of patients. Sometimes individuals spontane- often the result of dietary iodine deficiency. Impairment
ously develop thyroid hypofunction. Patients are at of thyroid hormone synthesis leads to a compensatory rise
increased risk for other autoimmune diseases, such as sys- in the serum TSH level, which, in turn, causes hypertrophy
temic lupus erythematosus, pernicious anemia, type 1 dia- and hyperplasia of thyroid follicular cells and, ultimately,
betes, and Addison disease. gross enlargement of the thyroid gland. The compensatory
Laboratory findings in Graves disease include elevated increase in functional mass of the gland overcomes the
free T4 and T3 levels and depressed TSH levels. Because of hormone deficiency, ensuring a euthyroid metabolic state in
ongoing stimulation of the thyroid follicles by thyroid- most individuals. If the underlying disorder is sufficiently
stimulating immunoglobulins, radioiodine scans show a severe (e.g., a congenital biosynthetic defect or endemic
diffusely increased uptake of iodine. iodine deficiency, discussed later), the compensatory
Graves disease is treated with ~-blockers, which address responses may be inadequate, resulting in goitrous hypothy-
symptoms related to the increased ~-adrenergic tone (e.g., roidism. The degree of thyroid enlargement is proportional
tachycardia, palpitations, tremulousness, and anxiety), and to the level and duration of thyroid hormone deficiency.
by measures aimed at decreasing thyroid hormone syn- Goiters can broadly be divided into two types: diffuse non-
thesis, such as the administration of thionamides (e.g., toxic and multinodular.
 Thyroid gland

Diffuse Nontoxic (Simple) Goiter

Diffuse nontoxic (simple) goiter causes enlargement of
the entire gland without producing nodularity. Because
the enlarged follicles are filled with colloid, the term colloid
goiter has been applied to this condition. This disorder
occurs in both an endemic and a sporadic distribution.
• Endemic goiter occurs in geographic areas where the soil,
water, and food supply contain low levels of iodine. The
term endemic is used when goiters are present in more
than 10% of the population in a given region. Such con-
ditions are particularly common in mountainous areas
of the world, including the Andes and Himalayas,
where iodine deficiency is widespread. The lack of
iodine leads to decreased synthesis of thyroid hormone
and a compensatory increase in TSH, leading to follicu-
lar cell hypertrophy and hyperplasia and goitrous
enlargement. With increasing dietary iodine supple-
mentation, the frequency and severity of endemic goiter
have declined significantly, although as many as 200
million people worldwide continue to be at risk for
severe iodine deficiency.
Variations in the prevalence of endemic goiter in
regions with similar levels of iodine deficiency point to Figure 24-14 A 52-year-old woman with a huge colloid goiter who developed
the existence of other causative influences, particularly compressive symptoms. (Reproduced w ith permission from Lloyd RV, et al
dietary substances, referred to as goitrogens. The inges- (eds): Atlas of Nontumor Pathology: Endocrine Diseases. Washington, DC,
tion of substances that interfere with thyroid hormone American Registry of Pathology, 2002.)
synthesis at some level, such as vegetables belonging
to the Brassicaceae (Cruciferae) family (e.g., cabbage,
cauliflower, Brussels sprouts, turnips, and cassava), has goiter). In these cases the cut surface of the thyroid is usually
been documented to be goitrogenic. Native populations brown, somewhat glassy, and translucent. Histologically the
subsisting on cassava root are particularly at risk. follicular epithelium is flattened and cuboidal, and colloid is
Cassava contains a thiocyanate that inhibits iodide abundant during periods of involution.
transport within the thyroid, worsening any possible
concurrent iodine deficiency.
• Sporadic goiter occurs less frequently than does endemic Clinical Course. As stated earlier, the vast majority of
goiter. There is a striking female preponderance and a persons with simple goiters are clinically euthyroid.
peak incidence at puberty or in young adult life. Sporadic Therefore, the clinical manifestations are primarily related
goiter can be caused by several conditions, including to mass effects from the enlarged thyroid gland (Fig. 24-14).
the ingestion of substances that interfere with thyroid Although serum T3 and T4 levels are normal, the serum
hormone synthesis. In other instances, goiter may result TSH is usually elevated or at the upper range of normal,
from hereditary enzymatic defects that interfere with as is expected in marginally euthyroid individuals. In chil-
thyroid hormone synthesis, all transmitted as autosomal- dren, dyshormonogenetic goiter, caused by a congenital
recessive conditions (dyshormonogenetic goiter; see biosynthetic defect, may induce cretinism.
earlier). In most cases, however, the cause of sporadic
goiter is not apparent. Multinodular Goiter
With time, recurrent episodes of hyperplasia and involu-
tion combine to produce a more irregular enlargement of
the thyroid, termed multinodular goiter. Virtually all long-
Two phases can be identified in the evolution of diffuse nontoxic
standing simple goiters convert into multinodular goiters.
goiter: the hyperplastic phase and the phase of colloid invo-
Multinodular goiters produce the most extreme thyroid
lution. In the hyperplastic phase, the thyroid gland is diffusely
enlargements and are more frequently mistaken for neo-
and symmetrically enlarged, although the increase is usually
plasms than any other form of thyroid disease. Because
modest, and the gland rarely exceeds 100 to 150 gm. The fol-
they derive from simple goiter, they occur in both sporadic
licles are lined by crowded columnar cells, which may pile up
and endemic forms, having the same female-to-male dis-
tribution and presumably the same origins but affecting
and form projections similar to those seen in Graves disease.
The accumulation is not uniform throughout the gland, and
older individuals because they are late complications.
some follicles are hugely distended, whereas others remain
It is believed that multinodular goiters arise because of
small. If dietary iodine subsequently increases or if the demand
variations among follicular cells in their response to exter-
for thyroid hormone decreases, the stimulated follicular epithe-
nal stimuli, such as trophic hormones. If some cells in a
lium involutes to form an enlarged, colloid-rich gland (colloid
follicle have a growth advantage, perhaps because of
intrinsic genetic abnormalities similar to those that give
 CHAPTER 24 The Endocrine System

Figure 24-15 Multinodular goiter. A, Gross morphology demonstrating a coarsely nodular gland, containing areas of fibrosis and cystic change.
B, Photomicrograph of a hyperplastic nodule, with compressed residual thyroid parenchyma on the periphery. Note absence of a prominent capsule, a dis-
tinguishing feature from follicular neoplasms. (B, Courtesy Dr. William Westra, Department of Pathology, Johns Hopkins University, Baltimore, Md.)

rise to adenomas, such cells can give rise to clones of pro- in the neck and upper thorax (superior vena cava syndrome).
liferating cells. This may result in the formation of a nodule Most patients are euthyroid or have subclinical hyperthy-
whose continued growth is autonomous, without the roidism (identified only by reduced TSH levels), but in a
external stimulus. Consistent with this model, both poly- substantial minority of patients an autonomous nodule
clonal and monoclonal nodules coexist within the same may develop within a long-standing goiter and produce
multinodular goiter, the latter presumably having arisen hyperthyroidism (toxic multinodular goiter). This condition,
because of the acquisition of a genetic abnormality favor- known as Plummer syndrome, is not accompanied by the
ing growth. Not surprisingly, activating mutations affect- infiltrative ophthalmopathy and dermopathy of Graves
ing proteins of the TSH-signaling pathway have been disease. It is estimated that clinically apparent autonomous
identified in a subset of autonomous thyroid nodules nodules develop in approximately 10% of multinodular
(TSH-signaling pathway mutations and their implications goiters over a 10-year follow-up. The incidence of malig-
are discussed under "Adenomas"). The uneven follicular nancy in long-standing multinodular goiters is low (<5%)
hyperplasia, generation of new follicles, and accumulation but not zero, and concern for malignancy arises in goiters
of colloid produce physical stress that may lead to rupture that demonstrate sudden changes in size or symptoms
of follicles and vessels followed by hemorrhages, scarring, (e.g., hoarseness). Dominant nodules in a multinodular
and sometimes calcifications. With scarring, nodularity goiter can present as a "solitary thyroid nodule", mimick-
appears, which may be accentuated by the preexisting ing a thyroid neoplasm. A radioiodine scan demonstrates
stromal framework of the gland. uneven iodine uptake (including the occasional "hot"
autonomous nodule) consistent with the diffuse parenchy-
mal involvement, and an admixture of hyperplastic and
involuting nodules. A fine-needle aspiration biopsy is
Multinodular goiters are multilobulated, asymmetrically enlarged helpful and can often, albeit not always, facilitate the dis-
glands that can reach weights of more than 2000 gm. The tinction of follicular hyperplasia from a thyroid neoplasm
pattern of enlargement is quite unpredictable and may involve (see later).
one lobe far more than the other, producing lateral pressure on
midline structures, such as the trachea and esophagus. In other
instances the goiter grows behind the sternum and clavicles to Neoplasms of the Thyroid
produce the so-called intrathoracic or plunging goiter.
Occasionally, most of it is hidden behind the trachea and The solitary thyroid nodule is a palpably discrete swelling
esophagus; in other instances one nodule may stand out, within an otherwise apparently normal thyroid gland. The
imparting the clinical appearance of a solitary nodule. On cut estimated incidence of solitary palpable nodules in the
section, irregular nodules containing variable amounts of brown, adult population of the United States varies between 1%
gelatinous colloid are present (Fig. 24-15A). Older lesions have and 10%, but is significantly higher in endemic goitrous
areas of hemorrhage, fibrosis, calcification, and cystic change. regions. Single nodules are about four times more common
The microscopic appearance includes colloid-rich follicles lined in women than in men. The incidence of thyroid nodules
by flattened, inactive epithelium and areas of follicular hyper- increases throughout life.
plasia, accompanied by degenerative changes related to phys- From a clinical standpoint, the major concern in persons
ical stress. In contrast to follicular neoplasms, a prominent who present with thyroid nodules is the possibility of
capsule between the hyperplastic nodules and residual com- a malignant neoplasm. Fortunately, the overwhelming
pressed thyroid parenchyma is not present (Fig. 24-158). majority of solitary nodules of the thyroid prove to be
localized, nonneoplastic lesions (e.g., a dominant nodule
in multinodular goiter, simple cysts, or foci of thyroiditis)
Clinical Course. The dominant clinical features of multi- or benign neoplasms such as follicular adenoma. In fact,
nodular goiter are those caused by mass effects. In addition benign neoplasms outnumber thyroid carcinomas by a ratio of
to the obvious cosmetic effects, goiters may cause airway nearly 10:1. While less than 1% of solitary thyroid nodules
obstruction, dysphagia, and compression of large vessels are malignant, this still represents about 15,000 new cases
 Thyroid gland

of thyroid carcinoma per year in the United States.

Fortunately, most of these cancers are indolent; more than
90 % of affected patients are alive 20 years after being
diagnosed.
Several clinical criteria provide clues to the nature of a
thyroid nodule:
• Solitary nodules, in general, are more likely to be neoplas-
tic than are multiple nodules.
• Nodules in younger patients are more likely to be neoplas-
tic than are those in older patients.
• Nodules in males are more likely to be neoplastic than are
those in females .
• A history of radiation treatment to the head and neck
region is associated with an increased incidence of
thyroid malignancy.
• Functional nodules that take up radioactive iodine in
imaging studies (hot nodules) are much more likely to be
benign than malignant.
These associations and statistics, however, are of little
comfort to a patient, in whom the timely recognition of a
malignancy can be lifesaving. Ultimately, morphologic
evaluation of a given thyroid nodule, by fine-needle aspira-
tion and surgical resection, provides the most definitive
information about its nature. The following sections con-
sider the major thyroid tumors, including adenoma and
carcinoma in its various forms.

Figure 24-16 Follicular adenoma of the thyroid. A, A solitary, well-

Adenomas circumscribed nodule is seen. B, The photomicrograph shows well -
differentiated follicles resembling normal thyroid parenchyma.
Adenomas of the thyroid are typically discrete, solitary
masses, derived from follicular epithelium, and hence
they are also known as follicular adenomas. Clinically, gene, genetic alterations that are shared with follicular
follicular adenomas can be difficult to distinguish from carcinomas. These are discussed in further detail under
dominant nodules of follicular hyperplasia or from the less "Carcinomas" (see later).
common follicular carcinomas. In general, follicular adeno-
mas are not forerunners to carcinomas; nevertheless, shared
genetic alterations support the possibility that at least of
subset of follicular carcinomas arises in preexisting adeno-
The typical thyroid adenoma is a solitary, spherical , encapsu-
mas (see later). Although the vast majority of adenomas lated lesion that is demarcated from the surrounding thyroid
are nonfunctional, a small subset produces thyroid hor-
parenchyma by a well-defined, intact capsule (Fig. 24-16A).
mones and causes clinically apparent thyrotoxicosis. These features are important in making the distinction
Hormone production in functional adenomas ("toxic ade-
from multinodular goiters, which contain multiple nodules
nomas") is independent of TSH stimulation. even in patients presenting clinically with a solitary dominant
nodule. Follicular adenomas average about 3 em in diameter,
Pathogenesis. Somatic mutations of the TSH receptor sig-
but some are much larger (~I 0 em in diameter). In freshly
naling pathway are found in toxic adenomas, as well as resected specimens the adenoma bulges from the cut surface
in toxic multinodular goiter. Gain-of-function mutations
and compresses the adjacent thyroid . The color ranges from
in one of two components of this signaling system- most gray-white to red-brown, depending on the cellularity of the
often the gene encoding the TSH receptor (TSHR) or the adenoma and its colloid content. Areas of hemorrhage, fibrosis,
a-subunit of G, (GNAS) -cause follicular cells to secrete
calcification , and cystic change , similar to those encountered in
thyroid hormone independent of TSH stimulation(" thyroid
multinodular goiters, are common in follicular adenomas, par-
autonomy") . This leads to symptoms of hyperthyroidism
ticularly within larger lesions.
and produces a functional "hot" nodule on imaging. Microscopically, the constituent cells often form uniform-
Overall, mutations in the TSH receptor signaling pathway
appearing follicles that contain colloid (Fig. 24-168). The follicu-
are present in slightly over half of toxic thyroid nodules.
lar growth pattern is usually quite distinct from the adjacent
Notably, TSHR and GNAS mutations are rare in follicular
nonneoplastic thyroid. The neoplastic cells show little variation
carcinomas; thus, toxic adenomas and toxic multinodular in cell size, cell shape, or nuclear morphology, and mitotic
goiter do not seem to be forerunners of malignancy. figures are rare. Occasionally the neoplastic cells acquire
A minority (<20 %) of nonfunctioning follicular adeno-
brightly eosinophilic granular cytoplasm (oxyphil or Hurth!e cell
mas have mutations of RAS or PIK3CA, which encodes a
change) (Fig. 24-17). The hallmark of all follicular adenomas is
subunit of the PI-3 kinase, or bear a PAX8-PPARG fusion
 C H A PT E R 24 The Endocrine System

• Anaplastic (undifferentiated) carcinoma (<5% of cases)

• Medullary carcinoma (5 % of cases)
Most thyroid carcinomas (except medullary carcino-
mas) are derived from the thyroid follicular epithelium,
and of these, the vast majority are well-differentiated
lesions. Because of the unique clinical, molecular and bio-
logic features associated with each variant of thyroid car-
cinoma, these subtypes are described separately. We begin
with a discussion of the molecular pathogenesis of all
thyroid cancers.

Pathogenesis
Genetic Factors. Distinct genetic events are involved in
the pathogenesis of the four major histologic variants of
thyroid cancer. As stated, medullary carcinomas do not
Figure 24-17 Hurthle cell (oxyphil) adenoma. A high-power view showing that arise from the follicular epithelium. Genetic alterations in
the tumor is composed of cells with abundant eosinophilic cytoplasm and the three follicular cell-derived malignancies are in
small regular nuclei. (Courtesy Dr. Mary Sunday, Duke University, Durham,
N.C .)
growth factor receptor signaling pathways (Fig. 24-18).
You will recall that in normal cells, these pathways are
transiently activated by binding of soluble growth factor
ligands to the extracellular domain of receptor tyrosine
the presence of an intact, well-formed capsule encircling the kinases, which results in autophosphorylation of the cyto-
tumor. Careful evaluation of the integrity of the capsule is plasmic domain of the receptor. This in turn sets in motion
therefore critical in distinguishing follicular adenomas events that lead to activation of RAS and two downstream
from follicular carcinomas, which demonstrate capsular signaling arms involving MAP kinase (MAPK) and PI-3
and/ or vascular invasion (see later). Extensive mitotic activity, kinase (PI3K). In thyroid carcinomas, as with many cancers
necrosis, or high cellularity also warrants close inspection to (Chapter 7), gain-of-function mutations in components
exclude follicular carcinoma and the follicular variant of papillary of these pathways lead to their constitutive activation,
carcinoma (see later). driving excessive cellular proliferation and increased cell
survival.

Clinical Features. Many follicular adenomas present as

unilateral painless masses that are discovered during
a routine physical examination. Larger masses may pro-
duce local symptoms, such as difficulty in swallowing.
Nonfunctioning adenomas take up less radioactive iodine
than does normal thyroid parenchyma. On radionuclide
scanning, therefore, nonfunctioning adenomas appear as
cold nodules relative to the adjacent thyroid tissue.
However, as many as 10% of cold nodules are malignant.
Other techniques used to evaluate suspected adenomas Follicular and
are ultrasonography and fine-needle aspiration biopsy. anaplastic carcinoma - Follicular and
Because of the need for evaluating capsular integrity, the (point mutations) --- anaplastic carcinoma
(point mutations and
definitive diagnosis of adenomas can be made only after
- -- - / amplifications)
careful histologic examination of the resected specimen.
Suspected adenomas of the thyroid are therefore removed
surgically to exclude malignancy. Follicular adenomas do
not recur or metastasize and have an excellent prognosis.

Carcinomas t
Follicular and
anaplastic
Carcinomas of the thyroid are relatively uncommon in the carcinoma
United States, accounting for about 1.5% of all cancers. A Follicular (point mutations)
female predominance has been noted among patients who
develop thyroid carcinoma in the early and middle adult
years. In contrast, cases presenting in childhood and late r--....:~oor-- Cell growth,
adult life are distributed equally among males and females . proliferation ,
The major subtypes of thyroid carcinoma and their rela- differentiation
tive frequencies are as follows :

• Papillary carcinoma (>85 % of cases) Figure 24-18 Genetic alterations in follicular cell-derived malignancies of the
• Follicular carcinoma (5 % to 15 % of cases) thyroid gland.
 Thyroid gland

Papillary Carcinomas. Most papillary carcinomas have one half of follicular thyroid carcinomas harbor gain-of-
gain-of-function mutations involving the genes encoding function point mutations of RAS or PIK3CA (the gene that
the RET or NTRK1 receptor tyrosine kinases, or in the encodes PI-3 kinase), PIK3CA amplifications, or loss-of-
serine/threonine kinase BRAF, which you will recall lies function mutations of PTEN, a tumor suppressor gene
in the MAPK pathway (Fig. 24-18). and negative regulator of this pathway (Fig. 24-18). These
genetic alterations are almost always mutually exclusive
• The RET gene is located on chromosome 10qll, and the in follicular carcinomas, in line with their functional equiv-
receptor tyrosine kinase it encodes is normally not alence. The progressive increase in the prevalence of RAS
expressed in thyroid follicular cells. In papillary cancers, and PIK3CA mutations from benign follicular adenomas to
either a paracentric inversion of chromosome 10 or a follicular carcinomas to anaplastic carcinomas (see later)
reciprocal translocation between chromosomes 10 and suggests a shared histogenesis and molecular evolution
17 places the tyrosine kinase domain of RET under the among these follicular tumors.
transcriptional control of genes that are constitutively A unique (2;3)(q13;p25) translocation has been described
expressed in the thyroid epithelium. The novel fusion in one third to one half of follicular carcinomas. This trans-
genes that are so formed are known as RET/PTC (RET j location creates a fusion gene composed of portions of
papillary thyroid carcinoma) and are present in approx- PAXS, a paired homeobox gene that is important in thyroid
imately 20% to 40% of papillary thyroid cancers. There development, and the peroxisome proliferator-activated
are more than 15 fusion partners of RET, and two- receptor gene (PPARG), whose gene product is a nuclear
designated as PTCl and PTC2- are most commonly hormone receptor implicated in terminal differentiation of
observed in sporadic papillary cancers. The frequency cells. Fewer than 10% of follicular adenomas harbor PAXS-
of RET j PTC rearrangements is significantly higher in ppARG fusion genes, and these have not been documented
papillary cancers arising in the backdrop of radiation thus far in other thyroid neoplasms.
exposure. The RET'jPTC rearrangements produce genes Anaplastic (Undifferentiated) Carcinomas. These highly ag-
that encode fusion proteins with constitutive tyrosine gressive and lethal tumors can arise de novo, or more
kinase activity. Similarly, paracentric inversions or commonly, by "dedifferentiation" of a well-differentiated
translocations of NTRKl on chromosome 1q21 are papillary or follicular carcinoma. Molecular alterations
present in 5% to 10% of papillary thyroid cancers. These present in anaplastic carcinomas include those also seen in
genetic events also produce constitutively active NTRK1 well-differentiated carcinomas (e.g., RASor PIK3CA muta-
fusion proteins. tions) . Other genetic "hits," such as inactivation of TP53 or
• BRAF encodes an intermediate signaling component in activating mutations of P-catenin, are essentially restricted
the MAP kinase pathway. One third to one half of papil- to anaplastic carcinomas and may contribute to their ag-
lary thyroid carcinomas harbor a gain-of-function muta- gressive behavior.
tion in the BRAF gene, which is most commonly a Medullary Thyroid Carcinomas. Familial medullary thyroid
valine-to-glutamate change in codon 600 (BRAfY 600 E). carcinomas occur in multiple endocrine neoplasia type 2
The presence of BRAF mutations in papillary carcino- (MEN-2, see later) and are associated with germline RET
mas correlates with adverse prognostic factors like mutations that lead to constitutive activation of the recep-
metastatic disease and extrathyroidal extension. As dis- tor. RET mutations are also seen in approximately one half
cussed in other chapters, a similar BRAF mutation is of nonfamilial (sporadic) medullary thyroid cancers.
found in some other cancers as well, including melano- Chromosomal rearrangements involving RET, such as the
mas, hairy cell leukemia and a subset of colon cancers, RET/PTC translocations reported in papillary cancers, are
suggesting that diverse tumors may share a similar not seen in medullary carcinomas.
pathway to malignancy.
Environmental Factors. The major risk factor predispos-
Because chromosomal rearrangements of the RET or ing to thyroid cancer is exposure to ionizing radiation, par-
NTRKl genes and mutations of BRAF have redundant ticularly during the first 2 decades of life. In keeping with
effects on MAP kinase signaling, it is not surprising that this, there was a marked increase in the incidence of papil-
they are usually (but not always) mutually exclusive lary carcinomas among children exposed to ionizing radia-
events. The histologic variants of papillary carcinoma tion after the Chernobyl nuclear disaster in 1986. Deficiency
demonstrate some unique characteristics vis-a-vis the of dietary iodine (and by extension, an association with
frequency or nature of BRAF mutation (see later). Of fur- goiter) is linked with a higher frequency of follicular
ther interest, RET j PTC rearrangements and BRAF point carcinomas.
mutations are not observed in follicular adenomas or
carcinomas. Papillary Carcinoma
Follicular Carcinomas. In contrast to papillary carcinomas, Papillary carcinomas are the most common form of
follicular carcinomas are associated with acquired muta- thyroid cancer, accounting for nearly 85% of primary
tions that activate RAS or the PI-3K/AKT arm of the thyroid malignancies in the United States. They occur
receptor tyrosine kinase signaling pathway. It is evident throughout life but most often between the ages of 25 and
from Figure 24-18 that activated mutations in RAS would 50, and account for the majority of thyroid carcinomas
be expected to stimulate both the MAPK and PI3K signal- associated with previous exposure to ionizing radiation.
ing pathways. Why RAS mutations produce follicular neo- The diagnosis of papillary carcinoma has increased mark-
plasms, rather than papillary neoplasms, is not understood, edly in the last 30 years, partly because of the recognition
a point that highlights our lack of insight into the nuances of follicular variants (see later) that were misclassified in
of intracellular signaling. Approximately one third to the past.
 CHAPTER 24 The Endocrine System

Figure 24-19 Papillary carcinoma of the thyroid. A, The macroscopic appearance of a papillary carcinoma with grossly discernible papillary structures. B, This
particular example contains well-formed papillae. C, High power shows cells with characteristic empty-appearing nuclei, sometimes called "Orphan Annie eye"
nucle. D, Cells obtained by fine-needle aspiration of a papillary carcinoma. Characteristic intranuclear inclusions are visible in some of the aspirated cells.

• Concentrically calcified structures termed psammoma

bodies are often present, usually within the cores of papillae.
Papillary carcinomas may be solitary or multifocal. Some tumors
These structures are almost never found in follicular and
are well circumscribed and even encapsulated; others infiltrate
medullary carcinomas, and so, when present in fine-needle
the adjacent parenchyma and have ill-defined margins. The
aspiration material, they are a strong indication that the lesion
tumors may contain areas of fibrosis and calcification and are
is a papillary carcinoma.
often cystic. The cut surface sometimes reveals papillary foci
• Foci of lymphatic invasion by tumor are often present, but
that point to the diagnosis. The microscopic hallmarks of
involvement of blood vessels is relatively uncommon, particu-
papillary neoplasms include the following (Fig. 24-19):
larly in smaller lesions. Metastases to adjacent cervical lymph
• Papillary carcinomas may contain branching papillae having nodes occur in up to half of cases.
a fibrovascular stalk covered by a single to multiple layers of There are over a dozen histologic variants of papillary carci-
cuboidal epithelial cells. In most neoplasms, the epithelium noma that can mimic other thyroid lesions or harbor distinct
covering the papillae consists of well-differentiated, uniform, prognostic implications; most are beyond the scope of this
orderly cuboidal cells, but at the other extreme are those with book. The most common variant, and the one most liable to
fairly anaplastic epithelium showing considerable variation in misdiagnosis, is the follicular variant, which has the charac-
cell and nuclear morphology. When present, the papillae of teristic nuclear features of papillary carcinoma and an almost
papillary carcinoma differ from those seen in areas of hyper- totally follicular architecture. Follicular variant papillary carcino-
plasia in being more complex and having dense fibrovascular mas can be either encapsulated or poorly circumscribed and
cores. infiltrative. The encapsulated follicular variant of papillary carci-
• The nuclei of papillary carcinoma cells contain finely dis- noma has a generally favorable prognosis, while the poorly
persed chromatin, which imparts an optically clear or circumscribed and infiltrative lesions need to be treated more
empty appearance, giving rise to the designation ground- aggressively. The genetic alterations in the follicular variant ,
glass or Orphan Annie eye nuclei . In addition, invagina- especially the encapsulated tumors, demonstrate several dis-
tions of the cytoplasm may give the appearance of tinctions from conventional papillary carcinomas, including a
intranuclear inclusions ("pseudo-inclusions") or intranuclear lower frequency of RETIPTC rearrangements, a lower frequency
grooves. The diagnosis of papillary carcinoma can be and different spectrum of BRAF mutations, and a significantly
made based on these nuclear features, even in the higher frequency of RAS mutations. When considered in con-
absence of papillary architecture. junction with their higher propensity for angioinvasion and lower
 Thyroid gland

incidence of lymph node metastases, it has become evident Follicular Carcinoma

that at least a subset of the encapsulated follicular variant
Follicular carcinomas account for 5% to 15% of primary
display biological features that are more comparable to mini-
thyroid cancers, but are more frequent in areas with
mally invasive follicular carcinomas (see later) than conventional
dietary iodine deficiency, where they constitute 25% to
papillary carcinomas.
40% of thyroid cancers. They are more common in women
The tall-cell variant has tall columnar cells with intensely
(3: 1) and present more often in older patients than do
eosinophilic cytoplasm lining the papillary structures. These
papillary carcinomas; the peak incidence is between 40 and
tumors tend to occur in older individuals and have higher
60 years of age.
frequencies of vascular invasion, extrathyroidal extension, and
cervical and distant metastases than conventional papillary
thyroid carcinoma. Tall-cell variant papillary carcinomas harbor
BRAF mutations in most (55% to I 00%) cases, and often
have RET/PTC translocations as well. The occurrence of Follicular carcinomas are single nodules that may be well cir-
these two aberrations together may synergistically enhance cumscribed or widely infiltrative (Fig. 24-20A). Sharply demar-
MAPK signaling, contributing to the aggressive behavior of this cated lesions may be exceedingly difficult to distinguish from
variant. follicular adenomas by gross examination. Larger lesions may
An unusual diffuse sclerosing variant of papillary carci- penetrate the capsule and infiltrate well beyond the thyroid
noma occurs in younger individuals, including children. The capsule into the adjacent neck. They are gray to tan to pink on
tumor has a prominent papillary growth pattern intermixed with cut section and may be somewhat translucent due to the pres-
solid areas containing nests of squamous metaplasia. As the ence of large, colloid-filled follicles. Degenerative changes, such
name suggests, there is extensive, diffuse fibrosis throughout as central fibrosis and foci of calcification, are sometimes
the thyroid gland, often associated with a prominent lympho- present.
cytic infiltrate, simulating Hashimoto thyroiditis. Lymph node
metastases are present in almost all cases. The diffuse scleros-
ing variant carcinomas lack BRAF mutations, but RETIPTC
translocations are found in approximately half the cases.
Finally, the papillary microcarcinoma is defined as an
otherwise conventional papillary carcinoma less than I em in
size. These lesions most commonly come to attention as an
incidental finding in patients undergoing surgery, and may be
precursors of typical papillary carcinomas.

Clinical Course. Most conventional papillary carcinomas

present as asymptomatic thyroid nodules, but the first
manifestation may be a mass in a cervical lymph node.
Interestingly, the presence of isolated cervical nodal metas-
tases does not have a significant influence on prognosis,
which is generally good. Most carcinomas are single
nodules that move freely with the thyroid gland during
swallowing and are not distinguishable on examination
from benign nodules. Hoarseness, dysphagia, cough, or
dyspnea suggests advanced disease. In a minority of
patients, hematogenous metastases are present at the time
of diagnosis, most commonly in the lung.
A variety of diagnostic tests have been used to help
separate benign from malignant thyroid nodules, including
radionuclide scanning and fine-needle aspiration. Papillary
carcinomas are cold masses on scintiscans. Improvements
in cytologic analysis have made fine-needle aspiration
cytology a reliable test for distinguishing between benign
and malignant nodules. The nuclear features are often dem-
onstrated nicely in aspirated specimens.
Papillary thyroid cancers have an excellent prognosis,
with a 10-year survival rate in excess of 95%. Between 5%
and 20% of patients have local or regional recurrences, and
10% to 15% have distant metastases. The prognosis of
someone with papillary thyroid cancers is dependent on
several factors including age (in general, being less favor- Figure 24-20 Follicular carcinoma. A, Cut surface of a follicular carcinoma
able among patients older than 40 years), the presence of with substantial replacement of the lobe of the thyroid. The tumor has a
extrathyroidal extension, and presence of distant metasta- light-tan appearance and contains small foci of hemorrhage. B, A few of the
ses (stage). glandular lumens contain recognizable colloid.
 CHAPTER 24 The Endocrine System

carcinoma often presents with systemic metastases, and as

Microscopically, most follicular carcinomas are composed of
many as half of affected patients succumb to thei~ ~isease
fairly uniform cells forming small follicles containing colloid , quite within 10 years. This is in sharp contrast to mimmally
reminiscent of normal thyroid (Fig. 24-208). In other cases fol- invasive follicular carcinomas, which have a 10-year sur-
licular differentiation may be less apparent, and there may be vival rate of greater than 90% . Most follicular carcinomas
nests or sheets of cells without colloid. Occasional tumors are are treated with total thyroidectomy followed by the
dominated by cells with abundant granular, eosinophilic cyto- administration of radioactive iodine, which can be used to
plasm (Hurthle cell or oncocytic variant of follicular carci- identify metastases and to ablate such lesions. In addition,
noma). Whatever the pattern , the nuclei lack the features
because any residual follicular carcinoma may respond to
typical of papillary carcinoma, and psammoma bodies are TSH stimulation, patients are usually treated with thyroid
not present. While nuclear features (optically clear nuclei, hormone after surgery to suppress endogenous TSH levels.
nuclear grooves) are helpful in distinguishing papillary from fol- Serum thyroglobulin levels are used for monitoring tumor
licular neoplasms, there is no reliable cytologic difference recurrence, because this thyroid protein should be barely
between follicular adenomas and minimally invasive fol-
detectable in a patient who is free of disease.
licular carcinomas. Making this distinction requires extensive
histologic sampling of the tumor-capsule-thyroid interface to Anaplastic (Undifferentiated) Carcinoma
exclude capsular and/or vascular invasion (Fig . 24-21 ). The Anaplastic carcinomas are undifferentiated tumors of the
criterion for vascular invasion is applicable only to capsular thyroid follicular epithelium, accoun~ing f~r less than~%
vessels and vascular spaces beyond the capsule; the presence of thyroid tumors. They are aggressive, with a mortahty
of tumor plugs within intra-tumoral blood vessels has little prog- rate approaching 100%. Patients with anaplastic carcinoma
nostic significance. Unlike in papillary cancers, lymphatic spread are older than those with other types of thyroid cancer,
is uncommon in follicular cancers. with a mean age of 65 years. Approximately a quarter of
In contrast to minimally invasive follicular cancers, the diagno- patients with anaplastic thyroid carcinomas have a past
sis of carcinoma is obvious in widely invasive follicular carci- history of a well-differentiated thyroid carcinoma, and
nomas, which infiltrate the thyroid parenchyma and extrathyroidal
another quarter harbors a concurrent well-differentiated
soft tissues. Histologically, these cancers tend to have a greater tumor in the resected specimen.
proportion of solid or trabecular growth pattern, less evidence of
follicular differentiation, and increased mitotic activity.

Clinical Course. Follicular carcinomas present as slowly Microscopically, these neoplasms are composed of highly
enlarging painless nodules. Most frequently t~ey ar~ cold anaplastic cells, with variable morphology, including (1) large,
nodules on scintigrams, although rare, better-differentiated pleomorphic giant cells, including occasional osteoclast-like
lesions may be hyperfunctional, take up radioactive
multinucleate giant cells; (2) spindle cells with a sarcomatous
iodine and appear warm on scintiscan. Because follicular
appearance; and (3) mixed spindle and giant cells. Foci of
carcinomas have little propensity for invading lymphat-
papillary or follicular differentiation may be present in some
ics, regional lymph nodes are rarely involved, but v~s­ tumors, suggesting an origin from a better-differentiated carci-
cular (hematogenous) dissemination is common, with noma. The neoplastic cells express epithelial markers like
metastases to bone, lungs, liver, and elsewhere. cytokeratin, but are usually negative for markers of thyroid dif-
The prognosis depends largely on the extent of invasion
ferentiation, like thyroglobulin.
and stage at presentation. Widely invasive follicular
 Thyroid gland

Clinical Course. Anaplastic carcinomas usually present as

a rapidly enlarging bulky neck mass. In most cases, the
disease has already spread beyond the thyroid capsule into
adjacent neck structures or has metastasized to the lungs
at the time of presentation. Symptoms related to compres-
sion and invasion, such as dyspnea, dysphagia, hoarse-
ness, and cough, are common. There are no effective
therapies, and the disease is almost uniformly fatal.
Although metastases to distant sites are common, in
most cases death occurs in less than 1 year as a result of
aggressive growth and compromise of vital structures in
the neck.

Medullary Carcinoma
Medullary carcinomas of the thyroid are neuroendocrine
neoplasms derived from the parafollicular cells, or C
cells, of the thyroid, and account for approximately 5% of
thyroid neoplasms. Medullary carcinomas, similar to
normal C cells, secrete calcitonin, the measurement of which
plays an important role in the diagnosis and postoperative
follow-up of patients. In some instances the tumor cells
elaborate other polypeptide hormones, such as serotonin,
ACTH, and vasoactive intestinal peptide (VIP). About 70%
of tumors arise sporadically. The remainder occurs in the
setting of MEN syndrome 2A or 2B or as familial tumors
without an associated MEN syndrome (familial medullary
thyroid carcinoma, or FMTC; see "Multiple Endocrine
Neoplasia Syndromes"). Recall that activating point muta-
tions in the RET proto-oncogene play an important role in the
development of both familial and sporadic medullary car-
cinomas. Cases associated with MEN types 2A or 2B occur
in younger patients, and may even arise during the first
decade of life. In contrast, sporadic as well as familial med-
ullary carcinomas are lesions of adulthood, with a peak
incidence in the 40s and 50s. Figure 24-22 Medullary carcinoma of thyroid. A, These tumors typically
show a solid pattern of growth and do not have connective tissue capsules.
B, Histology demonstrates abundant deposition of amyloid, visible here
as homogeneous extracellular material, derived from calcitonin molecules
secreted by the neoplastic cells. (A, Courtesy Dr. Joseph Corson, Brigham
Sporadic medullary thyroid carcinomas present as a solitary and Women's Hospital, Boston, Mass.)
nodule (Fig. 24-22A). In contrast. bilaterality and multicen-
tricity are common in familial cases. Larger lesions often
contain areas of necrosis and hemorrhage and may extend prominent clusters of C cells scattered throughout the paren-
through the capsule of the thyroid. The tumor tissue is firm, pale chyma should raise the specter of an inherited predisposition,
gray to tan, and infiltrative. There may be foci of hemorrhage even if a family history is not present.
and necrosis in the larger lesions.
Microscopically, medullary carcinomas are composed of
Clinical Course. Sporadic cases of medullary carcinoma
polygonal to spindle-shaped cells, which may form nests, tra-
come to medical attention most often as a mass in the neck,
beculae, and even follicles. Small, more anaplastic cells are
present in some tumors and may be the predominant cell type. sometimes associated with dysphagia or hoarseness. In
some instances, the initial manifestations are those of a
Acellular amyloid deposits derived from calcitonin polypep-
paraneoplastic syndrome caused by the secretion of a
tides are present in the stroma in many cases (Fig. 24-228).
peptide hormone (e.g., diarrhea due to the secretion of VIP,
Calcitonin is readily demonstrable within the cytoplasm of the
or Cushing syndrome due to ACTH). Notably, hypocalce-
tumor cells as well as in the stromal amyloid by immunohisto-
chemical methods. As with all neuroendocrine tumors, elec- mia is not a prominent feature, despite the presence of
raised calcitonin levels. In addition to circulating calcito-
tron microscopy reveals variable numbers of membrane-bound
nin, secretion of carcinoembryonic antigen by the neoplas-
electron-dense granules within the cytoplasm of the neoplastic
tic cells is a useful biomarker, especially for presurgical
cells (Fig. 24-23). One of the features of familial medullary
assessment of tumor load and in calcitonin-negative
cancers is the presence of multicentric C-cell hyperplasia in
the surrounding thyroid parenchyma, a feature that is usually tumors.
Patients with familial syndromes may come to attention
absent in sporadic lesions, and that is believed to be a precur-
sor lesion in familial cases. Thus, the presence of multiple because of symptoms localized to the thyroid or as a result
of endocrine neoplasms in other organs (e.g., adrenal or
 C H A PT E R 24 The Endocrine System

genes or mutations that activate RAS or PI-3K (in follicular

carcinomas), chromosomal rearrangements involving the
RET oncogene or mutations in BRAF (in papillary carcino-
mas), and mutations of RET (in medullary carcinomas).
• Follicular adenomas and carcinomas both are composed
of well-differentiated follicular epithelial cells; the latter are
distinguished by evidence of capsular and/or vascular
invasion.
• Papillary carcinomas are recognized based on nuclear fea-
tures (ground-glass nuclei, pseudoinclusions) even in the
absence of papillae. Psammoma bodies are a character-
istic feature of papillary cancers; these neoplasms often
metastasize by way of lymphatics, but the prognosis is
excellent.
• Anaplastic carcinomas are thought to arise by dedifferen-
Figure 24-23 Electron micrograph of medullary thyroid carcinoma. These
cells contain membrane-bound secretory granules that are the sites of
tiation of more differentiated neoplasms. They are highly
storage of calcitonin and other peptides. aggressive, uniformly lethal cancers.
• Medullary cancers are neoplasms arising from the parafol-
licular C cells and can occur in either sporadic (70%) or
parathyroid glands). Medullary carcinomas arising in the familial (30%) settings. Multicentricity and C cell hyperpla-
context of MEN-2B are generally more aggressive and sia are features of familial cases. Amyloid deposits are a
metastasize more frequently than those occurring in characteristic histologic finding.
patients with sporadic tumors, MEN-2A, or FMTC. As will
be discussed later, asymptomatic MEN-2 patients carrying
germline RET mutations are offered prophylactic thyroid-
ectomy as early as possible to prevent the otherwise inevi- Congenital Anomalies
table development of medullary carcinomas, the major risk
factor for poor outcome in these individuals. Sometimes Thyroglossal duct cyst is the most common clinically signif-
the only histologic finding in the resected thyroid of icant congenital anomaly of the thyroid. A sinus tract
asymptomatic carriers is the presence of C-cell hyperplasia may persist as a vestige of the tubular development of
or small (<1 em) "micromedullary" carcinomas. Several the thyroid gland. Parts of this tube may be obliterated,
small-molecule inhibitors of RET tyrosine kinase have leaving small segments to form cysts. These occur at any
recently been developed, and are being tested in individu- age and might not become evident until adult life.
als with medullary carcinomas. Mucinous, clear secretions may collect within the cysts to
form either spherical masses or fusiform swellings, rarely
~ KEY CONCEPTS over 2 to 3 em in diameter, that present in the midline of
the neck anterior to the trachea. Segments of the duct and
Thyroid Neoplasms cysts that occur high in the neck are lined by stratified
• Most thyroid neoplasms manifest as solitary thyroid squamous epithelium resembling the covering of the pos-
nodules; only 1% of all thyroid nodules are neoplastic. terior portion of the tongue in the region of the foramen
• Follicular adenomas are the most common benign neo- cecum. Anomalies that occur in the lower neck more prox-
plasms, while papillary carcinoma is the most common imal to the thyroid gland are lined by epithelium resem-
malignancy. bling the thyroidal acinar epithelium. Characteristically,
• Multiple genetic pathways are involved in thyroid carcino- subjacent to the lining epithelium, there is an intense lym-
genesis. Some of the genetic abnormalities that are fairly
phocytic infiltrate. Superimposed infection may convert
unique to thyroid cancers include PAXBIPPARG fusion
these lesions into abscess cavities, and rarely, they give
rise to cancers.

PARATHYROID GLANDS
The four parathyroid glands are composed of two cell are slightly larger than the chief cells, have acidophilic
types: chief cells and oxyphil cells. Chief cells predomi- cytoplasm, and are tightly packed with mitochondria.
nate; they are are polygonal, 12 to 20 llm in diameter, and Glycogen granules are also present in these cells, but
have central, round, uniform nuclei and light to dark pink secretory granules are sparse or absent. In early infancy
cytoplasm. Sometimes these cells take on a water-clear and childhood, the parathyroid glands are composed
appearance due to the presence of large amounts of cyto- almost entirely of solid sheets of chief cells. The amount
plasmic glycogen. In addition, they have secretory gran- of stromal fat increases up to age 25, reaching a maximum
ules containing parathyroid hormone (PTH) . Oxyphil cells of approximately 30% of the gland, and then plateaus.
and transitional oxyphils are found throughout the nor- The function of the parathyroid glands is to regulate
mal parathyroid, either singly or in small clusters. They calcium homeostasis. The activity of the parathyroid
 Parathyroid glands

glands is controlled by the level of free (ionized) calcium

in the bloodstream. Normally, decreased levels of free
calcium stimulate the synthesis and secretion of PTH. The R
I L
metabolic functions of PTH that regulate serum calcium G E
levels are several. Specifically, PTH: H F
T T
• Increases the renal tubular reabsorption of calcium,
thereby conserving free calcium
• Increases the conversion of vitamin D to its active dihy-
droxy form in the kidneys
• Increases urinary phosphate excretion, thereby lower-
ing serum phosphate levels
• Augments gastrointestinal calcium absorption
The net result of these activities is to elevate the level of
free calcium, which, in turn, inhibits further PTH secretion Figure 24-24 Parathyroid adenoma imaging . Technetium- 99 m-sestamibi
in a classic feedback loop. Similar to the other endocrine radionuclide scan demonstrates an area of increased uptake corresponding
organs, abnormalities of the parathyroid glands include to the left inferior parathyroid gland (arrow}, which contained a parathyroid
both hyperfunction and hypofunction. Tumors of the para- adenoma. Preoperative scintigraphy is useful in localizing and distinguishing
thyroid glands, in contrast to thyroid tumors, usually come adenomas from parathyroid hyperplasia, where more than one gland would
to attention because of excessive secretion of PTH rather demonstrate increased uptake.
than mass effects.

adenomas are monoclonal, consistent with their being neo-

plasms. As with nodules in goitrous thyroids, sporadic
Hyperparathyroidism parathyroid "hyperplasia" is also monoclonal in many
instances, particularly when associated with a persistent
Hyperparathyroidism is caused by elevated parathyroid stimulus for parathyroid growth (refractory secondary or
hormone and is classified into primary, secondary, and tertiary parathyroidism; see later), suggesting that these
least commonly, tertiary types. lesions lie in the gray zone between reactive hyperplasias
and neoplasia. There are two molecular defects that
• Primary hyperparathyroidism: an autonomous overpro- have an established role in the development of sporadic
duction of parathyroid hormone (PTH), usually result- adenomas:
ing from an adenoma or hyperplasia of parathyroid
tissue • Cyclin Dl gene inversions leading to overexpression of cyclin
• Secondary hyperparathyroidism: compensatory hyperse- Dl, a major regulator of the cell cycle. A pericentromeric
cretion of PTH in response to prolonged hypocalcemia, inversion on chromosome 11 results in relocation of the
most commonly from chronic renal failure cyclin Dl gene (normally on llq), so that it is positioned
• Tertiary hyperparathyroidism: persistent hypersecretion of adjacent to the 5'-flanking region of the PTH gene (on
PTH even after the cause of prolonged hypocalcemia is llp). As a consequence of these changes, a regulatory
corrected, for example after renal transplant element from the PTH gene 5'-flanking sequence directs
overexpression of cyclin D1 protein, causing the cells to
proliferate. Between 10% and 20% of adenomas have
Primary Hyperparathyroidism this clonal rearrangement. In addition, cyclin D1 is over-
expressed in approximately 40% of parathyroid adeno-
Primary hyperparathyroidism is one of the most common mas, suggesting that mechanisms other than cyclin Dl
endocrine disorders, and it is an important cause of gene inversion can lead to its overexpression.
hypercalcemia. The frequency of the various parathyroid • MENl mutations: Approximately 20 % to 30% of sporadic
lesions underlying the hyperfunction is as follows: parathyroid tumors have mutations in both copies of the
• Adenoma: 85% to 95% MENl gene, a tumor suppressor gene on chromosome
• Primary hyperplasia (diffuse or nodular): 5% to 10% llq13. Germline mutations of MENl are also found in
• Parathyroid carcinoma: ~1% patients with familial parathyroid adenomas (see later).
The spectrum of MENl mutations in sporadic tumors
Primary hyperparathyroidism is usually a disease of is virtually identical to that in familial parathyroid
adults and is more common in women than in men by a adenomas.
ratio of nearly 4: 1. The annual incidence is now estimated
to be about 25 cases per 100,000 in the United States and Familial syndromes are a distant second to sporadic
Europe; as many as 80% of patients with this condition are adenomas as causes of primary hyperparathyroidism.
identified in the outpatient setting, when hypercalcemia is The genetic syndromes associated with familial parathyroid
discovered incidentally on a serum electrolyte panel. Most adenomas include Multiple Endocrine Neoplasia, types 1
cases occur in the 50s or later in life. and 2, caused by germline mutations of MENl and RET,
The most common cause of primary hyperparathy- respectively (both are discussed in further detail later),
roidism is a solitary parathyroid adenoma arising spo- and familial hypocalciuric hypercalcemia, a rare autosomal-
radically (Fig. 24-24). Most, if not all, sporadic parathyroid dominant disorder caused by loss-of-function mutations in
 CHAPTER 24 The Endocrine System

the parathyroid calcium-sensing receptor gene (CASR): which

within adenomas (so-called endocrine atypia) ; this is not a
results in decreased sensitivity to extracellular calcmm.
criterion for malignancy. In contrast to the normal parathyroid
parenchyma, adipose tissue is inconspicuous.
Primary hyperplasia may occur sporadically or as a com-
ponent of MEN syndrome. Although classically all four glands
The morphologic changes seen in primary hyperparathyroidism
are involved , there is frequently asymmetry with apparent
include those in the parathyroid glands as well as those in other
sparing of one or two glands, making the distinction between
organs affected by elevated levels of PTH and calcium.
hyperplasia and adenoma difficult. The combined weight of all
Parathyroid adenomas are almost always solitary and, similar
glands rarely exceeds 1 gm and is often less. Microscopically,
to the normal parathyroid glands, may lie in close proximity to
the most common pattern seen is that of chief cell hyperplasia,
the thyroid gland or in an ectopic site (e.g., the mediastinum).
which may involve the glands in a diffuse or multinodular
The typical parathyroid adenoma averages 0.5 to 5 gm and
pattern. Less commonly, the constituent cells contain abundant
consists of a well-circumscribed, soft, tan to reddish-brown
water-clear cells ("water-clear cell hyperplasia"). In many
nodule invested by a delicate capsule. In contrast to primary
instances there are islands of oxyphils, and poorly developed,
hyperplasia, the glands outside the adenoma are usually normal
delicate fibrous strands may envelop the nodules. As in the
in size or somewhat shrunken because of feedback inhibition
case of adenomas, stromal fat is inconspicuous w ithin hyper-
by elevated levels of serum calcium. Microscopically, parathy-
plastic glands.
roid adenomas are mostly composed of uniform, polygonal
Parathyroid carcinomas may be circumscribed lesions that
chief cells with small, centrally placed nuclei (Fig . 24-25). At
are difficult to distinguish from adenomas, or they may be
least a few nests of larger oxyphil cells are present as well;
clearly invasive neoplasms. These tumors enlarge one parathy-
uncommonly, adenomas are composed entirely of this cell type
roid gland and consist of gray-white, irregular masses that
(oxyphil adenomas). These may resemble Hurthle cell tumors
sometimes exceed 10 gm in weight. The cells are usually
in the thyroid. A rim of compressed, nonneoplastic parathyroid
uniform and resemble normal parathyroid cells, and are arrayed
tissue, generally separated by a fibrous capsule, is often visible
in nodular or trabecular patterns. The mass is usually enclosed
at the edge of the adenoma. Mitotic figures are rare, but it is
by a dense, fibrous capsule. Diagnosis of carcinoma based
not uncommon to find bizarre and pleomorphic nuclei even
on cytologic detail is unreliable, and invasion of sur-
rounding tissues and metastasis are the only reliable cri-
teria. Local recurrence occurs in one third of cases, and more
distant dissemination occurs in another third.
Morphologic changes of hyperparathyroidism in the skeletal
system (Chapter 26) and the urinary tract deserve special
mention. Symptomatic, untreated primary hyperparathyroidism
manifests w ith three interrelated skeletal abnormalities: osteo-
porosis, brown tumors and osteitis fibrosa cystica. The osteo-
porosis results in decreased bone mass, with preferential
involvement of the phalanges, vertebrae and proximal femur.
For unknown reasons, the increased osteoclast activity in hyper-
parathyroidism affects cortical bone (subperiosteal and endos-
teal surfaces) more severely than medullary bone. In medullary
bone, osteoclasts tunnel into and dissect centrally along the
length of the trabeculae, creating the appearance of railroad
tracks and producing what is known as dissecting osteitis (Fig.
24-26). The marrow spaces around the affected surfaces are
replaced by fibrovascular tissue. The correlative radiographic
finding is a decrease in bone density or osteoporosis.
The bone loss predisposes to microfractures and secondary
hemorrhages that elicit an influx of macrophages and an
ingrowth of reparative fibrous tissue, creating a mass of reactive
tissue, known as a brown tumor (Fig. 26-16, Chapter 26). The
brown color is the result of the vascularity, hemorrhage, and
hemosiderin deposition, and it is not uncommon for the lesions
to undergo cystic degeneration. The combination of increased
osteoclast activity, peritrabecular fibrosis, and cystic brown
tumors is the hallmark of severe hyperparathyroidism and
is known as generalized osteitis fibrosa cystica (von
Recklinghausen disease of bone) . Osteitis fibrosa cystica is
now rarely encountered because hyperparathyroidism is usually
diagnosed on routine blood tests and treated at an early,
Figure 24-25 Parathyroid adenoma. A, Solitary chief cell parathyroid adenoma asymptomatic stage (see later).
(low-power photomicrograph) revealing clear delineation from the residual PTH-induced hypercalcemia favors formation of urinary
gland below. B, High -power detail of a chief cell parathyroid adenoma. There tract stones (nephrolithiasis) as well as calcification of the
is some slight variation in nuclear size but no anaplasia and some slight
renal interstitium and tubules (nephrocalcinosis). Metastatic
tendency to follicular formation.
 Parathyroid glands

multiple myeloma. The most common mechanism (in

-80 % of cases) through which osteolytic tumors induce
hypercalcemia is by secretion of PTH-related peptide
(PTHrP), whose functions are similar to PTH in inducing
osteoclastic bone resorption and hypercalcemia; the
remaining 20 % induce hypercalcemia through metastases
to the bone and subsequent cytokine-induced bone resorp-
tion. In individuals with primary hyperparathyroidism,
serum PTH levels are inappropriately elevated for the level
of serum calcium, whereas PTH levels are low to undetect-
able in hypercalcemia caused by of nonparathyroid dis-
eases (Table 24-5). Radioimmunoassays specific for PTH
and PTHrP are available and can be useful in distinguish-
ing primary hyperparathyroidism and malignancy-
associated hypercalcemia. Other laboratory alterations
referable to PTH excess include hypophosphatemia and
increased urinary excretion of both calcium and phosphate.
Secondary renal disease may lead to phosphate retention
~· with normalization of serum phosphate levels.
Figure 24-26 Hyperparathyroidism with osteoclasts boring into the center of
Symptomatic Primary Hyperparathyroidism. The signs and
the trabeculum (dissecting osteitis). (Photomicrograph reproduced from
Horvai A: Bone and Soft Tissue Pathology: A Volume in the High Yield
symptoms of hyperparathyroidism reflect the combined
Pathology Series, Elsevier, Philadelphia, 2012.) effects of increased PTH secretion and hypercalcemia.
Primary hyperparathyroidism is associated with " painful
bones, renal stones, abdominal groans, and psychic moans."
calcification secondary to hypercalcemia may also be seen in
The constellation of symptoms includes:
other sites, including the stomach , lungs , myocardium, and • Bone disease and bone pain secondary to fractures of
blood vessels. bones weakened by osteoporosis or osteitis fibrosa
cystica.
Clinical Course. Primary hyperparathyroidism may be (1) • Nephrolithiasis (renal stones) in 20 % of newly diagnosed
asymptomatic and identified on routine blood chemistry patients, with attendant pain and obstructive uropathy.
profile, or (2) associated with the classic clinical manifesta- Chronic renal insufficiency and abnormalities in renal
tions of primary hyperparathyroidism. function lead to polyuria and secondary polydipsia.
Asymptomatic Hyperparathyroidism. Because serum cal- • Gastrointestinal disturbances, including constipation,
cium levels are routinely assessed, most patients with nausea, peptic ulcers, pancreatitis, and gallstones.
primary hyperparathyroidism are diagnosed incidentally, • Central nervous system alterations, including depres-
on the basis of clinically silent hypercalcemia. In fact, sion, lethargy, and eventually seizures.
primary hyperparathyroidism is the most common cause • Neuromuscular abnormalities, including weakness and
of asymptomatic hypercalcemia. Hence, many of the classic fatigue.
manifestations, particularly those referable to bone and • Cardiac manifestations, including aortic or mitral valve
renal disease, are now seen infrequently in clinical practice. calcifications (or both).
Among other causes of hypercalcemia (Table 24-5), malig-
nancy stands out as the most frequent cause of symptomatic The abnormalities most directly related to hyper-
h ypercalcemia in adults, and must be excluded by appro- parathyroidism are nephrolithiasis and bone disease,
priate clinical and laboratory investigations. As discussed whereas those attributable to hypercalcemia include
in Chapter 7, hypercalcemia can occur both with solid fatigue, weakness, pancreatitis, metastatic calcifications,
tumors, such as lung, breast, head and neck, and renal and constipation.
cancers, and with hematologic malignancies, notably
Secondary Hyperparathyroidism
Table 24-5 Causes of Hypercalcemia Secondary hyperparathyroidism is caused by any condi-
Raised [PTH] Decreased [PTH] tion that gives rise to chronic hypocalcemia, which in
Hyperparathyroidism Hypercalcemia of malignancy* turn leads to compensatory overactivity of the parathy-
Primary (adenoma > hyperplasia)* Vitamin D toxicity roid glands. Renal failure is by far the most common cause
Secondaryt Immobilization of secondary hyperparathyroidism, although several other
Tertiaryt Thiazide diuretics diseases, including inadequate dietary intake of calcium,
Familial hypocalciuric hypercalcemia Granulomatous disease steatorrhea, and vitamin D deficiency, may also cause this
(sarcoidosis) disorder. The mechanisms by which chronic renal failure
[PTH], Parathyroid hormone concentration. induces secondary hyperparathyroidism are complex and
' Primary hyperparathyroidism is the most common cause of hypercalcemia overall. Malignancy
is the most common cause of symptomatic hypercalcemia. Primary hyperparathyroidism and
not fully understood. Chronic renal insufficiency is associ-
malignancy account for nearly 90% of cases of hypercalcemia. ated with decreased phosphate excretion, which in turn
1Secondary and tertiary hyperparathyroidism are most commonly associated with progressive
results in hyperphosphatemia. The elevated serum phos-
renal failure.
phate levels directly depress serum calcium levels and
 C H A PT E R 24 The Endocrine System

thereby stimulate parathyroid gland activity. In addition,

• Secondary hyperparathyroidism most often is caused by
loss of renal substance reduces the availability of a-1-
renal failure, which lowers serum calcium levels, resulting
hydroxylase necessary for the synthesis of the active form
in reactive hyperplasia of parathyroid glands.
of vitamin D, which in turn reduces intestinal absorption
of calcium (Chapter 9). Because vitamin D has suppressive • Malignancies are the most important cause of symptom-
effects on parathyroid growth and PTH secretion, its rela- atic hypercalcemia, which results from osteolytic metasta-
tive deficiency compounds the hyperparathyroidism in ses or release of PTH-related protein from nonparathyroid
renal failure. tumors.

Hypoparathyroidism
The parathyroid glands in secondary hyperparathyroid-
ism are hyperplastic. As in primary hyperparathyroidism, the Hypoparathyroidism is far less common than is hyper-
degree of glandular enlargement is not necessarily symmetric. parathyroidism. Acquired hypoparathyroidism is almost
Microscopically, the hyperplastic glands contain an increased always an inadvertent consequence of surgery; in addition,
number of chief cells, or cells with more abundant, clear cyto- there are several genetic causes of hypoparathyroidism.
plasm (so-called water-clear cells) in a diffuse or multinodular
distribution. Fat cells are decreased in number. Metastatic • Surgically induced hypoparathyroidism occurs with inad-
calcification may be seen in many tissues, including lungs, vertent removal of all the parathyroid glands during
heart, stomach, and blood vessels. thyroidectomy, excision of the parathyroid glands in the
mistaken belief that they are lymph nodes during radical
neck dissection for some form of malignant disease, or
Clinical Course. The clinical features of secondary hyper- removal of too large a proportion of parathyroid tissue
parathyroidism are usually dominated by the inciting in the treatment of primary hyperparathyroidism.
chronic renal failure. Secondary hyperparathyroidism per • Autoimmune hypoparathyroidism is often associated with
se is usually not as severe or as prolonged as primary chronic mucocutaneous candidiasis and primary
hyperparathyroidism, hence the skeletal abnormalities adrenal insufficiency; this syndrome is known as auto-
(referred to as renal osteodystrophy) tend to be milder. immune polyendocrine syndrome type 1 (APS1) and is
Control of the hyperparathyroidism allows the bony caused by mutations in the autoimmune regulator (AIRE)
changes to regress significantly or disappear completely. gene. The syndrome typically presents in childhood
The vascular calcification associated with secondary hyper- with the onset of candidiasis, followed several years
parathyroidism may occasionally result in significant isch- later by hypoparathyroidism and then adrenal insuffi-
emic damage to skin and other organs, a process sometimes ciency during adolescence. APS1 is discussed further
referred to as calciphylaxis. Patients with secondary hyper- under "Adrenal Glands."
parathyroidism often respond to dietary vitamin D supple- • Autosomal-dominant hypoparathyroidism is caused by
mentation, as well as phosphate binders, which decrease gain-of-function mutations in the calcium-sensing recep-
the prevailing hyperphosphatemia. tor (CASR) gene. Inappropriate CASR activity due to
In a minority of patients, parathyroid activity may heightened calcium sensing suppresses PTH, resulting
become autonomous and excessive, with resultant hyper- in hypocalcemia and hypercalciuria. Recall that loss-of-
calcemia, a process that is sometimes termed tertiary hyper- function CASR mutations are a rare cause of familial
parathyroidism. Parathyroidectomy may be necessary to parathyroid adenomas.
control the hyperparathyroidism in such patients. • Familial isolated hypoparathyroidism (FIH) is a rare condi-
tion with either autosomal dominant or autosomal
recessive patterns of inheritance. Autosomal-dominant
FIH is caused by a mutation in the gene encoding PTH
" KEY CONCEPTS precursor peptide, which impairs its processing to the
Hyperparathyroidism mature hormone. Autosomal-recessive FIH is caused by
loss-of-function mutations in the transcription factor
• Primary hyperparathyroidism is the most common cause gene glial cells missing-2 (GCM2), which is essential for
of asymptomatic hypercalcemia. development of the parathyroid.
• In a majority of cases, primary hyperparathyroidism is • Congenital absence of parathyroid glands can occur in
caused by a sporadic parathyroid adenoma and, less com- conjunction with other malformations, such as thymic
monly, by parathyroid hyperplasia.
aplasia and cardiovascular defects, or as a component
• Parathyroid adenomas are solitary, while hyperplasia typi- of the 22q11 deletion syndrome. As discussed in Chapter
cally is a multiglandular process. 6, when thymic defects are present, the condition is
• Skeletal manifestations of hyperparathyroidism include called DiGeorge syndrome.
bone resorption, osteitis fibrosa cystica, and brown tumors.
Renal changes include nephrolithiasis (stones) and Clinical Features. The major clinical manifestations of
nephrocalcinosis. hypoparathyroidism are related to the severity and chro-
• The clinical manifestations of hyperparathyroidism can be nicity of the hypocalcemia.
summarized as "painful bones, renal stones, abdominal
groans, and psychic moans." • The hallmark of hypocalcemia is tetany, which is char-
acterized by neuromuscular irritability, resulting from
 The endocrine pancreas

decreased serum calcium levels. The symptoms range • Cardiovascular manifestations include a conduction defect
from circumoral numbness or paresthesias (tingling) of that produces a characteristic prolongation of the QT
the distal extremities and carpopedal spasm, to life- interval in the electrocardiogram.
threatening laryngospasm and generalized seizures. • Dental abnormalities occur when hypocalcemia is present
The classic findings on physical examination are Chvostek during early development. These findings are highly
sign and Trousseau sign. Chvostek sign is elicited in sub- characteristic of hypoparathyroidism and include dental
clinical disease by tapping along the course of the facial hypoplasia, failure of eruption, defective enamel and
nerve, which induces contractions of the muscles of the root formation, and abraded carious teeth.
eye, mouth, or nose. Trousseau sign refers to carpal
spasms produced by occlusion of the circulation to the
forearm and hand with a blood pressure cuff for several Pseudohypoparathyroidism
minutes. In this condition, hypoparathyroidism occurs because
• Mental status changes include emotional instability, of end-organ resistance to the actions of PTH. Indeed,
anxiety and depression, confusional states, hallucina- serum PTH levels are normal or elevated. In one form of
tions, and frank psychosis. pseudohypoparathyroidism, there is end-organ resistance
• Intracranial manifestations include calcifications of the to TSH and FSH/LH as well as PTH. All of these hormones
basal ganglia, parkinsonian-like movement disorders, signal via G-protein-coupled receptors, and the disorder
and increased intracranial pressure with resultant pap- results from genetic defects in components of this pathway
illedema. The paradoxical association of hypocalcemia that are shared across endocrine tissues. PTH resistance is
with calcifications may be because of an increase in the most obvious clinical manifestation. It presents as
phosphate levels, resulting in tissue deposits with hypocalcemia, hyperphosphatemia, and elevated circulat-
calcium that exists in local extracellular milieu. ing PTH. TSH resistance is generally mild, while LH/FSH
• Ocular disease takes the form of calcification of the lens resistance manifests as hypergonadotropic hypogonadism
and cataract formation. in females.

THE ENDOCRINE PANCREAS

The endocrine pancreas consists of about 1 million clusters in diabetes results from defects in insulin secretion, insulin
of cells, the islets of Langerhans, which contain four major action, or, most commonly, both. The chronic hyperglyce-
and two minor cell types. The four main types are ~' a, 8, mia and attendant metabolic dysregulation may be associ-
and PP (pancreatic polypeptide) cells. They can be differ- ated with secondary damage in multiple organ systems,
entiated by the ultrastructural characteristics of their gran- especially the kidneys, eyes, nerves, and blood vessels. In
ules, and by their hormone content (Fig. 24-27). The [3 cells the United States, diabetes is the leading cause of end-
produce insulin, which regulates glucose utilization in stage renal disease, adult-onset blindness and non-
tissues and reduces blood glucose levels, as will be detailed traumatic lower extremity amputations resulting from
in the discussion of diabetes. a cells secrete glucagon, which atherosclerosis of the arteries.
stimulates glycogenolysis in the liver and thus increases Diabetes and related disorders of glucose metabolism
blood sugar. 8 cells secrete somatostatin, which suppresses are extremely common. According to the American
both insulin and glucagon release. PP cells secrete pancreatic Diabetes Association, diabetes affects more than 25 million
polypeptide, which exerts several gastrointestinal effects, children and adults, or more than 8% of the population,
such as stimulation of secretion of gastric and intestinal in the United States, nearly a third of whom are currently
enzymes and inhibition of intestinal motility. These cells unaware that they have hyperglycemia. Approximately
not only are present in islets but also are scattered in the 1.9 million new cases of adult diabetes are diagnosed
exocrine pancreas. The two rare cell types are Dl cells each year in the United States. Furthermore, a staggering
and enterochromaffin cells. D1 cells elaborate vasoactive 79 million adults in this country have impaired glucose
intestinal polypeptide (VIP), a hormone that induces gly- tolerance or "prediabetes," which is defined as elevated
cogenolysis and hyperglycemia; it also stimulates gastro- blood sugar that does not reach the criterion accepted
intestinal fluid secretion and causes secretory diarrhea. for an outright diagnosis of diabetes (see later), and
Enterochromaffin cells synthesize serotonin and are the source individuals with prediabetes are at high risk for develop-
of pancreatic tumors that cause the carcinoid syndrome ing frank diabetes. Compared to non-Hispanic whites,
(Chapter 19). Native Americans, African Americans, and Hispanics
The following discussion focuses on the two main dis- are 1.5 to 2 times more likely to develop diabetes in their
orders of islet cells: diabetes mellitus and pancreatic endo- lifetimes. The World Health Organization estimates
crine tumors. that as many as 346 million people suffer from diabetes
worldwide, with India and China being the largest
contributors to the world's diabetic load. Increasingly
Diabetes Mellitus sedentary life styles and poor eating habits have contrib-
uted to the simultaneous escalation of diabetes and
Diabetes mellitus is a group of metabolic disorders shar- obesity, which some have called the diabesity epidemic.
ing the common feature of hyperglycemia. Hyperglycemia Sadly, obesity and diabetes have now extended even to