Pathology_Robbins

Pathology_Robbins. Pituitary adenomas are designated as microadenomas if they are less than 1 cm in diameter and macroadenomas if they exceed 1 cm in diameter. Table20.1ClassificationofPituitaryAdenomas • Nonfunctioning adenomas are likely to come to clinical attention at a later stage and are, therefore, more likely to be macroadenomas. Because of their larger size, nonfunctioning adenomas may encroach upon and destroy adjacent anterior pituitary parenchyma, leading to hypopituitarism. Several genetic abnormalities associated with pituitary adenomas have been identified: • G-protein mutations are one of the most common genomic alterations in pituitary adenomas. G-proteins play a critical role in signal transduction, transmitting signals from cell surface receptors e.g. growth MammosomatotrophProlactin,GHMammosomatotrophadenomasCombinedfeaturesofGHandprolactinexcess GonadotrophFSH,LHGonadotrophadenomasHypogonadism,masseffects,Silentgonadotrophadenomas(“nullcell,”oncocyticadenomas)andhypopituitarism


Pathology_Robbins

Pathology_Robbins. GonadotrophFSH,LHGonadotrophadenomasHypogonadism,masseffects,Silentgonadotrophadenomas(“nullcell,”oncocyticadenomas)andhypopituitarism ACTH,Adrenocorticotrophichormone;FSH,follicle-stimulatinghormone;GH,growthhormone;LH,luteinizinghormone;POMC,pro-opiomelanocortin;TSH,thyroid-stimulatinghormone.*Notethatnonfunctional(silent)adenomasineachcategoryexpressthecorrespondinghormone(s)withintheneoplasticcells,asdeterminedbyspecialimmunohistochemicalstainingontissues.However,theseadenomasdonotproducetheassociatedclinicalsyndrome,andtypicallypresentwithmass effects accompaniedbyhypopituitarism duetodestructionofnormalpituitaryparenchyma.Thesefeaturesareparticularlycommonwithgonadotrophadenomas.PartiallyadaptedfromAsaSL,EssatS:Thepathogenesisofpituitarytumors.AnnuRevPathol4:97,2009. http://ebooksmedicine.net P P GDP ˜°˛P P P GTP P P GDP Receptor Ligand (GHRH, TSH, PTH) ˜°˛P P P GTP Adenyl cyclase cAMP Proliferation Hormone synthesis and secretion Mutation ˜°˛


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net P P GDP ˜°˛P P P GTP P P GDP Receptor Ligand (GHRH, TSH, PTH) ˜°˛P P P GTP Adenyl cyclase cAMP Proliferation Hormone synthesis and secretion Mutation ˜°˛ Fig.20.3G-proteinsignalinginendocrineneoplasia.MutationsthatleadtoG-proteinhyperactivityareseeninavarietyofendocrineneoplasms,includingpituitary,thyroid,andparathyroidadenomas.Gproteinsplayacriticalroleinsignaltransduction,transmittingsignalsfromcellsurfacereceptors(GHRH,TSH,orPTHreceptor)tointracellulareffectors(e.g.,adenylcyclase),whichthengeneratesecondmessengers(cAMP,cyclicadenosinemonophosphate).GDP, Guanosinediphosphate;GTP, guanosinetriphosphate;P, inorganicphosphate. hormone–releasing hormone (GHRH) receptor, to intracellular effectors (e.g., adenyl cyclase), which then generate second messengers (e.g., cAMP). G-proteins are heterotrimeric proteins, composed of a specific α-subunit that binds guanine nucleotides and interacts with both cell surface receptors and intracellular effectors (


Pathology_Robbins

Pathology_Robbins. Fig. 20.3 ); the β-and γ-subunits are noncovalently bound to the α-subunit. Gs is a stimulatory G protein that has a pivotal role in signal transduction in several endocrine organs, including the pituitary. The α-subunit of Gs (Gsα) is encoded by the GNAS gene. In the basal state, Gs exists in an inactive state, with guanosine diphosphate (GDP) bound to the guanine nucleotide-binding site of Gsα. On interaction with the ligand-bound cell surface receptor, GDP dissociates, and guanosine triphosphate (GTP) binds to Gsα, activating the G protein. The activation of Gsα results in the generation of cAMP, which is a potent mitogenic stimulus in several endocrine cells (e.g., pituitary somatotrophs and corticotrophs, thyroid follicular cells, parathyroid cells), promoting cellular proliferation and hormone synthesis and secretion. Normally, Gsα activation is transient because of an intrinsic GTPase activity in the α-subunit, which hydrolyzes GTP into GDP. Approximately 40% of somatotroph


Pathology_Robbins

Pathology_Robbins. and hormone synthesis and secretion. Normally, Gsα activation is transient because of an intrinsic GTPase activity in the α-subunit, which hydrolyzes GTP into GDP. Approximately 40% of somatotroph cell adenomas bear GNAS mutations that abrogate the GTPase activity of Gsα, leading to constitutive activation of Gsα, persistent generation of cAMP, and unchecked cellular proliferation. GNAS mutations also have been described in a minority of corticotroph adenomas; but are absent in thyrotroph, lactotroph, and gonadotroph adenomas, which arise from cells whose hypothalamic release hormones do not signal via cAMP-dependent pathways.


Pathology_Robbins

Pathology_Robbins. Approximately 5% of pituitary adenomas arise as a result of an inherited predisposition. Four genes have been identified thus far as a cause of familial pituitary adenomas: MEN1, CDKN1B, PRKAR1A, and AIP. These genes regulate transcription and the cell cycle. Of note, somatic mutations of these four genes are rarely encountered in sporadic pituitary adenomas. Molecular abnormalities associated with aggressive behavior include aberrations in cell cycle checkpoint genes, such as overexpression of cyclin D1, mutations of TP53, and epigenetic silencing of the retinoblastoma gene (RB). In addition, activating mutations of the RAS oncogene are observed in rare pituitary carcinomas. The functions of these genes were discussed in Chapter 6. MORPHOLOGYTheusualpituitaryadenomaisawell-circumscribed,softlesion.Smalltumorsmaybeconfinedtothesellaturcica,whilelargerlesionsmaycompresstheopticchiasmandadjacentstructures(


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Fig.20.1 .Notealsotheabsenceofthereticulinnetwork. Themostcommoncauseofhyperpituitarismisananteriorlobepituitaryadenoma. Pituitaryadenomascanbemacroadenomas(>1cmindiameter)ormicroadenomas(<1cmacross),andonclinicalevaluation,theycanbefunctionalornonfunctioning. Macroadenomasmaypotentiallyleadtomasseffects,includingvisualdisturbances. Functioningadenomasareassociatedwithdistinctendocrinesignsandsymptoms. MutationoftheGNAS gene,whichresultsinconstitutiveactivationofastimulatoryGprotein,isoneofthemorecommongeneticalterations. Thetwodistinctivemorphologicfeaturesofmostadenomasaretheircellularmonomorphismandabsenceofareticulinnetwork. Adenomas arising from different pituitary cells produce hormones characteristic of that cell type and cause clinical syndromes that reflect the activity of the hormones.


Pathology_Robbins

Pathology_Robbins. Adenomas arising from different pituitary cells produce hormones characteristic of that cell type and cause clinical syndromes that reflect the activity of the hormones. Prolactin-secreting lactotroph adenomas are the most frequent type of hyperfunctioning pituitary adenoma, accounting for about 30% of all clinically recognized cases. They range in size from microadenomas to large, expansile tumors associated with considerable mass effect. Prolactin is demonstrable within the cytoplasm of the neoplastic cells by immunohistochemical techniques. Prolactin secretion by lactotroph adenomas is highly efficient, such that even microadenomas can secrete sufficient hormone to induce systemic symptoms.


Pathology_Robbins

Pathology_Robbins. Hyperprolactinemia causes amenorrhea, galactorrhea, loss of libido, and infertility. Because manifestations of hyperprolactinemia (e.g., amenorrhea) are obvious in premenopausal women, prolactinomas are diagnosed at an earlier stage in women of reproductive age than in others with these tumors. By contrast, the effects of hyperprolactinemia are subtle in men and older women, in whom the tumor may reach a large size before coming to clinical attention. Hyperprolactinemia also is a feature of other conditions, including pregnancy, high-dose estrogen therapy, renal failure, hypothyroidism, hypothalamic lesions, and dopamine-inhibiting drugs (e.g., reserpine). In addition, any mass in the suprasellar compartment may disturb the normal inhibitory influence of hypothalamus on prolactin secretion, resulting in hyperprolactinemia—a mechanism known as the stalk effect. Thus, mild elevations of serum prolactin (<200 µg/L) in a patient with a pituitary adenoma do not necessarily indicate a


Pathology_Robbins

Pathology_Robbins. resulting in hyperprolactinemia—a mechanism known as the stalk effect. Thus, mild elevations of serum prolactin (<200 µg/L) in a patient with a pituitary adenoma do not necessarily indicate a prolactin-secreting neoplasm.


Pathology_Robbins

Pathology_Robbins. Growth hormone–secreting somatotroph adenomas are the second most common type of functioning pituitary adenoma, and cause gigantism in children or acromegaly in adults. Because the clinical manifestations of excess growth hormone may be subtle, somatotroph cell adenomas may be quite large by the time they come to clinical attention. On microscopic examination, growth hormone– producing adenomas are composed of densely or sparsely granulated cells, and immunohistochemical staining demonstrates growth hormone within the cytoplasm of the neoplastic cells. Small amounts of immunoreactive prolactin often are present as well.


Pathology_Robbins

Pathology_Robbins. Persistent growth hormone excess stimulates the hepatic secretion of insulin-like growth factor 1 (IGF1), which acts in conjunction with growth hormone to induce overgrowth of bones and muscle. If a growth hormone– secreting adenoma develops before the epiphyses close, as is the case in prepubertal children, excessive levels of growth hormone and IGF1 result in gigantism. This condition is characterized by a generalized increase in body size, with disproportionately long arms and legs. If elevated levels of growth hormone and IGF1 persist or develop after closure of the epiphyses, affected individuals develop acromegaly, in which growth is most conspicuous in soft tissues, skin, viscera, and the bones of the face, hands, and feet. Enlargement of the jaw results in its protrusion (prognathism), broadening of the lower face, and separation of the teeth. The hands and feet are enlarged, and the fingers are broad and sausage-like. In most instances gigantism is accompanied by evidence of


Pathology_Robbins

Pathology_Robbins. broadening of the lower face, and separation of the teeth. The hands and feet are enlarged, and the fingers are broad and sausage-like. In most instances gigantism is accompanied by evidence of acromegaly. These changes may develop slowly over decades before being recognized, hence the adenoma may be quite large before it is detected.


Pathology_Robbins

Pathology_Robbins. Persistent growth hormone excess also is associated with metabolic abnormalities, the most important of which is diabetes mellitus. This arises because of growth hormone–induced peripheral insulin resistance, which “blunts” the body’s response to elevated glucose levels (see “ ”, later). Failure to suppress growth hormone production in response to an oral load of glucose is one of the most sensitive tests for acromegaly. Other manifestations of growth hormone excess include gonadal dysfunction, generalized muscle weakness, hypertension, arthritis, congestive heart failure, and an increased risk for gastrointestinal cancers. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Excess production of ACTH by functioning corticotroph adenomas leads to adrenal hypersecretion of cortisol and the development of hypercortisolism (also known as Cushing syndrome). Cushing syndrome (discussed later with diseases of the adrenal gland) may be caused by other conditions as well. When the hypercortisolism is caused by excessive production of ACTH by the pituitary, it is called Cushing disease after the neurosurgeon Harvey Cushing who first described the disorder.


Pathology_Robbins

Pathology_Robbins. Most corticotroph adenomas are small (microadenomas) at the time of diagnosis. These adenomas stain positively with periodic acid–Schiff (PAS) stains, as a result of the accumulation of glycosylated ACTH protein. ACTH also can be specifically detected by immunohistochemical methods. Large, clinically aggressive corticotroph cell adenomas may develop after surgical removal of the adrenal glands for treatment of Cushing syndrome. In most instances this condition, known as Nelson syndrome, results from loss of the inhibitory effect of adrenal corticosteroids on a preexisting corticotroph microadenoma. Because the adrenals are absent in individuals with Nelson syndrome, hypercortisolism does not develop. Instead, patients present with the mass effects of the pituitary tumor. Patients with Cushing syndrome often have hyperpigmented skin because of increased production of melanocyte stimulating hormone (MSH), which is derived from the same precursor as ACTH so its synthesis accompanies that


Pathology_Robbins

Pathology_Robbins. syndrome often have hyperpigmented skin because of increased production of melanocyte stimulating hormone (MSH), which is derived from the same precursor as ACTH so its synthesis accompanies that of ACTH.


Pathology_Robbins

Pathology_Robbins. Other pituitary adenomas are associated with hormonal disorders not considered part of hyperpituitarism, or are nonfunctional and do not produce hormonal disturbances. Gonadotroph adenomas are so named because they produce hormones (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) that act on reproductive organs (gonads). These adenomas can be difficult to recognize because they secrete hormones inefficiently and variably and the secretory products usually do not cause a recognizable clinical syndrome. They are typically detected when the tumors become large enough to cause signs and symptoms related to local mass effects, such as impaired vision, headaches, diplopia, or pituitary apoplexy. The neoplastic cells usually demonstrate immunoreactivity for the common gonadotropin α-subunit and the specific β-FSH and β-LH subunits; FSH usually is the predominant secreted hormone.


Pathology_Robbins

Pathology_Robbins. Thyrotroph (thyroid-stimulating hormone [TSH]–producing) adenomas account for about 1% of all pituitary adenomas and constitute a rare cause of hyperthyroidism. Nonfunctioning pituitary adenomas are a heterogeneous group that constitutes 25% to 30% of all pituitary tumors. Not surprisingly, the typical presentation is characterized by mass effects. These lesions also may impinge on the residual anterior pituitary and produce hypopituitarism, which may appear slowly due to gradual enlargement of the adenoma or abruptly because of acute intratumoral hemorrhage (pituitary apoplexy). Pituitary carcinomas are exceedingly rare. In addition to local extension beyond the sella turcica, these tumors virtually always metastasize to distant sites. Prolactinomas: amenorrhea,galactorrhea,lossoflibido,andinfertility Growth hormone (somatotroph cell) adenomas: gigantism(children),acromegaly(adults),andimpairedglucosetoleranceanddiabetesmellitus


Pathology_Robbins

Pathology_Robbins. Prolactinomas: amenorrhea,galactorrhea,lossoflibido,andinfertility Growth hormone (somatotroph cell) adenomas: gigantism(children),acromegaly(adults),andimpairedglucosetoleranceanddiabetesmellitus Corticotrophcelladenomas:Cushingsyndrome,hyperpigmentation Allpituitaryadenomas,particularlynonfunctioningadenomas,maybeassociatedwithmasseffectsandhypopituitarism.


Pathology_Robbins

Pathology_Robbins. Corticotrophcelladenomas:Cushingsyndrome,hyperpigmentation Allpituitaryadenomas,particularlynonfunctioningadenomas,maybeassociatedwithmasseffectsandhypopituitarism. Clinically significant hypopituitarism may occur with loss or absence of 75% or more of the anterior pituitary parenchyma. It may be congenital (exceedingly rare) or result from a wide range of acquired intrinsic abnormalities of the pituitary. Less frequently, disorders that interfere with the delivery of pituitary hormone–releasing factors from the hypothalamus, such as hypothalamic tumors, cause hypofunction of the anterior pituitary. Hypopituitarism accompanied by evidence of posterior pituitary dysfunction in the form of diabetes insipidus (discussed later) is almost always of hypothalamic origin. Most cases of anterior pituitary hypofunction are caused by the following:


Pathology_Robbins

Pathology_Robbins. Ischemic necrosis of the anterior pituitary, called Sheehan syndrome, or postpartum necrosis of the anterior pituitary, is the most common form of clinically significant necrosis of the anterior pituitary. During pregnancy, the anterior pituitary enlarges, mainly because of an increase in the size and number of prolactin-secreting cells. This hyperplasia is not accompanied by an increase in blood supply from the low-pressure hypophyseal portal venous system. The enlarged gland is thus vulnerable to ischemic injury, especially in women who experience hypotension during the peripartal period. By contrast, the posterior pituitary receives its blood directly from arterial branches and is much less susceptible to ischemic injury. Pituitary necrosis also may occur in the setting of disseminated intravascular coagulation, sickle cell anemia, elevated intracranial pressure, traumatic injury, and shock of any origin.


Pathology_Robbins

Pathology_Robbins. Iatrogenic causes include ablation of the pituitary by surgery or radiation http://ebooksmedicine.net • Other, less common causes of anterior pituitary hypo-function include inflammatory lesions such as sarcoidosis or tuberculosis, trauma, and metastatic tumors involving the pituitary


Pathology_Robbins

Pathology_Robbins. The clinical manifestations of anterior pituitary hypo-function 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 hypothyroidism and hypoadrenalism, respectively (discussed later). 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 of skin from loss of stimulatory effects of MSH on melanocytes.


Pathology_Robbins

Pathology_Robbins. 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: anti-diuretic hormone (ADH) and oxytocin. They are stored in axon terminals in the neurohypophysis and released into the circulation in response to appropriate stimuli. ADH is a nonapeptide hormone synthesized predominantly in the supraoptic nucleus. In response to several different stimuli, including increased plasma osmotic 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. Oxytocin stimulates the contraction of smooth muscle in the pregnant uterus and of muscle surrounding the lactiferous ducts of the mammary


Pathology_Robbins

Pathology_Robbins. of the kidney to promote the resorption of free water. 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.


Pathology_Robbins

Pathology_Robbins. The clinically important posterior pituitary syndromes involve ADH underor overproduction.


Pathology_Robbins

Pathology_Robbins. ADH deficiency causes diabetes insipidus, a condition characterized by excessive urination (polyuria) due to an inability of the kidney to resorb water properly 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). Diabetes insipidus from ADH deficiency is designated central, to differentiate it from nephrogenic diabetes insipidus, which is caused by 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 compensate for urinary


Pathology_Robbins

Pathology_Robbins. 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 compensate for urinary losses, but patients who are obtunded, bedridden, or otherwise limited in their ability to obtain water may develop life-threatening dehydration.


Pathology_Robbins

Pathology_Robbins. The syndrome of inappropriate ADH (SIADH) secretion is typically associated with ADH excess, which causes resorption of excessive amounts of free water, resulting in hyponatremia. 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.


Pathology_Robbins

Pathology_Robbins. The thyroid gland consists of two bulky lateral lobes connected by a relatively thin isthmus, usually located below and anterior to the larynx. The thyroid gland develops embryologically from an evagination of the developing pharyngeal epithelium that descends from the foramen cecum at the base of the tongue to its normal position in the anterior neck. This pattern of descent explains the occasional presence of ectopic thyroid tissue, most commonly located at the base of the tongue (lingual thyroid) or at other sites abnormally high in the neck.


Pathology_Robbins

Pathology_Robbins. The thyroid is divided into lobules, each composed of about 20 to 40 evenly dispersed follicles. The follicles are lined by cuboidal to low columnar epithelium, which is filled with thyroglobulin, the iodinated precursor protein of active thyroid hormone. In response to trophic factors from the hypothalamus, TSH (also called thyrotropin) is released by thyrotrophs in the anterior pituitary into the circulation. The binding of TSH to its receptor on thyroid follicular epithelial cells results in activation and conformational change in the receptor, allowing it to associate with a stimulatory G-protein ( Fig. 20.6 ). As illustrated in


Pathology_Robbins

Pathology_Robbins. Fig. 20.6 ). As illustrated in Fig. 20.3, activation of stimulatory G-protein results in an increase in intracellular cAMP levels, which stimulates thyroid hormone synthesis and release. Thyroid follicular epithelial cells convert thyroglobulin into thyroxine (T4) and lesser amounts of triiodothyronine (T3). T4 and T3 are released into the systemic circulation, where most of these peptides are bound to circulating plasma proteins, such as T4-binding globulin, for transport to peripheral tissues. The binding proteins maintain the serum unbound (free) T3 and T4 concentrations within narrow limits while ensuring that the hormones are readily available to the tissues. http://ebooksmedicine.net TRH Pituitary Thyroid T3, T4 T3, T4 Thyroid hormone receptor Target gene TSH TSH receptor G protein GTP GDP cAMP G Gene expression on


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. In the periphery, the majority of free T4 is deiodinated to T3; the latter binds to thyroid hormone nuclear receptors in target cells with 10-fold greater affinity than T4 and has proportionately greater activity. Binding of thyroid hormone to its nuclear thyroid hormone receptor (TR) creates a hormone-receptor complex that regulates the transcription of a subset of cellular genes. This produces diverse cellular effects, including increased carbohydrate and lipid catabolism and protein synthesis in a wide range of cell types. The net result of these processes is an increase in the basal metabolic rate.


Pathology_Robbins

Pathology_Robbins. Clinical recognition of diseases of the thyroid is important, because most are amenable to medical or surgical management. Such diseases include conditions associated with excessive release of thyroid hormones (hyperthyroidism), thyroid hormone deficiency (hypothyroidism), and mass lesions of the thyroid. Considered next are the clinical consequences of disturbed thyroid function, followed by an overview of the disorders that generate these problems. Thyrotoxicosis is a hypermetabolic state caused by 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 preformed thyroid hormone (e.g., in thyroiditis) or comes from an extrathyroidal source, rather than a hyperfunctioning gland (


Pathology_Robbins

Pathology_Robbins. Table 20.2 ). 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. The three most common causes of thyrotoxicosis are associated with hyperfunction of the gland: Diffuse hyperplasia of the thyroid associated with Graves disease, a form of autoimmune thyroid disease (accounts for 85% of cases) Hyperfunctional (“toxic”) adenoma of the thyroid The clinical manifestations of thyrotoxicosis are protean and are mainly attributable to the hypermetabolic state induced by thyroid hormone and overactivity of the sympathetic nervous system:


Pathology_Robbins

Pathology_Robbins. The clinical manifestations of thyrotoxicosis are protean and are mainly attributable to the hypermetabolic state induced by thyroid hormone and overactivity of the sympathetic nervous system: Constitutional symptoms: The skin of thyrotoxic individuals tends to be soft, warm, and flushed because of increased blood flow and peripheral vasodilation to increase heat loss; heat intolerance and excessive sweating are common. Increased sympathetic activity and hypermetabolism result in weight loss despite increased appetite. Gastrointestinal: Stimulation of the gut results in rapid transit time (hypermotility), which can cause fat malabsorption and steatorrhea. Cardiac: Palpitations and tachycardia are common due to both increased cardiac contractility and increased Table20.2CausesofThyrotoxicosis TSH, Thyroid-stimulatinghormone.*AssociatedwithincreasedTSH;allothercausesofthyrotoxicosisassociatedwithdecreasedTSH. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Table20.2CausesofThyrotoxicosis TSH, Thyroid-stimulatinghormone.*AssociatedwithincreasedTSH;allothercausesofthyrotoxicosisassociatedwithdecreasedTSH. http://ebooksmedicine.net Fig.20.7Apatientwithhyperthyroidism.Awide-eyed,staringgaze,causedbyoveractivityofthesympatheticnervoussystem,isoneoftheclassicfeaturesofthisdisorder.InGravesdisease,oneofthemostimportantcausesofhyperthyroidism,accumulationoflooseconnectivetissuebehindtheorbitsalsoaddstotheprotuberantappearanceoftheeyes. peripheral oxygen requirements. Older adult patients with preexisting heart disease may develop congestive heart failure. Neuromuscular: Patients frequently experience nervousness, tremor, and irritability due to the sympathetic overactivity. Nearly 50% develop proximal muscle weakness (thyroid myopathy).


Pathology_Robbins

Pathology_Robbins. Neuromuscular: Patients frequently experience nervousness, tremor, and irritability due to the sympathetic overactivity. Nearly 50% develop proximal muscle weakness (thyroid myopathy). Ocular changes often call attention to hyperthyroidism. A wide, staring gaze and lid lag are present because of sympathetic overstimulation of the superior tarsal muscle (Müller’s muscle), which functions alongside the levator palpebrae superioris muscle to raise the upper eyelid ( Fig. 20.7 ). However, fullblown thyroid ophthalmopathy associated with proptosis is a feature seen only in Graves disease (discussed later).


Pathology_Robbins

Pathology_Robbins. Fig. 20.7 ). However, fullblown thyroid ophthalmopathy associated with proptosis is a feature seen only in Graves disease (discussed later). Thyroid storm designates the abrupt onset of severe hyperthyroidism. It occurs most often in patients with Graves disease and probably results from an acute elevation in catecholamine levels, as might be encountered during infection, surgery, cessation of anti-thyroid medication, or any form of stress. Thyroid storm is a medical emergency, as a significant number of untreated patients die of cardiac arrhythmias. Apathetic hyperthyroidism refers to thyrotoxicosis occurring in older adults, in whom the typical features of thyroid hormone excess often are blunted. The underlying thyroid disease is usually detected during laboratory workup for unexplained weight loss or worsening cardiovascular disease.


Pathology_Robbins

Pathology_Robbins. 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 pituitaryor 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 can be valuable in determining the etiology. For example, such scans may show diffusely increased uptake in Graves disease,


Pathology_Robbins

Pathology_Robbins. assays, measurement of radioactive iodine uptake by the thyroid gland can be valuable in determining the etiology. For example, such scans may show diffusely increased uptake in Graves disease, increased uptake in a solitary nodule in toxic adenoma, or decreased uptake in thyroiditis.


Pathology_Robbins

Pathology_Robbins. Hypothyroidism is caused by structural or functional derangements that interfere with thyroid hormone production. This disorder may be divided into primary and secondary categories, depending on whether it arises from an intrinsic abnormality in the thyroid or from hypothalamic or pituitary disease ( Table 20.3 ). Primary hypothyroidism can be secondary to congenital, autoimmune, or iatrogenic causes. Genetic defects that perturb thyroid development (thyroid dysgenesis) or the synthesis of thyroid hormone (dyshormonogenetic goiter) are rare overall but the most common cause of congenital hypothyroidism in the U.S. Endemic deficiency of dietary iodine is typically manifested by hyothryoidism early in childhood and has been also called congenital, but is not caused by genetic defects. It is a common cause of hypothyroidism in infants and children worldwide.


Pathology_Robbins

Pathology_Robbins. Autoimmune thyroid disease is a common cause of hypothyroidism in regions of the world where iodine is supplemented in dietary salt products. The vast majority of cases of autoimmune hypothyroidism are due to Hashimoto thyroiditis (discussed later). Iatrogenic hypothyroidism can be caused by either surgical or radiation-induced ablation of thyroid parenchyma, or as an unintended adverse effect of certain drugs. The clinical manifestations of hypothyroidism include cretinism and myxedema. Cretinism refers to hypothyroidism developing in infancy or early childhood. This disorder formerly was Table20.3CausesofHypothyroidism PostablativeSurgery,radioiodinetherapy,orexternalirradiationAutoimmunehypothyroidism Drugs(lithium,iodides,p-aminosalicylicacid) *Associatedwithenlargementofthyroid(“goitroushypothyroidism”).Hashimotothyroiditisandpostablativehypothyroidismaccountforthemajorityofcasesofhypothyroidismindevelopedcountries.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net fairly common in areas of the world where dietary iodine deficiency is endemic, including mountainous areas such as the Himalayas and the Andes (endemic cretinism). It is now much less frequent because of the widespread supplementation of salt with iodine. By contrast, enzyme defects that interfere with thyroid hormone synthesis are a cause of sporadic cretinism. Clinical features of cretinism include impaired development of the skeletal system and central nervous system, severe mental retardation, short stature, coarse facial features, a protruding tongue, and umbilical hernia. The severity of the mental impairment in cretinism seems to be influenced by the time of onset of the deficient state in utero. Normally, maternal hormones that are critical to fetal brain development, including T3 and T4, cross the placenta. If maternal thyroid deficiency is present before the development of the fetal thyroid gland, mental retardation is severe. By contrast,


Pathology_Robbins

Pathology_Robbins. brain development, including T3 and T4, cross the placenta. If maternal thyroid deficiency is present before the development of the fetal thyroid gland, mental retardation is severe. By contrast, reduction in maternal thyroid hormones later in pregnancy, after the fetal thyroid has developed, allows normal brain development.


Pathology_Robbins

Pathology_Robbins. • Hypothyroidism in older children and adults results in a condition known as myxedema. The initial symptoms include generalized fatigue, apathy, and mental sluggishness, which may mimic depression. Decreased sympathetic activity results in constipation and decreased sweating. The skin is cool and pale because of decreased blood flow. Reduced cardiac output contributes to shortness of breath and decreased exercise capacity, two frequent complaints. Thyroid hormones regulate the transcription of several sarcolemmal genes, such as calcium ATPases, whose encoded products are critical in maintaining efficient cardiac output. In addition, hypothyroidism promotes an atherogenic lipid profile—an increase in total cholesterol and low-density lipoprotein (LDL) levels—that may contribute to the adverse cardiovascular mortality rates in this disease. Histologically, there is an accumulation of matrix substances, such as glycosaminoglycans and hyaluronic acid, in skin, subcutaneous tissue, and


Pathology_Robbins

Pathology_Robbins. cardiovascular mortality rates in this disease. Histologically, there is an accumulation of matrix substances, such as glycosaminoglycans and hyaluronic acid, in skin, subcutaneous tissue, and viscera. This results in nonpitting edema, broadening and coarsening of facial features, enlargement of the tongue, and deepening of the voice.


Pathology_Robbins

Pathology_Robbins. The diagnosis of hypothyroidism is based on laboratory evaluation. As in the case of hyperthyroidism, measurement of serum TSH is the most sensitive screening test. The serum TSH concentration 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 individuals with hypothyroidism caused by primary hypothalamic or pituitary disease. Serum T4 is decreased in patients with hypothyroidism of any origin. Autoimmunity is the underlying cause of a variety of thyroid diseases, which are collectively referred to as autoimmune thyroid disease (AITD). These disorders include thyroiditis, and antibody-mediated disturbances in thyroid function that are not necessarily associated with inflammation (exemplified by Graves disease). We discuss first the various forms of thyroiditis.


Pathology_Robbins

Pathology_Robbins. Thyroiditis encompasses a diverse group of disorders characterized by some form of thyroid inflammation. This discussion focuses on the three most common and clinically significant subtypes: (1) Hashimoto thyroiditis, (2) granulomatous (de Quervain) thyroiditis, and (3) subacute lymphocytic 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 45 and 65 years of age and is more common in women with a female to male ratio of 10:1 to 20:1. Although it is primarily a disease of older women, it can occur at any age, including childhood.


Pathology_Robbins

Pathology_Robbins. Hashimoto thyroiditis is an autoimmune disease caused by an immune response to thyroid autoantigens (Chapter 5). Circulating autoantibodies against thyroid antigens are present in the vast majority of patients. The immune response leads to progressive depletion of thyroid epithelial cells associated with lymphocytic infiltrates and fibrosis. The inciting events leading to the autoimmune response have not been fully elucidated, but multiple immunologic mechanisms that may contribute to thyroid cell damage have been identified ( Fig. 20.8 ), including the following: CD8+ cytotoxic T-cell–mediated killing of thyroid epithelial cells. Cytokine-mediated cell death. 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.


Pathology_Robbins

Pathology_Robbins. Binding of anti-thyroid antibodies (anti-thyroglobulin, and anti-thyroid peroxidase antibodies), followed by antibody-dependent cell–mediated cytotoxicity (Chapter 5). The disease appears to have a significant genetic component, based on a concordance rate of about 40% in mono-zygotic twins and the presence of anti-thyroid antibodies in approximately 50% of asymptomatic siblings of affected patients. Increased susceptibility to Hashimoto thyroiditis is associated with polymorphisms in immune regulation– associated genes, the most significant of which is the cytotoxic T lymphocyte–associated antigen-4 gene (CTLA4), which codes for a negative regulator of T-cell responses (Chapter 5). MORPHOLOGYThethyroidusuallyisdiffuselyandsymmetricallyenlarged.Microscopicexaminationrevealswidespreadinfiltrationoftheparenchymabyamononuclearinflammatoryinfiltratecontainingsmalllymphocytes,plasmacells,andwell-developed http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Breakdown in self-tolerance and induction of thyroid autoimmunity Fig. 20.8 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. Fig. 20.9 ). 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 normal 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).


Pathology_Robbins

Pathology_Robbins. Hashimoto thyroiditis comes to clinical attention as painless enlargement of the thyroid, usually associated with some degree of hypothyroidism, often in a middle-age woman. Fig. 20.9 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.


Pathology_Robbins

Pathology_Robbins. 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 12), 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


Pathology_Robbins

Pathology_Robbins. 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.


Pathology_Robbins

Pathology_Robbins. Subacute granulomatous thyroiditis, also known as de Quervain thyroiditis, is much less common than Hashimoto disease. De Quervain thyroiditis is most common between 30 and 50 years of age and, like other forms of thyroiditis, occurs more frequently in women than in men. Subacute thyroiditis is believed to be caused by a viral infection or an inflammatory process triggered by viral infections, and not by an autoimmune process. A majority of patients have a history of an upper-respiratory infection shortly before the onset of thyroiditis. Unlike in autoimmune thyroid disease, the immune response in subacute granulomatous thyroiditis is not self-perpetuating, so the process spontaneously remits.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. The onset of this form of thyroiditis often is acute. It is characterized by neck pain (particularly with swallowing), fever, malaise, and variable enlargement of the thyroid. Transient hyperthyroidism may occur, as in other cases of thyroiditis, as a result of disruption of thyroid follicles and release of excessive thyroid hormone. The leukocyte count and erythrocyte sedimentation rates are increased. With progression of the gland destruction, a transient hypothyroid phase may ensue. The condition typically is self-limited, with most patients returning to a euthyroid state within 6 to 8 weeks.


Pathology_Robbins

Pathology_Robbins. Subacute lymphocytic thyroiditis also is known as silent or painless thyroiditis; in a subset of patients, the onset follows pregnancy (postpartum thyroiditis). This disease is most likely autoimmune in etiology, as circulating antithyroid antibodies are found in a majority of patients. It mostly affects middle-aged women, who present with a painless neck mass or features of thyroid hormone excess. The initial phase of thyrotoxicosis (which is likely to be secondary to thyroid tissue damage) is followed by return to a euthyroid state within a few months. In a minority of affected individuals, the condition eventually progresses to hypothyroidism. Except for possible mild symmetric enlargement, the thyroid appears normal on gross inspection. The histologic features consist of lymphocytic infiltration and hyperplastic germinal centers within the thyroid parenchyma.


Pathology_Robbins

Pathology_Robbins. Riedel thyroiditis, a rare disorder that is a manifestation of IgG4-related disease (Chapter 5), is characterized by extensive fibrosis involving the thyroid and contiguous neck structures. Clinical evaluation demonstrates a hard and fixed thyroid mass, simulating a thyroid neoplasm. It may be associated with idiopathic fibrosis in other sites in the body, such as the retroperitoneum. •Chroniclymphocytic(Hashimoto)thyroiditisisthemostcommoncauseofhypothyroidisminregionswheredietaryiodinelevelsaresufficient. Hashimotothyroiditisisanautoimmunediseasecharacterizedbyprogressivedestructionofthyroidparenchyma,Hürthlecellchange,andmononuclear(lymphoplasmacytic)infiltrates,withorwithoutextensivefibrosis. MultipleautoimmunemechanismsaccountforthyroidinjuryinHashimotodisease,includingcytotoxicitymediatedbyCD8+ Tcells,cytokines(IFN-γ),andanti-thyroidantibodies.


Pathology_Robbins

Pathology_Robbins. MultipleautoimmunemechanismsaccountforthyroidinjuryinHashimotodisease,includingcytotoxicitymediatedbyCD8+ Tcells,cytokines(IFN-γ),andanti-thyroidantibodies. Subacutegranulomatous(deQuervain)thyroiditisisaself-limiteddisease,probablysecondarytoaviralinfection,andischaracterizedbypainandthepresenceofagranulomatousinflammationinthethyroid. Subacutelymphocyticthyroiditisisaself-limiteddiseasethatoftenoccursafterapregnancy(postpartumthyroiditis),typicallyispainless,andischaracterizedbylymphocyticinflammationinthethyroid. 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: Thyrotoxicosis, caused by a diffusely enlarged, hyper-functional thyroid


Pathology_Robbins

Pathology_Robbins. Thyrotoxicosis, caused by a diffusely enlarged, hyper-functional thyroid An infiltrative ophthalmopathy with resultant exophthalmos, noted in as many as 40% of patients A localized, infiltrative dermopathy (sometimes designated pretibial myxedema), seen in a minority of cases


Pathology_Robbins

Pathology_Robbins. A localized, infiltrative dermopathy (sometimes designated pretibial myxedema), seen in a minority of cases Graves disease has a peak incidence between 20 and 40 years of age, with women being affected up to seven times more commonly than men. This is a common disorder, estimated to affect 1.5% to 2% of women in the United States. Genetic factors are important in 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 whose products regulate T-cell responses, including the inhibitory T-cell receptor CTLA-4 and the tyrosine phosphatase PTPN22.


Pathology_Robbins

Pathology_Robbins. Many manifestations of Graves disease are caused by autoantibodies against the TSH receptor that bind to, and stimulate, thyroid follicular cells independent of endogenous trophic hormones. Multiple autoantibodies are produced in Graves disease, including the following: • Thyroid-stimulating immunoglobulin (TSI). This IgG antibody binds to the TSH receptor and mimics the action of TSH, stimulating adenyl cyclase, with resultant increased release of thyroid hormones. Almost all individuals with Graves disease have detectable amounts of this autoantibody, which is relatively specific for Graves disease. http://ebooksmedicine.net Thyroid growth-stimulating immunoglobulins. Also directed against the TSH receptor, these antibodies have been implicated in the proliferation of thyroid follicular epithelium.


Pathology_Robbins

Pathology_Robbins. Thyroid growth-stimulating immunoglobulins. Also directed against the TSH receptor, these antibodies have been implicated in the proliferation of thyroid follicular epithelium. TSH-binding inhibitor immunoglobulins. These anti-TSH receptor antibodies prevent TSH from binding to its receptor on thyroid epithelial cells and in so doing may inhibit thyroid cell function. The coexistence of stimulating and inhibiting immunoglobulins in the serum of the same patient is not unusual, and may explain why some patients develop episodes of hypothyroidism.


Pathology_Robbins

Pathology_Robbins. A T-cell–mediated autoimmune phenomenon also is involved in the development of the infiltrative ophthalmopathy characteristic of Graves disease. In Graves ophthalmopathy, the volume of the retroorbital connective tissues and extraocular muscles is increased due to (1) marked infiltration of the retroorbital space by mononuclear cells, predominantly T cells; (2) inflammatory edema and swelling of extraocular muscles; (3) accumulation of extracellular matrix components, specifically hydrophilic glycosaminoglycans such as hyaluronic acid and chondroitin sulfate; and (4) increased numbers of adipocytes (fatty infiltration). These changes displace the eyeball forward, potentially interfering with the function of the extraocular muscles.


Pathology_Robbins

Pathology_Robbins. Autoimmune thyroid diseases thus span a continuum in 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, while at other times individuals 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.


Pathology_Robbins

Pathology_Robbins. The clinical manifestations of Graves disease include those common to all forms of thyrotoxicosis (discussed earlier), as well as those associated uniquely with Graves disease: diffuse hyperplasia of the thyroid, ophthalmopathy, and dermopathy. The degree of thyrotoxicosis varies from case to case, and the related changes may sometimes be less conspicuous than other manifestations of the disease. Increased flow of blood through the hyperactive gland often produces an audible bruit. Sympathetic overactivity produces a characteristic wide, staring gaze and lid lag. The ophthalmopathy of Graves disease results in abnormal protrusion of the eyeball (exophthalmos). The exophthalmos may persist or progress despite successful treatment of the thyrotoxicosis, sometimes resulting in corneal injury. The extraocular muscles often are weak. The infiltrative dermopathy most commonly involves the skin overlying the shins, where it manifests as scaly thickening and induration of the skin (pretibial


Pathology_Robbins

Pathology_Robbins. The extraocular muscles often are weak. The infiltrative dermopathy most commonly involves the skin overlying the shins, where it manifests as scaly thickening and induration of the skin (pretibial myxedema). The skin lesions may be slightly pigmented papules or nodules and often have an orange peel texture. Laboratory findings in Graves disease include elevated serum free T4 and T3 and depressed serum TSH. Because of ongoing stimulation of the thyroid follicles by TSIs, radioactive iodine uptake is increased diffusely.


Pathology_Robbins

Pathology_Robbins. LaboratoryfeaturesincludeelevationsinserumfreeT3andT4anddecreasedserumTSH. Enlargement of the thyroid, or goiter, is the most common manifestation of thyroid disease. Diffuse and multinodular goiters are the result of 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 drives the hypertrophy and hyperplasia of thyroid follicular cells and, ultimately, enlargement of the thyroid gland. The degree of thyroid enlargement is proportional to the level and duration of thyroid hormone deficiency. These compensatory changes overcome the hormone deficiency and maintain a euthyroid metabolic state in the vast majority of affected individuals. However, if the underlying disorder is severe (e.g., a congenital biosynthetic defect), the compensatory responses may be inadequate, resulting in goitrous hypothyroidism. Goiters can be endemic or sporadic.


Pathology_Robbins

Pathology_Robbins. Goiters can be endemic or sporadic. • Endemic goiter occurs in geographic areas where the diet contains little iodine. The designation endemic is used when goiters are present in more than 10% of the population in a given region. Such conditions are particularly common in mountainous areas of the world, including the Himalayas and the Andes. With increased availability of dietary iodine supplementation, the frequency and severity of endemic goiter have declined significantly.


Pathology_Robbins

Pathology_Robbins. • Sporadic goiter occurs less frequently than endemic goiter. The condition is more common in females than in males, with a peak incidence in puberty or young adulthood, when there is an increased physiologic demand for T4. Sporadic goiter may be caused by several conditions, including the excessive ingestion of substances that interfere with thyroid hormone synthesis, such as calcium and vegetables belonging to the Brassicaceae (also called Cruciferae) family (e.g., cabbage, cauliflower, Brussels sprouts, turnips). In other instances goiter may result from inherited enzymatic defects that interfere with thyroid hormone synthesis (dyshormonogenetic goiter). In most cases, however, the cause of sporadic goiter is not apparent.


Pathology_Robbins

Pathology_Robbins. Fig.20.11B Fig.20.11Multinodulargoiter.(A)Grossmorphologicappearance.Thecoarselynodularglandcontainsareasoffibrosisandcysticchange.(B)Photomicrographofaspecimenfromahyperplasticnodule,withcompressedresidualthyroidparenchymaontheperiphery.Thehyperplasticfolliclescontainabundantpink“colloid”withintheirlumina.Notetheabsenceofaprominentcapsule,afeaturedistinguishingsuchlesionsfromneoplasmsofthethyroid.(B, Courtesy of Dr.William Westra,Department of Pathology,Johns Hopkins University,Baltimore,Maryland.) http://ebooksmedicine.net The dominant clinical features of goiter are those caused by the mass effects of the enlarged gland. In addition to the obvious cosmetic problem of a large neck mass, goiters also may cause airway obstruction, dysphagia, and compression of large vessels in the neck and upper thorax (so-called “superior vena cava syndrome”).


Pathology_Robbins

Pathology_Robbins. Multinodular goiters typically are hormonally silent, but a minority (approximately 10% over 10 years) 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. The incidence of malignancy in long-standing multinodular goiters is low (<5%) but not zero, and concern for malignancy arises with goiters that demonstrate sudden changes in size or associated symptoms (e.g., hoarseness).


Pathology_Robbins

Pathology_Robbins. Thyroid tumors range 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 benign 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 less than 1% of solitary thyroid nodules. Several clinical criteria provide a clue to the nature of a given thyroid nodule: Solitary nodules, in general, are more likely to be neoplastic than are multiple nodules. Nodules in very young (<20 years) or very old (>70 years) individuals are more likely to be neoplastic. Nodules in males are more likely to be neoplastic than are those in females.


Pathology_Robbins

Pathology_Robbins. Nodules in very young (<20 years) or very old (>70 years) individuals are more likely to be neoplastic. Nodules in males are more likely to be neoplastic than are those in females. A history of radiation exposure is associated with an increased incidence of thyroid malignancy. Nodules that take up radioactive iodine in imaging studies (hot nodules) are more likely to be benign. Such associations, however, are of little significance in the evaluation of a given patient, in whom the timely recognition of a malignancy may be lifesaving. Ultimately, morphologic evaluation of a thyroid nodule by fine-needle aspiration, combined with the histologic study of surgically resected thyroid tissue, provide the most definitive information about the nature of the nodule.


Pathology_Robbins

Pathology_Robbins. Adenomas of the thyroid are benign neoplasms derived from follicular epithelium. 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 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. Driver mutations in the TSH receptor signaling pathway play an important role in the pathogenesis of toxic adenomas (see


Pathology_Robbins

Pathology_Robbins. Fig. 20.6 ). 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 Gs (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 are 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, discussed earlier. Thus, autonomy in both toxic goiter and toxic adenomas stems from the ability of follicular cells to release thyroid hormone independent of trophic factors (i.e., TSH). A minority of nonfunctioning follicular adenomas (<20%) exhibit mutations in RAS or other other genes, genetic alterations


Pathology_Robbins

Pathology_Robbins. cells to release thyroid hormone independent of trophic factors (i.e., TSH). A minority of nonfunctioning follicular adenomas (<20%) exhibit mutations in RAS or other other genes, genetic alterations that are shared with follicular carcinomas (discussed later).


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. 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. Individuals with toxic adenomas may 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, 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 uncommon 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 microscopic examination of the resected specimen.


Pathology_Robbins

Pathology_Robbins. aspiration biopsy. Because of the need for evaluating capsular integrity, the definitive diagnosis of thyroid adenoma can be made only after careful microscopic 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.


Pathology_Robbins

Pathology_Robbins. The detection of small , clinically asymptomatic cancerous nodules of the thyroid gland has increased dramatically in the United States over the last few years, largely due to the increasing use of thyroid ultrasound and other imaging studies. Nonetheless, deaths from thyroid cancer have remained relatively stable during this period, underscoring the favorable outcome for such incidentally detected thyroid carcinomas (and also raising questions about the value of detecting clinically insignificant cancers). A female predominance has been noted among patients who develop thyroid carcinoma in the early and middle adult years. By contrast, cases seen 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 as follows:


Pathology_Robbins

Pathology_Robbins. Papillary carcinoma (accounting for more than 85% of cases) Follicular carcinoma (5% to 15% of cases) Anaplastic (undifferentiated) carcinoma (<5% of cases) Medullary carcinoma (5% of cases) Because of the unique clinical and biologic features associated with each type of thyroid carcinoma, these are described separately. Presented next is an overview of the molecular pathogenesis of all thyroid cancers. Distinct molecular events are involved in the pathogenesis of the four major variants of thyroid cancer. Genetic alterations in the three follicular cell–derived malignancies are clustered along two oncogenic pathways that lie downstream of growth factor receptors and RAS—the mitogen-activated protein (MAP) kinase pathway and the phosphatidylinositol-3-kinase (PI-3K)/AKT pathway


Pathology_Robbins

Pathology_Robbins. Fig.20.13Hürthlecelladenoma.Onthishigh-powerview,thetumoriscomposedofcellswithabundanteosinophiliccytoplasmandsmallregularnuclei.(Courtesy of Dr. Mary Sunday, Brigham and Women’s Hospital, Boston, Massachusetts.) http://ebooksmedicine.net PAX8:PPARG Fig. 20.14 ). In normal cells, these pathways are transiently activated by binding of growth factors to receptor tyrosine kinases, which results in signal transduction. In thyroid carcinomas, as with many solid cancers (Chapter 6), gain-of-function mutations in components of these pathways lead to constitutive activation, even in the absence of growth factors, thus promoting carcinogenesis.


Pathology_Robbins

Pathology_Robbins. Papillary thyroid carcinomas. Activation of the MAP kinase pathway is a feature of most papillary carcinomas. The most common mechanisms of MAP kinase signaling are: (1) rearrangements in genes that encode the receptor tyrosine kinases RET and NTRK1 (neurotrophic tyrosine kinase receptor 1); and (2) activating point mutations in BRAF, whose product is a component of the MAP kinase pathway (see Fig. 20.14 ). One third to one half of papillary thyroid carcinomas harbor a gain-of-function mutation in BRAF, which is the most common driver mutation in this neoplasm. Since chromosomal rearrangements of the RET or NTRK1 genes and mutations of BRAF have redundant effects, papillary thyroid carcinomas demonstrate either one or the other molecular abnormality, but not both.


Pathology_Robbins

Pathology_Robbins. Follicular thyroid carcinomas. Follicular thyroid carcinomas frequently harbor driver mutations in RAS or in components of the PI3K/AKT signaling pathway. Both gain-of-function mutation in PI3K and loss-of-function mutations in PTEN, a negative regulator of PI3K, are seen. RAS and PI3K mutations also are found in benign follicular adenomas to and anaplastic carcinomas (see next) suggesting a shared histogenesis. One third to one half of follicular carcinomas also have a unique (2;3) (q13;p25) translocation that disrupts 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.


Pathology_Robbins

Pathology_Robbins. Anaplastic carcinomas. These highly aggressive tumors can arise de novo or, more commonly, by progression 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), as well as additional mutations that are specific to anaplastic carcinoma. The most common of these unique mutations are loss-of-function mutations in TP53, which are believed to have an important role in the development of anaplastic carcinomas.


Pathology_Robbins

Pathology_Robbins. 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 germ line RET proto-oncogene mutations that lead to constitutive activation of the RET tyrosine kinase receptor. RET mutations are also seen in approximately one-half of nonfamilial (sporadic) medullary thyroid cancers.


Pathology_Robbins

Pathology_Robbins. 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. As mentioned earlier, papillary carcinomas are 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. Papillary carcinomas are solitary or multifocal lesions. Some tumors may be well circumscribed and encapsulated; others infiltrate the adjacent parenchyma and have ill-defined margins. The cut surface sometimes reveals papillary foci that point to the diagnosis (


Pathology_Robbins

Pathology_Robbins. Fig. 20.15A ). The microscopic hallmarks of papillary neoplasms include the following: Fig. 20.15B ). In most cases, the epithelium covering the papillae haswell-differentiated, uniform, orderly cuboidal cells, but morepleomorphic or even anaplastic morphologies may be seen. Fig.20.15Papillarycarcinomaofthethyroidgland.(AtoC)Apapillarycarcinomawithgrosslydiscerniblepapillarystructures.Inthisparticularexample,well-formedpapillae(B)arelinedbycellswithcharacteristicempty-appearingnuclei,sometimestermedOrphan Annie eye nuclei(C).(D)Cellsobtainedbyfine-needleaspirationofapapillarycarcinoma.Characteristicintranuclearinclusionsarevisibleinsomeoftheaspiratedcells(arrows). (Courtesy of Dr. S. Gokasalan,Department of Pathology,University of Texas Southwestern Medical School,Dallas,Texas.) Nucleiwithfinelydispersedchromatin,whichimpartsanopticallyclearoremptyappearance,givingrisetothedesignationground-glassorOrphanAnnieeyenuclei(see Fig.


Pathology_Robbins

Pathology_Robbins. Papillary carcinomas are nonfunctional tumors, so they manifest most often as a painless mass in the neck, either within the thyroid or as a metastasis in a cervical lymph node. A preoperative diagnosis usually can be established by fine-needle aspiration based on 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 node metastases does not have a significant influence on prognosis. 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 of age), presence of extrathyroidal extension, and presence of distant metastases (stage).


Pathology_Robbins

Pathology_Robbins. Recent studies have shown that follicular variants of papillary carcinoma that lack evidence of invasion have essentially no potential for malignant behavior. In recognition of this, forthcoming recommendations from the World Health Organization suggest the name carcinoma should be stripped from these tumors, which will henceforth be classified as benign neoplasms to prevent overtreatment. 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 papillary carcinomas, with a peak incidence between 40 and 60 years of age. Follicular carcinoma is more frequent in areas with dietary iodine deficiency (accounting for 25%–40% of thyroid cancers), while its incidence has either decreased or remained stable in iodine-sufficient areas of the world. http://ebooksmedicine.net Fig.20.16Follicularcarcinomaofthethyroidgland.Afewoftheglandularluminacontainrecognizablecolloid.


Pathology_Robbins

Pathology_Robbins. Fig.20.17 ).Asdiscussedearlier,invasivefollicularlesionsinwhichthenuclearfeaturesaretypicalofpapillarycarcinomasareregardedasfollicularvariantsofpapillarycancers. 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 one-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.


Pathology_Robbins

Pathology_Robbins. 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 one-fourth of patients with anaplastic thyroid carcinomas have a history of a well-differentiated thyroid carcinoma, and another one-fourth harbor a concurrent well-differentiated tumor in the resected specimen. MORPHOLOGYAnaplasticcarcinomasmanifestasbulkymassesthattypicallygrowrapidlybeyondthethyroidcapsuleintoadjacentneckstructures.Onmicroscopicexamination,theseneoplasmsarecomposedofhighlyanaplasticcells,whichmaybelargeandpleomorphicorspindleshapedandinsomecasesmixtureofthetwocelltypes. Fociofpapillaryorfolliculardifferentiationmaybepresentinsometumors,suggestingoriginfromabetter-differentiatedcarcinoma.


Pathology_Robbins

Pathology_Robbins. Fociofpapillaryorfolliculardifferentiationmaybepresentinsometumors,suggestingoriginfromabetter-differentiatedcarcinoma. Fig.20.17Capsularinvasioninfollicularcarcinoma.Evaluatingtheintegrityofthecapsuleiscriticalindistinguishingfollicularadenomasfromfollicularcarcinomas.(A)Inadenomas,afibrouscapsule,usuallythinbutoccasionallymoreprominent,surroundstheneoplasticfolliclesandnocapsularinvasionisseen;compressednormalthyroidparenchymausuallyispresentexternaltothecapsule(top). (B)Bycontrast,follicularcarcinomasdemonstratecapsularinvasionthatmaybeminimal,asinthiscase,orwidespread,withextensionintolocalstructuresoftheneck. http://ebooksmedicine.net 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.


Pathology_Robbins

Pathology_Robbins. Medullary carcinomas of the thyroid are neuroendocrine tumors derived from the parafollicular cells, or C cells, of the thyroid. Like normal C cells, medullary carcinomas secrete calcitonin, measurement of which plays an important role in the diagnosis and postoperative follow-up of patients. In some cases, the tumor cells elaborate other polypeptide hormones such as somatostatin, serotonin, and vasoactive intestinal peptide. Medullary carcinomas arise sporadically in about 70% of cases. The remaining 30% are familial, occurring in the setting of multiple endocrine neoplasia (MEN) syndrome 2A or 2B, or familial medullary thyroid carcinoma without an associated MEN syndrome, as discussed later. Both familial and sporadic medullary forms are associated with gain-of-function driver mutations in the RET receptor tyrosine kinase. 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


Pathology_Robbins

Pathology_Robbins. in the RET receptor tyrosine kinase. 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, tend to occur in younger patients, including children.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. In 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 vasoactive intestinal peptide). Screening of the patient’s relatives for elevated calcitonin levels or RET mutations permits early detection of tumors in familial cases. As discussed later, 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 (<1 cm) micromedullary carcinomas. Fig.20.18Medullarycarcinomaofthethyroidgland.Thesetumorstypicallycontainamyloid,visiblehereashomogeneousextracellularmaterial,derivedfromcalcitoninmoleculessecretedbytheneoplasticcells.


Pathology_Robbins

Pathology_Robbins. Fig.20.18Medullarycarcinomaofthethyroidgland.Thesetumorstypicallycontainamyloid,visiblehereashomogeneousextracellularmaterial,derivedfromcalcitoninmoleculessecretedbytheneoplasticcells. Mostthyroidneoplasmsmanifestassolitary thyroid nodules, butonly1%ofallthyroidnodulesareneoplastic. Follicular adenomas arethemostcommonbenignneoplasms,whilepapillarycarcinomaisthemostcommonmalignancy. Multiplegeneticpathwaysareinvolvedinthyroid carcinogenesis. SomeofthedrivermutationsthatarefairlyuniquetothyroidcancersincludePAX8/PPARG fusion(infollicularcarcinoma),chromosomalrearrangementsinvolvingtheRET oncogene(inpapillarycancers),andmutationsofRET (inmedullarycarcinomas). Follicular adenomas and carcinomas botharecomposedofwell-differentiatedfollicularepithelialcells;thelatteraredistinguishedbypresenceofcapsularand/orvascularinvasion.


Pathology_Robbins

Pathology_Robbins. Follicular adenomas and carcinomas botharecomposedofwell-differentiatedfollicularepithelialcells;thelatteraredistinguishedbypresenceofcapsularand/orvascularinvasion. Papillary carcinomas arerecognizedbynuclearfeatures(groundglassnuclei,pseudoinclusions),evenintheabsenceofpapillae.Theseneoplasmstypicallymetastasizebywayofthelymphatics,buttheprognosisisexcellent. Anaplastic carcinomas arethoughttoarisebyprogressionofmoredifferentiatedneoplasms.Theyarehighlyaggressive,uniformlylethalcancers. Medullary cancers arenonepithelialneoplasmsarisingfromtheparafollicularCcellsandcanoccurineithersporadic(70%)orfamilial(30%)settings.MulticentricityandCcellhyperplasiaarefeaturesoffamilialcases.Amyloiddepositsareacharacteristichistologicfinding. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net The parathyroid glands are derived developmentally from pharyngeal pouches that also give rise to the thymus. They are most commonly located in close proximity to the upper and lower poles of each thyroid lobe but may be found anywhere along the pathway of descent of the pharyngeal pouches, including the carotid sheath, the thymus, and elsewhere in the anterior mediastinum. Most of the gland is composed of chief cells which have secretory granules containing parathyroid hormone (PTH). Oxyphil cells are found throughout the normal parathyroid either singly or in small clusters. They are slightly larger than the chief cells, have acidophilic cytoplasm, and are tightly packed with mitochondria.


Pathology_Robbins

Pathology_Robbins. Parathyroid glands are key regulators of calcium homeostasis. The activity of the parathyroid glands is controlled by the level of free (ionized) calcium in the blood, rather than by trophic hormones secreted by the hypothalamus and pituitary. Normally, decreased levels of free calcium stimulate the synthesis and secretion of PTH, which has the following effects on its target tissues, the kidneys and the bones: Increased renal tubular reabsorption of calcium Increased urinary phosphate excretion, thereby lowering serum phosphate levels (since phosphate binds to ionized calcium) Increased conversion of vitamin D to its active dihydroxy form in the kidneys, which in turn augments lesions underlying primary hyperparathyroidism is as follows: • Adenoma—85% to 95% • Primary hyperplasia (diffuse or nodular)—5% to 10% • Parathyroid carcinoma—1% Abnormalities in two genes are commonly associated with parathyroid tumors:


Pathology_Robbins

Pathology_Robbins. Abnormalities in two genes are commonly associated with parathyroid tumors: Cyclin D1 gene rearrangements. Cyclin D1 is a positive regulator of the cell cycle. An inversion on chromosome 11 repositions the cyclin D1 gene (normally on 11q), so that it resides adjacent to genomic elements that regulate the PTH gene (on 11p). These elements drive abnormal expression of cyclin D1 in PTH-producing cells, leading to increased proliferation of these cells. Between 10% and 20% of adenomas have this acquired genetic defect. Cyclin D1 is overexpressed in approximately 40% of parathyroid adenomas, indicating the existence of additional mechanisms that lead to its dysregulation. MEN1 mutations. Approximately 20% to 30% of sporadic parathyroid tumors have mutations in both copies of the MEN1 tumor suppressor gene (see later). The spectrum of MEN1 mutations in the sporadic tumors is virtually identical to that in familial parathyroid adenomas.


Pathology_Robbins

Pathology_Robbins. • Enhanced osteoclastic activity (i.e., bone resorption, MORPHOLOGYthus releasing ionized calcium), mediated indirectly by promoting the differentiation of osteoclast progenitor cells into mature osteoclasts The net result of these activities is an increase in the level of free calcium in the blood, which inhibits PTH secretion from chief cells. Abnormalities of the parathyroids include both hyperfunction and hypofunction. Tumors of the parathyroid glands, unlike thyroid tumors, usually come to attention because of excessive secretion of PTH, rather than mass effects. 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.


Pathology_Robbins

Pathology_Robbins. Primary hyperparathyroidism is a common endocrine disorder and an important cause of hypercalcemia. There was a dramatic increase in the detection of cases in the latter half of the 20th century, mainly due to routine performance of serum calcium assays in hospitalized patients. The frequency of occurrence of the various parathyroid Themorphologicchangesinprimaryhyperparathyroidismincludethoseintheparathyroidglandsandinotherorgansaffectedbyhypercalcemia.In75%to80%ofcases,oneoftheparathyroidglandsharborsasolitaryadenoma.Thetypicalparathyroidadenomaisawell-circumscribed,soft,tannodule,investedbyadelicatecapsule.Bydefinition,parathyroidadenomasareconfinedtoasinglegland( Fig.20.19 ).Theotherglandsarenormalinsizeorsomewhatshrunken,asaresultoffeedbackinhibitionbyelevatedserumcalcium.Mostparathyroidadenomasweighbetween0.5and5g.Onmicroscopicexamination,parathyroidadenomasarecomposedpredominantlyofchiefcells(


Pathology_Robbins

Pathology_Robbins. •Metastaticcalcificationsecondarytohypercalcemiaalsomaybeseeninothersites,includingthestomach,lungs,myocardium,andbloodvessels. 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. Other conditions also may produce hypercalcemia ( Table 20.4 ). The most common cause of clinically apparent hypercalcemia Table20.4CausesofHypercalcemia PTH, Parathyroidhormone;PTH-rP, PTH-relatedprotein.*Primaryhyperparathyroidismisthemostcommoncauseofhypercalcemiaoverall. †Secondaryandtertiaryhyperparathyroidismaremostcommonlyassociatedwithprogressiverenalfailure.


Pathology_Robbins

Pathology_Robbins. †Secondaryandtertiaryhyperparathyroidismaremostcommonlyassociatedwithprogressiverenalfailure. http://ebooksmedicine.net in adults is cancer, which can cause hypercalcemia through a variety of mechanisms, including secretion of PTH-like polypeptides and osteolytic bone metastases (Chapter 6). The prognosis for patients with malignancy-associated hypercalcemia is poor, because it often occurs in those with advanced cancers. In individuals 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.


Pathology_Robbins

Pathology_Robbins. Primary hyperparathyroidism traditionally has been associated with a constellation of symptoms that include 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 most patients who need blood tests for unrelated conditions, hyperparathyroidism is usually detected early in its course. 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 the following: Gastrointestinal disturbances, including constipation, nausea, peptic ulcers, pancreatitis, and gallstones Central nervous system alterations, including depression, lethargy, and seizures


Pathology_Robbins

Pathology_Robbins. 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 Although some of these alterations (e.g., polyuria and muscle weakness) are clearly related to hypercalcemia, the pathophysiology of many of the other manifestations of the disorder remains poorly understood.


Pathology_Robbins

Pathology_Robbins. Secondary hyperparathyroidism is caused by chronic depression of serum calcium levels, most often as a result of renal failure, leading to compensatory overactivity of the parathyroids. The mechanisms by which chronic renal failure induces secondary hyperparathyroidism are complex and not fully understood. Chronic renal insufficiency is associated with decreased phosphate excretion, which in turn results in hyperphosphatemia. The elevated serum phosphate levels directly depress serum calcium levels. In addition, loss of renal α1-hydroxylase activity, which is required for the synthesis of the active form of vitamin D, reduces the intestinal absorption of calcium (Chapter 8). These alterations cause chronic hypocalcemia, which stimulates the activity of the parathyroid glands.


Pathology_Robbins

Pathology_Robbins. The clinical manifestations of secondary hyperparathyroidism usually are dominated by those related to chronic renal failure. Bone abnormalities (renal osteodystrophy) and other changes associated with PTH excess are, in general, less severe than those seen in primary hyperparathyroidism. Serum calcium remains near normal because the compensatory increase in PTH levels sustains serum calcium. The metastatic calcification of blood vessels (secondary to hyperphosphatemia) occasionally may result in significant ischemic damage to skin and other organs—a process referred to as calciphylaxis. In a minority of patients, parathyroid activity may become autonomous and excessive, with resultant hypercalcemia—a process sometimes termed tertiary hyperparathyroidism. Parathyroidectomy may be necessary to control the hyperparathyroidism in such patients. Primaryhyperparathyroidismisthemostcommoncauseofasymptomatichypercalcemia.


Pathology_Robbins

Pathology_Robbins. Malignanciesarethemostimportantcauseofsymptomatichypercalcemia,whichresultsfromosteolyticmetastasesorreleaseofPTH-relatedproteinfromnonparathyroidtumors. Hypoparathyroidism is far less common than hyperparathyroidism. The major causes of hypoparathyroidism include the following: • Surgical ablation: The most common cause is inadvertent removal of parathyroids during thyroidectomy or other surgical neck dissections. http://ebooksmedicine.net Congenital absence: This occurs in conjunction with thymic aplasia (Di George syndrome) and cardiac defects, secondary to deletions on chromosome 22q11.2 (Chapter 7). Autoimmune hypoparathyroidism: This is a hereditary polyglandular deficiency syndrome arising from auto-antibodies to multiple endocrine organs (parathyroid, thyroid, adrenals, and pancreas). This condition is caused by mutations in the autoimmune regulator (AIRE) gene and is discussed more extensively later, in the context of autoimmune adrenalitis.


Pathology_Robbins

Pathology_Robbins. The major clinical manifestations of hypoparathyroidism are secondary to hypocalcemia. Acute cases (as may occur after surgical ablation) manifest as increased neuromuscular irritability (tingling, muscle spasms, facial grimacing, and sustained carpopedal spasm or tetany), cardiac arrhythmias, and, on occasion, increased intracranial pressure and seizures. Manifestations of chronic hypoparathyroidism include cataracts, calcification of the cerebral basal ganglia, and dental abnormalities.


Pathology_Robbins

Pathology_Robbins. The endocrine pancreas consists of the islets of Langerhans, which contain four major cell types—beta, alpha, delta, and PP (pancreatic polypeptide) cells. The beta cell produces insulin, which regulates glucose utilization in tissues and reduces blood glucose levels, as will be detailed in the discussion of diabetes; the alpha cell secretes glucagon, which raises glucose levels through its glycogenolytic activity in the liver; delta cells secrete somatostatin, which suppresses both insulin and glucagon release; and PP cells secrete pancreatic polypeptide, which exerts several gastrointestinal effects, such as stimulation of secretion of gastric and intestinal enzymes and inhibition of intestinal motility. The most important disease of the endocrine pancreas is diabetes mellitus, caused by deficient production or action of insulin.


Pathology_Robbins

Pathology_Robbins. Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia. Hyperglycemia in diabetes (in common parlance, the suffix “mellitus” is often not used) results from defects in insulin secretion, insulin action, or, most commonly, both. The chronic hyperglycemia and attendant metabolic abnormalities of diabetes are often associated with secondary damage in multiple organ systems, especially the kidneys, eyes, nerves, and blood vessels. In the United States, diabetes is the leading cause of end-stage renal disease, adult-onset blindness, and nontraumatic lower-extremity amputations resulting from atherosclerosis of arteries.


Pathology_Robbins

Pathology_Robbins. According to the American Diabetes Association, diabetes affects over 29 million children and adults, or 9.3% of the population, in the United States, nearly one-third of whom are currently unaware that they have hyperglycemia. Approximately 1.4 million new cases of diabetes are diagnosed each year in the United States, and there is a wide variability in prevalence between different ethnic groups. For example, the prevalence of diabetes in American Indian/Alaskan Natives is almost twice that of Caucasians. Increasingly sedentary lifestyles and poor eating habits have contributed to the increases in diabetes and obesity, which some have termed the diabesity epidemic. A staggering 86 million adults in the United States have prediabetes, which is defined as elevated blood sugar that does not reach the criterion accepted for an outright diagnosis of diabetes (discussed next); individuals with prediabetes have an elevated risk for development of frank diabetes.


Pathology_Robbins

Pathology_Robbins. Blood glucose is normally maintained in a very narrow range, usually 70 to 120 mg/dL. According to the American Diabetes Association (ADA) and the World Health Organization (WHO), diagnostic criteria for diabetes include the following: 1. A fasting plasma glucose greater than or equal to 126 mg/dL, and/or 2. A random plasma glucose greater than or equal to 200 mg/dL (in a patient with classic hyperglycemic signs, discussed later), and/or 3. A 2-hour plasma glucose greater than or equal to 200 mg/dL during an oral glucose tolerance test with a loading dose of 75 gm, and/or 4. A glycated hemoglobin (HbA1C) level greater than or equal to 6.5% (glycated hemoglobin is further discussed under chronic complications of diabetes)


Pathology_Robbins

Pathology_Robbins. A glycated hemoglobin (HbA1C) level greater than or equal to 6.5% (glycated hemoglobin is further discussed under chronic complications of diabetes) All tests, except the random blood glucose test in a patient with classic hyperglycemic signs, need to be repeated and confirmed on a separate day. Of note, many acute conditions associated with stress, such as severe infections, burns, or trauma, can lead to transient hyperglycemia due to secretion of hormones such as catecholamines and cortisol that oppose the effects of insulin. The diagnosis of diabetes requires persistence of hyperglycemia following resolution of the acute illness. Impaired glucose tolerance (prediabetes) is defined as: 1. A fasting plasma glucose between 100 and 125 mg/dL (“impaired fasting glucose”), and/or 2. during an oral glucose tolerance test, and/or 3. HbA1C level between 5.7% and 6.4%


Pathology_Robbins

Pathology_Robbins. A fasting plasma glucose between 100 and 125 mg/dL (“impaired fasting glucose”), and/or 2. during an oral glucose tolerance test, and/or 3. HbA1C level between 5.7% and 6.4% As many as one-fourth of individuals with impaired glucose tolerance will develop overt diabetes in the next 5 years, with additional risk factors such as obesity and family history compounding such risk. In addition, individuals with prediabetes have an elevated risk of cardiovascular disease. Although all forms of diabetes share hyperglycemia as a common feature, the underlying causes of hyperglycemia vary widely. Previous classification schemes of diabetes were based on age at onset of the disease http://ebooksmedicine.net Table20.5SimplifiedClassificationofDiabetes 1. Type 1 Diabetes Betacelldestruction,usuallyleadingtoabsoluteinsulindeficiency 2. 3. Genetic Defects of Beta Cell Function Maturity-onsetdiabetesoftheyoung(MODY)(seetext)Insulingenemutations 4. 5. 6. 7. 8. 9.


Pathology_Robbins

Pathology_Robbins. 3. Genetic Defects of Beta Cell Function Maturity-onsetdiabetesoftheyoung(MODY)(seetext)Insulingenemutations 4. 5. 6. 7. 8. 9. ModifiedfromDiagnosisandclassificationofdiabetesmellitus(AmericanDiabetesAssociation).Diabetes Care 37:S81-S90;2014. or on the mode of therapy; in contrast, the current etiologic classification reflects a greater understanding of the pathogenesis of each variant ( Table 20.5 ). The vast majority of cases of diabetes fall into one of two broad classes: Type 1 diabetes is an autoimmune disease characterized by pancreatic β-cell destruction and an absolute deficiency of insulin. It accounts for approximately 5% to 10% of all cases, and is the most common subtype diagnosed in patients younger than 20 years of age.


Pathology_Robbins

Pathology_Robbins. Type 2 diabetes is caused by a combination of peripheral resistance to insulin action and an inadequate secretory response by the pancreatic β cells (“relative insulin deficiency”). Approximately 90% to 95% of diabetic patients have type 2 diabetes, and many of them are overweight. Although classically considered “adult-onset,” the prevalence of type 2 diabetes in children and adolescents is increasing at an alarming pace due to the increasing rates of obesity in these age groups. A variety of monogenic and secondary causes are responsible for the remaining cases (discussed later). Of note, when combined, monogenic and secondary forms of diabetes account for >10% of diabetes (which together makes them more common than type 1 diabetes). An important point is that although the major types of diabetes arise by different pathogenic mechanisms, the long-term complications in kidneys, eyes, nerves, and blood vessels are the same and are the principal causes of morbidity and death.


Pathology_Robbins

Pathology_Robbins. Before discussing the pathogenesis of the two major types of diabetes, we briefly review normal insulin physiology and glucose metabolism. Normal glucose homeostasis is tightly regulated by three interrelated processes: (1) glucose production in the liver; (2) glucose uptake and utilization by peripheral tissues, chiefly skeletal muscle; and (3) the actions of insulin and counterregulatory hormones (especially glucagon).


Pathology_Robbins

Pathology_Robbins. The principal function ofinsulin is toincrease therate of glucose transport into certain cells in the body (Fig. 20.21 ). These are the striated muscle cells (including myocardial cells) and, to a lesser extent, adipocytes, representing collectively about two thirds of total body weight. Glucose uptake in other peripheral tissues, most notably the brain, is insulin-independent. In muscle cells, glucose is then either stored as glycogen or oxidized to generate adenosine triphosphate (ATP) and metabolic intermediates needed for cell growth. In adipose tissue, glucose is metabolized to lipids, which are stored as fat. Besides promoting lipid synthesis (lipogenesis), insulin also inhibits lipid degradation (lipolysis) in adipocytes. Similarly, insulin promotes amino acid uptake and protein synthesis while inhibiting protein degradation. Thus, the metabolic effects of insulin can be summarized as anabolic, with increased synthesis and reduced degradation of glycogen, lipid, and protein. In


Pathology_Robbins

Pathology_Robbins. while inhibiting protein degradation. Thus, the metabolic effects of insulin can be summarized as anabolic, with increased synthesis and reduced degradation of glycogen, lipid, and protein. In addition to these metabolic effects, insulin has several mitogenic functions, including initiation of DNA synthesis in certain cells and stimulation of their growth and differentiation.


Pathology_Robbins

Pathology_Robbins. Insulin reduces the production of glucose from the liver. Insulin and glucagon have opposing regulatory effects on glucose homeostasis. During fasting states, low Fig.20.21Metabolicactionsofinsulininstriatedmuscle,adiposetissue,andliver. http://ebooksmedicine.net insulin and high glucagon levels facilitate hepatic gluconeogenesis and glycogenolysis (glycogen breakdown) while decreasing glycogen synthesis, thereby preventing hypoglycemia. Thus, fasting plasma glucose levels are determined primarily by hepatic glucose output. After a meal, insulin levels rise and glucagon levels fall in response to the large glucose load.


Pathology_Robbins

Pathology_Robbins. The most important stimulus that triggers insulin release from pancreatic beta cells is glucose itself. Oral intake of food leads to secretion of multiple hormones, notably the incretins produced by cells in the intestines. These hormones stimulate insulin secretion from beta cells, and also reduce glucagon secretion and delay gastric emptying, which promotes satiety. The incretin effect is significantly blunted in patients with type 2 diabetes, and restoring incretin function can lead to improved glycemic control and loss of weight (through restoration of satiety). These observations have resulted in the development of new classes of drugs for patients with type 2 diabetes that mimic incretins or enhance the levels of endogenous incretins through delaying their degradation.