Multiple Diseases Endocrine Patho.pdf

780 SECTION II Pathology of Organ Systems by chemical or infectious agents that arrive hematogenously. Most endocrine glands are protected from the external environment by their deep-seated location and from neighboring tissues or body cavities by a thin capsule of fibrous tissue. Diseases Affecting...

780 SECTION II Pathology of Organ Systems by chemical or infectious agents that arrive hematogenously. Most endocrine glands are protected from the external environment by their deep-seated location and from neighboring tissues or body cavities by a thin capsule of fibrous tissue. Diseases Affecting Multiple Species of Domestic Animalse Disorders of the Adenohypophysis Adenohypophyseal proliferation (hyperplasia or pituitary adenoma) is the most common postmortem lesion in canine pituitary glands. Secondary neoplasia, inflammation, or degeneration and necrosis unassociated with a pituitary tumor are rare. This predominance of proliferations among adenohypophyseal lesions seems to be true for the other domestic species as well. The increasing use of transsphenoidal hypophysectomy in the diagnosis and treatment of pituitary tumors in dogs and cats has changed adenohypophyseal pathology from a strictly postmortem endeavor to an important surgical biopsy practice. A Proliferative Disorders of the Adenohypophysis Hyperplasia and neoplasia are important lesions of the adenohypophysis. Physiologic hyperplasia is the result of stimulation through the hypothalamic-pituitary-target organ axis and tends to affect the trophic hormone-producing cells of interest throughout the adenohypophysis. In contrast, pathologic proliferation tends to be focal or multifocal. Nodular proliferations of cells in the pars distalis or pars intermedia that are multiple and smaller than 2 mm in diameter are typical of hyperplasia. Hyperplastic nodules do not disrupt the reticulin scaffolding of the adenohypophysis, but they can be recognized histologically because the nodule is composed mainly of one cell type (e.g., corticotrophs) (Fig. 12.18, A and E-Fig. 12.12), instead of the normal mixture of corticotrophs, somatotrophs, and other trophic hormone-producing cells. Immunohistochemistry can be used to identify the trophic hormone produced. Hyperplastic nodules are seldom large enough to be evident on clinical diagnostic imaging or gross examination; nevertheless, they can secrete excessive bioactive trophic hormones and thus be responsible for hyperplasia or even secondary hyperfunction of the targeted endocrine organ, depending on which trophic hormone is produced. Adenohypophyseal neoplasms are usually solitary and almost always classified as adenomas rather than carcinomas. It is plausible that hyperplastic nodules of adenohypophyseal cells could become clonal or that multiple nodules could coalesce to form an adenoma. Importantly, smaller adenohypophyseal lesions (whether hyperplastic or neoplastic [microadenomas]) are likely to be functional—that is, to produce and release trophic hormones into the peripheral blood—whereas large macroadenomas (see Fig. 12.18, B) may exert their effect mainly through destruction of adjacent pituitary parenchyma, often resulting in insufficient (rather than excessive) trophic hormone(s) or through compression of surrounding tissue, such as optic nerves or overlying hypothalamus. In addition to classifying nonphysiologic pituitary proliferations as hyperplastic nodules, microadenomas, or macroadenomas, it is useful to determine the type of trophic hormone produced by the proliferating cells. In veterinary medicine, this goal is generally accomplished by a combination of biochemical analysis of serum, clinical signs, and/ or immunohistochemistry on surgical biopsy or autopsy (syn: necropsy; see E-Appendix 12.1) specimens of affected pituitary gland. ePostmortem examination of the endocrine system is discussed in E-Appendix 12.1. Disorders that are known or thought to have a genetic basis are listed in E-Tables 12.1 and 1.2. a B Figure 12.18 Adenohypophyseal Hyperplasia and Neoplasia, Pituitary Gland. A, Corticotroph hyperplasia, dog. A hyperplastic nodule (lower twothirds), about 1 mm in diameter, consists of corticotrophs with basophilic granular cytoplasm that are hypertrophied, but retain the normal acinar pattern. Adjacent normal adenohypophyseal tissue (upper one-third) is a mixture of acidophils and (smaller) basophils or chromophobes. Note a few acidophils scattered through the hyperplastic nodule (arrow). Hematoxylin and eosin (H&E) stain. B, Pituitary macroadenoma, dog. The large adenoma (a) compresses the brain and optic chiasm (arrow). The adenohypophysis, neurohypophysis, and hypothalamus have been destroyed by the neoplasm. (A courtesy Dr. M.A. Miller, College of Veterinary Medicine, Purdue University. B courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University.) Immunohistochemical expression of trophic hormone in the cytoplasm of adenohypophyseal cells does not necessarily correlate with increased plasma concentrations of bioactive hormone. In poorly differentiated pituitary neoplasms that do not express detectable immunoreactive hormone, polymerase chain reaction (PCR) testing for mRNA of trophic hormones can be used to determine the cell of origin. Pituitary Carcinomas. Pituitary carcinomas are exceedingly rare, but that is at least partly because of stringent classification criteria. By convention, to be classified as malignant, a pituitary neoplasm must metastasize, not merely invade, either within the central nervous system or systemically. Adenomas of the Pars Distalis. Adenomas can arise from any of the trophic hormone-producing cells of the pars distalis. Depending on the cell lineage, the neoplastic cells may produce more than one type of trophic hormone. Of the domestic animal species, pars distalis adenomas are most commonly diagnosed in dogs and cats. CHAPTER 12 Endocrine System E-Table 12.1 780.e1 Inherited Endocrine Diseases of Animals Condition Species/Breed Pattern of Inheritance Adenohypophyseal aplasia Pituitary dwarfism Dyshormonogenetic goiter Jersey and Guernsey cattle German shepherd dogs, Karelian bear dogs, Spitz, toy poodles Abyssinian cats, Afrikaner cattle, rat and toy fox terriers, Saanen dwarf goats, sheep Beagles, Doberman pinschers, golden retrievers, Labrador retrievers Miniature schnauzers Bearded collies, Nova Scotia duck tolling retriever, Portuguese water dogs, standard poodles Chow Chows, Pomeranians, poodles, Samoyeds Keeshond Miniature horses and ponies, miniature swine, Ossabaw pigs Guernsey cattle Unknown Autosomal recessive Autosomal recessive Hypothyroidism Hypoparathyroidism Hypoadrenocorticism Adrenal hyperplasia-like syndrome Diabetes mellitus Metabolic syndrome Concurrent pheochromocytomas and thyroid medullary neoplasms E-Figure 12.12 Corticotroph Hyperplasia, Cat. A hyperplastic nodule (lower right two-thirds), less than 1 mm in diameter, is composed of packets of monomorphic chromophobes with abundant amphophilic cytoplasm. Adjacent normal adenohypophyseal tissue (upper left one-third) is a mixture of acidophils and (smaller) chromophobes. Hematoxylin and eosin (H&E) stain. (Courtesy Dr. M.A. Miller, College of Veterinary Medicine, Purdue University.) Unknown Unknown Unknown or autosomal recessive Unknown Unknown Unknown Unknown CHAPTER 12 Endocrine System Most canine pars distalis adenomas are derived from corticotrophs. Feline pars distalis adenomas in one case series were derived mainly from somatotrophs or gonadotrophs. Pars distalis adenomas that are less than 5 mm in diameter are classified as microadenomas; those adenomas that are larger are classified as macroadenomas (see Fig. 12.18, B). Somewhat surprisingly, the smaller microadenomas may be more likely to secrete bioactive trophic hormone, whereas large macroadenomas may have more of a compressive mass effectf rather than a trophic hormone effect. In fact, very large pituitary neoplasms are likely to result in decreased trophic hormone secretion with panhypopituitarism and atrophy (secondary hypofunction) of the targeted endocrine glands. Histologically, pituitary adenomas are composed of polyhedral or piriform cells that tend to be larger, with more abundant cytoplasm, than nonneoplastic pars distalis cells, but they usually have only mild nuclear atypia and few mitotic figures. Because corticotroph adenomas, somatotroph adenomas, and gonadotroph adenomas are the more common pars distalis neoplasms, they are discussed in the following sections. Lactotroph adenomas are reported mainly in sheep but are not common. Neoplasms of thyrotrophs have been reported in cats, but seem to be rare in all species. Although melanotrophs are scattered lightly through the pars distalis, most neoplasms of melanotrophs arise in the pars intermedia, where they are the predominant cell type (see next section). Corticotroph Adenomas. Functional (ACTH-secreting) corticotroph adenomas are an important cause of canine hypercortisolism (secondary adrenocortical hyperfunction or pituitary-dependent hyperadrenocorticism). Corticotroph adenomas are rare in the other domestic species. The larger macroadenomas can obliterate most of the pituitary gland, resulting in panhypopituitarism with secondary hypofunction of target endocrine organs, and compress the neurohypophysis, optic chiasm, hypothalamus, and thalamus. Histologically, corticotroph adenomas are composed of basophilic (densely granulated) to chromophobic (sparsely granulated) cells arranged in sinusoidal or diffuse patterns (see Fig. 12.16, B and E-Fig. 12.10); the granules are periodic acid-Schiff (PAS)-positive. The sinusoidal pattern consists of packets of polyhedral neoplastic cells surrounded by thin fibrovascular septa and more elongated neoplastic cells that palisade around sinusoids. In the diffuse pattern, neoplastic cells are arranged in sheets. Neoplastic cells in both patterns are often larger than nonneoplastic corticotrophs, with a large hypochromatic nucleus, one or two distinct nucleoli, few mitotic figures, and ample pale eosinophilic to amphophilic cytoplasm with distinct cell boundaries. Secretory granules may be dense and basophilic or sparse and inconspicuous in more chromophobic cells. The neoplastic cells are immunohistochemically positive for ACTH. Ultrastructurally, the neoplastic cells have well-developed rough ER and Golgi apparatus and numerous small (∼170 nm in diameter) dense-core secretory granules. Somatotroph Adenomas. Somatotroph adenoma is the most common pituitary adenoma in cats (also see Diseases of Cats, Hypersomatotropism). It is rare in the other domestic species. Neoplastic somatotrophs are usually larger than their nonneoplastic counterparts and have numerous eosinophilic secretory granules; however, large neoplastic cells with few cytoplasmic granules or only faintly eosinophilic granules are the predominant cell type in some somatotroph adenomas. Hypersecretion of GH, also known as STH, can lead to acromegaly (see Diseases of Cats, Hypersomatotropism); it also promotes hepatocellular synthesis and secretion of insulin-like growth factor-1 (IGF-1), so serum assay for IGF-1 concentration can be used diagnostically. fCompression of normal tissues adjacent to the mass resulting in atrophy and/ or necrosis of affected cells and reduced blood supply to the tissue. 781 Gonadotroph Adenomas. Immunohistochemistry to detect follicle stimulating hormone (FSH) or luteinizing hormone (LH) is not routine in most diagnostic laboratories, so gonadotroph adenomas may be underdiagnosed. Nevertheless, gonadotroph adenoma was the second most common tumor type (after somatotroph adenoma) in a series of feline pituitary adenomas. Histologically, the neoplastic cells were chromophobic and PAS-negative. No clinical evidence of hypergonadotropism or other endocrinopathy was observed in any of the cats; however, all affected cats had been spayed or castrated before diagnosis of the pituitary adenoma. Adenomas of the Pars Intermedia. Adenomas in the pars intermedia are usually derived from melanotrophs. Equine pituitary adenomas (Fig. 12.19) almost always develop in the pars intermedia. In addition, the pars intermedia is a major site (along with the pars distalis) for canine pituitary adenomas. The pars intermedia is also an important site of feline pituitary adenomas. Interestingly, pars intermedia adenomas are practically nonexistent in human beings because the pars intermedia shrinks after fetal life and is only vestigial in adults. Melanotroph Adenomas. Melanotroph adenomas, derived from cells that, like corticotrophs, produce POMC-derived peptides, are the major pituitary neoplasm in horses (see Diseases of Horses) and account for about half of canine pituitary adenomas and a smaller proportion of feline pituitary adenomas. Like corticotroph adenomas, they typically are composed of hypertrophied cells with basophilic to chromophobic, densely to sparsely granulated cytoplasm. The granules are PAS-positive. The presence of colloid-filled follicles in the neoplastic tissue can help distinguish the pars intermedia adenoma from one that originated in the pars distalis, but in large adenomas or in fragmented surgical biopsy specimens, the precise location of the tumor is not always apparent. Immunohistochemically, the neoplastic cells express both α-MSH and ACTH. Functional adenomas that produce and secrete bioactive ACTH can result in hypercortisolism in 50% or more of the canine and feline cases. Nonfunctional adenomas can cause hypopituitarism secondary to destruction of the adenohypophysis (anterior pituitary a Figure 12.19 Adenoma, Brain, Pituitary Gland, Horse. The pituitary gland is enlarged by an adenoma (a) in the pars intermedia. (Courtesy College of Veterinary Medicine, University of Illinois.) 782 SECTION II Pathology of Organ Systems (hypophysitis). The term pituitary apoplexy is used for acute hemorrhagic infarction of the hypophysis, usually in association with a pituitary neoplasm. This condition is diagnosed mainly in human beings but is also observed in dogs and horses. o Inflammation. The pituitary gland can become inflamed as part of a systemic infection, but there are few, if any, infectious agents that target the hypophysis. In a systemic infection, the microbial agent reaches the hypophysis hematogenously. (The blood-brain barrier does not protect the hypophysis.) Pituitary inflammation can also develop as an extension from adjacent tissue (e.g., meninges, brain, pharynx). Lymphoplasmacytic hypophysitis is thought to be an immune-mediated (probably autoimmune) disease and has been described in the canine pituitary gland, but it is less common than similar inflammatory processes in the thyroid or adrenal glands. Disorders of the Neurohypophysis Diabetes Insipidus Figure 12.20 Iatrogenic Adenohypophyseal Atrophy, Dog. The adenohypophysis in this dog, treated with the somatostatin analog pasireotide for a corticotroph macroadenoma, was so small that it was detectable only histologically. o, Optic chiasm. (Courtesy Dr. D. Bruyette, VCA West Los Angeles Animal Hospital and Dr. M.A. Miller, College of Veterinary Medicine, Purdue University.) gland) or diabetes insipidus secondary to destruction of the neurohypophysis (posterior pituitary gland) or compression of the hypothalamus (i.e., mass effect). Miscellaneous Disorders of the Adenohypophysis Cellular Atrophy, Degeneration, and Death. Physiologic hypophyseal atrophy is the result of negative feedback from targeted endocrine organs through the hypothalamic-pituitary-target organ axis. This results in selective atrophy of a specific type of trophic hormone-producing cell. For example, increased plasma concentration of thyroxine causes atrophy of thyrotrophs without affecting other adenohypophyseal cells. Therefore, physiologic atrophy seldom causes grossly appreciable shrinkage of the adenohypophysis. In contrast, profound and generalized adenohypophyseal atrophy can be induced by treatment with the somatostatin analogue pasireotide (Fig. 12.20).g Somatostatin is so named because it inhibits the release of GH from somatotrophs. Injectable pasireotide has been used as treatment of canine and feline pituitary adenomas, and it works by binding somatostatin receptors, which are present on somatotrophs, corticotrophs, and perhaps other trophic-hormone producing cells of the adenohypophysis. In addition to the hypothalamus, other organs and tissues, notably the δ cells of the pancreatic islets, produce somatostatin. Somatostatin inhibits not only the release of GH from somatotrophs but also that of insulin and glucagon from pancreatic islet cells and that of ACTH from corticotrophs. Hypophyseal degeneration or necrosis can also result from compression by a mass within the pituitary gland or in adjacent tissue (see Fig. 12.15). Alternatively, degeneration can be secondary to vascular disturbances or to inflammation in the pituitary gland gPasireotide is a somatostatin analogue that has a 40-fold increased affinity for somatostatin receptor type 5 (SSTR5). Its trade name is Signifor (Novartis Pharmaceuticals Corporation). Diabetes insipidus is a form of polyuria caused by an inability to concentrate urine. It is the result of inadequate synthesis and release of ADH in the central or hypophyseal form of the disorder or the result of the failure of renal tubular epithelial cells to respond to ADH in the nephrogenic form. In either form, hypotonic urine (with osmolality equivalent to or less than that of plasma) is produced, even in the face of water deprivation. The hypophyseal form of diabetes insipidus can be caused by any process that compresses or destroys the pars nervosa, infundibular stalk, or the supraoptic nucleus (so named for its hypothalamic location just dorsal to the optic chiasm). The hypophyseal form can be distinguished from the nephrogenic form of diabetes insipidus by the ability of the patient to concentrate urine after administration of ADH. Neoplasms Most neoplasms of the pars nervosa are extensions of adenohypophyseal adenomas. Brain tumors, particularly ependymomas (see Chapter 14, Nervous System) of the third ventricle, also can extend through the infundibular stalk into the pars nervosa. The pituicytoma is a primary neoplasm of the pituicyte, the glial cell of the pars nervosa. The pituicyte is considered a variant of astrocytes and expresses glial fibrillary acidic protein immunohistochemically. Pituicytomas are rare but have been observed in the domestic species, often as incidental findings in animals with an adenohypophyseal adenoma. Other Neoplastic Disorders of the Hypophysis Secondary Neoplasms Unprotected by the blood-brain barrier, the pituitary gland is vulnerable to metastatic neoplasia. The pars nervosa may be particularly susceptible because of its direct blood supply from the carotid artery. The more common secondary neoplasms of the hypophysis are lymphoma in various species, equine and canine melanoma, and canine thyroid and mammary carcinomas. Secondary neoplasms can also be extensions from adjacent tumors, such as osteosarcoma of the sella turcica or ependymoma of the third ventricle. Suprasellar Neoplasms Although most tumors arising in or above the sella turcica (i.e., suprasellar) originate in the pituitary gland, less common suprasellar neoplasms include meningioma, craniopharyngioma, and germ cell tumors. Suprasellar meningiomas resemble those at other locations (see Chapter 14, Nervous System). Whereas pituitary neoplasms are more common in older animals, craniopharyngiomas and germ cell tumors tend to arise in young adult animals. CHAPTER 12 Endocrine System Craniopharyngiomas (Fig. 12.21, A and B) are rare epithelial tumors that are thought to be derived from the craniopharyngeal duct and Rathke’s pouch remnants. Two histologic patterns are recognized in human beings: the adamantinomatous form, which is more common in childhood and resembles odontogenic tumors such as ameloblastoma, and the squamous (pseudo)papillary form, which c m t A 783 occurs mainly in adults and is thought to develop from metaplasia of adenohypophyseal cells in the pars tuberalis. Both histologic patterns are recognized in domestic mammals, in which craniopharyngioma has been reported only in dogs and cats, and usually in young animals. The neoplastic tissue consists of nests of polyhedral epithelial cells in fibrous stroma. The neoplastic cells have eosinophilic cytoplasm, distinct cell borders, and faint intercellular bridges. The cells express cytokeratins immunohistochemically. Tubular formations lined by ciliated cells and goblet cells in some areas of the tumor reflect its association with the craniopharyngeal duct. Reported veterinary cases have been expansile or infiltrative, but the mitotic index is typically low. Although malignant craniopharyngioma was diagnosed in two cats, metastasis was not reported. Suprasellar neoplasms with a population of germ cells, teratomatous features, or immunoreactivity for α-fetoprotein should be classified as suprasellar germ cell tumors (see Fig. 12.21, C). Intracranial germ cell tumors have been described only in the suprasellar location and only in dogs of the domestic animal species. These infiltrative neoplasms obliterate the pituitary gland and compress the hypothalamus. The predominant cell type is a germ cell that resembles the neoplastic cells of testicular seminoma. As in seminoma, aggregates of small lymphocytes are commonly scattered through the neoplastic stroma. Suprasellar germ cell tumors also include nests of lipid-laden hepatoid cells and may have scattered tubular formations lined by endodermal cells or other teratomatous features. Disorders of the Thyroid Gland Disorders of the thyroid gland are clinically important if they result in thyroid hormone deficiency (hypothyroidism) or excess (hyperthyroidism) or if they produce a mass effect. Other disorders of the thyroid gland may be subclinical and of little importance to the animal. Developmental Malformations B Ectopic Thyroid Tissue. Ectopic thyroid tissue is usually encountered from the base of the tongue along the path of descent of the developing gland, but it can migrate as far caudally as the diaphragm. In dogs, functional nodules of thyroid tissue are common near the ascending aorta at the base of the heart. Functional ectopic thyroid tissue is a source of hormone production after thyroidectomy. It also can be a site of thyroid carcinoma, mainly in dogs, and usually in a mediastinal location (see Diseases of Dogs). Accessory Thyroid Tissue and Thyroglossal Duct Cysts. C Figure 12.21 Non-Pituitary Suprasellar Neoplasms, Dogs. A, Craniopharyngioma (c), left and right adrenal glands and thyroid lobes. The neoplasm has extended dorsally through the hypothalamus and compressed the thalamus (black arrows). Destruction of the pituitary gland resulted in trophic atrophy of the adrenal cortices (white arrows), leaving a prominent medulla (m) surrounded by remaining cortical tissue (mainly zona glomerulosa). Thyroid follicles were also atrophied, but colloid involution maintained the overall thyroid (t) size within normal limits. B, The craniopharyngioma is composed of interconnecting nests of keratinizing epithelial cells in fibrous stroma. Hematoxylin and eosin (H&E) stain. C, Suprasellar germ cell tumors consist predominantly of seminoma-like germ cells with fewer lipid-laden hepatoid cells and scattered aggregates of small lymphocytes. H&E stain. (A courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University. B and C courtesy Dr. M.A. Miller, College of Veterinary Medicine, Purdue University.) Accessory thyroid tissue is derived from remnants of the thyroglossal duct. Thyroglossal duct remnants can also form cysts or sinus tracts along the ventral midline of the neck. The cysts that develop near the base of the tongue are typically lined by stratified squamous epithelium, whereas those nearer the thyroid cartilage of the larynx are more likely to be lined by epithelium that resembles that of thyroid follicles. Grossly, the cysts contain watery to mucoid secretions. They seldom exceed 1 cm in diameter, but they can become inflamed, rupture, and form a fistulous tract to the skin. Rarely, thyroglossal duct cysts undergo neoplastic transformation to carcinoma. Follicular Hyperplasia and Goiter The term goiter denotes a nonneoplastic enlargement of the thyroid gland (Fig. 12.22, A) as a result of follicular cell hyperplasia (see Fig. 12.22, B; also see Fig. 12.8, A), although follicular hyperplasia does not always cause grossly appreciable enlargement. The causes for follicular hyperplasia include iodine deficiency, iodine excess, goitrogens, and defects in the synthesis of thyroid hormones. Goiter can be 784 SECTION II Pathology of Organ Systems diffuse (throughout the gland) or multinodular. Diffuse goiter is typically a compensatory, thyroid stimulating hormone (TSH)-induced response to hypothyroidism (decreased plasma concentrations of T4 A B Figure 12.22 Hyperplastic Goiter, Thyroid Gland, Goat. A, Deficiency of maternal dietary iodine during pregnancy resulted in hyperplasia (and hypertrophy) of thyroid follicular cells in this perinatal goat with symmetric enlargement of both lobes (goiter). B, Follicular cells are increased in number and size, impinging on the follicular lumen. Hematoxylin and eosin (H&E) stain. (A courtesy Dr. O. Hedstrom, College of Veterinary Medicine, Oregon State University; and Noah’s Arkive, College of Veterinary Medicine, The University of Georgia. B courtesy Dr. B. Harmon, College of Veterinary Medicine, The University of Georgia; and Noah’s Arkive, College of Veterinary Medicine, The University of Georgia.) and T3). In contrast, multinodular goiter in old cats (Fig. 12.23, A-B and E-Fig. 12.13) consists of hyperplastic follicular cells that function autonomously (independent of TSH) with resultant hyperthyroidism. Unaffected follicular cells (those outside the hyperplastic nodules) undergo atrophy because of the low plasma concentration of TSH (Fig. 12.23, C). Iodine Deficiency. Iodine deficiency, especially during the fetal and neonatal period when the need for thyroid hormones is greatest, is the major cause of diffuse goiter in certain geographic regions—for example, the Pacific Northwest and the Great Lakes region—especially in horses, cattle, small ruminants, and pigs without dietary iodine supplementation. Without sufficient iodine, deficient synthesis of T4 and T3 results in TSH-induced hyperplastic goiter (see Fig. 12.8, A). Grossly, the thyroid gland in hyperplastic goiter is diffusely enlarged and reddened (Fig. 12.24, A; also see Fig. 12.22, A). Histologically, increased vascularity explains the reddening of the gland. Follicles are irregularly enlarged in hyperplastic goiter, but their luminal diameter is diminished because the crowded and hypertrophied (tall columnar) follicular cells form papillary projections into the follicular lumen (E-Fig. 12.14; also see Fig. 12.22, B). Colloid is paler (less eosinophilic) than normal. The periphery of the colloid has a scalloped appearance because of the formation of endocytic resorption vacuoles at the apical surface of the follicular cells (see Fig. 12.8, A). Some hyperplastic follicles may lack apparent colloid or have a collapsed lumen. Despite a robust response to TSH, many iodine-deficient fetuses and neonates have extrathyroidal lesions, such as myxedema (accumulation of glycosaminoglycans and water in the dermis and subcutis) or less hair or wool than expected for the gestational stage, that indicate hypothyroidism (see Fig. 12.24, B). Nevertheless, the hypertrophy and hyperplasia of follicular cells does increase their ability to extract available iodide from the blood. Therefore, with correction of the dietary iodine deficiency or with the decreased postnatal demand for thyroid hormones, the hyperplastic thyroid gland may produce sufficient circulating T4 and T3 to result in negative feedback on the hypothalamus and hypophysis with diminished TSH secretion. In response to decreased TSH, hyperplastic goiter undergoes involution to colloid goiter (see Fig. 12.24, C). The thyroid gland remains enlarged, but its color fades from a deep redbrown to pale brown (because of decreased vascularity) and takes on a translucent appearance because of the colloid-distended follicles. * A B C Figure 12.23 Hyperplasia, Hyperthyroidism, Thyroid Gland, Cats. A, Larynx, trachea, esophagus, and thyroid gland. Multinodular hyperplasia in the left (arrow) thyroid lobe. The right lobe is not visible in this view. B, Thyroid gland, formalin-fixed. Multinodular follicular hyperplasia (arrowheads) involves both thyroid lobes. C, Thyroid gland. A hyperplastic nodule is well demarcated from atrophied follicles just beneath the thyroid capsule (asterisk), and it consists of follicles of various diameter, lined by hypertrophied but well-differentiated follicular cells and filled with pale eosinophilic colloid with peripheral resorption vacuoles. Hematoxylin and eosin (H&E) stain. (A courtesy Dr. M.A. Miller, College of Veterinary Medicine, Purdue University. B courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University. C courtesy Dr. M.A. Miller, College of Veterinary Medicine, Purdue University.) CHAPTER 12 Endocrine System E-Figure 12.13 Hyperplasia, Hyperthyroidism, Thyroid Gland, Cat. Larynx, trachea, and thyroid gland. Multinodular hyperplasia in the left (arrow) thyroid lobe with atrophy of the right (arrowhead) lobe. (Courtesy Dr. M.A. Miller, College of Veterinary Medicine, Purdue University.) 784.e1 E-Figure 12.14 Hyperplastic Goiter, Thyroid Gland, Dog. Hyperplastic follicular epithelium forms papillary projections (arrow) that extend into the follicular lumen devoid of colloid. Note that many follicular lumens are collapsed. Periodic acid-Schiff reaction. (Courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University.) CHAPTER 12 Endocrine System A B 785 C Figure 12.24 Iodine-Deficiency Goiter in Fetal or Neonatal Animals. A, Hyperplastic goiter in a foal. Thyroid-stimulating hormone (TSH)-induced follicular cell hyperplasia and increased blood supply impart a deep red color to the enlarged thyroid lobes (arrows). B, Near-term bovine fetus with goiter (thyroid gland, not visible), alopecia, and myxedema causing swelling of the soft tissues of the neck. C, Colloid goiter in a foal. If iodine deficiency is corrected, hyperplastic goiter undergoes colloid involution. The thyroid lobes remain enlarged (arrows), but they become pale from the accumulation of colloid and decreased vascularity. (Courtesy Dr. M.A. Miller, College of Veterinary Medicine, Purdue University.) Histologically, the follicles are distended by intensely stained (eosinophilic or PAS-positive) colloid without the endocytic resorption vacuoles of hyperplastic goiter (see Fig. 12.8, B). Although a few papillary projections may remain, the atrophied follicular epithelium becomes low cuboidal. Foals born to mares that grazed endophyteinfected fescue pasture during pregnancy may have thyroid follicular atrophy with colloid-distended follicles, low thyroid hormone concentrations, and delayed parturition. This is because ergovaline, the major toxic component produced by the endophyte, is an agonist of dopamine D2 receptors. l Goitrogens. Goitrogens are compounds, including plants, drugs, and other chemicals, that cause hyperplastic goiter. Marginal iodine deficiency increases the sensitivity of the thyroid gland to goitrogens. Cruciferous plants (genus Brassica) are goitrogenic because they contain glucosinolates (sulfur-containing glucosides) that are converted in the intestine to glucose and by-products, such as isothiocyanates, by the enzyme myrosinase derived from the plant or from the intestinal tract. Thiocyanates, perchlorates, and certain other ions compete with iodide for uptake by thyroid follicular cells. Phenobarbital, rifampin, and certain other medicinal compounds are goitrogenic because they increase the degradation of T4 and T3. Somewhat paradoxically, excessive iodine can also be goitrogenic, perhaps by interfering with the proteolysis of colloidal thyroglobulin and thereby inhibiting thyroid hormone secretion. Because iodide is concentrated in the milk, foals of mares fed kelp or seaweed as an iodine supplement are exposed to higher iodide concentrations than their dams and can develop hyperplastic goiter. Thyroid Dyshormonogenesis. Mutations of any of the genes involved in thyroid hormone synthesis can result in dyshormonogenesis (defective hormone synthesis). Congenital dyshormonogenetic goiter has been described as an autosomal recessive trait, mainly in sheep (Fig. 12.25) and goats, and rarely in cattle, dogs, and cats. Affected animals are born with massive TSHinduced hyperplastic goiter and typically have features of hypothyroidism, such as myxedema, sparse wool or hair, and decreased somatic growth in those that survive the neonatal period. Thyroid peroxidase mutations that result in defective iodide oxidation and organification have been documented in dogs and cats. Ruminants with congenital dyshormonogenetic goiter had defective thyroglobulin synthesis despite normal iodide uptake and organification. t t Figure 12.25 Congenital Dyshormonogenetic Goiter, Thyroid Gland, Lamb. The symmetrically enlarged thyroid (t) lobes are fused at the midline ventral to the larynx (l) and trachea. (Courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University.) Multinodular Goiter. Multifocal follicular hyperplasia in geriatric horses or dogs is typically an incidental finding without notable enlargement of the thyroid gland or functional consequences. In contrast, middle-aged to older cats develop multinodular toxic (hyperthyroid) goiter (see Fig. 12.23; also see Diseases of Cats). Follicular Atrophy Colloid Goiter. Colloid goiter is the involutional stage of hyperplastic goiter after repletion of dietary iodine in the case of iodine-deficient goiter (see the preceding section) or with diminished need for thyroid hormones as the animal matures. Although CHAPTER 12 Endocrine System B M L P C E-Figure 12.15 Lymphocytic Thyroiditis in a Dog with Severe Hypothyroidism. A lymphocyte (L) and macrophage (M) are present in the colloid (C) of a thyroid follicle. A plasma cell (P) within the follicular basement membrane (B) is infiltrating between thyroid follicular cells. Transmission electron microscopy (TEM). Uranyl acetate and lead citrate stain. (From Gosselin SJ, Capen CC, Martin SL: Vet Immunol Immunopathol 3:185-201, 1982.) 785.e1 786 SECTION II Pathology of Organ Systems the thyroid gland remains enlarged in colloid goiter, the follicular cells have undergone atrophy because of decreased TSH release from adenohypophyseal thyrotrophs. Lymphocytic (Immune-Mediated) Thyroiditis. Autoimmune thyroid disease, with infiltration of the gland by thyroid-reactive lymphocytes, is thought to be triggered by the interaction of genetic and environmental factors (e.g., excessive iodine, infections, pregnancy). In Hashimoto’s thyroiditis, considered not only the most common human autoimmune disease but also the most common endocrine disorder, destruction of follicular cells by cytotoxic T lymphocytes leads to thyroid atrophy and hypothyroidism. Histologic features are follicular atrophy with increased interstitial fibrous tissue and lymphocytes with fewer plasma cells and macrophages. The lymphocytes can form lymphoid follicles with germinal centers. Remaining thyroid follicles are lined by so-called Hürthle cells (enlarged follicular cells with granular eosinophilic cytoplasm, a hyperchromatic nucleus, and prominent nucleolus). Hashimoto’s thyroiditis is distinct from human Grave’s disease, in which autoantibodies bind the TSH receptor on follicular cells, leading to thyroid hyperplasia and hyperthyroidism. Lymphocytic thyroiditis (Fig. 12.26; E-Fig. 12.15) is the histologic lesion in many cases of canine hypothyroidism (see Diseases of Dogs). Lymphocytic thyroiditis with fibrosis has also been reported in a subset of thyroid glands from eastern European horses imported for slaughter in Italy and examined because of macroscopic alterations in their thyroid glands. The authors noted the similarity to Hashimoto’s thyroiditis and documented increased thyroglobulin concentration in serum in addition to the presence of antibodies to both thyroglobulin and thyroid peroxidase. A Follicular Neoplasms B commonly diagnosed in cats than in dogs. In dogs, most thyroid follicular neoplasms are carcinomas (see next section). Feline follicular adenomas are often functional and result in hyperthyroidism. Macroscopically, adenomas appear as discrete tan to brown nodules that compress adjacent atrophied parenchyma (Fig. 12.27, A). Histologically, they resemble nodules of adenomatous hyperplasia with which they may coexist, but they tend to be larger, solitary, and encapsulated (see Fig. 12.27, B). Most adenomas have a follicular pattern (see Fig. 12.27, C). The follicles can be smaller or larger than nonneoplastic follicles and have variable colloid production. The neoplastic follicular cells are generally larger than nonneoplastic follicular cells, but mitotic figures are few, and the neoplastic tissue can be quite similar in histologic appearance to that of nodular hyperplasia. C Follicular Adenomas. Thyroid follicular adenomas are more Follicular Carcinomas. Thyroid follicular carcinomas are diag- nosed mainly in dogs. Follicular carcinomas (Fig. 12.28; E-Fig. 12.16) can become quite large (thus they are palpable in most cases) and are typically invasive, with early metastasis, especially to the lungs. Because most follicular carcinomas are nonfunctional, affected animals can develop hypothyroidism when large tumors destroy most of the thyroid gland (i.e., mass effect). Follicular carcinomas can also arise from ectopic thyroid tissue (see Diseases of Dogs). Nuclear atypia and a high mitotic count are histologic features that help distinguish a well-differentiated follicular carcinoma from an adenoma; however, proof of malignancy requires documentation of invasion of neoplastic cells through the capsule of the thyroid gland. Immunohistochemistry for thyroid transcription factor-1 (TTF-1) and thyroglobulin may be needed to document follicular cell origin in compact (with minimal follicle formation) or poorly differentiated thyroid carcinomas. Because TTF-1 is also expressed by pulmonary epithelial cells and Figure 12.26 Lymphoplasmacytic Thyroiditis, Dog. A, Lymphocytic inflammation can lead to formation of lymphoid follicles (arrow) with germinal centers. Hematoxylin and eosin (H&E) stain. B, Numerous lymphocytes and plasma cells, and few macrophages, are in the interstitium of the thyroid gland. Remaining follicles contain pale colloid with peripheral resorption vacuoles. Follicular cells are columnar. H&E stain. C, More chronic lymphoplasmacytic thyroiditis is accompanied by interstitial fibrosis, follicular atrophy, and greater loss of follicles. Remaining follicles have intensely eosinophilic colloid without resorption vacuoles and are lined by low cuboidal cells. H&E stain. (Courtesy Dr. J.A. Ramos-Vara, College of Veterinary Medicine, Purdue University.) pulmonary carcinomas, another immunohistochemical marker, paired box gene 8 (Pax8), can be used to distinguish metastatic thyroid carcinomas in the canine lung from primary pulmonary carcinomas. Pax8 is a nuclear protein active in thyroid follicular cell development and in the expression of thyroid-specific genes. CHAPTER 12 Endocrine System E ca e A B E-Figure 12.16 Thyroid Carcinoma, Thyroid Gland, Dogs. A, The poorly demarcated and well-vascularized thyroid carcinoma (ca) is locally invasive and has extended into the wall of the esophagus. B, Neoplastic cells are haphazardly arranged into discrete islands. There is moderate variation in cellular and nuclear size and shape. Note the invasion of the tumor into the capsule of the thyroid gland (upper left). Inset, Higher magnification of the cells in the thyroid carcinoma. Hematoxylin and eosin (H&E) stain. e, Esophageal mucosa. (A courtesy College of Veterinary Medicine, University of Illinois. B courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) 786.e1 CHAPTER 12 Endocrine System 787 * A B C Figure 12.27 Follicular Adenoma, Thyroid Gland, Hyperthyroid Cats. A, The left thyroid lobe contains an expansile, pale tan mass (asterisk) that is well demarcated from adjacent parenchyma. Nodules of adenomatous hyperplasia are in the contralateral lobe. B, The follicular adenoma (left) is thinly encapsulated and well demarcated from adjacent atrophied thyroid gland. Hematoxylin and eosin (H&E) stain. C, Note increased cell density and size of follicular cells in the adenoma. Follicles are collapsed or filled by pale colloid with numerous resorption vacuoles. H&E stain. (A courtesy Dr. J.A. Ramos-Vara, College of Veterinary Medicine, Purdue University. B and C courtesy Dr. M.A. Miller, College of Veterinary Medicine, Purdue University.) Thyroid Medullary (C-Cell) Proliferative Lesions Disorders of the Parathyroid Glands calcium diet designed for dairy cows, are likely to develop C-cell hyperplasia. Physiologic C-cell hyperplasia is an expected response to hypercalcemia and is typically distributed throughout the thyroid gland. Diffuse or multifocal nodular hyperplasia of thyroid C cells also may precede the development of C-cell neoplasms. Parathyroid (Kürsteiner’s) Cysts. Cysts (Fig. 12.31; E-Fig. 12.20) in or immediately adjacent to a parathyroid gland, presumably derived from remnants of the duct that connects the developing gland to the thymus, are relatively common, usually incidental, findings in domestic animal species. The multilocular cysts are lined by ciliated columnar epithelial cells and filled with eosinophilic (proteinaceous) secretion. The cysts vary in diameter, but marked accumulation of inspissated proteinaceous secretion can impart the gross appearance, on superficial inspection, of an enlarged parathyroid gland. Thyroid C-Cell Hyperplasia. Bulls, especially those fed a high- Thyroid C-Cell Neoplasms. Thyroid C-cell neoplasms are diagnosed mainly in older horses and dairy bulls, in which they can be associated with increased bone density; occasionally in dogs; and infrequently in other species. C-cell neoplasms can develop concurrently with other endocrine neoplasms, particularly bilateral pheochromocytomas. This arrangement resembles human multiple endocrine neoplasia (MEN) type II syndrome (MEN2), in which C-cell hyperplasia and carcinomas are associated with pheochromocytomas. Mutations in the RET proto-oncogene result in human MEN2; however, such mutations have not been documented in bulls. Amyloid deposits, apparently produced by the neoplastic cells and derived from calcitonin, are found in some C-cell adenomas and carcinomas. C-Cell Adenomas. The C-cell adenoma is the most common equine thyroid tumor and is usually an incidental finding at autopsy (see E-Appendix 12.1) of geriatric horses. These tumors are solitary or multiple, off-white to tan, well-circumscribed nodular masses from a few millimeters to several centimeters in diameter (Fig. 12.29; E-Figs. 12.17 and 12.18). Histologically, C-cell adenomas consist of solid packets of polyhedral cells with few mitotic figures and ample pale amphophilic and faintly granular cytoplasm. Fine fibrovascular septa separate the packets. Entrapment of thyroid follicles can cause confusion with a follicular cell adenoma, but C-cell adenomas are immunohistochemically positive for generic neuroendocrine markers, such as chromogranin and protein gene product 9.5 (PGP 9.5), and specifically for calcitonin. They also express TTF-1 but not thyroglobulin, thus distinguishing themselves from follicular cells. C-Cell Carcinomas. C-cell carcinomas are invasive tumors that can replace much of the thyroid gland. Whereas C-cell neoplasms in horses are typically benign, those in dogs and bulls are commonly malignant with metastasis to regional lymph nodes (Fig. 12.30; E-Fig. 12.19) or to the lungs. Histologically, in addition to invasiveness, the neoplastic cells are less well differentiated than those of C-cell adenoma and are associated with more abundant fibrous stroma. Malformations Chief Cell Atrophy and Hypoparathyroidism Hypoparathyroidism is the result either of insufficient PTH secretion by parathyroid chief cells or an inability of target cells, mainly in renal tubules and bone, to respond to PTH. Affected animals tend to develop hypocalcemia because of decreased bone resorption and hyperphosphatemia because of increased renal tubular reabsorption (E-Fig. 12.21). Atrophy or destruction of parathyroid chief cells is a major cause of inadequate PTH production and secretion. In dogs, hypoparathyroidism may be familial in miniature schnauzers and other breeds. Lymphocytic parathyroiditis (E-Fig. 12.22) seems to be less common than lymphocytic inflammation of other endocrine organs, such as thyroid or adrenal glands, but results in chief cell atrophy and loss, and it has been described in dogs as a presumably autoimmune cause of primary hypoparathyroidism. Cats can develop hypoparathyroidism after thyroidectomy (with inadvertent parathyroidectomy) as a treatment for hyperthyroidism. Destruction of parathyroid glands by primary or secondary neoplasms is another uncommon cause of hypoparathyroidism. Persistent hypercalcemia should, although this is not always the case, cause trophic atrophy of parathyroid chief cells with decreased production of PTH. Trophic atrophy results in shrinkage of all parathyroid glands. Histologically, the atrophied gland has small chief cells with diminished vascularity and a relative increase in stroma. Chief Cell Proliferation and Hyperparathyroidism Primary Hyperparathyroidism. Primary hyperparathyroidism is the result of autonomous hypersecretion of PTH by hyperplastic or neoplastic chief cells. Parathyroid (chief cell) adenomas (Fig. 12.32), diagnosed mainly in dogs, are more common than parathyroid carcinomas or primary hyperplasia. Adenomas typically affect only one parathyroid gland with formation of a nodule up to 1 cm CHAPTER 12 Endocrine System 787.e1 E-Figure 12.17 Thyroid Adenoma, Thyroid Gland, Horse. The thyroid gland contains an expansile, encapsulated, round, white-yellow mass that is well demarcated from normal thyroid gland. Note the fibrous capsule surrounding the adenoma. (Courtesy College of Veterinary Medicine, University of Illinois.) E-Figure 12.19 C-Cell Carcinoma and Metastases, Thyroid and Cervical Lymph Nodes, Holstein Bull. Note the swellings in the neck (arrows) as a result of metastases to the cervical lymph nodes. (Courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University.) a p t E-Figure 12.18 C-Cell Adenoma, Thyroid Gland, Horse. The adenoma (a) is confined by the thyroid capsule and a rim of compressed thyroid gland (arrow) at the periphery of the mass. (Courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University.) E-Figure 12.20 Parathyroid Cyst (Kürsteiner’s Cyst), Dog. The multilocular cyst is derived from the duct that connects embryonic parathyroid-thymic primordia in pharyngeal pouches III and IV. Part of the parathyroid cyst (p) is distended with inspissated, opaque secretion; the arrow points to a locule with more watery secretion. t, Thyroid gland. (Courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University.) 787.e2 SECTION II Pathology of Organ Systems Serum concentration (mg/dL) Calcium 10 Phosphorus 4 Onset of impaired PTH secretion Hypoparathyroidism t ( ) Bone resorption ( ) Renal tubular reabsorption Hyperphosphatemia —Hypophosphaturia Hypocalcemia —Hypercalciuria: early —Hypocalciuria: late p Time E-Figure 12.21 Schematic Diagram of the Alterations in Serum Calcium and Phosphorus Concentrations in Response to an Inadequate Secretion of Parathyroid Hormone (PTH). A progressive increase in serum phosphorus concentration and a notable decline in the concentration of serum calcium resulted in increased neuromuscular excitability and tetany. (Redrawn with permission from Dr. C. Capen, College of Veterinary Medicine, The Ohio State University.) E-Figure 12.22 Diffuse Lymphocytic Parathyroiditis, Parathyroid Gland, Dog. The external parathyroid gland (p) has been completely replaced by lymphocytes, plasma cells, fibroblasts, and neocapillaries. t, Thyroid gland. Hematoxylin and eosin (H&E) stain. (Courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University.) 788 SECTION II Pathology of Organ Systems A A t e B f B f C C Figure 12.28 Thyroid Follicular Carcinoma, Dog. A, A follicular carcinoma has obliterated the right thyroid lobe, but the left lobe is grossly normal. B, Cross section through a large follicular carcinoma that has destroyed the entire thyroid gland, surrounded the trachea (t) and esophagus (e), and invaded adjacent tissue and vasculature. C, Neoplastic follicular cells are arranged in compact nests with negligible follicle formation. Hematoxylin and eosin (H&E) stain. Inset, Immunohistochemical expression of thyroglobulin indicates follicular origin of the neoplastic cells. Immunohistochemistry with diaminobenzidine chromogen. (A courtesy Dr. W. Crowell, College of Veterinary Medicine, The University of Georgia; and Noah’s Arkive, College of Veterinary Medicine, The University of Georgia. B and C courtesy Dr. M.A. Miller, College of Veterinary Medicine, Purdue University.) in diameter. Microscopically (see Fig. 12.32, B; E-Figs. 12.23 and 12.24), a parathyroid adenoma is at least partially encapsulated and compresses adjacent parathyroid parenchyma. The neoplastic chief cells have an enlarged nucleus and ample cytoplasm with few mitotic figures. The increase in chief cell size and number compresses the Figure 12.29 C-Cell Adenoma, Thyroid Gland, Horse. A, The adenoma is pale gray to pink, thinly encapsulated, and contained within the thyroid gland. B, The C-cell adenoma is multinodular but well demarcated from adjacent thyroid parenchyma. Hematoxylin and eosin (H&E) stain. C, The neoplastic cells are typical neuroendocrine cells, but the presence of entrapped thyroid follicles (f) can cause confusion with follicular adenomas. H&E stain. (Courtesy Dr. M.A. Miller, College of Veterinary Medicine, Purdue University.) interstitium of the adenoma with a relative decrease in fibrovascular stroma. Adjacent parathyroid tissue and remaining parathyroid glands undergo chief cell atrophy in response to the hypercalcemia of hyperparathyroidism. Chief cell carcinomas tend to be larger than adenomas with destruction of much of the parathyroid gland and invasion of surrounding tissues. The neoplastic cells may have features of malignancy, such as nuclear atypia and increased mitotic count. Primary (idiopathic), usually multinodular, hyperplasia of chief cells is also observed in dogs, but it is less common than secondary chief cell hyperplasia (see the next section). The cytologic features of hyperplastic chief cells can resemble those of neoplastic chief cells, but the presence of multiple unencapsulated nodules distinguishes primary hyperplasia from the typically solitary and encapsulated adenoma and from secondary hyperplasia, which tends to CHAPTER 12 Endocrine System 788.e1 M E S G E-Figure 12.23 Adenoma, Parathyroid Gland, Dog. The adenoma consists of closely packed chief cells arranged in small groups separated by fine fibrous septa containing capillaries (arrowheads). It is partially encapsulated and has compressed the adjacent, nonneoplastic parathyroid tissue (arrows), which has undergone trophic atrophy. Hematoxylin and eosin (H&E) stain. (Courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University.) N E-Figure 12.24 Adenoma, Parathyroid Gland, Dog. Active chief cells have large lamellar arrays of rough endoplasmic reticulum (E), prominent Golgi apparatus (G), and large mitochondria (M) but few secretory granules (S). N, Nucleus of chief cell. Transmission electron microscopy (TEM). Uranyl acetate and lead citrate stain. (Courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University.) CHAPTER 12 Endocrine System 789 v v Figure 12.30 Thyroid C-Cell Carcinoma, Dog. The carcinoma (lower right) has invaded the thyroid capsule and its vasculature. Clusters of neoplastic cells are in vascular lumina (v). Hematoxylin and eosin (H&E) stain. (Courtesy Dr. J.A. Ramos-Vara, College of Veterinary Medicine, Purdue University.) A be diffuse. Hyperparathyroidism, whether primary or secondary, can result in severe bone resorption and osteopenia (E-Fig. 12.25). Secondary Hyperparathyroidism. Secondary chief cell hyperplasia is typically diffuse, affecting all parathyroid glands (Fig. 12.33, A), and is usually the result of either a nutritional imbalance of calcium and phosphorus (for responses of bone, see Chapter 16, Bones, Joints, Tendons, and Ligaments) or chronic renal failure (see Chapter 11, The Urinary System). Histologically (see Fig. 12.33, B and C), the chief cells are diffusely hypertrophied and crowded, compressing the fibrovascular stroma and capsule. Dietary imbalances that stimulate chief cell hyperplasia and lead to secondary hyperparathyroidism include insufficient calcium, excessive phosphorus, or cholecalciferol deficiency. Renal disease decreases urinary phosphate excretion, resulting in hyperphosphatemia and a corresponding decline in plasma Ca : P ratio. Progressive renal disease also causes decreased production of 1,25-dihydroxyvitamin D3, which exacerbates the relative hypocalcemia. In long-standing renal failure in human beings and in dogs, the proliferation of parathyroid chief cells in secondary hyperparathyroidism can become autonomous (no longer responsive to blood Ca2+ concentration) and continue even in the presence of persistent hypercalcemia. Tertiary hyperparathyroidism is the term used for this conversion of secondary hyperparathyroidism to an autonomous state. The histologic features are indistinguishable from those of secondary hyperparathyroidism, with diffuse chief cell hyperplasia in all parathyroid glands, but the history and serum calcium concentration distinguish tertiary hyperparathyroidism. Nutritional Imbalances. The most frequent dietary cause of secondary hyperparathyroidism is excessive phosphorus. Hyperphosphatemia stimulates the parathyroid gland indirectly by reciprocal lowering of the blood calcium concentration. Horses with nutritional secondary hyperparathyroidism usually have been fed grain diets with low-quality roughage. Because bran is often the source of excess phosphorus in equine diets, the disease has been called “bran disease” or “big head.” The latter name refers to the hyperostotic fibrous osteodystrophy that is typically most severe in the mandibles and maxillae (see Figs. 16.53-16.55). The high-phosphorus diet often has marginal or deficient calcium content, so even though a greater proportion of ingested calcium is absorbed, hypocalcemia develops. The increased PTH secretion acts on renal tubules to increase phosphorus excretion and to decrease calcium loss in the urine. Changes in urinary calcium and phosphorus concentrations are more consistent and diagnostically useful in horses than changes in blood calcium and phosphorus concentrations. B C Figure 12.31 Parathyroid Cyst (Kürsteiner’s Cyst), Dog. A, The multilocular cyst, situated just dorsal to the thyroid lobe, is derived from the duct that connects embryonic parathyroid-thymic primordia in pharyngeal pouches III and IV. The parathyroid cyst (arrows) is distended with secretion. B, A large parathyroid cyst dwarfs the adjacent parathyroid gland (arrow). Hematoxylin and eosin (H&E) stain. C, Smaller parathyroid cyst locules are scattered through adjacent thyroid interstitium. Their ciliated columnar epithelial lining distinguishes them from thyroid follicles. H&E stain. (Courtesy Dr. M.A. Miller, College of Veterinary Medicine, Purdue University.) CHAPTER 12 Endocrine System E-Figure 12.25 Primary Hyperparathyroidism, Humerus, Dog. Severe thinning of cortical bone and large resorptive cavities (arrow) have resulted from localized resorption of bone by osteoclasts. (Courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University.) 789.e1 790 SECTION II Pathology of Organ Systems p p p a p A A t B c B Figure 12.32 Adenoma, Parathyroid Gland, Dog. A, The parathyroid adenoma (A) forms a discrete nodular mass that is well demarcated from the thyroid gland. B, The adenoma consists of packets of hypertrophied chief cells separated by fine fibrovascular septa. A fibrous capsule (arrows) separates the adenoma (lower right) from adjacent, atrophied parathyroid tissue. ­Hematoxylin and eosin (H&E) stain. (A courtesy College of Veterinary Medicine, University of Illinois. B courtesy Dr. M.A. Miller, College of Veterinary Medicine, Purdue ­University.) Renal Disease. If renal disease is extensive enough to reduce the glomerular filtration rate, phosphorus is retained and hyperphosphatemia develops. The increased phosphorus concentration causes a reciprocal decline in ionized blood calcium concentration. Chronic renal disease also impairs 1,25-dihydroxyvitamin D3 (calcitriol) synthesis, thereby diminishing intestinal absorption of calcium. Increased synthesis and secretion of PTH is a response to hyperphosphatemia, hypocalcemia, or low blood concentrations of calcitriol. Diffuse chief cell hyperplasia results in increased size of all parathyroid glands (see Fig. 12.33). The fibrous osteodystrophy (see Chapter 16, Bones, Joints, Tendons, and Ligaments) that develops in chronic renal disease is, as in nutritional secondary hyperparathyroidism, most severe in bones of the skull. Canine mandibles and maxillae may be so severely affected that the dog develops “rubber jaw” (see E-Fig. 16.22). Pseudohyperparathyroidism: Humoral Hypercalcemia of Malignancy Pseudohyperparathyroidism is characterized by persistent hypercalcemia without elevated PTH secretion. The source of the excessive calcium is mainly osteoclastic bone resorption, with a lesser contribution from kidneys and the intestinal tract. Malignant neoplasia is the usual cause of pseudohyperparathyroidism, hence the name C Figure 12.33 Renal Secondary Hyperparathyroidism, Dog. A, All four parathyroid glands (p) are enlarged in this dog with chronic renal failure. The size of the thyroid gland is normal. B, Hyperplasia of the parathyroid gland in secondary hyperparathyroidism is typically diffuse. Hematoxylin and eosin (H&E) stain. C, Hyperplastic chief cells are crowded, enlarged with ample cytoplasm, and impinge on the fibrovascular stroma and the parathyroid capsule (c). H&E stain. t, Thyroid gland. (A courtesy Dr. D.-Y. Cho, College of Veterinary Medicine, Louisiana State University. B and C courtesy College of Veterinary Medicine, Purdue University.) humoral hypercalcemia of malignancy (HHM). The neoplasms that cause pseudohyperparathyroidism do not arise in the parathyroid glands. In fact, the parathyroid chief cells in affected animals undergo atrophy in physiologic response to the elevated plasma Ca2+ concentration. Lymphoma is the most common neoplastic cause of hypercalcemia in dogs and is also associated with hypercalcemia in cats. The pathogenesis of the increased bone resorption in lymphoma has been attributed both to an osteolytic factor released locally by neoplastic cells that invade bone marrow and to the release of a circulating humoral factor (PTHrP and others) by the neoplastic cells. Most dogs with lymphoma and persistent hypercalcemia of malignancy have increased circulating PTHrP concentrations but less so than in dogs with apocrine carcinomas of the anal sac glands CHAPTER 12 Endocrine System and HHM. The lack of correlation between PTHrP concentration and serum calcium concentration indicates that PTHrP is not the sole humoral factor responsible for osteoclastic bone resorption and development of hypercalcemia. Other substances, such as interleukin (IL)-1, tumor necrosis factor (TNF), or 1,25-dihydroxycholecalciferol, probably contribute to the hypercalcemia of malignancy in canine lymphoma. In dogs with lymphoma and hypercalcemia, concentrations of parathyroid hormone, which are antigenically distinct from PTHrP, usually are less than or within the normal range. Hypercalcemia often develops in dogs with apocrine carcinoma of the anal sac glands (see Diseases of Dogs and Chapter 17, The Integument) because the neoplastic cells secrete PTHrP. Neoplasms that are prone to invade multiple bones, such as multiple myeloma (a neoplasm of plasma cells), can result in hypercalcemia, although this seems to be much less common in domestic animals than it is in human beings. In addition to the osteopenic effect of increased osteoclastic bone resorption (see Chapter 16, Bones, Joints, Tendons, and Ligaments), the persistent hypercalcemia results in metastatic calcification of many tissues, especially the kidneys, gastric mucosa, endocardium, pleura, and lungs. 791 A Disorders of the Adrenal Gland Disorders of the Adrenal Cortex Developmental Disorders of the Adrenal Cortex. Maturation of the fetal adrenal gland and the onset of parturition depend on an intact hypothalamic-pituitary-adrenal axis. Therefore, malformations of the brain, especially those that affect the hypothalamic-hypophyseal axis, disrupt adrenal function and can result in prolonged gestation or delayed parturition. Accessory Adrenal Tissue. Accessory or ectopic adrenocortical tissue is encountered occasionally, usually as an incidental finding, but it can undergo neoplastic transformation. The ectopic tissue is often near the normal site (e.g., in perirenal adipose tissue). It also can attach or become embedded in the wall of the reproductive or gastrointestinal tracts. In many animals, especially horses, the adrenal cortex bulges into the capsule or into the medulla. This anatomic variation is generally of no functional significance and should be distinguished from accessory adrenal tissue (because it is not separated from the adrenal gland) or hyperplastic nodules. Congenital Adrenal Hyperplasia (Adrenogenital Syndrome). Congenital adrenal hyperplasia is caused by an autosomal recessive defect in one of the genes that encode the various hydroxylases involved in corticosteroid synthesis. The enzyme deficiency generally results in decreased cortisol production (with diversion to androgen synthesis) and, therefore, increased ACTH secretion from adenohypophyseal corticotrophs (hence the adrenocortical hyperplasia). The condition is well documented in human beings, in which case it is usually because of mutation of the gene for steroid 21-hydroxylase, but is rarely reported in domestic animal species. A case of congenital adrenal hyperplasia in a male cat with gynecomastia and virilization (despite previous castration) was associated with mutation of an 11β-hydroxylase-like gene. Proliferative Disorders of the Adrenal Cortex Adrenocortical Hyperplasia. Hyperplasia of adrenocortical cells is relatively common, especially in older dogs. Adrenocortical hyperplasia can be diffuse (E-Fig. 12.26, A; also see Fig. 12.16, A and C) or nodular (Fig. 12.34, A and B; see E-Fig. 12.26, B). Hyperplastic nodules are generally multiple, unencapsulated, often paler than adjacent cortical tissue, and seldom larger than a few millimeters in diameter. Histologically (see Fig. 12.34, B), the hyperplastic cortical cells typically are in the zonae fasciculata and reticularis, and they resemble B Figure 12.34 Nodular Adrenocortical Hyperplasia, Adrenal Glands, Dog. A, Discrete pale tan nodules (arrows) are disseminated through the zonae fasciculata and reticularis. B, Hyperplastic nodules (arrows) are not encapsulated but are well demarcated, and consist of cells that are larger and paler than those in adjacent adrenal cortex. (Courtesy Dr. M.A. Miller, College of Veterinary Medicine, Purdue University.) their normal counterparts but tend to be larger (hypertrophied). The usual cause of adrenocortical hyperplasia is unregulated hypersecretion of ACTH from hyperplastic or neoplastic adenohypophyseal (anterior pituitary) corticotrophs. In dogs with adrenocortical hyperplasia without a proliferative pituitary lesion, it has been proposed that increased hypothalamic catabolism of dopamine (attributed to an age-related increase in monoamine oxidase-β activity) could disrupt negative feedback control in the hypothalamic-pituitary-adrenal axis. Adrenocortical hyperplasia, whether diffuse or nodular, typically results in hyperfunction (hypercortisolism or Cushing’s syndrome; Fig. 12.35). Hypercortisolism affects a variety of tissues or organs, especially the liver (see Fig. 8.77, A), skin (see Fig. 17.83), and skeletal muscles (see Chapter 8, Hepatobiliary System and Exocrine Pancreas; Chapter 15, Skeletal Muscle; and Chapter 17, The Integument). Adrenocortical Adenomas and Carcinomas. Neoplasms of adrenocortical cells can be benign (adenomas) or malignant (carcinomas) and functional or nonfunctional. Although most functional canine adrenocortical neoplasms secrete cortisol, functional neoplasms less commonly arise from aldosterone-secreting cells of the zona glomerulosa (especially in cats) or from estrogen-secreting cells of the zona reticularis (mainly in ferrets [see next section]). Adrenocortical adenomas (Fig. 12.36, A; see E-Fig. 12.26, C) typically are well-demarcated, partially encapsulated, solitary and unilateral, yellowish nodules, seldom larger than 2 cm in diameter. Histologically, they are composed of trabeculae or nests of cells that resemble the nonneoplastic cortical cells and usually have numerous cytoplasmic lipid vacuoles. Like other steroid hormone-producing cells, neoplastic adrenocortical cells usually express Melan A. Adrenocortical adenomas are most common in old dogs and cattle, but they also develop in the other domestic animal species. CHAPTER 12 Endocrine System A B C D E-Figure 12.26 Adrenal Cortices, Disturbances of Growth, Adrenal Glands, Dogs. A, Laminar hyperplasia: diffuse thickening of the zona fasciculata and zona reticularis secondary to the effects of a “functional” corticotroph adenoma in the pituitary gland. B, Nodular hyperplasia: multiple discrete hyperplastic nodules extending from the cortex into the medulla. C, Adenoma: note the well-demarcated, large, yellow-tan adenoma compressing the adjacent medulla. D, Carcinoma: large carcinoma with hemorrhage and necrosis. (A courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University. B courtesy Dr. W. Crowell, College of Veterinary Medicine, The University of Georgia; and Noah’s Arkive, College of Veterinary Medicine, The University of Georgia. C courtesy Dr. B. Weeks, College of Veterinary Medicine, Texas A&M University; and Noah’s Arkive, College of Veterinary Medicine, The University of Georgia. D courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University.) 791.e1 792 SECTION II Pathology of Organ Systems A Figure 12.35 Hyperadrenocorticism (Cushing’s-Like Disease), Dog. Hyperadrenocorticism after exogenous glucocorticosteroid administration as treatment for idiopathic adrenocortical hyperplasia. Muscle asthenia (weakness) explains the pendulous abdomen. Alopecia (hair loss) on the abdomen, ventral aspect of the neck, and tail is another feature of hyperadrenocorticism. (Courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University.) Adrenocortical carcinomas (see Fig. 12.36, B; see also E-Fig. 12.26, D) are generally larger than adenomas, are invasive, and can be bilateral. Again, cattle and dogs develop adrenocortical carcinomas more commonly than do the other domestic species. Histologically (see Fig. 12.36, C), the neoplastic cells have greater nuclear atypia than their benign counterparts with an increased mitotic count, but the best indicator of malignancy is invasion of the adrenal capsule or vasculature. Bovine adrenocortical carcinomas metastasize most commonly to the lungs; canine adrenocortical carcinomas tend to invade the caudal vena cava and spread to kidney, liver, and lymph nodes. Secondary Neoplasms of the Adrenal Gland. The adrenal gland, especially at the corticomedullary junction, is a major site for tumor metastasis. In one study, the adrenal gland was involved in 15% to 30% of metastatic cancer cases in dogs, cats, horses, and cattle. In animals with adrenal metastases, carcinomas and melanoma were most common in dogs, hemangiosarcoma and melanoma were most common in horses, and lymphoma was most common in cattle and cats. Metastatic neoplasms, if extensive, can result in adrenocortical hypofunction. Functional Proliferative Lesions in Ferrets Information on this topic is available at www.expertconsult.com. Adrenocortical Atrophy, Degeneration, or Cell Death. Atrophy of the zonae fasciculata and reticularis is often secondary to insufficient adenohypophyseal secretion of ACTH. Iatrogenic causes of atrophy of the zonae fasciculata and reticularis include excessive administration of exogenous glucocorticoids, which causes negative feedback on adenohypophyseal corticotrophs and on hypothalamic corticotrophin-releasing factor, or administration (as treatment for adrenocortical hyperplasia or neoplasia) of o,p′dichlorodiphenyldichloroethane (o,p′-DDD; also known as mitotane), which causes lysis of the adrenal cortex. Primary hypoadrenocorticism (Addison’s disease), with insufficient mineralocorticoid and glucocorticoid production (even after administration of exogenous ACTH), generally requires destruction of almost 90% of the adrenal cortex. Although systemic infectious diseases, such as tuberculosis, can destroy the adrenal cortex by B C Figure 12.36 Adrenocortical Neoplasia, Adrenal Glands. A, Adrenocortical adenoma, ox. The solitary yellow adenoma is thinly encapsulated and contained within the adrenal cortex. B, Adrenocortical carcinoma, dog. The adrenal gland (right) is mostly replaced by an adrenocortical carcinoma that is almost half the size of the kidney (left). Note coalescing areas of hemorrhage and necrosis (arrowheads) in the carcinoma. The contralateral adrenal cortex (lower center, arrow) has undergone trophic atrophy of the zonae fasciculata and reticularis. C, Adrenocortical carcinoma, dog. The carcinoma (right) has invaded the adrenal capsule and its vasculature (left). Inset, Cells are haphazardly arranged with variable cellular and nuclear size, typical of malignant neoplasms. Hematoxylin and eosin (H&E) stain. (A courtesy Dr. J.A. RamosVara, College of Veterinary Medicine, Purdue University. B courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University. C courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) means of chronic inflammation and result in hypoadrenocorticism, most human cases in developed countries are considered an autoimmune disease with the enzyme 21-hydroxylase as a major antigenic target. The histologic lesion of autoimmune hypoadrenocorticism is lymphoplasmacytic adrenalitis. Lysis of the cortical cells in all three CHAPTER 12 Endocrine System The adrenal gland is a common site of proliferative lesions in ferrets, and approximately 45% of the proliferations are classified as hyperplasia. The remainder are adrenocortical adenomas (∼10%) or carcinomas (45%). Functional adrenocortical tumors in ferrets usually produce and secrete 17β-estradiol rather than cortisol, so it is not surprising that early gonadectomy (with loss of the negative feedback on pituitary gonadotrophs) seems to predispose ferrets to development of adrenocortical proliferation. The left adrenal gland is affected more often than the right, and females are affected more often than male ferrets. With increased plasma estradiol concentration, affected females have vulvar enlargement and bilaterally symmetric alopecia. Adrenocortical tumors of ferrets often have a spindle cell component that expresses smooth muscle actin, but this has no prognostic significance. In contrast, myxoid differentiation is a harbinger of invasiveness. 792.e1 CHAPTER 12 Endocrine System zones (zonae glomerulosa, fasciculata, and reticularis) is attributed mainly to the actions of chemical mediators from T lymphocytes, but humoral immunity probably contributes to the disease. Dogs are the domestic species most commonly affected by primary hypoadrenocorticism (see Diseases of Dogs). Miscellaneous Disorders of the Adrenal Cortex Adrenal Inflammation (Adrenalitis). Diffuse lymphoplasma- cytic inflammation that is confined to the adrenal cortex suggests an autoimmune disease in which adrenocortical cells are the target. The adrenal gland is also subjected to inflammation in systemic infections. Cattle with malignant catarrhal fever from ovine herpesvirus-2 infection typically have lymphocytic adrenalitis. Systemic herpesvirus infection in fetuses and neonates of various species is commonly associated with multifocal necrotizing inflammation in the adrenal glands (as well as in other organs). Likewise, granulomatous or suppurative adrenalitis that is part of systemic infection is also typically multifocal. Because adrenocortical cells are not the target in systemic inflammatory diseases, cortical destruction is usually not severe enough to result in functional hypoadrenocorticism. Vascular Disorders of the Adrenal Gland. The vascular network at the interface between the adrenal cortex and medulla is a prime site for thrombosis in disseminated intravascular coagulation and for embolization of infectious microbes or metastatic neoplastic cells. The adrenal gland frequently develops hemorrhages or infarcts in sepsis. Acute adrenal failure because of massive adrenocortical hemorrhage associated with bacterial sepsis is known as Waterhouse-Friderichsen syndrome (Fig. 12.37; E-Fig. 12.27). In addition to bacterial infection, severe stress increases the risk for adrenal hemorrhage, perhaps because elevated ACTH secretion results in increased blood supply to an organ with limited venous drainage. 793 Disorders of the Adrenal Medulla Proliferative Lesions Adrenal Medullary Hyperplasia. Adrenal medullary hyperplasia occurs occasionally in all domestic animal species, but it may be more common in older dairy bulls (E-Fig. 12.28) and horses (Fig. 12.38), especially mares. Adrenal medullary hyperplasia can be associated with pheochromocytoma (i.e., adrenal medullary neoplasia) or with MEN of the adrenal and thyroid medullary cells. Adrenal medullary hyperplasia can be diffuse or nodular. Measurement of adrenal medullary volume or area in cross section is necessary to document diffuse A B A C B Figure 12.37 Adrenocortical Hemorrhage (Waterhouse-Friderichsen Syndrome), Adrenal Gland, Foal. A, Diffuse hemorrhage in the adrenal cortex is common in endotoxic shock. B, Subgross photomicrograph of diffuse adrenocortical hemorrhage (arrows). Hematoxylin and eosin (H&E) stain. (A courtesy Dr. J.A. Ramos-Vara, College of Veterinary Medicine, Purdue University. B courtesy College of Veterinary Medicine, University of Illinois.) Figure 12.38 Hyperplasia, Adrenal Medulla, Horse. A, Bilateral nodular hyperplasia of the adrenal medulla in a mare with concomitant thyroid medullary C-cell hyperplasia and a pituitary pars intermedia adenoma. Hematoxylin and eosin (H&E) stain. B, Enlargement of A. One hyperplastic nodule is shown within the rectangle. H&E stain. C, The discrete but nonencapsulated nodules consist of cells with more abundant and paler cytoplasm than in adjacent chromaffin cells. H&E stain. (Courtesy Dr. M.A. Miller, College of Veterinary Medicine, Purdue University.) CHAPTER 12 Endocrine System 793.e1 E-Figure 12.27 Adrenocortical Hemorrhage (Waterhouse-Friderichsen Syndrome), Adrenal Gland, Foal. Diffuse adrenocortical hemorrhage (arrow) is frequently seen in endotoxic shock. (Courtesy College of Veterinary Medicine, University of Illinois.) E-Figure 12.28 Hyperplasia, Adrenal Medulla, Bull. Diffuse adrenal medullary hyperplasia in a bull with a concomitant C-cell carcinoma of the thyroid gland. The expanded adrenal medulla (bottom) has compressed the surrounding adrenal cortex (arrows). Hematoxylin and eosin (H&E) stain. (Courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University.) 794 SECTION II Pathology of Organ Systems hyperplasia. Hyperplastic nodules typically are multiple, small (up to 5 mm in diameter), and nonencapsulated aggregates of hypertrophied cells with ample cytoplasm that may be less densely granular than that of normal chromaffin cells. Neoplasms Pheochromocytomas. Pheochromocytomas (Figs. 12.39 and 12.40) are neoplasms of the chromaffin cells of the adrenal medulla. They occur in all species but are more commonly seen in cattle, horses, and dogs. These tumors can be benign or malignant and functional or nonfunctional. Although epinephrine is the predominant catecholamine of the normal adult adrenal medulla, functional pheochromocytomas tend to produce mainly norepinephrine. Excessive catecholamine production by a pheochromocytoma can cause systemic hypertension. Whereas hyperplastic nodules in the adrenal medulla are often multiple, pheochromocytomas are usually solitary but may be present bilaterally. Smaller pheochromocytomas are partially encapsulated red-brown nodules. Histologically (see Fig. 12.39, B), the neoplastic tissue consists of packets of neuroendocrine cells separated by fine fibrovascular stroma. The neoplastic cells are polyhedral, tend to be larger than nonneoplastic chromaffin cells, and have ample faintly granular pale amphophilic cytoplasm. The mitotic index varies. The neoplastic cells express generic neuroendocrine markers (e.g., PGP 9.5 or chromogranin) immunohistochemically; this immunoreactivity can be useful in distinguishing poorly differentiated pheochromocytomas from adrenocortical carcinomas. Malignant pheochromocytomas tend to be larger than benign tumors, have extensive hemorrhage and necrosis, obliterate the adrenal gland, and invade the vena cava. There is overlap in the histologic features of benign and malignant pheochromocytomas, so proof of malignancy requires invasion through the adrenal capsule A k l p B A C Figure 12.39 Pheochromocytoma, Adrenal Gland, Horse. A, A welldemarcated pheochromocytoma is contained within the adrenal medulla. The red-brown neoplastic tissue resembles that of adjacent adrenal medulla in contrast to the pale-yellow cast of the adrenal cortex. B, Low magnification of a pheochromocytoma similar to the tumor shown in A. Hematoxylin and eosin (H&E) stain. C, Neoplastic chromaffin cells are arranged in poorly demarcated lobules. Inset, Higher magnification of the chromaffin cells. There is moderate variation in cellular and nuclear size and shape. H&E stain. (Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) B Figure 12.40 Malignant Pheochromocytoma, Adrenal Gland, Dog. A, A pheochromocytoma (p) has obliterated the adrenal gland and grown into the vena cava (arrow). B, Adrenal gland cross section. The malignant pheochromocytoma extends through the compressed adrenal cortex and capsule and into adjacent tissue. k, Kidney; l, liver. (A courtesy Dr. A. Paulman, College of Veterinary Medicine, University of Illinois. B courtesy Dr. M.A. Miller, College of Veterinary Medicine, Purdue University.) CHAPTER 12 Endocrine System (see Fig. 12.40) or distant metastasis. Concurrent pheochromocytoma and thyroid medullary neoplasms may have autosomal dominant inheritance in Guernsey cattle. Neuroblastomas and Ganglioneuromas. Neuroblastomas are primitive neuroectodermal tumors that can develop in the central or peripheral nervous systems. In the latter, they are frequently located in the adrenal medulla or within sympathetic ganglia. In ganglioneuroma, which can develop in the adrenal medulla or in ganglia, the neoplastic cells differentiate into multipolar ganglionic neurons. Thus, the neoplastic tissue consists of neuronal cell bodies and bundles of axons. Adrenal and para-adrenal neuroblastomas and ganglioneuromas resemble their counterparts elsewhere in the nervous system (see Chapter 14, Nervous System). Disorders of Pancreatic Islet Cells 795 e A Hypofunction of Pancreatic Islet Cells Diabetes Mellitus. Diabetes mellitus, diagnosed mainly in dogs and cats, is the result of a relative or absolute deficiency of insulin production and secretion by islet β cells or of a failure of target cells to respond to insulin. The major metabolic consequence of inadequate insulin activity is decreased movement of glucose into insulin-sensitive cells (particularly hepatocytes, adipocytes, and skeletal myocytes), with a corresponding increase in hepatic glucose production and hyperglycemia. As a functional disorder, diabetes mellitus is not necessarily accompanied by lesions in pancreatic islets. Nevertheless, microscopic lesions are noted in some cases of diabetes. Aplasia or hypoplasia of pancreatic islets (within normal exocrine pancreatic tissue) has been reported in diabetic puppies. Degeneration (Fig. 12.41, A) or necrosis of pancreatic islets is more common than failure of development as a cause of insulin deficiency. Immune-mediated lymphoplasmacytic inflammation (see Fig. 12.41, B) can cause selective islet cell destruction. Autoimmune destruction of islet cells is considered the major cause of human type 1 diabetes mellitus. Chronic pancreatitis (Figs. 12.42 and 12.43) indiscriminately destroys both exocrine and endocrine pancreatic tissue. The inability of target cells to respond adequately to a hormone can be caused by a lack of adenyl cyclase as a second messenger within the cytosol or by an alteration or downregulation of cellsurface receptors. Human type 2 diabetes mellitus is characterized by insulin resistance with insufficient insulin secretion to meet the increased requirement. Hypertrophy or hyperplasia of islet β cells, a response to persistent hyperglycemia, may be detected in insulinresistant diabetes, but it tends to be a subtle change. Genetic factors predispose to insulin resistance, but obesity is the most common cause of acquired type 2 diabetes. In domestic mammals, insulinresistant diabetes mellitus, with normal or even elevated blood concentrations of insulin, is most commonly recognized in cats affected by obesity or pituitary somatotroph adenomas (see Diseases of Cats). Horses with metabolic syndrome also develop insulin resistance, but they usually do not develop diabetes (see Diseases of Horses). Often, the lesions of diabetes mellitus are more striking in extrapancreatic organs or tissues than in the pancreatic islets (see Chapter 8, Hepatobiliary System and Exocrine Pancreas; Chapter 11, The Urinary System; and Chapter 21, The Eye). Although most lesions of diabetes are attributed to insufficient insulin or insulin resistance, an absolute or relative increase in glucagon secretion can contribute to the clinical disease and its lesions. Increased blood glucagon concentration promotes hepatic gluconeogenesis and fatty acid oxidation, thereby contributing to hyperglycemia and ketoacidosis. Increased secretion of glucocorticoids, catecholamines, or GH also promotes hyperglycemia. Diabetes mellitus is an insidious disease with clinical signs that reflect its grave effects on nearly every system in the body. The persistent hyperglycemia and glucosuria lead to polydipsia and polyuria. B Figure 12.41 Pancreatic Islets, Cat. A, Hydropic degeneration. Islet cells are diffusely swollen with un­stained vacuolated cytoplasm (arrowheads). Hematoxylin and eosin (H&E) stain. e, Exocrine pancreas. B, Inflammation. Numerous lymphocytes and plasma cells are in a pancreatic islet. Most of the few remaining islet cells have undergone hydropic degeneration (arrows). H&E stain. (A courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University. B courtesy Dr. M.A. Miller, College of Veterinary Medicine, Purdue University.) D Figure 12.42 Chronic Relapsing Pancreatitis, Pancreas and Duodenum, Cross Section, Dog. The pancreas is multinodular and firm with areas of hemorrhage (arrow), fibrosis, and necrosis. D, Duodenum. (Courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University.) 796 SECTION II Pathology of Organ Systems p d Figure 12.43 Chronic Pancreatitis, Pancreas, Dog. The pancreas (p) is markedly atrophied with extensive parenchymal replacement by fibrous tissue in “end-stage” pancreatitis. d, Duodenum. (Courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University.) Diabetic animals have diminished resistance to infection, attributed in part to impaired leukocyte function. Urinary tract infection by glucose-fermenting organisms, especially Escherichia coli in dogs, can lead to emphysematous cystitis. Hepatomegaly in diabetic animals is mainly the result of steatosis (E-Figs. 12.29 and 12.30; also see Figs. 1.28 and 8.40). Lipids accumulate in hepatocytes because of increased mobilization of fatty acids and decreased utilization by hepatocytes injured by ketonemia. Cataracts can develop in dogs with poorly controlled diabetes mellitus (E-Fig. 12.31; also see E-Fig. 21.35) because of the sorbitol pathway of glucose metabolism in the lens. Other extrapancreatic lesions of diabetes mellitus, such as glomerulopathy (see Chapter 11, The Urinary System), retinopathy (see Chapter 21, The Eye), and gangrene, are the result of a microangiopathy (i.e., disorder of the small vessels [capillaries] of organ systems). Other renal lesions include accumulation of glycogen within renal tubular epithelial cells (E-Fig. 12.32). See the sections on Diseases of Dogs and Diseases of Cats. A B Hyperfunction of Pancreatic Islet Cells β-Cell (Insulin-Secreting) Neoplasms (Insulinomas). Islet cell neoplasms (adenomas or carcinomas) are often functional. Most are derived from β cells, but immunohistochemistry for insulin is necessary to document β-cell origin (and many β-cell neoplasms are multihormonal). Neoplasms of β cells develop most commonly in dogs (and in ferrets, in which they are generally benign), but they are also recognized in other domestic species, such as cats and cattle. Clinical signs are often neurologic and reflect hypoglycemia, the result of excessive insulin secretion from functional β-cell neoplasms. Unlike other islet cell neoplasms, β-cell neoplasms may be associated with amyloid deposition derived from islet amyloid polypeptide (IAPP). Adenomas of β cells are typically solitary, yellow to red, small (