The Endocrine System PDF

See TARGETED THERAPY available online at www.studentconsult.com C H A P T E R The Endocrine System Anirban Maitra...

See TARGETED THERAPY available online at www.studentconsult.com C H A P T E R The Endocrine System Anirban Maitra 24 CHAPTER CONTENTS PITUITARY GLAND 1066 Follicular Carcinoma 1089 Morphology of Chronic Complications of Clinical Manifestations of Pituitary Poorly Differentiated and Anaplastic Diabetes 1108 Disease 1067 (Undifferentiated) Carcinoma 1090 Clinical Manifestations of Chronic Pituitary Adenomas and Medullary Carcinoma 1091 Diabetes 1111 Hyperpituitarism 1067 Congenital Anomalies 1092 Pancreatic Neuroendocrine Lactotroph Adenoma 1070 Tumors 1113 PARATHYROID GLANDS 1093 Somatotroph Adenoma 1071 Hyperinsulinism (Insulinoma) 1113 Hyperparathyroidism 1093 Corticotroph Adenoma 1071 Zollinger-Ellison Syndrome (Gastrinoma) 1114 Primary Hyperparathyroidism 1093 Other Anterior Pituitary Other Rare Pancreatic Endocrine Secondary Hyperparathyroidism 1096 Tumors 1072 Neoplasms 1114 Hypoparathyroidism 1096 Hypopituitarism 1072 Pseudohypoparathyroidism 1097 ADRENAL GLANDS 1114 Posterior Pituitary Syndromes 1073 Adrenal Cortex 1115 Hypothalamic Suprasellar THE ENDOCRINE Adrenocortical Hyperfunction Tumors 1074 PANCREAS 1097 (Hyperadrenalism) 1115 Diabetes Mellitus 1097 THYROID GLAND 1075 Hypercortisolism (Cushing Syndrome) 1115 Glucose Homeostasis 1100 Hyperthyroidism 1075 Primary Hyperaldosteronism 1118 Regulation of Insulin Release 1100 Hypothyroidism 1077 Adrenogenital Syndromes 1120 Insulin Action and Insulin-Signaling Cretinism 1078 Adrenocortical Insufficiency 1122 Pathways 1101 Myxedema 1078 Primary Acute Adrenocortical Insufficiency 1122 Pathogenesis of Type 1 Diabetes 1101 Thyroiditis 1078 Waterhouse-Friderichsen Syndrome 1122 Genetic Susceptibility 1101 Hashimoto Thyroiditis 1078 Primary Chronic Adrenocortical Insufficiency Environmental Factors 1102 Subacute Lymphocytic (Painless) (Addison Disease) 1123 Mechanisms of β-Cell Destruction 1102 Thyroiditis 1080 Secondary Adrenocortical Insufficiency 1124 Pathogenesis of Type 2 Diabetes 1103 Granulomatous Thyroiditis 1080 Adrenocortical Neoplasms 1125 Genetic Factors 1103 Graves Disease 1081 Other Adrenal Lesions 1126 Environmental Factors 1103 Diffuse and Multinodular Adrenal Medulla 1126 Metabolic Defects in Type 2 Diabetes 1104 Goiter 1082 Pheochromocytoma 1127 Monogenic Forms of Diabetes 1105 Diffuse Nontoxic (Simple) Goiter 1083 Genetic Defects in β-Cell Function 1105 MULTIPLE ENDOCRINE Multinodular Goiter 1083 Genetic Defects That Impair Tissue Response to NEOPLASIA SYNDROMES 1129 Neoplasms of the Thyroid 1084 Insulin 1105 Multiple Endocrine Neoplasia, Thyroid Adenomas 1085 Diabetes and Pregnancy 1105 Type 1 1129 Thyroid Carcinomas 1086 Clinical Features of Diabetes 1106 Multiple Endocrine Neoplasia, Papillary Carcinoma and Follicular Variants, The Classic Triad of Diabetes 1106 Type 2 1130 Including Invasive Encapsulated Follicular Acute Metabolic Complications of Variant of PTC and Noninvasive Follicular PINEAL GLAND 1130 Diabetes 1106 Thyroid Neoplasm With Papillary-like Nuclear Pinealoma 1131 Chronic Complications of Diabetes 1107 Features 1088 The endocrine system consists of a highly integrated and acts. In endocrine signaling, the secreted molecules, also widely distributed group of organs, called glands, that known as hormones, act on target cells that are distant orchestrate a state of metabolic equilibrium among the from their sites of synthesis. An endocrine hormone is various organs of the body. Signaling by secreted molecules frequently carried by the blood from its site of release to can be classified into three types—autocrine, paracrine, or its target. The production of several hormones from endocrine endocrine—on the basis of the distance over which the signal glands is stimulated by trophic factors released from the 1065 1066 C H A P T E R 24 The Endocrine System pituitary. The endocrine hormone inhibits production of of underproduction or overproduction of hormones and the trophic factors, a process known as feedback inhibition, their resulting biochemical and clinical consequences, and thus maintaining physiologic levels of the hormone. (2) diseases associated with the development of mass lesions. Several processes can disturb the normal activity of the Such lesions might be nonfunctional, or they might be associ- endocrine system, including impaired synthesis or release ated with overproduction or underproduction of hormones. of hormones, abnormal interactions between hormones and The study of endocrine diseases requires integration of their target tissues, and abnormal responses of target organs. morphologic findings with biochemical measurements of the Endocrine diseases can be generally classified as (1) diseases levels of hormones, their regulators, and other metabolites. Pituitary Gland The pituitary gland is a small, bean-shaped structure that lies differentiation of multipotent stem cells within the Rathke at the base of the brain within the sella turcica. Its function is pouch into the various cell types of the anterior pituitary. For controlled by the hypothalamus, to which it is connected by example, somatotrophs, mammosomatotrophs, lactotrophs, a stalk containing axons extending from the hypothalamus and thyrotrophs are all derived from a common precursor and a rich venous plexus. Along with the hypothalamus, that expresses the transcription factor PIT-1 (lactrotrophs the pituitary has a central role in regulating the function also express the alpha subunit of the estrogen receptor, ERα). of most of the other endocrine glands. By contrast, corticotrophs are derived from progenitor cells The pituitary gland is composed of two morphologically expressing the transcription factor TPIT (also known as T-box and functionally distinct components: the anterior lobe protein 19 or Tbx19), and gonadotrophs are derived from (adenohypophysis) and the posterior lobe (neurohypophysis). precursor cells expressing steroidogenic factor-1 (SF-1) and The anterior pituitary, or adenohypophysis, which con- GATA-2. The expression of these lineage-specific transcrip- stitutes about 80% of the gland, produces trophic hormones tion factors is retained in pituitary adenomas and is used that stimulate the production of hormones from the thyroid, to classify these tumors (see later). adrenal, and other glands. The anterior pituitary is composed of epithelial cells derived embryologically from the develop- ing oral cavity. In routine histologic sections, it contains a colorful array of cells that variously have eosinophilic cytoplasm (acidophils), basophilic cytoplasm (basophils), or poorly staining cytoplasm (chromophobe cells) (Fig. 24.1). Detailed studies have demonstrated that the distinct staining properties of these cells are related to the presence of different polypeptide hormones within their cytoplasm that control the activity of other endocrine glands. There are six terminally differentiated cell types in the anterior pituitary, each of which is defined by the hormones that it synthesizes: Somatotrophs produce growth hormone (GH). Mammosomatotrophs produce GH and prolactin (PRL). Lactotrophs produce PRL. Corticotrophs produce adrenocorticotropic hormone A (ACTH), pro-opiomelanocortin (POMC), and melanocyte- stimulating hormone (MSH). Thyrotrophs produce thyroid-stimulating hormone (TSH). Gonadotrophs produce follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In women, FSH stimulates the formation of graafian follicles in the ovary, and LH induces ovulation and the formation of corpora lutea in the ovary. The same two hormones also regulate sper- matogenesis and testosterone production in males. The production of most pituitary hormones is controlled by positively and negatively acting factors from the hypothalamus (Fig. 24.2), which are carried to the anterior pituitary by the portal venous plexus. While most hypo- thalamic factors promote pituitary hormone release, others B (e.g., somatostatin and dopamine) are inhibitory. Rarely, Figure 24.1 (A) Photomicrograph of a normal pituitary. The gland is signs and symptoms of pituitary disease may be caused populated by several distinct cell populations containing a variety of by overproduction or underproduction of hypothalamic stimulating (tropic) hormones. Each hormone has different staining factors, rather than a primary pituitary abnormality. During characteristics, resulting in a mixture of cell types in routine histologic embryogenesis, specific transcription factors regulate the preparations. (B) Immunostain for human growth hormone.  Pituitary gland 1067 TRH PIF CRH Hypothalamus GHRH GH-RIH GnRH (Dopamine) (Somatostatin) Stalk Anterior Posterior TSH PRL ACTH Pituitary GH FSH LH Figure 24.2 Hormones released by the anterior pituitary. The adenohypophysis (anterior pituitary) releases five hormones that are, in turn, under the control of various stimulatory and inhibitory hypothalamic releasing factors. The stimulatory releasing factors are TRH (thyrotropin-releasing hormone), CRH (corticotropin-releasing hormone), GHRH (growth hormone–releasing hormone), and GnRH (gonadotropin-releasing hormone). The inhibitory hypothalamic influences comprise PIF (prolactin inhibitory factor or dopamine) and growth hormone–release inhibiting hormone (GH-RIH or somatostatin). TSH, Thyroid-stimulating hormone (thyrotropin); PRL, prolactin; ACTH, adrenocorticotropic hormone (corticotropin); GH, growth hormone (somatotropin); FSH, follicle-stimulating hormone; LH, luteinizing hormone. The posterior pituitary consists of modified glial cells hyperpituitarism are discussed later in the context of (termed pituicytes) and axonal processes extending from individual tumors. the hypothalamus through the pituitary stalk to the Hypopituitarism results from deficiency of trophic hor- posterior lobe (axon terminals). Two peptide hormones mones. It may be caused by ischemic injury, surgery or are secreted from the posterior pituitary, oxytocin and radiation, inflammatory disorders, and the mass effects antidiuretic hormone (ADH, also called arginine vasopressin of nonfunctional pituitary adenomas. or A P). These hormones are actually synthesized in the Symptoms related to local mass effects. Because of the close hypothalamus and are transported through axons to the proximity of the optic nerves and chiasm to the sella, posterior pituitary. In response to appropriate stimuli, expanding pituitary lesions often compress decussating the preformed hormones are then released directly into the fibers in the optic chiasm. This gives rise to visual field systemic circulation. For example, dilation of the cervix in abnormalities, classically in the form of defects in both pregnancy results in oxytocin release, leading to contraction lateral (temporal) visual fields, so-called bitemporal of the uterine smooth muscle, facilitating parturition (uterine hemianopsia. Like any expanding intracranial mass, labor). Similarly, oxytocin released on nipple stimulation pituitary adenomas can produce signs and symptoms of in the postnatal period acts on the smooth muscles sur- elevated intracranial pressure, including headache, nausea, rounding the lactiferous ducts of the mammary glands and and vomiting. On occasion, acute hemorrhage into an facilitates lactation. Synthetic oxytocin can be given to adenoma is associated with clinical evidence of rapid pregnant women to induce labor. The most important enlargement of the lesion, a situation appropriately termed function of ADH is to conserve water by restricting diuresis pituitary apoplexy. Acute pituitary apoplexy is a neuro- during periods of dehydration and hypovolemia. Decreased surgical emergency because it can cause sudden death blood pressure, sensed by baroreceptors (pressure-sensing (see later). receptors) in the cardiac atria and carotids, stimulates ADH release. An increase in plasma osmotic pressure detected Diseases of the posterior pituitary often come to clinical by osmoreceptors also triggers ADH secretion. In contrast, attention because of increased or decreased secretion of states of hypervolemia and increased atrial distention result ADH and associated changes in fluid and electrolyte in inhibition of ADH secretion. balances. CLINICAL MANIFESTATIONS OF PITUITARY ADENOMAS AND PITUITARY DISEASE HYPERPITUITARISM The manifestations of pituitary disorders are related to The most common cause of hyperpituitarism is an adenoma either e cess or deficiency of pituitary hormones, or to arising in the anterior lobe. Pituitary adenomas are classified mass effects. on the basis of the hormones and cell type specific transcrip- Hyperpituitarism arises from excess secretion of trophic tion factors that are expressed by the tumor cells (Table hormones. The causes of hyperpituitarism include 24.1). Some pituitary adenomas secrete two hormones (GH hyperplasias, adenomas, and carcinomas of the anterior and prolactin being the most common combination), and pituitary, secretion of hormones by nonpituitary tumors, rarely, pituitary adenomas are plurihormonal. Less common and certain hypothalamic disorders. The symptoms of causes of hyperpituitarism include pituitary carcinomas and 1068 C H A P T E R 24 The Endocrine System Table 24.1 Classification of Pituitary Adenomas Transcription Adenoma Type Hormone Factor Morphologic Variant Associated Syndromea Somatotroph adenoma GH PIT-1 Densely granulated adenoma Gigantism (children) GH PIT-1 Sparsely granulated adenoma Acromegaly (adults) GH, PRL (in same cells) PIT-1, ERα Mammosomatotroph adenoma GH, PRL (in different cells) PIT-1, ERα Mixed somatotroph-lactotroph adenoma Lactotroph adenoma PRL PIT-1, ERα Sparsely granulated adenoma Galactorrhea and amenorrhea PRL PIT-1, ERα Densely granulated adenoma (in females) PRL, GH (focal and PIT-1, ERα Acidophilic stem cell adenoma Sexual dysfunction, infertility variable) Thyrotroph adenoma TSH PIT-1 Thyrotroph adenoma Hyperthyroidism Corticotroph adenoma ACTH TPIT Densely granulated adenoma Cushing syndrome ACTH TPIT Sparsely granulated adenoma Nelson syndrome ACTH TPIT Crooke cell adenoma Mass effects (20% of (prominent intracytoplasmic corticotroph adenomas are cytokeratin filaments) hormonally silent) Gonadotroph FSH, LH SF-1, GATA-2, ERα Gonadotroph adenoma Mass effects and hypopituitarism adenoma (most gonadotroph adenomas are hormonally silent) Null cell adenoma None None Mass effects Plurihormonal adenoma GH, PRL, TSH PIT-1 a Note that nonfunctional (“silent”) adenomas in each category express the corresponding hormone(s) and transcription factor within the neoplastic cells, as determined by special immunohistochemical staining on tissues. However, these adenomas do not produce the associated clinical syndrome and typically present with mass effects accompanied by hypopituitarism due to destruction of normal pituitary parenchyma. These features are particularly common with gonadotroph adenomas and up to one-fifth of corticotroph adenomas, while rarely observed with somatotroph or lactotroph adenomas. Null cell adenomas, by definition, only present with mass effects. ACTH, Adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; PRL, prolactin; TSH, thyroid-stimulating hormone. Partially modified from Lopes MBS: The 2017 World Health Organization classification of tumors of the pituitary gland: a summary, Acta Neuropathol 134:521–535, 2017. some hypothalamic disorders. By contrast, large pituitary with cell surface receptors and intracellular effectors adenomas, and particularly nonfunctioning ones, may cause (Fig. 24.3), and β- and γ-subunits that noncovalently hypopituitarism by destroying the adjacent normal anterior bind α-subunits. Gs is a stimulatory G-protein with a pituitary parenchyma. pivotal role in signal transduction in several endocrine Pituitary adenomas are usually found in adults; the peak organs, including the pituitary. The α-subunit of Gs (Gsα) incidence is from 35 to 60 years of age. They are designated, is encoded by the GNAS gene, located on chromosome somewhat arbitrarily, microadenomas if they are less than 20q13. In the basal state, Gs exists in an inactive state, 1 cm in diameter and macroadenomas if they exceed 1 cm in with guanosine diphosphate (GDP) bound to the guanine diameter. Nonfunctional adenomas are likely to come to nucleotide-binding site of Gsα. On interaction with the clinical attention at a later stage than those associated with ligand-bound cell surface receptor, GDP dissociates, and endocrine abnormalities and are therefore more likely to guanosine triphosphate (GTP) binds to Gsα, activating the be macroadenomas. Based on autopsy studies, the prevalence G-protein. The activation of Gsα generates cAMP, a potent of pituitary adenomas in the population is estimated to be mitogen for several types of endocrine cells (e.g., pituitary about 14%, but the vast majority of these lesions are clinically somatotrophs and corticotrophs, thyroid follicular cells, silent microadenomas (“pituitary incidentaloma”). parathyroid cells). Normally, Gsα activation is transient because of an intrinsic GTPase activity in the α-subunit, Pathogenesis which hydrolyzes GTP into GDP. Approximately 40% of As with other neoplasms, pituitary adenomas are caused somatotroph cell adenomas bear somatic GNAS mutations by mutations in cancer genes, which are most commonly that abrogate the GTPase activity of Gsα, leading to con- acquired somatic mutations but which may also be germline stitutive activation of Gsα, persistent generation of cAMP, mutations associated with an inherited predisposition to and unchecked cellular proliferation (see Table 24.2). pituitary neoplasms (Table 24.2): GNAS mutations have also been described in a minority Activating G-protein mutations are one of the most common of corticotroph adenomas; in contrast, GNAS mutations alterations in pituitary adenomas. As described in Chapter are absent in thyrotroph, lactotroph, and gonadotroph 1, G-proteins normally play a critical role in signal adenomas, because their trophic hypothalamic release transduction, transmitting signals from particular cell hormones act via other signaling pathways. surface receptors (e.g., GHRH receptor) to intracellular Activating mutations of ubiquitin-specific protease 8 (USP8) effectors (e.g., adenyl cyclase), which then generate also occur in 30% to 60% of corticotroph adenomas. The second messengers (e.g., cyclic adenosine monophosphate, encoded protein is an enzyme that removes ubiquitin cAMP). They are heterotrimeric proteins, composed of residues from proteins like epidermal growth factor recep- α-subunits that bind guanine nucleotide and interact tor (EGFR), protecting them from proteasome-dependent  Pituitary gland 1069 Table 24.2 Genetic Alterations in Pituitary Tumors Most Commonly Gene Protein Function Oncogenic Mutations Associated Pituitary Tumor GNAS α subunit of stimulatory G-protein, Gsα Somatic activating mutation Somatotroph adenoma USP8 Deubiquitinase Somatic activating mutation Corticotroph adenoma Protein kinase A, regulatory Negative regulator of protein kinase A (PKA), Germline inactivating mutations Somatotroph or lactotroph subunit 1α (PRKAR1A)a leading to increased cAMP production (Carney complex) adenoma MEN1a Transcription regulator Germline inactivating mutations Somatotroph, lactotroph, or (multiple endocrine corticotroph adenoma neoplasia, type 1) CDKN1B (p27/KIP1)a Negative cell cycle regulator Germline inactivating mutations Corticotroph adenoma (“MEN-1-like” syndrome) Aryl hydrocarbon receptor Receptor for aryl hydrocarbons and a Germline inactivating mutations Somatotroph or lactotroph interacting protein (AIP)a ligand-activated transcription factor (familial isolated pituitary adenoma (especially in patients adenoma syndrome) younger than 35 years of age) HRAS Mitogenic signaling, cell growth and survival Somatic activating mutation Pituitary carcinoma a DICER1 MicroRNA processing Germline inactivating mutation Pituitary blastoma a Genetic alterations associated with familial or germline predisposition to pituitary adenomas. degradation. Aberrant activation of USP8 thus enhances note, somatic mutations of these four genes are rarely the activity of EGFR and other pro-growth signaling encountered in sporadic pituitary adenomas. pathways in pituitary adenomas. Approximately 5% of pituitary adenomas are caused by germline loss-of-function mutations in genes such as MORPHOLOGY MEN1, CDKN1B, PRKAR1A, or AIP (see Table 24.2). Of The typical pituitary adenoma is soft and well-circumscribed. Small adenomas may be confined to the sella turcica, but with Ligand expansion they frequently erode the sella turcica and anterior (GHRH, TSH, PTH) clinoid processes. Larger lesions may extend superiorly through Receptor the diaphragm sella into the suprasellar region, compressing the optic chiasm and adjacent structures, such as cranial nerves (Fig. 24.4). In as many as 30% of cases, the adenomas are not encap- sulated and infiltrate neighboring tissues such as the cavernous a bg and sphenoid sinuses, dura, and on occasion, the brain itself. Such lesions are termed aggressive adenomas. Not unexpectedly, a bg macroadenomas are more likely to be invasive and to have foci P P P P P P P of hemorrhage and necrosis. GDP GTP GDP Histologically, typical pituitary adenomas are composed of uniform (monomorphic), polygonal cells arrayed in sheets or cords. bg a Mutation P P P GTP Adenyl cyclase cAMP Proliferation Hormone synthesis and secretion Figure 24.3 G-protein signaling in endocrine neoplasia. Mutations that lead to G-protein hyperactivity are seen in a variety of endocrine neoplasms, including pituitary, thyroid, and parathyroid adenomas. G-proteins (composed of α and βγ subunits) play a critical role in signal transduction, transmitting signals from cell surface receptors (GHRH, TSH, or PTH receptor) to intracellular effectors (e.g., adenyl cyclase), which then generate second messengers (cAMP, cyclic adenosine monophosphate) that stimulate cellular responses. GDP, Guanosine Figure 24.4 Pituitary adenoma. This massive, nonfunctional adenoma has diphosphate; GTP, guanosine triphosphate; Pi, inorganic phosphate. See grown beyond the confines of the sella turcica, distorting the overlying Fig. 24.2 for other abbreviations. brain. On average, nonfunctional adenomas are larger at time of diagnosis. 1070 C H A P T E R 24 The Endocrine System include radiographic abnormalities of the sella turcica, visual field abnormalities, signs and symptoms of elevated intra- cranial pressure, and occasionally hypopituitarism. Acute hemorrhage into an adenoma is sometimes associated with pituitary apoplexy, as noted earlier. The biologic behavior of a pituitary adenoma cannot always be reliably predicted from its histologic appearance. This has led some to suggest that the term “adenoma” (which implies a benign course) should be replaced by pituitary neuroendocrine tumor, a name that does not reflect any specific expectation about a tumor s behavior. The following is a description of the individual types of tumors. Lactotroph Adenoma Figure 24.5 Pituitary adenoma. The monomorphism of these cells contrasts markedly with the mixture of cells seen in the normal anterior Prolactin-secreting lactotroph adenomas are the most pituitary. Note also the absence of reticulin network. common type of hyperfunctioning pituitary adenoma, accounting for about 30% of clinically recognized cases. These lesions range from small microadenomas to large, The supporting connective tissue, or reticulin, is sparse, accounting expansile tumors associated with symptomatic mass effects. for the soft, gelatinous consistency of many of these tumors. This cellular monomorphism and the absence of a significant reticulin MORPHOLOGY network distinguish pituitary adenomas from normal anterior pituitary parenchyma (Fig. 24.5). Immunohistochemical stains for The large majority of lactotroph adenomas are composed of hormones and lineage-specific transcription factors are used to chromophobe cells with juxtanuclear localization of the transcrip- identify specific pituitary adenoma subtypes (see Table 24.1). Mitotic tion factor PIT-1; these are known as sparsely granulated activity and expression of Ki-67 (MIB-1, a marker of cycling cells) lactotroph adenomas (Fig. 24.6A). Much rarer are the eosino- are typically low in pituitary adenomas; higher-than-normal rates philic densely granulated lactotroph adenomas, characterized of cell division are associated with more aggressive tumors. by diffuse cytoplasmic PIT-1 localization (Fig. 24.6B). Prolactin can be demonstrated within cytoplasmic secretory granules with immunohistochemical stains, and estrogen receptor alpha (ERα) Clinical Features is co-expressed along with PIT-1, consistent with lactotroph differentiation. Lactotroph adenomas often undergo dystrophic The signs and symptoms of pituitary adenomas are related calcification, ranging from isolated psammoma bodies to extensive to endocrine abnormalities and mass effects. The effects of calcification (“pituitary stone”). Prolactin secretion by functioning excessive secretion of anterior pituitary hormones are adenomas is usually efficient and proportional, in that serum mentioned later, when the specific types of pituitary adenoma prolactin concentrations tend to correlate with the size of the are described. Local mass effects may be produced by any adenoma. type of pituitary tumor. As mentioned earlier, these effects A B Figure 24.6 Ultrastructural features of prolactinoma. (A) Electron micrograph of a sparsely granulated prolactinoma. The tumor cells contain abundant granular endoplasmic reticulum (indicative of active protein synthesis) and small numbers of electron-dense secretory granules. (B) Electron micrograph of a densely granulated growth hormone–secreting adenoma. The tumor cells are filled with numerous large, electron-dense secretory granules. (Courtesy Dr. Eva Horvath, St. Michael’s Hospital, Toronto, Ontario, Canada.)  Pituitary gland 1071 Clinical Features Clinical Features Increased serum levels of prolactin, or prolactinemia, cause In contrast to corticotroph or gonadotroph adenomas, amenorrhea, galactorrhea, loss of libido, and infertility. The silent somatotroph adenomas are rare. Persistently elevated diagnosis of an adenoma is made more readily in women levels of GH stimulate the hepatic secretion of insulin-like than in men, especially between 20 and 40 years of age, growth factor-1 (IGF-1), which causes many of the clinical because hyperprolactinemia disrupts the menstrual cycle. manifestations. Lactotroph adenoma is the cause of almost one-fourth of If a somatotroph adenoma appears in children before cases of amenorrhea. In contrast, in men and older women, the epiphyses have closed, the elevated levels of GH the hormonal manifestations may be subtle, allowing the (and IGF-1) result in gigantism. This is characterized by tumors to reach considerable size (macroadenomas) before a generalized increase in body size with disproportionately being detected clinically. long arms and legs. Hyperprolactinemia may result from causes other than If the levels of GH are increased after closure of the prolactin-secreting pituitary adenomas. Physiologic hyper- epiphyses, acromegaly develops. In this condition, growth prolactinemia occurs in pregnancy. Prolactin levels are also is most conspicuous in skin and soft tissues, viscera elevated by nipple stimulation, as occurs during suckling (thyroid, heart, liver, and adrenals), and the bones of the in lactating women, and as a response to many types of face, hands, and feet. Bone density may increase (hyper- stress. Pathologic hyperprolactinemia can also result from ostosis) in both the spine and the hips. Enlargement of lactotroph hyperplasia caused by loss of dopamine-mediated the jaw results in its protrusion (prognathism) and broaden- inhibition of prolactin secretion. This may occur due to ing of the lower face. The feet and hands are enlarged, damage of the dopaminergic neurons of the hypothalamus and the fingers become thickened and sausage-like. In or the pituitary stalk (e.g., due to head trauma), or exposure most instances, gigantism is also accompanied by evidence to drugs that block dopamine receptors on lactotroph cells. of acromegaly. These changes may develop slowly over Any suprasellar mass (e.g., a pituitary adenoma) may disturb decades before being recognized, and hence the underly- the inhibitory influence of the hypothalamus on prolactin ing adenoma may reach substantial size. secretion, resulting in hyperprolactinemia. Therefore, mild GH excess can also be associated with a variety of other hyperprolactenemia in a person with a pituitary adenoma disturbances, including gonadal dysfunction, diabetes does not necessarily indicate a prolactin-secreting tumor. mellitus, generalized muscle weakness, hypertension, Other causes of hyperprolactinemia include renal failure arthritis, congestive heart failure, and an increased risk and hypothyroidism. Lactotroph adenomas are treated by of gastrointestinal cancers. surgery or, more commonly, with bromocriptine, a dopamine receptor agonist that causes the lesions to diminish in size. The diagnosis relies on documenting elevated serum GH and IGF-1 levels. In addition, failure to suppress GH produc- Somatotroph Adenoma tion in response to an oral load of glucose is one of the most sensitive tests for acromegaly. The causative pituitary Growth hormone (GH)-secreting somatotroph adenomas adenoma can be removed surgically or treated by pharma- are the second most common type of functioning pituitary cologic means. The latter includes somatostatin analogues adenoma, and cause gigantism in children and acromegaly (recall that somatostatin inhibits pituitary GH secretion) in adults. Somatotroph adenomas may be quite large by and GH receptor antagonists, which prevent hormone the time they come to clinical attention because the manifesta- binding to target organs such as the liver. When effective tions of excessive GH may be subtle. control of high GH levels is achieved, the characteristic tissue overgrowth and related symptoms gradually recede, and the metabolic abnormalities improve. Overall, sparsely granulated somatotroph adenomas tend to have a more MORPHOLOGY aggressive course than densely granulated adenomas and may be less responsive to somatostatin analogues. Thus, Histologically, pure somatotroph adenomas are also classified into accurate subtyping of somatotroph adenomas is of prognostic densely granulated and sparsely granulated subtypes. Densely importance. granulated somatotroph adenomas are composed of monomorphic, eosinophilic cells with granular cytoplasm and a large central nucleus with prominent nucleoli.The cells have diffuse, Corticotroph Adenoma strong immunoreactivity for GH. In contrast, the sparsely Excess production of ACTH by functioning corticotroph granulated variants are composed of chromophobe cells with adenomas leads to adrenal hypersecretion of cortisol and patchy, weak staining for GH and a characteristic paranuclear the development of hypercortisolism (also known as Cushing glossy inclusion known as a fibrous body, composed of intermediate syndrome). filaments that stain for cytokeratin. Bihormonal mammosom- atotroph adenomas that synthesize GH and prolactin in the same cell are being increasingly recognized; morphologically, most MORPHOLOGY resemble densely granulated somatotroph adenomas, but have immunohistochemical reactivity for prolactin and GH. These are Corticotroph adenomas are usually microadenomas at the time to be contrasted with mixed somatotroph-lactotroph adeno- of diagnosis. These tumors are most often basophilic (densely mas, which have GH and prolactin expression in different cells. granulated) and occasionally chromophobic (sparsely 1072 C H A P T E R 24 The Endocrine System adenomas typically present with symptoms stemming granulated). Both variants stain positively with periodic acid-Schiff from mass effects. These lesions may also compromise (PAS) because of the presence of carbohydrate in proopiomela- the residual anterior pituitary and cause hypopituitarism, nocortin (POMC), the precursor of ACTH. Nuclear TPIT is also which may appear slowly due to gradual enlargement positive in the neoplastic cells, consistent with corticotroph lineage. of the adenoma or abruptly because of acute intratumor A third uncommon variant, called Crooke cell adenoma, is hemorrhage (pituitary apoplexy). characterized by ringlike deposition of cytokeratin called Crooke change. This variant has an aggressive natural history compared Pituitary carcinoma is rare, accounting for less than 1% with other subtypes of corticotroph adenomas. of pituitary tumors. The presence of craniospinal or systemic metastases is a sine qua non of a pituitary carcinoma. Most pituitary carcinomas are functional, with prolactin and ACTH Clinical Features being the most commonly secreted products. Metastases The manifestations of Cushing syndrome are discussed in usually appear late in the course, following multiple local more detail later with the diseases of the adrenal gland. The recurrences. syndrome can be caused by a wide variety of conditions in Pituitary blastoma is an entity that occurs in children addition to ACTH-producing pituitary tumors. When the (typically younger than 2 years of age) who carry germline hypercortisolism is due to excessive production of ACTH mutations of DICER1, the gene encoding a microRNA- by the pituitary, it is designated Cushing disease. Large processing protein. Morphologically, these tumors are destructive pituitary adenomas can develop in patients composed of immature “blastema-like” cells (so-called “small after surgical removal of the adrenal glands for treatment round blue cells”) and rosette-like formations resembling of Cushing syndrome. This condition, known as Nelson the primitive Rathke epithelium from which the pituitary syndrome, occurs because of loss of the inhibitory effect of develops. Pituitary blastoma presents with signs and adrenal corticosteroids on a corticotroph microadenoma. symptoms of Cushing disease. These children also develop Because the adrenals are absent in persons with Nelson primitive “blastema-like” neoplasms in other organs, most syndrome, hypercortisolism does not develop. Patients commonly pleuropulmonary blastoma. present with mass effects due to the pituitary tumor, and there can be hyperpigmentation because melanotropin, which has trophic effects on melanocytes, is also derived KEY CONCEPTS from POMC. HYPERPITUITARISM Other Anterior Pituitary Tumors The most common cause of hyperpituitarism is an anterior lobe pituitary adenoma. Several less frequent types of pituitary adenoma also merit Pituitary adenomas can be macroadenomas greater than cm brief comment (see Table 24.1). in diameter) or microadenomas. Gonadotroph (LH-producing and FSH-producing) adeno- Functioning adenomas are associated with distinct endocrine mas can be difficult to recognize because they secrete signs and symptoms, while nonfunctioning (silent) adenomas small amounts of hormones that usually do not cause typically present with mass effects, including visual disturbances. a recognizable clinical syndrome (i.e., most are non- Lactotroph adenomas secrete prolactin and can present with functioning). Gonadotroph adenomas most frequently amenorrhea, galactorrhea, loss of libido, and infertility. present in middle-aged men and women with neurologic Somatotroph adenomas secrete H and present with gigantism symptoms, such as impaired vision, headaches, diplopia, in children and acromegaly in adults, impaired glucose tolerance, or pituitary apoplexy. Pituitary hormone deficiencies and diabetes mellitus. can also be found, most commonly impaired secretion Corticotroph adenomas secrete ACTH and present with Cushing of LH, which causes decreased energy and libido in syndrome and hyperpigmentation. men (due to reduced testosterone) and amenorrhea in The two distinctive morphologic features of most adenomas premenopausal women. The neoplastic cells express are their cellular monomorphism and absence of a reticulin the common gonadotropin α-subunit and the specific network. β-FSH and β-LH subunits; FSH is usually the predominant secreted hormone. Gonadotroph adenomas also usually express steroidogenic factor-1 (SF-1), GATA-2, and ERα, transcription factors associated with normal gonadotroph HYPOPITUITARISM differentiation. Thyrotroph (TSH-producing) adenomas are uncommon, Hypopituitarism refers to decreased secretion of pituitary accounting for approximately 1% of pituitary adenomas. hormones, which can result from diseases of the hypo- They are a rare cause of hyperthyroidism. Due to their thalamus or of the pituitary. Hypofunction of the anterior shared lineage with lactotroph and somatotroph adeno- pituitary occurs when approximately 5% of the parenchyma mas, these tumors also express PIT-1. is lost or absent. When accompanied by evidence of posterior Pituitary adenomas may also secrete multiple hormones; pituitary dysfunction in the form of diabetes insipidus (see such “plurihormonal” adenomas are usually aggressive. later), hypopituitarism is almost always of hypothalamic Most are derived from cells of PIT-1 expressing lineage. origin. Null cell adenomas do not express any markers of hormonal Most cases of hypopituitarism arise from destructive or lineage differentiation. Not surprisingly, null cell processes involving the anterior pituitary, as follows:  Pituitary gland 1073 Tumors and other mass lesions: Pituitary adenomas, other removed or undergoes infarction, leading to loss of benign tumors arising within the sella, primary and pituitary function. metastatic malignancies, and cysts can cause hypopitu- Hypothalamic lesions: As mentioned earlier, hypothalamic itarism. Any mass lesion in the sella can cause damage lesions can also affect the pituitary by causing a deficiency by exerting pressure on adjacent normal pituitary cells. of pituitary hormone–releasing factors. In contrast to Traumatic brain injury and subarachnoid hemorrhage are diseases that involve the pituitary directly, hypothalamic among the most common causes of pituitary hypofunction. abnormalities can also diminish the secretion of ADH, Pituitary surgery or radiation: Surgical excision of a pituitary resulting in diabetes insipidus (discussed later). Hypo- adenoma may inadvertently include the nonadenomatous thalamic lesions that cause hypopituitarism include pituitary. Radiation of the pituitary, used to prevent tumors, which may be benign (e.g., craniopharyngioma) regrowth of residual tumor after surgery, can damage or malignant; most of the latter are metastases from tumors the nonadenomatous pituitary. such as breast and lung carcinoma. Hypothalamic insuf- Pituitary apoplexy: As mentioned earlier, this is caused ficiency may also appear following irradiation of the by a sudden hemorrhage into the pituitary gland, brain. often occurring into a pituitary adenoma. In its most Inflammatory disorders and infections, such as sarcoidosis dramatic presentation, apoplexy causes the abrupt onset or tuberculous meningitis, can involve the hypothalamus of excruciating headache, diplopia due to pressure on and cause deficiencies of anterior pituitary hormones the oculomotor nerves, and acute hypopituitarism. In and diabetes insipidus. severe cases, it can cause cardiovascular collapse, loss Genetic defects: Congenital deficiency of transcription of consciousness, and even sudden death. The combi- factors required for normal pituitary function is a rare nation of mass effect from the hemorrhage and acute cause of hypopituitarism. For example, mutation of the hypopituitarism makes pituitary apoplexy a neurosurgical pituitary-specific gene PIT1 results in combined pituitary emergency. hormone deficiency, characterized by deficiencies of GH, Ischemic necrosis of the pituitary (Sheehan syndrome), also prolactin, and TSH. known as postpartum necrosis, is the most common form of ischemic necrosis of the anterior pituitary. During The clinical manifestations of anterior pituitary hypo- pregnancy, the anterior pituitary enlarges to almost twice function vary depending on the specific hormones that are its normal size. This physiologic expansion of the gland lacking. is not accompanied by an increase in blood supply from Children can develop growth failure (pituitary dwarfism) the low-pressure venous system; hence, there is relative due to growth hormone deficiency. hypoxia. Any further reduction in blood supply caused Gonadotropin (LH and FSH) deficiency leads to amenor- by obstetric hemorrhage or shock may precipitate infarc- rhea and infertility in women and decreased libido, tion of the anterior lobe. Because the posterior pituitary impotence, and loss of pubic and axillary hair in men. is supplied directly from arterial branches, it is much TSH and ACTH deficiencies result in symptoms of less susceptible to ischemic injury and is therefore usually hypothyroidism and hypoadrenalism, respectively, and unaffected. Pituitary necrosis may also be encountered are discussed later in this chapter. in disseminated intravascular coagulation and, less com- Prolactin deficiency results in failure of postpartum monly, in sickle cell anemia, elevated intracranial pressure, lactation. traumatic injury, and shock of any origin. Whatever the The anterior pituitary is also a rich source of melanotropins pathogenesis, the ischemic area is resorbed and replaced (also known as melanocyte-stimulating hormone), syn- by a nubbin of fibrous tissue attached to the wall of an thesized from the same precursor molecule that produces empty sella. ACTH; therefore, one of the manifestations of hypopi- Rathke cleft cyst: These cysts, lined by ciliated cuboidal tuitarism includes pallor due to a loss of stimulatory epithelium with occasional goblet cells and anterior effects on melanocytes. pituitary cells, can accumulate proteinaceous fluid and expand, compromising the normal gland. Empty sella syndrome: Any condition or treatment that destroys part or all of the pituitary gland, such as ablation POSTERIOR PITUITARY SYNDROMES of the pituitary by surgery or radiation, can result in an empty sella and the empty sella syndrome. There are The clinically relevant posterior pituitary syndromes involve two types: (1) In a primary empty sella, a defect in the ADH and include diabetes insipidus and syndrome of diaphragma sella allows the arachnoid mater and cere- inappropriate secretion of ADH. brospinal fluid to herniate into the sella, expanding the Diabetes insipidus. ADH deficiency causes diabetes sella and compressing the pituitary. Classically, this occurs insipidus, a condition characterized by excessive urination in obese women with a history of multiple pregnancies. (polyuria) due to an inability of the kidney to resorb Affected individuals often present with visual field defects water properly from the urine. Diabetes insipidus can and occasionally with endocrine anomalies, such as occur in a variety of conditions, including head trauma, hyperprolactinemia, due to interruption of inhibitory tumors, inflammatory disorders of the hypothalamus and hypothalamic inputs. Sometimes the loss of functioning pituitary, and surgical complications. Rarely, diabetes parenchyma is sufficient to produce hypopituitarism. (2) insipidus has a genetic basis, either because of autosomal In secondary empty sella, a mass, such as a pituitary dominant mutations of the arginine vasopressin (AVP) adenoma, enlarges the sella and is then either surgically gene, or mutations of arginine vasopressin receptor type 1074 C H A P T E R 24 The Endocrine System 2 (AVPR2), an X-linked condition that usually presents in young boys. Diabetes insipidus from ADH deficiency is designated as central to differentiate it from nephrogenic diabetes insipidus, which is a result of renal tubular unresponsiveness to circulating ADH. The clinical manifestations of these two disorders are similar and include the excretion of large volumes of dilute urine with a lower than normal specific gravity. Serum sodium and osmolality are increased by the excessive renal loss of free water, resulting in thirst and polydipsia. Patients who can drink water generally compensate for the urinary losses, but patients who are obtunded, bedridden, or otherwise limited in their ability to obtain water may develop life-threatening dehydration. Syndrome of inappropriate ADH (SIADH) secretion. ADH excess causes over-resorption of free water, resulting in hyponatremia. The most frequent causes of SIADH are the secretion of ectopic ADH by malignant neoplasms Figure 24.7 Adamantinomatous craniopharyngioma, demonstrating (particularly small-cell carcinoma of the lung), drugs that characteristic compact, lamellar “wet” keratin (right half of photomicrograph) increase ADH secretion, and a variety of central nervous and cords of squamous epithelium with peripheral palisading on the left. system disorders, including infections and trauma. The (Courtesy Dr. Charles Eberhart, Department of Pathology, Johns Hopkins clinical manifestations of SIADH are dominated by University, Baltimore, Md.) hyponatremia, cerebral edema, and resultant neurologic dysfunction. Although total body water is increased, blood volume remains normal, and peripheral edema does not develop. frequently contains radiologically demonstrable calcifications; the HYPOTHALAMIC SUPRASELLAR papillary variant calcifies only rarely. Adamantinomatous craniopharyngioma consists of nests TUMORS or cords of stratified squamous epithelium embedded in a spongy “reticulum” that becomes more prominent in the internal layers. Neoplasms in this location may induce hypofunction or “Palisading” of the squamous epithelium is frequently observed hyperfunction of the anterior pituitary, diabetes insipidus, at the periphery. Compact, lamellar keratin formation (“wet or combinations of these manifestations. The most com- keratin”) is a diagnostic feature of this tumor (Fig. 24.7). As monly implicated tumors are glioma (sometimes arising in mentioned earlier, dystrophic calcification is a frequent finding. the chiasm; Chapter 28) and craniopharyngioma. Cranio- Additional features include cyst formation, fibrosis, and chronic pharyngioma is thought to arise from vestigial remnants inflammation.The cysts of adamantinomatous craniopharyngiomas of Rathke pouch. These slow-growing tumors account for often contain a cholesterol-rich, thick brownish-yellow fluid that 1% to 5% of intracranial tumors. A small minority of these has been compared to “machine oil.” These tumors extend fin- lesions occurs within the sella, but most are suprasellar, gerlets of epithelium into adjacent brain, where they elicit a brisk with or without intrasellar extension. A bimodal age dis- glial reaction. This subtype of craniopharyngioma is characterized tribution is observed, with one peak in childhood (5 to 15 by recurrent mutations of the CTNNB1 (β-catenin) gene, which years) and a second peak in adults 65 years of age or older. leads to aberrant activation of the Wnt signaling pathway. Patients usually come to attention because of headaches and Papillary craniopharyngiomas contain both solid sheets visual disturbances, while children sometimes present with of cells and papillae lined by well-differentiated squamous epithe- growth retardation due to pituitary hypofunction and GH lium.These tumors usually are distinguished from the adamantinous deficiency. type by the lack of lamellar keratin, calcification, cysts, peripheral palisading of squamous cells, and a spongy reticulum. Also unlike adamantinomatous craniopharyngioma, this subtype is characterized MORPHOLOGY by activating mutations of the BRAF oncogene at codon 600. The identification of BRAFV600E mutations has therapeutic implications Craniopharyngiomas average 3 to 4 cm in diameter; they may due to availability of small-molecule BRAF inhibitor drugs that be encapsulated and solid, but more commonly they are cystic and inhibit the BRAF serine-threonine kinase (Chapter 7). sometimes multiloculated.They often encroach on the optic chiasm Patients with craniopharyngiomas, especially those less than or cranial nerves, and not infrequently they bulge into the floor 5 cm in diameter, have an excellent recurrence-free and overall of the third ventricle and base of the brain. Two distinct histologic survival. Larger lesions are more invasive, but this does not impact variants are recognized: adamantinomatous craniopharyngioma on the prognosis. Malignant transformation of craniopharyngiomas (most often observed in children) and papillary craniopharyngioma into squamous carcinomas is rare and usually occurs only after (most often observed in adults). The adamantinomatous type irradiation.