Hyperpituitarism and Pituitary Adenomas

The most common cause of hyperpituitarism is an adenoma arising in the anterior lobe. Other, less common, causes include hyperplasia and carcinomas of the anterior pituitary, secretion of hormones by some extrapituitary tumors, and certain hypothalamic disorders. Some salient features of pituitary adenomas are as follows:

Table 19–1 Classification of Pituitary Adenomas

Morphology

The usual pituitary adenoma is a well-circumscribed, soft lesion that may, in the case of smaller tumors, be confined by the sella turcica. Larger lesions may compress the optic chiasm and adjacent structures (Fig. 19–3), erode the sella turcica and anterior clinoid processes, and extend locally into the cavernous and sphenoidal sinuses. In as many as 30% of cases, the adenomas are nonencapsulated and infiltrate adjacent bone, dura, and (uncommonly) brain. Foci of hemorrhage and/or necrosis are common in larger adenomas.

Figure 19–3 Pituitary adenoma. This massive, nonfunctioning adenoma has grown far beyond the confines of the sella turcica and has distorted the overlying brain. Nonfunctioning adenomas tend to be larger at the time of diagnosis than those that secrete a hormone.

Pituitary adenomas are composed of relatively uniform, polygonal cells arrayed in sheets, cords, or papillae. Supporting connective tissue, or reticulin, is sparse, accounting for the soft, gelatinous consistency of many of these tumors. The nuclei of the neoplastic cells may be uniform or pleomorphic. Mitotic activity usually is scanty. The cytoplasm of the constituent cells may be acidophilic, basophilic, or chromophobic, depending on the type and amount of secretory product within the cell, but it is fairly uniform throughout the neoplasm. This cellular monomorphism and the absence of a significant reticulin network distinguish pituitary adenomas from non-neoplastic anterior pituitary parenchyma (Fig. 19–4). The functional status of the adenoma cannot be reliably predicted from its histologic appearance. Adenomas that harbor TP53 mutations often demonstrate brisk mitotic activity and higher proliferation rates and are designated atypical adenomas to reinforce their potential for aggressive behavior.

Figure 19–4 Pituitary adenoma. The monomorphism of these cells contrasts markedly with the admixture of cells seen in the normal anterior pituitary in Figure 19–1. Note also the absence of reticulin network.

Hypopituitarism

Hypofunction of the anterior pituitary may occur with loss or absence of 75% or more of the anterior pituitary parenchyma. This may be congenital (exceedingly rare) or may result from a wide range of acquired abnormalities that are intrinsic to the pituitary. Less frequently, disorders that interfere with the delivery of pituitary hormone–releasing factors from the hypothalamus, such as hypothalamic tumors, also may cause hypofunction of the anterior pituitary. Hypopituitarism accompanied by evidence of posterior pituitary dysfunction in the form of diabetes insipidus (see later) is almost always of hypothalamic origin. Most cases of anterior pituitary hypofunction are caused by

The clinical manifestations of anterior pituitary hypofunction depend on the specific hormones that are lacking. In children, growth failure (pituitary dwarfism) may occur as a result of growth hormone deficiency. Gonadotropin or gonadotropin-releasing hormone (GnRH) deficiency leads to amenorrhea and infertility in women and to decreased libido, impotence, and loss of pubic and axillary hair in men. TSH and ACTH deficiencies result in symptoms of hypothyroidism and hypoadrenalism, respectively, and are discussed later in the chapter. Prolactin deficiency results in failure of postpartum lactation. The anterior pituitary also is a rich source of MSH, synthesized from the same precursor molecule that produces ACTH; therefore, one of the manifestations of hypopituitarism is pallor from loss of stimulatory effects of MSH on melanocytes.

Posterior Pituitary Syndromes

The posterior pituitary, or neurohypophysis, is composed of modified glial cells (termed pituicytes) and axonal processes extending from nerve cell bodies in the supraoptic and paraventricular nuclei of the hypothalamus. The hypothalamic neurons produce two peptides: antidiuretic hormone (ADH) and oxytocin. They are stored in axon terminals in the neurohypophysis and released into the circulation in response to appropriate stimuli. Oxytocin stimulates the contraction of smooth muscle in the pregnant uterus and of muscle surrounding the lactiferous ducts of the mammary glands. Impairment of oxytocin synthesis and release has not been associated with significant clinical abnormalities. The clinically important posterior pituitary syndromes involve ADH production. They include diabetes insipidus and secretion of inappropriately high levels of ADH.

ADH is a nonapeptide hormone synthesized predominantly in the supraoptic nucleus. In response to several different stimuli, including increased plasma oncotic pressure, left atrial distention, exercise, and certain emotional states, ADH is released from axon terminals in the neurohypophysis into the general circulation. The hormone acts on the collecting tubules of the kidney to promote the resorption of free water. ADH deficiency causes diabetes insipidus, a condition characterized by excessive urination (polyuria) caused by an inability of the kidney to properly resorb water from the urine. Diabetes insipidus can result from several causes, including head trauma, neoplasms, and inflammatory disorders of the hypothalamus and pituitary, and from surgical procedures involving the hypothalamus or pituitary. The condition sometimes arises spontaneously (idiopathic) in the absence of an underlying disorder. Diabetes insipidus from ADH deficiency is designated as central, to differentiate it from nephrogenic diabetes insipidus as a result of renal tubular unresponsiveness to circulating ADH. The clinical manifestations of both diseases are similar and include the excretion of large volumes of dilute urine with an inappropriately low specific gravity. Serum sodium and osmolality are increased as a result of excessive renal loss of free water, resulting in thirst and polydipsia. Patients who can drink water generally can compensate for urinary losses; patients who are obtunded, bedridden, or otherwise limited in their ability to obtain water may develop life-threatening dehydration.

In the syndrome of inappropriate ADH (SIADH) secretion, ADH excess is caused by several extracranial and intracranial disorders. This condition leads to resorption of excessive amounts of free water, with resultant hyponatremia. The most common causes of SIADH include the secretion of ectopic ADH by malignant neoplasms (particularly small cell carcinomas of the lung), non-neoplastic diseases of the lung, and local injury to the hypothalamus or neurohypophysis. The clinical manifestations of SIADH are dominated by hyponatremia, cerebral edema, and resultant neurologic dysfunction. Although total body water is increased, blood volume remains normal, and peripheral edema does not develop.

Hyperthyroidism

Thyrotoxicosis is a hypermetabolic state due to elevated circulating levels of free T₃ and T₄. Because it is caused most commonly by hyperfunction of the thyroid gland, thyrotoxicosis often is referred to as hyperthyroidism. In certain conditions, however, the oversupply either is related to excessive release of pre-formed thyroid hormone (e.g., in thyroiditis) or comes from an extrathyroidal source, rather than a hyperfunctioning gland (Table 19–2). Thus, strictly speaking, hyperthyroidism is only one (albeit the most common) category of thyrotoxicosis. Despite this clear distinction, the following discussion adheres to the common practice of using the terms thyrotoxicosis and hyperthyroidism interchangeably.

Table 19–2 Causes of Thyrotoxicosis

TSH, thyroid-stimulating hormone.

* Associated with increased TSH; all other causes of thyrotoxicosis associated with decreased TSH.

The clinical manifestations of thyrotoxicosis are truly protean and include changes referable to the hypermetabolic state induced by excessive amounts of thyroid hormone as well as those related to overactivity of the sympathetic nervous system:

Figure 19–6 Patient with hyperthyroidism. A wide-eyed, staring gaze, caused by overactivity of the sympathetic nervous system, is one of the classic features of this disorder. In Graves disease, one of the most important causes of hyperthyroidism, accumulation of loose connective tissue behind the orbits also adds to the protuberant appearance of the eyes.

The diagnosis of hyperthyroidism is based on clinical features and laboratory data. The measurement of serum TSH is the most useful single screening test for hyperthyroidism, because TSH levels are decreased even at the earliest stages, when the disease may still be subclinical. In rare cases of pituitary- or hypothalamus-associated (secondary) hyperthyroidism, TSH levels are either normal or raised. A low TSH value usually is associated with increased levels of free T₄. In the occasional patient, hyperthyroidism results predominantly from increased circulating levels of T₃ (T₃ toxicosis). In such cases, free T₄ levels may be decreased, and direct measurement of serum T₃ may be useful. Once the diagnosis of thyrotoxicosis has been confirmed by a combination of TSH and free thyroid hormone assays, measurement of radioactive iodine uptake by the thyroid gland often is valuable in determining the etiology. For example, such scans may show diffusely increased (whole-gland) uptake in Graves disease, increased uptake in a solitary nodule in toxic adenoma, or decreased uptake in thyroiditis.

Hypothyroidism

Hypothyroidism is caused by any structural or functional derangement that interferes with the production of adequate levels of thyroid hormone. As in the case of hyperthyroidism, this disorder is sometimes divided into primary and secondary categories, depending on whether the hypothyroidism arises from an intrinsic abnormality in the thyroid or from hypothalamic or pituitary disease (Table 19–3). Worldwide, the most common cause of hypothyroidism is dietary deficiency of iodine (see further on), while in most developed nations, autoimmune causes predominate. Genetic defects that perturb thyroid development itself (thyroid dysgenesis) or the synthesis of thyroid hormone (dyshormonogenetic goiter) are relatively rare.

Table 19–3 Causes of Hypothyroidism

FOXE1, forkhead box E1 gene; PAX8, paired box 8 gene.

* Associated with enlargement of thyroid (“goitrous hypothyroidism”). Hashimoto thyroiditis and postablative hypothyroidism account for a majority of cases of hypothyroidism in developed countries.

The clinical manifestations of hypothyroidism include cretinism and myxedema.

Laboratory evaluation has a vital role in the diagnosis of suspected hypothyroidism. As in the case of hyperthyroidism, measurement of serum TSH is the most sensitive screening test for this disorder. The serum TSH is increased in primary hypothyroidism because of a loss of feedback inhibition of thyrotropin-releasing hormone (TRH) and TSH production by the hypothalamus and pituitary, respectively. The TSH concentration is not increased in persons with hypothyroidism caused by primary hypothalamic or pituitary disease. Serum T₄ is decreased in patients with hypothyroidism of any origin.

Thyroiditis

Thyroiditis, or inflammation of the thyroid gland, encompasses a diverse group of disorders characterized by some form of thyroid inflammation. These diseases include conditions that result in acute illness with severe thyroid pain (e.g., infectious thyroiditis, granulomatous [de Quervain] thyroiditis) and disorders in which relatively little inflammation occurs and the illness is manifested primarily by thyroid dysfunction (subacute lymphocytic [“painless”] thyroiditis and fibrous [Reidel] thyroiditis). This section focuses on the more common and clinically significant types of thyroiditis: (1) Hashimoto thyroiditis (or chronic lymphocytic thyroiditis); (2) granulomatous (de Quervain) thyroiditis; and (3) subacute lymphocytic thyroiditis.

Chronic Lymphocytic (Hashimoto) Thyroiditis

Hashimoto thyroiditis is the most common cause of hypothyroidism in areas of the world where iodine levels are sufficient. It is characterized by gradual thyroid failure secondary to autoimmune destruction of the thyroid gland. It is most prevalent between the ages of 45 and 65 years and is more common in women than in men, with female predominance in a ratio of 10:1 to 20:1. Although it is primarily a disease of older women, it can occur in children and is a major cause of nonendemic goiter in children.

Pathogenesis

Hashimoto thyroiditis is caused by a breakdown in self-tolerance (Chapter 4) to thyroid autoantigens. Thus, circulating autoantibodies against thyroid antigens are present in the vast majority of patients, who demonstrate progressive depletion of thyroid epithelial cells (thyrocytes) and their replacement by mononuclear cell infiltration and fibrosis. The inciting events leading to breakdown in self-tolerance have not been fully elucidated, but multiple immunologic mechanisms that may contribute to thyrocyte damage have been identified (Fig. 19–7), including

• CD8+ cytotoxic T cell–mediated cell death: CD8+ cytotoxic T cells may cause thyrocyte destruction.

• Cytokine-mediated cell death: Excessive T cell activation leads to the production of inflammatory cytokines such as interferon-γ in the thyroid gland, with resultant recruitment and activation of macrophages and damage to follicles.

• Binding of antithyroid antibodies (antithyroglobulin, and antithyroid peroxidase antibodies), followed by antibody-dependent cell–mediated cytotoxicity (Chapter 4).

Figure 19–7 Pathogenesis of Hashimoto thyroiditis. Breakdown of immune tolerance to thyroid autoantigens results in progressive autoimmune destruction of thyrocytes by infiltrating cytotoxic T cells, locally released cytokines, or antibody-dependent cytotoxicity.

A significant genetic component to the disease pathogenesis is supported by the concordance of disease in as many as 40% of monozygotic twins, as well as the presence of circulating antithyroid antibodies in approximately 50% of asymptomatic siblings of affected patients. Increased susceptibility to Hashimoto thyroiditis is associated with polymorphisms in multiple immune regulation–associated genes, the most significant of which is the linkage to cytotoxic T lymphocyte–associated antigen-4 gene (CTLA4), which codes for a negative regulator of T cell function (Chapter 4).

Morphology

The thyroid usually is diffusely and symmetrically enlarged, although more localized enlargement may be seen in some cases. The cut surface is pale and gray-tan in appearance, and the tissue is firm and somewhat friable. Microscopic examination reveals widespread infiltration of the parenchyma by a mononuclear inflammatory infiltrate containing small lymphocytes, plasma cells, and well-developed germinal centers (Fig. 19–8). The thyroid follicles are atrophic and are lined in many areas by epithelial cells distinguished by the presence of abundant eosinophilic, granular cytoplasm, termed Hürthle, or oxyphil, cells. This is a metaplastic response of the normally low cuboidal follicular epithelium to ongoing injury; on ultrastructural examination, the Hürthle cells are characterized by numerous prominent mitochondria. Interstitial connective tissue is increased and may be abundant. Less commonly, the thyroid is small and atrophic as a result of more extensive fibrosis (fibrosing variant). Unlike in Reidel thyroiditis, the fibrosis does not extend beyond the capsule of the gland.

Figure 19–8 Hashimoto thyroiditis. The thyroid parenchyma contains a dense lymphocytic infiltrate with germinal centers. Residual thyroid follicles lined by deeply eosinophilic Hürthle cells also are seen.

Clinical Features

Hashimoto thyroiditis comes to clinical attention as painless enlargement of the thyroid, usually associated with some degree of hypothyroidism, in a middle-aged woman. The enlargement of the gland usually is symmetric and diffuse, but in some cases it may be sufficiently localized to raise suspicion for neoplasm. In the usual clinical course, hypothyroidism develops gradually. In some cases, however, it may be preceded by transient thyrotoxicosis caused by disruption of thyroid follicles, with secondary release of thyroid hormones (hashitoxicosis). During this phase, free T₄ and T₃ concentrations are elevated, TSH is diminished, and radioactive iodine uptake is decreased. As hypothyroidism supervenes, T₄ and T₃ levels progressively fall, accompanied by a compensatory increase in TSH. Patients with Hashimoto thyroiditis often have other autoimmune diseases and are at increased risk for the development of B cell non-Hodgkin lymphomas (Chapter 11), which typically arise within the thyroid gland. The relationship between Hashimoto disease and thyroid epithelial cancers remains controversial, with some morphologic and molecular studies suggesting a predisposition to papillary carcinomas.

Graves Disease

In 1835 Robert Graves reported on his observations of a disease characterized by “violent and long continued palpitations in females” associated with enlargement of the thyroid gland. Graves disease is the most common cause of endogenous hyperthyroidism. It is characterized by a triad of manifestations:

Graves disease has a peak incidence between the ages of 20 and 40, with women being affected up to seven times more commonly than men. This very common disorder is estimated to affect 1.5% to 2.0% of women in the United States. Genetic factors are important in the causation of Graves disease; the incidence is increased in relatives of affected patients, and the concordance rate in monozygotic twins is as high as 60%. As with other autoimmune disorders, a genetic susceptibility to Graves disease is associated with the presence of certain human leukocyte antigen (HLA) haplotypes, specifically HLA-DR3, and polymorphisms in genes encoding the inhibitory T cell receptor CTLA-4 and the tyrosine phosphatase PTPN22.

Autoimmune disorders of the thyroid thus span a continuum on which Graves disease, characterized by hyperfunction of the thyroid, lies at one extreme and Hashimoto disease, manifesting as hypothyroidism, occupies the other end. Sometimes hyperthyroidism may supervene on preexisting Hashimoto thyroiditis (hashitoxicosis), while at other times persons with Graves disease may spontaneously develop thyroid hypofunction; occasionally, Hashimoto thyroiditis and Graves disease may coexist within an affected kindred. Not surprisingly, there is also an element of histologic overlap between the autoimmune thyroid disorders (most characteristically, prominent intrathyroidal lymphoid cell infiltrates with germinal center formation). In both disorders, the frequency of other autoimmune diseases, such as systemic lupus erythematosus, pernicious anemia, type 1 diabetes, and Addison disease, is increased.

Morphology

In the typical case of Graves disease, the thyroid gland is enlarged (usually symmetrically) due to diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells. The gland is usually smooth and soft, and its capsule is intact. On microscopic examination, the follicular epithelial cells in untreated cases are tall, columnar, and more crowded than usual. This crowding often results in the formation of small papillae, which project into the follicular lumen (Fig. 19–9). Such papillae lack fibrovascular cores, in contrast with those of papillary carcinoma. The colloid within the follicular lumen is pale, with scalloped margins. Lymphoid infiltrates, consisting predominantly of T cells, with fewer B cells and mature plasma cells, are present throughout the interstitium; germinal centers are common.

Figure 19–9 Graves disease. The thyroid is diffusely hyperplastic. The follicles are lined by tall columnar epithelial cells that project into the lumina. These cells actively resorb the colloid in the centers of the follicles, resulting in the “scalloped” appearance of the edges of the colloid.

Changes in extrathyroidal tissues include generalized lymphoid hyperplasia. In persons with ophthalmopathy, the tissues of the orbit are edematous because of the presence of hydrophilic glycosaminoglycans. In addition, there is infiltration by lymphocytes, mostly T cells. Orbital muscles initially are edematous but may undergo fibrosis late in the course of the disease. The dermopathy, if present, is characterized by thickening of the dermis, as a result of deposition of glycosaminoglycans and lymphocyte infiltration.

Diffuse and Multinodular Goiter

Enlargement of the thyroid, or goiter, is the most common manifestation of thyroid disease. Diffuse and multinodular goiters reflect impaired synthesis of thyroid hormone, most often caused by dietary iodine deficiency. Impairment of thyroid hormone synthesis leads to a compensatory rise in the serum TSH, which in turn causes hypertrophy and hyperplasia of thyroid follicular cells and, ultimately, gross enlargement of the thyroid gland. The compensatory increase in functional mass of the gland is enough to overcome the hormone deficiency, ensuring a euthyroid metabolic state in the vast majority of affected persons. If the underlying disorder is sufficiently severe (e.g., a congenital biosynthetic defect), the compensatory responses may be inadequate to overcome the impairment in hormone synthesis, resulting in goitrous hypothyroidism. The degree of thyroid enlargement is proportional to the level and duration of thyroid hormone deficiency.

Goiters can be endemic or sporadic.

Morphology

In most cases, TSH-induced hypertrophy and hyperplasia of thyroid follicular cells result initially in diffuse, symmetric enlargement of the gland (diffuse goiter). The follicles are lined by crowded columnar cells, which may pile up and form projections similar to those seen in Graves disease. If dietary iodine subsequently increases, or if the demands for thyroid hormone decrease, the stimulated follicular epithelium involutes to form an enlarged, colloid-rich gland (colloid goiter). The cut surface of the thyroid in such cases usually is brown, somewhat glassy-appearing, and translucent. On microscopic examination, the follicular epithelium may be hyperplastic in the early stages of disease or flattened and cuboidal during periods of involution. Colloid is abundant during the latter periods. With time, recurrent episodes of hyperplasia and involution combine to produce a more irregular enlargement of the thyroid, termed multinodular goiter. Virtually all long-standing diffuse goiters convert into multinodular goiters. Multinodular goiters typically are hormonally silent, although a minority (approximately 10% over 10 years) can manifest with thyrotoxicosis secondary to the development of autonomous nodules that produce thyroid hormone independent of TSH stimulation. This condition, known as toxic multinodular goiter or Plummer syndrome, is not accompanied by the infiltrative ophthalmopathy and dermopathy of Graves disease–associated thyrotoxicosis.

Multinodular goiters are multilobulate, asymmetrically enlarged glands, which may attain massive size. On cut surface, irregular nodules containing variable amounts of brown, gelatinous colloid are evident (Fig. 19–10, A). Older lesions often show areas of fibrosis, hemorrhage, calcification, and cystic change. The microscopic appearance includes colloid-rich follicles lined by flattened, inactive epithelium and areas of follicular epithelial hypertrophy and hyperplasia, accompanied by the regressive changes just noted (Fig. 19–10, B).

Figure 19–10 Multinodular goiter. A, Gross morphologic appearance. The coarsely nodular gland contains areas of fibrosis and cystic change. B, Photomicrograph of specimen from a hyperplastic nodule, with compressed residual thyroid parenchyma on the periphery. The hyperplastic follicles contain abundant pink “colloid” within their lumina. Note the absence of a prominent capsule, a feature distinguishing such lesions from neoplasms of the thyroid.

(B, Courtesy of Dr. William Westra, Department of Pathology, Johns Hopkins University, Baltimore, Maryland.)

Neoplasms of the Thyroid

The thyroid gland gives rise to a variety of neoplasms, ranging from circumscribed, benign adenomas to highly aggressive, anaplastic carcinomas. From a clinical standpoint, the possibility of a tumor is of major concern in patients who present with thyroid nodules. Fortunately, the overwhelming majority of solitary nodules of the thyroid prove to be either follicular adenomas or localized, non-neoplastic conditions (e.g., a dominant nodule in multinodular goiter, simple cysts, or foci of thyroiditis). Carcinomas of the thyroid, by contrast, are uncommon, accounting for much less than 1% of solitary thyroid nodules. Several clinical criteria provide a clue to the nature of a given thyroid nodule:

Such statistics and general trends, however, are of little significance in the evaluation of a given patient, in whom the timely recognition of a malignancy, however uncommon, can be lifesaving. Ultimately, it is the morphologic evaluation of a given thyroid nodule by fine needle aspiration, combined with histologic study of surgically resected thyroid parenchyma, that provides the most definitive information about its nature. This section presents an overview of the major thyroid neoplasms, including adenomas and carcinomas of various types.

Adenomas

Adenomas of the thyroid are benign neoplasms derived from follicular epithelium. As in the case of all thyroid neoplasms, follicular adenomas usually are solitary. On clinical and morphologic grounds, they may be difficult to distinguish from a dominant nodule in multinodular goiter, for example, or from the less common follicular carcinomas. Although the vast majority of adenomas are nonfunctional, a small proportion produce thyroid hormones (toxic adenomas), causing clinically apparent thyrotoxicosis. In general, follicular adenomas are not forerunners to carcinomas; nevertheless, shared genetic alterations support the possibility that at least a subset of follicular carcinomas arise in preexisting adenomas (see further on).

Pathogenesis

The TSH receptor signaling pathway plays an important role in the pathogenesis of toxic adenomas. Activating (gain-of-function) somatic mutations in one of two components of this signaling system—most often the gene encoding the TSH receptor itself (TSHR) and, less commonly, the α-subunit of G_s (GNAS)—allow follicular cells to secrete thyroid hormone independent of TSH stimulation (thyroid autonomy). The result of this overabundance is symptomatic hyperthyroidism, with a “hot” thyroid nodule seen on imaging studies. Overall, somatic mutations in the TSH receptor signaling pathway seem to be present in slightly over half of toxic adenomas. Not surprisingly, such mutations also are observed in a subset of autonomous nodules that give rise to toxic multinodular goiters, as described earlier. A minority of nonfunctioning follicular adenomas (less than 20%) exhibit mutations of RAS or phosphatidylinositol-3-kinase (PIK3CA), or bear a PAX8/PPARG fusion gene, all of which are genetic alterations shared with follicular carcinomas. These are discussed in further detail under “Carcinomas” (see further on).

Morphology

The typical thyroid adenoma is a solitary, spherical lesion that compresses the adjacent non-neoplastic thyroid. The neoplastic cells are demarcated from the adjacent parenchyma by a well-defined, intact capsule (Fig. 19–11, A). These features are important in making the distinction from multinodular goiters, which contain multiple nodules on their cut surface (even though the patient may present clinically with a solitary dominant nodule), do not demonstrate compression of the adjacent thyroid parenchyma, and lack a well-formed capsule. On microscopic examination, the constituent cells are arranged in uniform follicles that contain colloid (Fig. 19–11, B). Papillary growth patterns, if present, should raise suspicion for an encapsulated papillary carcinoma (discussed later). Occasionally, the neoplastic cells acquire brightly eosinophilic granular cytoplasm (oxyphil or Hürthle cell change) (Fig. 19–12); the clinical presentation and behavior of a Hürthle cell adenoma are no different from those of a conventional adenoma. Similar to endocrine tumors at other anatomic sites, even benign follicular adenomas may, on occasion, exhibit focal nuclear pleomorphism, atypia, and prominent nucleoli (endocrine atypia); by themselves, these features do not constitute evidence of malignancy. The hallmark of all follicular adenomas is the presence of an intact well-formed capsule encircling the tumor. Careful evaluation of the integrity of the capsule is therefore critical in distinguishing follicular adenomas from follicular carcinomas, which demonstrate capsular and/or vascular invasion (see later).

Figure 19–11 Follicular adenoma of the thyroid. A, A solitary, well-circumscribed nodule is visible in this gross specimen. B, The photomicrograph shows well-differentiated follicles resembling those of normal thyroid parenchyma.

Figure 19–12 Hürthle cell adenoma. On this high-power view, the tumor is composed of cells with abundant eosinophilic cytoplasm and small regular nuclei.

(Courtesy of Dr. Mary Sunday, Brigham and Women’s Hospital, Boston, Massachusetts.)

Clinical Features

Most adenomas of the thyroid manifest as painless nodules, often discovered during a routine physical examination. Larger masses may produce local symptoms such as difficulty in swallowing. As previously stated, persons with toxic adenomas can present with features of thyrotoxicosis. After injection of radioactive iodine, most adenomas take up iodine less avidly than normal thyroid parenchyma. On radionuclide scanning, therefore, adenomas appear as cold nodules relative to the adjacent normal thyroid gland. Toxic adenomas, however, will appear as warm or hot nodules in the scan. As many as 10% of cold nodules eventually prove to be malignant. By contrast, malignancy is rare in hot nodules. Essential techniques used in the preoperative evaluation of suspected adenomas are ultrasonography and fine needle aspiration biopsy. Because of the need for evaluating capsular integrity, the definitive diagnosis of thyroid adenoma can be made only after careful histologic examination of the resected specimen. Suspected adenomas of the thyroid are therefore removed surgically to exclude malignancy. Thyroid adenomas carry an excellent prognosis and do not recur or metastasize.

Carcinomas

Carcinomas of the thyroid are relatively uncommon in the United States, accounting for about 1.5% of all cancers. A female predominance has been noted among patients who develop thyroid carcinoma in the early and middle adult years. By contrast, cases manifesting in childhood and late adult life are distributed equally between males and females. Most thyroid carcinomas (except medullary carcinomas) are derived from the thyroid follicular epithelium, and of these, the vast majority are well-differentiated lesions. The major subtypes of thyroid carcinoma and their relative frequencies are

• Papillary carcinoma (accounting for more than 85% of cases)

• Follicular carcinoma (5% to 15% of cases)

• Anaplastic (undifferentiated) carcinoma (less than 5% of cases)

• Medullary carcinoma (5% of cases)

Because of the unique clinical and biologic features associated with each variant of thyroid carcinoma, these subtypes are described separately. Presented next is an overview of the molecular pathogenesis of all thyroid cancers.

Pathogenesis

Both genetic and environmental factors are implicated in the pathogenesis of thyroid cancers.

Genetic Factors

Distinct molecular events are involved in the pathogenesis of the four major variants of thyroid cancer. As stated, medullary carcinomas do not arise from the follicular epithelium. Genetic alterations in the three follicular cell–derived malignancies are clustered along two oncogenic pathways—the mitogen-activated protein (MAP) kinase pathway and the phosphatidylinositol-3-kinase (PI-3K)/AKT pathway (Fig. 19–13). In normal cells, these pathways are transiently activated by binding of soluble growth factor ligands to the extracellular domain of receptor tyrosine kinases, which results in autophosphorylation of the cytoplasmic domain of the receptor, permitting intracellular signal transduction. In thyroid carcinomas, as with many solid cancers (Chapter 5), gain-of-function mutations along components of these pathways lead to constitutive activation even in the absence of ligand, thus promoting carcinogenesis.

• Papillary thyroid carcinomas: Activation of the MAP kinase pathway is a feature of most papillary carcinomas and can occur by one of two major mechanisms. The first mechanism involves rearrangements of RET or NTRK1 (neurotrophic tyrosine kinase receptor 1), both of which encode transmembrane receptor tyrosine kinases, and the second mechanism involves activating point mutations in BRAF, whose product is an intermediate signaling component in the MAP kinase pathway (Fig. 19–13). The RET gene is not normally expressed in thyroid follicular cells. In papillary cancers, chromosomal rearrangements place the tyrosine kinase domain of RET under the transcriptional control of genes that are constitutively expressed in the thyroid epithelium. The novel fusion proteins that are so formed are known as RET/PTC (papillary thyroid carcinoma) and are present in approximately 20% to 40% of papillary thyroid cancers. The frequency of RET/PTC rearrangements is significantly higher in papillary cancers arising in the backdrop of radiation exposure. Similarly, rearrangements of NTRK1 are present in 5% to 10% of papillary thyroid cancers, and the resultant fusion proteins are constitutively expressed in thyroid cells, leading to activation of MAP kinase pathways. One third to one half of papillary thyroid carcinomas harbor a gain-of-function mutation in the BRAF gene, which most commonly is a valine-to-glutamate change on codon 600 (BRAF^V600E). Since chromosomal rearrangements of the RET or NTRK1 genes and mutations of BRAF have redundant effects on the thyroid epithelium (both mechanisms result in activation of the MAP kinase signaling pathway), papillary thyroid carcinomas demonstrate either one or the other molecular abnormality, but not both. RET/PTC rearrangements and BRAF point mutations are not observed in follicular adenomas or carcinomas.

• Follicular thyroid carcinomas: Approximately one third to one half of follicular thyroid carcinomas harbor mutations in the PI-3K/AKT signaling pathway, resulting in constitutive activation of this oncogenic pathway. This subset of tumors includes those with gain-of-function point mutations of RAS and PIK3CA, those with amplification of PIK3CA, and those with loss-of-function mutations of PTEN, a tumor suppressor gene and negative regulator of this pathway. The progressive increase in the prevalence of RAS and PIK3CA mutations from benign follicular adenomas to follicular carcinomas to anaplastic carcinomas (see next) suggests a shared histogenesis and molecular evolution among these follicular cell–derived tumors. A unique (2;3)(q13;p25) translocation has been described in one third to one half of follicular carcinomas. This translocation creates a fusion gene composed of portions of PAX8, a paired homeobox gene that is important in thyroid development, and the peroxisome proliferator–activated receptor gene (PPARG), whose gene product is a nuclear hormone receptor implicated in terminal differentiation of cells. Less than 10% of follicular adenomas harbor PAX8/PPARG fusion genes, and thus far these have not been documented in other thyroid neoplasms.

• Anaplastic carcinomas: These highly aggressive and lethal tumors can arise de novo or, more commonly, by dedifferentiation of a well-differentiated papillary or follicular carcinoma. Molecular alterations present in anaplastic carcinomas include those also seen in well-differentiated carcinomas (e.g., RAS or PIK3CA mutations), albeit at a significantly higher rate, suggesting that the presence of these mutations might predispose existing thyroid neoplasms to transform. Other genetic hits, such as inactivation of TP53, are essentially restricted to anaplastic carcinomas and may also relate to their aggressive behavior.

• Medullary thyroid carcinomas: In contrast with the subtypes described earlier, these neoplasms arise from the parafollicular C cells, rather than the follicular epithelium. Familial medullary thyroid carcinomas occur in multiple endocrine neoplasia type 2 (MEN-2) (see later) and are associated with germline RET proto-oncogene mutations that lead to constitutive activation of the receptor. RET mutations are also seen in approximately one half of nonfamilial (sporadic) medullary thyroid cancers. Chromosomal rearrangements involving RET, such as the RET/PTC translocations reported in papillary cancers, are not seen in medullary carcinomas.

Figure 19–13 Genetic alterations in follicular cell–derived malignancies of the thyroid gland.

Environmental Factors

The major risk factor predisposing to thyroid cancer is exposure to ionizing radiation, particularly during the first 2 decades of life. In keeping with this finding, there was a marked increase in the incidence of papillary carcinomas among children exposed to ionizing radiation after the Chernobyl nuclear disaster in 1986. Deficiency of dietary iodine (and by extension, an association with goiter) is linked with a higher frequency of follicular carcinomas.

Papillary Carcinoma

As mentioned earlier, papillary carcinomas represent the most common form of thyroid cancer. These tumors may occur at any age, and they account for the vast majority of thyroid carcinomas associated with previous exposure to ionizing radiation.

Morphology

Papillary carcinomas may manifest as solitary or multifocal lesions within the thyroid. In some cases, they may be well circumscribed and even encapsulated; in other instances, they infiltrate the adjacent parenchyma with ill-defined margins. The lesions may contain areas of fibrosis and calcification and often are cystic. On cut surface, they may appear granular and sometimes contain grossly discernible papillary foci (Fig. 19–14, A). The definitive diagnosis of papillary carcinoma can be made only after microscopic examination. In current practice, the diagnosis of papillary carcinoma is based on nuclear features even in the absence of a papillary architecture. The nuclei of papillary carcinoma cells contain very finely dispersed chromatin, which imparts an optically clear appearance, giving rise to the designation ground glass or “Orphan Annie eye” nuclei (Fig. 19–14, C and D). In addition, invaginations of the cytoplasm may give the appearance of intranuclear inclusions (hence the designation pseudoinclusions) in cross-sections. A papillary architecture is common (Fig. 19–14, B); unlike hyperplastic papillary lesions seen in Graves disease, the neoplastic papillae have dense fibrovascular cores. Concentrically calcified structures termed psammoma bodies often are present within the papillae. Foci of lymphatic permeation by tumor cells are often present, but invasion of blood vessels is relatively uncommon, particularly in smaller lesions. Metastases to adjacent cervical lymph nodes are estimated to occur in about half of cases. There are over a dozen variants of papillary thyroid carcinoma, but the most common is one composed predominantly or exclusively of follicles (follicular variant of papillary thyroid carcinoma). The follicular variant more frequently is encapsulated and is associated with a lower incidence of lymph node metastases and extrathyroidal extension than that typical for conventional papillary carcinomas.

Figure 19–14 Papillary carcinoma of the thyroid. A–C, A papillary carcinoma with grossly discernible papillary structures. In this particular example, well-formed papillae (B) are lined by cells with characteristic empty-appearing nuclei, sometimes termed “Orphan Annie eye” nuclei (C). D, Cells obtained by fine-needle aspiration of a papillary carcinoma. Characteristic intranuclear inclusions are visible in some of the aspirated cells (arrows).

(Courtesy of Dr. S. Gokasalan, Department of Pathology, University of Texas Southwestern Medical School, Dallas, Texas.)

Clinical Features

Papillary carcinomas are nonfunctional tumors, so they manifest most often as a painless mass in the neck, either within the thyroid or as metastasis in a cervical lymph node. A preoperative diagnosis usually can be established by fine-needle aspiration on the basis of the characteristic nuclear features described earlier. Papillary carcinomas are indolent lesions, with 10-year survival rates in excess of 95%. Of interest, the presence of isolated cervical nodal metastases does not seem to have a significant influence on the generally good prognosis of these lesions. In a minority of patients, hematogenous metastases are present at the time of diagnosis, most commonly to the lung. The long-term survival of patients with papillary thyroid cancer is dependent on several factors, including age (in general, the prognosis is less favorable among patients older than 40 years), the presence of extrathyroidal extension, and presence of distant metastases (stage).

Follicular Carcinoma

Follicular carcinomas account for 5% to 15% of primary thyroid cancers. They are more common in women (occurring in a ratio of 3:1) and manifest at an older age than that typical for papillary carcinomas, with a peak incidence between the ages of 40 and 60 years. Follicular carcinoma is more frequent in areas with dietary iodine deficiency (accounting for 25% to 40% of thyroid cancers), while its incidence has either decreased or remained stable in iodine-sufficient areas of the world.

Morphology

On microscopic examination, most follicular carcinomas are composed of fairly uniform cells forming small follicles, reminiscent of normal thyroid (Fig. 19–15); in other cases, follicular differentiation may be less apparent. As with follicular adenomas, Hürthle cell variants of follicular carcinomas may be seen. Follicular carcinomas may be widely invasive, infiltrating the thyroid parenchyma and extrathyroidal soft tissues, or minimally invasive. The latter type are sharply demarcated lesions that may be impossible to distinguish from follicular adenomas on gross examination. This distinction requires extensive histologic sampling of the tumor capsule–thyroid interface, to exclude capsular and/or vascular invasion (Fig. 19–16). As mentioned earlier, follicular lesions in which the nuclear features are typical of papillary carcinomas should be regarded as follicular variants of papillary cancers.

Figure 19–15 Follicular carcinoma of the thyroid. A few of the glandular lumina contain recognizable colloid.

Figure 19–16 Capsular invasion in follicular carcinoma. Evaluating the integrity of the capsule is critical in distinguishing follicular adenomas from follicular carcinomas. A, In adenomas, a fibrous capsule, usually thin but occasionally more prominent, surrounds the neoplastic follicles and no capsular invasion is seen (arrows); compressed normal thyroid parenchyma usually is present external to the capsule (top). B, By contrast, follicular carcinomas demonstrate capsular invasion (arrows) that may be minimal, as in this case, or widespread, with extension into local structures of the neck.

Clinical Features

Follicular carcinomas manifest most frequently as solitary cold thyroid nodules. In rare cases, they may be hyperfunctional. These neoplasms tend to metastasize through the bloodstream (hematogenous dissemination) to the lungs, bone, and liver. In contrast with papillary carcinomas, regional nodal metastases are uncommon. As many as half of patients with widely invasive carcinomas succumb to their disease within 10 years, while less than 10% of patients with minimally invasive follicular carcinomas die within the same time span. Follicular carcinomas are treated with surgical excision. Well-differentiated metastases may take up radioactive iodine, which can be used to identify and also ablate such lesions. Because better-differentiated lesions may be stimulated by TSH, patients usually are placed on a thyroid hormone regimen after surgery to suppress endogenous TSH.

Anaplastic Carcinoma

Anaplastic carcinomas are undifferentiated tumors of the thyroid follicular epithelium, accounting for less than 5% of thyroid tumors. They are aggressive, with a mortality rate approaching 100%. Patients with anaplastic carcinoma are older than those with other types of thyroid cancer, with a mean age of 65 years. Approximately a quarter of patients with anaplastic thyroid carcinomas have a past history of a well-differentiated thyroid carcinoma, and another quarter harbor a concurrent well-differentiated tumor in the resected specimen.

Morphology

Anaplastic carcinomas manifest as bulky masses that typically grow rapidly beyond the thyroid capsule into adjacent neck structures. On microscopic examination, these neoplasms are composed of highly anaplastic cells, which may take on any of several histologic patterns, including those populated by

• Large, pleomorphic giant cells

• Spindle cells with a sarcomatous appearance

• Mixed spindle and giant cell lesions

Foci of papillary or follicular differentiation may be present in some tumors, suggesting origin from a better-differentiated carcinoma.

Clinical Features

Anaplastic carcinomas grow with wild abandon despite therapy. Metastases to distant sites are common, but in most cases death occurs in less than 1 year as a result of aggressive local 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. Like normal C cells, medullary carcinomas secrete calcitonin, the measurement of which plays an important role in the diagnosis and postoperative follow-up evaluation of patients. In some cases, the tumor cells elaborate other polypeptide hormones such as somatostatin, serotonin, and vasoactive intestinal peptide (VIP). Medullary carcinomas arise sporadically in about 70% of cases. The remaining 30% are familial cases occurring in the setting of MEN syndrome 2A or 2B, or familial medullary thyroid carcinoma without an associated MEN syndrome, as discussed later. Of note, both familial and sporadic medullary forms demonstrate activating RET mutations. Sporadic medullary carcinomas, as well as familial cases without an associated MEN syndrome, occur in adults, with a peak incidence in the fifth and sixth decades. Cases associated with MEN-2A or MEN-2B, by contrast, have been reported in younger patients, including children.

Morphology

Medullary carcinomas may arise as a solitary nodule or may manifest as multiple lesions involving both lobes of the thyroid. Multicentricity is particularly common in familial cases. Larger lesions often contain areas of necrosis and hemorrhage and may extend through the capsule of the thyroid. On microscopic examination, medullary carcinomas are composed of polygonal to spindle-shaped cells, which may form nests, trabeculae, and even follicles. Amyloid deposits, derived from altered calcitonin molecules, are present in the adjacent stroma in many cases (Fig. 19–17) and are a distinctive feature. Calcitonin is readily demonstrable both within the cytoplasm of the tumor cells and in the stromal amyloid by immunohistochemical methods. Electron microscopy reveals variable numbers of intracytoplasmic membrane-bound, electron-dense granules (Fig. 19–18). One of the peculiar features of familial medullary carcinomas is the presence of multicentric C cell hyperplasia in the surrounding thyroid parenchyma, a feature usually absent in sporadic lesions. Foci of C cell hyperplasia are believed to represent the precursor lesions from which medullary carcinomas arise.

Figure 19–17 Medullary carcinoma of the thyroid. These tumors typically contain amyloid, visible here as homogeneous extracellular material, derived from calcitonin molecules secreted by the neoplastic cells.

Figure 19–18 Electron micrograph of medullary thyroid carcinoma. These cells contain membrane-bound secretory granules, which are the sites of storage of calcitonin and other peptides. (Original magnification ×30,000.)

Clinical Features

In the sporadic cases, medullary carcinoma manifests most often as a mass in the neck, sometimes associated with compression effects such as dysphagia or hoarseness. In some instances, the initial manifestations are caused by the secretion of a peptide hormone (e.g., diarrhea caused by the secretion of VIP). Screening of the patient’s relatives for elevated calcitonin levels or RET mutations permits early detection of tumors in familial cases. As discussed at the end of this chapter, all members of MEN-2 kindreds carrying RET mutations are offered prophylactic thyroidectomies to preempt the development of medullary carcinomas; often, the only histologic finding in the resected thyroid of these asymptomatic carriers is the presence of C cell hyperplasia or small (less than 1 cm) micromedullary carcinomas. Recent studies have shown that specific RET mutations correlate with an aggressive behavior in medullary carcinomas.

Summary

Thyroid Neoplasms

• Most thyroid neoplasms manifest as solitary thyroid nodules, but only 1% of all thyroid nodules are neoplastic.

• Follicular adenomas are the most common benign neoplasms, while papillary carcinoma is the most common malignancy.

• Multiple genetic pathways are involved in thyroid carcinogenesis. Some of the genetic abnormalities that are fairly unique to thyroid cancers include PAX8/PPARG fusion (in follicular carcinoma), chromosomal rearrangements involving the RET oncogene (in papillary cancers), 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 features (ground glass nuclei, pseudoinclusions) even in the absence of papillae. These neoplasms typically metastasize by way of lymphatics, but the prognosis is excellent.

• Anaplastic carcinomas are thought to arise by dedifferentiation of more differentiated neoplasms. They are highly aggressive, uniformly lethal cancers.

• Medullary cancers are nonepithelial neoplasms arising from the parafollicular C cells and can occur in either sporadic (70%) or familial (30%) settings. Multicentricity and C cell hyperplasia are features of familial cases. Amyloid deposits are a characteristic histologic finding.

Hyperparathyroidism

Hyperparathyroidism occurs in two major forms, primary and secondary, and, less commonly, as tertiary hyperparathyroidism. The first condition represents an autonomous, spontaneous overproduction of PTH, while the latter two conditions typically occur as secondary phenomena in patients with chronic renal insufficiency.

Primary Hyperparathyroidism

Primary hyperparathyroidism is a common endocrine disorder, and an important cause of hypercalcemia. There has been a dramatic increase in the detection of cases in the latter half of the last century, mainly as a result of the routine inclusion of serum calcium assays in testing for a variety of clinical conditions that bring a patient to the hospital. The frequency of occurrence of the various parathyroid lesions underlying the hyperfunction is as follows:

• Adenoma—85% to 95%

• Primary hyperplasia (diffuse or nodular)—5% to 10%

• Parathyroid carcinoma—1%

In more than 95% of cases, primary hyperparathyroidism is caused by a sporadic parathyroid adenoma or sporadic hyperplasia. The genetic defects identified in familial primary hyperparathyroidism include multiple endocrine neoplasia syndromes, specifically MEN-1 and MEN-2A (see further on). Familial hypocalciuric hypercalcemia is a rare cause of hyperparathyroidism, caused by inactivating mutations in the calcium-sensing receptor gene on parathyroid cells, leading to constitutive PTH secretion.

PathogEnesis

Although the details of genetic alterations in sporadic parathyroid tumors are beyond the scope of this discussion, abnormalities in two specific genes are commonly associated with these tumors:

• Cyclin D1 gene inversions: Cyclin D1 is a positive regulator of the cell cycle. A chromosomal inversion on chromosome 11 results in relocation of the cyclin D1 gene (normally on 11q), so that it is now positioned adjacent to the 5′-flanking region of the PTH gene (on 11p), leading to abnormal expression of cyclin D1 protein and increased proliferation. Between 10% and 20% of adenomas have this clonal genetic defect. In addition, cyclin D1 is overexpressed in approximately 40% of parathyroid adenomas, suggesting that mechanisms other than cyclin D1 gene inversion can lead to its overexpression.

• MEN1 mutations: Approximately 20% to 30% of parathyroid tumors not associated with the MEN-1 syndrome have mutations in both copies of the MEN1 gene (see later). The spectrum of MEN1 mutations in the sporadic tumors is virtually identical to that in familial parathyroid adenomas.

Morphology

The morphologic changes seen in primary hyperparathyroidism include those in the parathyroid glands as well as those in other organs affected by elevated levels of calcium. In 75% to 80% of cases, one of the parathyroids harbors a solitary adenoma, which, like the normal parathyroids, may lie in close proximity to the thyroid gland or in an ectopic site (e.g., the mediastinum). The typical parathyroid adenoma is a well-circumscribed, soft, tan nodule, invested by a delicate capsule. By definition, parathyroid adenomas are almost invariably confined to single glands (Fig. 19–19), and the remaining glands are normal in size or somewhat shrunken, as a result of feedback inhibition by elevated serum calcium. Most parathyroid adenomas weigh between 0.5 and 5 g. On microscopic examination, parathyroid adenomas are composed predominantly of chief cells (Fig. 19–20). In most cases, at least a few nests of larger oxyphil cells also are present. A rim of compressed, non-neoplastic parathyroid tissue, generally separated by a fibrous capsule, often is visible at the edge of the adenoma. This finding constitutes a helpful internal control, since the chief cells of the adenoma are larger and show greater nuclear size variability than that typical for the normal chief cells. Cells with bizarre and pleomorphic nuclei are often seen within adenomas (so-called endocrine atypia) and must not be taken as a sign of malignancy. Mitotic figures are rare. In contrast with the normal parathyroid parenchyma, adipose tissue is inconspicuous within adenomas.

Figure 19–19 Technetium-99 radionuclide scan demonstrates an area of increased uptake corresponding to the left inferior parathyroid gland (arrow). This proved to be a parathyroid adenoma. Preoperative scintigraphy is useful in localizing and distinguishing adenomas from parathyroid hyperplasia, in which more than one gland will demonstrate increased uptake.

Figure 19–20 Chief cell parathyroid adenoma. A, On this low-power view, a solitary adenoma is clearly delineated from the residual gland below. B, High-power detail shows slight variation in nuclear size and tendency to follicular formation but no anaplasia.

Parathyroid hyperplasia is typically a multiglandular process. In some cases, however, enlargement may be grossly apparent in only one or two glands, complicating the distinction between hyperplasia and adenoma. The combined weight of all glands rarely exceeds 1.0 g and often is less. Microscopically, the most common pattern seen is that of chief cell hyperplasia, which may involve the glands in a diffuse or multinodular pattern. Less commonly, the constituent cells contain abundant clear cytoplasm as a consequence of accumulation of glycogen—a condition designated “water-clear cell hyperplasia.” As in the case of adenomas, stromal fat is inconspicuous within foci of hyperplasia.

Parathyroid carcinomas may be circumscribed lesions that are difficult to distinguish from adenomas, or they may be clearly invasive neoplasms. These tumors enlarge one parathyroid gland and consist of gray-white, irregular masses that sometimes exceed 10 g in weight. The cells usually are uniform and resemble normal parathyroid cells. They are arrayed in nodular or trabecular patterns with a dense, fibrous capsule enclosing the mass. There is general agreement that a diagnosis of carcinoma based on cytologic detail is unreliable, and invasion of surrounding tissues and metastasis are the only definitive criteria. Local recurrence occurs in one third of cases, and more distant dissemination occurs in another third.

Morphologic changes in other organs deserving special mention are found in the skeleton and kidneys. Skeletal changes include increased osteoclastic activity, which results in erosion of bone matrix and mobilization of calcium salts, particularly in the metaphyses of long tubular bones. Bone resorption is accompanied by increased osteoblastic activity and the formation of new bone trabeculae. In more severe cases the cortex is grossly thinned and the marrow contains increased amounts of fibrous tissue accompanied by foci of hemorrhage and cysts (osteitis fibrosa cystica) (Chapter 20). Aggregates of osteoclasts, reactive giant cells, and hemorrhagic debris occasionally form masses that may be mistaken for neoplasms (brown tumors of hyperparathyroidism). PTH-induced hypercalcemia favors the formation of urinary tract stones (nephrolithiasis) as well as calcification of the renal interstitium and tubules (nephrocalcinosis). Metastatic calcification secondary to hypercalcemia also may be seen in other sites, including the stomach, lungs, myocardium, and blood vessels.

Clinical Features

Primary hyperparathyroidism usually is a disease of adults and is much more common in women than in men (gender ratio of nearly 4:1). The most common manifestation of primary hyperparathyroidism is an increase in serum ionized calcium. In fact, primary hyperparathyroidism is the most common cause of clinically silent hypercalcemia. Of note, other conditions also may produce hypercalcemia (Table 19–4). The most common cause of clinically apparent hypercalcemia in adults is paraneoplastic syndromes associated with malignancy and bone metastases (Chapter 5). The prognosis for patients with malignancy-associated hypercalcemia is poor, because it often occurs in those with advanced cancers. In persons with hypercalcemia caused by parathyroid hyperfunction, serum PTH is inappropriately elevated, whereas serum PTH is low to undetectable in those with hypercalcemia caused by nonparathyroid diseases, including malignancy. Other laboratory alterations referable to PTH excess include hypophosphatemia and increased urinary excretion of both calcium and phosphate.

Table 19–4 Causes of Hypercalcemia

Raised PTH	Decreased PTH
Hyperparathyroidism Primary (adenoma > hyperplasia)* Secondary† Tertiary† Familial hypocalciuric hypercalcemia	Hypercalcemia of malignancy Osteolytic metastases PTH-rP–mediated Vitamin D toxicity Immobilization Drugs (thiazide diuretics) Granulomatous diseases (sarcoidosis)

PTH, parathyroid hormone; PTH-rP, PTH-related protein.

* Primary hyperparathyroidism is the most common cause of hypercalcemia overall. Malignancy is the most common cause of symptomatic hypercalcemia. Primary hyperparathyroidism and malignancy together account for nearly 90% of cases of hypercalcemia.

† Secondary and tertiary hyperparathyroidism are most commonly associated with progressive renal failure.

Primary hyperparathyroidism traditionally has been associated with a constellation of symptoms that included “painful bones, renal stones, abdominal groans, and psychic moans.” Pain, secondary to fractures of bones weakened by osteoporosis or osteitis fibrosa cystica and resulting from renal stones, with obstructive uropathy, was at one time a prominent manifestation of primary hyperparathyroidism. Because serum calcium is now routinely assessed in the workup of most patients who need blood tests for unrelated conditions, clinically silent hyperparathyroidism is detected early. Hence, many of the classic clinical manifestations, particularly those referable to bone and renal disease, are seen much less frequently. Additional signs and symptoms that may be encountered in some cases include

• Gastrointestinal disturbances, including constipation, nausea, peptic ulcers, pancreatitis, and gallstones

• Central nervous system alterations, including depression, lethargy, and seizures

• Neuromuscular abnormalities, including weakness and hypotonia

• Polyuria and secondary polydipsia

Although some of these alterations, for example, polyuria and muscle weakness, are clearly related to hypercalcemia, the pathogenesis of many of the other manifestations of the disorder remains poorly understood.

Hypoparathyroidism

Hypoparathyroidism is far less common than hyperparathyroidism. The major causes of hypoparathyroidism include the following:

The major clinical manifestations of hypoparathyroidism are secondary to hypocalcemia and include increased neuromuscular irritability (tingling, muscle spasms, facial grimacing, and sustained carpopedal spasm or tetany), cardiac arrhythmias, and, on occasion, increased intracranial pressures and seizures. Morphologic changes generally are inconspicuous but may include cataracts, calcification of the cerebral basal ganglia, and dental abnormalities.