Endocrine System*

Aplasia and Prolonged Gestation: See the section on Disorders of Ruminants for a discussion of aplasia and prolonged gestation.

Pituitary Cysts and Pituitary Dwarfism: See the section on Disorders of Dogs for a discussion of pituitary cysts and pituitary dwarfism.

Endocrinologically Inactive Chromophobe Adenomas: Nonfunctional pituitary neoplasms occur in dogs and cats but are uncommon in other species. Although chromophobe adenomas seem endocrinologically inactive, they can cause significant functional disturbances and clinical signs by compressing and causing atrophy of adjacent portions of the pituitary gland, as well as dorsal extension into the overlying brain (Fig. 12-20). The clinical disturbances result either from the lack of secreted pituitary trophic hormones and subsequent diminished target organ function (e.g., adrenal cortex; see Fig. 12-16) or from dysfunction of the CNS. Affected animals often have decreased spontaneous activity, incoordination, and disturbances of balance; are weak; and sometimes collapse after exercise. Chronically affected animals are blind and have dilated and fixed pupils because of compression and disruption of the optic nerves by dorsal extension of the pituitary neoplasms (see Fig. 12-20). Endocrinologically inactive pituitary adenomas often become large before they cause clinical signs or kill the animal (see Figs. 12-16 and 12-20).

Clinical signs reported with nonfunctional pituitary adenomas and hypopituitarism are not specific and could be confused with other disorders of the CNS, such as brain neoplasms and encephalitis, or with chronic renal disease. There is no effect on body stature secondary to compression of the pars distalis and interference with growth hormone secretion because these neoplasms usually arise in adult animals that have already completed their growth. However, atrophy of the skin and loss of muscle mass could be related in part to a lack of the protein anabolic effects of growth hormone. Impaired secretion of pituitary trophic hormones often leads to a reduced basal metabolic rate because of decreased TSH secretion and hypoglycemia secondary to trophic atrophy of the adrenal cortex (see Fig. 12-16).

Pituitary Gland Carcinomas: Pituitary gland carcinomas are uncommon neoplasms compared with adenomas but have been seen in older dogs and cattle. They usually are endocrinologically inactive but can cause significant functional disturbances by destroying the pars distalis and neurohypophyseal system, leading to panhypopituitarism and diabetes insipidus. Carcinomas are large and invade extensively into the overlying brain, along the ventral aspect of the cranial cavity, and into the basisphenoid bone where they cause osteolysis. Metastases occur infrequently to cervical lymph nodes or distant sites such as the spleen or liver. Carcinomas are highly cellular and often have large areas of hemorrhage and necrosis. Giant cells, nuclear pleomorphism, and mitotic figures are encountered more frequently than in adenomas.

Craniopharyngiomas (Intracranial Germ Cell Tumors): Craniopharyngiomas are benign neoplasms derived from epithelial remnants of the oropharyngeal ectoderm of the craniopharyngeal duct (Rathke’s pouch). They often occur in animals younger than those with other types of pituitary neoplasms and are present in either suprasellar or infrasellar locations. Craniopharyngioma is associated with dwarfism in young dogs because it causes subnormal secretion of somatotrophin and other trophic hormones at an early age, before closure of the growth plates.

The reclassification of some pleomorphic neoplasms in the suprasellar region of younger dogs from craniopharyngiomas to germ cell tumors has recently been proposed. The diagnosis of germ cell tumors was based on three criteria: (1) midline suprasellar location, (2) presence within the tumor of several distinct cell types (one population resembles a seminoma or dysgerminoma and others suggest teratomatous differentiation into secretory glandular and squamous elements), and (3) α-fetoprotein immunoreactivity.

Craniopharyngiomas and suprasellar germ cell tumors often are large and grow along the ventral aspect of the brain, where they can surround several cranial nerves. In addition, they extend dorsally into the hypothalamus and thalamus (Fig. 12-21). The resulting clinical signs often occur because of a combination of the following:

Microscopically, craniopharyngiomas have alternating solid and cystic areas. The solid areas are composed of nests of cuboidal, columnar, or squamous epithelial cells with focal areas of mineralization. The cystic spaces are lined by either columnar or squamous cells and contain keratin debris and colloid.

Pars Intermedia Adenomas: Adenomas derived from cells of the pars intermedia are the most common type of pituitary gland neoplasm in horses and the second most common type in dogs, but they are rare in other species. Adenomas develop in older horses, more frequently in females. Nonbrachycephalic breeds of dogs have adenomas of the pars intermedia more often than brachycephalic breeds.

Adenomas of the pars intermedia in dogs are either functionally inactive and result in varying degrees of hypopituitarism and diabetes insipidus, or endocrinologically active and secrete excessive levels of ACTH, leading to bilateral adrenal cortical hyperplasia and a syndrome of cortisol excess. Endocrinologically active (ACTH-secreting) adenomas of the pars intermedia in dogs have prominent groups of corticotrophs that have abundant eosinophilic cytoplasm and more widely scattered follicles.

Two cell populations have been identified in the pars intermedia of normal dogs by immunohistochemistry. The predominant cell type (A cell) is strongly immunoreactive for α-MSH, as in the pars intermedia of other species, whereas the second cell type (B cell) in the canine pars intermedia is strongly immunoreactive for ACTH. This second cell population accounts for the high bioactive ACTH concentration found in the pars intermedia of dogs and most likely gives rise to corticotroph adenomas of the pars intermedia in dogs with the syndrome of cortisol excess.

The clinical syndrome reported with neoplasms of the pars intermedia in horses is characterized by polyuria, polydipsia, polyphagia, muscle weakness, somnolence, intermittent hyperpyrexia, and generalized hyperhidrosis. The affected horses often develop hirsutism because of a failure to seasonally shed hair. The hair over most of the trunk and extremities is long (up to 10 to 12 cm), abnormally thick and wavy, and often matted (Fig. 12-22). Horses with larger neoplasms sometimes have insulin-resistant hyperglycemia and glycosuria, probably resulting from the downregulation of insulin receptors on target cells induced by chronic excessive intake of feed and hyperinsulinemia. The disturbances in carbohydrate metabolism, ravenous appetite, hypertrichosis, and hyperhidrosis reflect deranged hypothalamic function caused by compression of the overlying hypothalamus by the large pituitary neoplasms. The hypothalamus is the primary center for homeostatic regulation of body temperature, appetite, and cyclic shedding of hair.

In addition to their space-occupying effects, some adenomas of the pars intermedia are endocrinologically active. Plasma cortisol and immunoreactive adrenocorticotropin (iACTH, molecular weight 4500 Da) concentrations can be modestly elevated in horses with pars intermedia adenomas. The cortisol concentrations often lack normal diurnal rhythm and are not suppressed by either large or small doses of dexamethasone. The modest increases of plasma iACTH appear to be caused by the different processing of proopiomelanocortin (POMC) in neoplasms derived from cells of the pars intermedia. This could explain the normal or slightly increased blood cortisol concentrations and normal or mildly hyperplastic adrenal cortices observed in some horses with adenomas of the pars intermedia. The concentrations of ACTH in the neoplasm have been reported to be six times that of the normal pars intermedia and only approach the concentrations found in the pars distalis of normal horses. The plasma and neoplasm concentrations of pars intermedia–derived peptides (corticotrophin-like intermediate lobe peptide [CLIP], α-MSH, β-MSH, and β-endorphin [β-END]) are disproportionately increased (40 times or more) compared with those of ACTH, apparently as the result of selective posttranslational processing of POMC in a manner similar to that of the normal pars intermedia.

Adenomas of the pars intermedia have immunohistochemical staining similar to that of the nonneoplastic equine pars intermedia. The findings include a strong, diffuse cytoplasmic reaction for POMC, a moderately strong reaction for α-MSH and β-END, a weak reaction for ACTH, and negative immunostaining for prolactin, glial fibrillary acidic protein, and neuron-specific enolase. Two antisera directed against different parts of the N-terminal fragment of human (h) POMC differ in their immunoreactivity. Immunostaining of neoplastic cells was stronger with anti-h^1-48 N-POMC antisera than with anti-h^1-76 N-POMC antisera. These immunohistochemical findings support the biochemical studies that suggest horses with pituitary adenomas derived from the cells of the pars intermedia develop a unique clinical syndrome that is the result of hypothalamic and neurohypophyseal derangement and an autonomous production of excess amounts of POMC-derived peptides. Although many of the functional disturbances in horses with pituitary adenomas (e.g., diabetes insipidus, polyphagia, hyperpyrexia, hyperhidrosis, and hirsutism) appear to be the result of hypothalamic or neurohypophyseal dysfunction, other behavioral signs (e.g., docility and diminished responsiveness to painful stimuli) could be related to increased plasma and cerebrospinal fluid concentrations of β-END. The clinical syndrome in horses with pituitary neoplasms is distinctly different from that of Cushing’s disease in dogs and cats.

In dogs, adenomas of the pars intermedia result in only a moderate enlargement of the pituitary gland. The pars distalis is readily identifiable and sharply demarcated from the anterior margin of the neoplasm, usually by an incomplete layer of condensed stroma. The neoplasm can extend across the residual hypophyseal lumen and result in compression atrophy, but it usually does not invade the pars distalis. The posterior lobe is incorporated within the neoplasm, but the infundibular stalk is intact. Histologically, canine pars intermedia adenomas are composed of numerous large colloid-filled follicles lined by partially ciliated simple columnar epithelium scattered among nests of variably sized chromophobic cells.

In horses, adenomas of the pars intermedia often are large neoplasms that extend out of the fossa hypophysialis and severely compress the overlying hypothalamus (Fig. 12-23). The adenomas are yellow to white and multinodular and enclose the pars nervosa. When the neoplasm is incised, the pars distalis usually can be identified as a compressed subcapsular rim of tissue on the anterior margin. A sharp line of demarcation remains between the neoplasm and the compressed pars distalis. The neoplastic cells are arranged in cords and nests along the capillaries and connective tissue septae and are large, cylindrical, spindle-shaped, or polyhedral with oval hyperchromatic nuclei (Fig. 12-24). The pattern is often reminiscent of that of the prominent pars intermedia of normal horses. Ribbons of more cuboidal to columnar neoplastic cells occasionally form follicular structures that have dense eosinophilic colloid.

Adrenocorticotropic Hormone-Secreting (Corticotroph) Adenomas: Functional (endocrinologically active) neoplasms arise in the pituitary gland of dogs, particularly boxers, Boston terriers, and dachshunds, and increasingly in cats. They are derived from corticotroph (ACTH-secreting) cells in the pars distalis but can also arise from the pars intermedia. These neoplasms cause a clinical syndrome of cortisol excess (Cushing’s disease), resulting in gluconeogenic, lipolytic, protein catabolic, and antiinflammatory activities.

The pituitary gland is consistently enlarged (see Fig. 12-17); however, neither the occurrence nor the severity of functional disturbances appears to be directly related to the size of the neoplasm. Because the diaphragma sellae is incomplete in these species, the line of least resistance is dorsal expansion of the gradually enlarging pituitary mass. This results in invagination into the infundibular cavity, dilation of the infundibular recess and the third ventricle with eventual compression or replacement of the hypothalamus, and possible extension of the neoplasm into the thalamus (see Fig. 12-16).

Bilateral enlargement of the adrenal glands occurs with functional corticotroph adenomas (see Fig. 12-17). This enlargement is due to cortical hyperplasia, primarily of the zonae fasciculata and reticularis. Nodules of yellow-orange cortical tissue are often found outside the capsule and extending down into and compressing the adrenal medulla.

Pituitary corticotroph adenomas are composed of well-differentiated, large or small, chromophobic cells supported by fine connective tissue septa. The cytoplasm of the neoplastic cells usually is devoid of secretory granules but demonstrates immunoreactivity for ACTH +/− MSH, and hormone-containing secretory granules can be demonstrated by electron microscopy.

Adrenalitis: Bacterial and parasitic agents frequently localize in the adrenal glands and produce varying degrees of inflammation and necrosis. Focal inflammatory processes usually are suppurative, arising in the course of bacterial septicemias. The adrenal capsule provides an effective barrier against direct invasion by inflammatory reactions in adjacent tissue. Granulomatous adrenalitis caused by Histoplasma capsulatum, Coccidioides immitis, or Cryptococcus neoformans occasionally occurs in dogs and cats. Multiple granulomas with central areas of necrosis and calcification can destroy nearly the entire adrenal cortex. Toxoplasma gondii produces necrosis with an infiltration of histiocytes in the adrenal cortex of many species of animals. Experimental evidence suggests that large local concentrations of antiinflammatory steroids in the adrenal cortex (e.g., cortisol and corticosterone) suppress local cell-mediated immunity and permit the progressive growth of certain fungi (e.g., Histoplasma capsulatum, Coccidioides immitis), protozoa (e.g., Babesia darlingi, Babesia jellisoni, or Toxoplasma gondii), and bacteria (e.g., Mycobacterium tuberculosis).

Adrenocortical Hemorrhage (Waterhouse-Friderichsen Syndrome): Massive, diffuse, often bilateral adrenal cortical hemorrhage, a condition known as Waterhouse-Friderichsen syndrome, is an uncommon but fatal consequence of overwhelming sepsis (Fig. 12-25). Although frequently seen in conjunction with endotoxic shock, Waterhouse-Friderichsen syndrome can also result from Gram-positive organisms and noninfectious causes such as anticoagulant therapy and trauma.

Idiopathic Adrenocortical Atrophy: See the section on Disorders of Dogs for a discussion of idiopathic adrenocortical atrophy.

Congenital Adrenal Hyperplasia (Adrenogenital Syndrome): Congenital adrenal hyperplasia is a condition of hypoadrenocorticism and hyperadrenocorticism. Affected individuals are deficient in an enzyme, such as 21-hydroxylase, which is involved in both mineralocorticoid and glucocorticoid synthesis. As a consequence of reduced cortisol levels, there is a compensatory increase in ACTH secretion resulting in adrenal cortical hyperplasia. Subsequent steroid synthesis is diverted to the androgenic pathway, which is independent of 21-hydroxylase. Excessive androgen production leads to virilization and sexual ambiguity in newborns and premature closure of epiphyses. Pomeranians are predisposed to a congenital adrenal hyperplasia–like syndrome and associated dermatosis; however, no mutations in the 21-hydroxylase enzyme have been found in the small group of Pomeranians evaluated.

Hyperplasia and Neoplasia of Adrenal Cortex:

Adrenal Medullary Hyperplasia: Diffuse or nodular adrenal medullary hyperplasia appears to precede the development of pheochromocytoma in bulls with C-cell neoplasms of the thyroid gland. The proliferated chromaffin cells are nonencapsulated but compress the surrounding adrenal cortex (Fig. 12-29). Hyperplastic cells are round to oval and have pale basophilic cytoplasm. Some bulls with prominent diffuse medullary hyperplasia also often have a few small proliferative nodules. Medullary hyperplasia is diagnosed on the basis of the following criteria: an increased adrenal weight, a decrease in cortical to medullary ratio because of an increase in the size and number of medullary cells, and numerous mitotic figures in the adrenal medulla.

Neoplasms:

Accessory Thyroid Tissue: The thyroid gland originates embryologically as a thickened plate of epithelium in the ventral aspect of the pharynx. The complex embryogenesis of the thyroid frequently leads to the formation of accessory thyroid tissue. This accessory thyroid tissue is most typically located in the mediastinum but can be located anywhere from the base of the tongue to the diaphragm. About 50% of adult dogs have nodules of accessory thyroid tissue embedded in the adipose around the base of the heart and the origin of the aorta. The follicular structure and function are the same as those of the main thyroid lobes. Attempts to induce hypothyroidism in the dog by surgical thyroidectomy are usually unsuccessful because the accessory thyroid tissue readily responds to the prompt increase in endogenous TSH secretion and can undergo sufficient hyperplasia to sustain adequate hormone production. This accessory thyroid tissue can also undergo neoplastic transformation.

Thyroglossal Duct Cysts: Thyroglossal duct cysts develop most frequently in dogs and pigs and are present occasionally in other animals. They form as a result of persistence of portions of the midline embryologic primordia of the thyroid gland, which migrate caudally from the ventral aspect of the primitive pharynx to form the thyroid lobes postnatally. These cysts are present in the ventral aspect of the cervical region in dogs and are fluctuant masses that can rupture and form a tract to the exterior. Their lining epithelium consists of multiple layers of follicular cells in which colloid-containing follicles are found occasionally. These cells sometimes undergo neoplastic transformation and give rise to papillary carcinomas.

Congenital Dyshormonogenetic Goiter: Congenital dyshormonogenetic goiter in sheep (Corriedale, Dorset Horn, Merino, and Romney breeds), Afrikaner cattle, Saanen dwarf goats, dogs (rat and toy fox terriers), and cats (Abyssinian and Japanese) is inherited as an autosomal recessive trait. Indications that affected young are clinically hypothyroid include subnormal growth rate, abnormal wool or guard hair development, subcutaneous myxedematous swellings, lethargy, and abnormal mentation.

Thyroid lobes are symmetrically enlarged at birth because of an intense diffuse hyperplasia of follicular cells (Fig. 12-33). Thyroid follicles are often collapsed because of lack of colloid resulting from the notable endocytic activity. Follicles are lined by tall columnar follicular cells, which have dilated profiles of rough endoplasmic reticulum, large mitochondria, and dense lysosomal granules associated with the Golgi apparatus, but have few thyroglobulin-containing apical vesicles near the luminal plasma membrane. Numerous long microvilli extend into the follicular lumen.

Although thyroid scintigraphy can be normal, circulating T₃ and T₄ concentrations after TSH stimulation are consistently low. The lack of a defect in iodide uptake or organification, plus an absence of normal 19S thyroglobulin in goitrous thyroids and only minute amounts of thyroglobulin-related antigens (0.01% of normal) suggest impaired thyroglobulin biosynthesis in sheep, cattle, and goats. Organification defects caused by mutations in thyroid peroxidase have been documented in dogs and cats.

Idiopathic Follicular Atrophy: In follicular atrophy, or “collapse,” the loss of follicular epithelium and disruption of follicles is progressive and the gland is replaced by adipose connective tissue with only a minimal inflammatory response. The gland usually is smaller and lighter in color than normal (Fig. 12-34). The early lesion in dogs with mild clinical signs of hypothyroidism appears to be confined to one part of the thyroid gland. The affected part is composed of small follicles that contain little colloid and are lined by tall columnar follicular cells. A more advanced form of follicular atrophy is present in dogs with clinical hypothyroidism and low blood concentrations of thyroidal hormones. These thyroid glands are notably reduced in size and are composed predominantly of adipose connective tissue with only a few clusters of small follicles containing vacuolated colloid.

Lymphocytic (Immune-Mediated) Thyroiditis: Lymphocytic thyroiditis in dogs and a large European population of horses closely resembles Hashimoto’s disease of humans with evidence suggesting a polygenic mode of inheritance, particularly in affected breeds such as laboratory beagles, giant schnauzers, Doberman pinschers, and Labrador retrievers. The immunologic basis of the development of chronic lymphocytic thyroiditis is through production of autoantibodies, usually directed against thyroglobulin or a microsomal antigen such as thyroperoxidase and infrequently against the TSH receptor, a nuclear antigen, or a second colloid antigen from thyroid follicular cells.

Microscopic lesions consist of multifocal to diffuse infiltrates of lymphocytes which occasionally form nodules, plasma cells, and macrophages. Thyroid follicles are small and lined by columnar epithelial cells; lymphocytes, macrophages, and degenerate follicular cells are often present in the colloid, which is vacuolated (Fig. 12-35; also see Web Fig. 12-6). Thyroid C cells are present as small nests or nodules between follicles and often are more prominent than those in normal dogs. Some remaining follicular cells appear to be transformed into large oxyphilic cells with densely eosinophilic granular cytoplasm.

Functional Proliferative Lesions in Cats: A spectrum of proliferative lesions that secrete excess thyroidal hormones (e.g., adenomas and multinodular hyperplasia) is common in the thyroid glands of adult and aged cats. Since the late 1970s, there has been a dramatic increase in the incidence of neoplasms and other focal proliferative lesions in the thyroid glands of cats and these have resulted in hyperthyroidism. Hyperthyroidism is one of the two most common endocrine diseases in adult to aged cats (diabetes mellitus is the other). Before 1980, clinical hyperthyroidism was infrequently diagnosed in cats. The reason for the apparently increased incidence is uncertain but appears to be related in part to (1) a larger population of geriatric cats receiving veterinary medical care, (2) improved assays for thyroid hormones, (3) detailed characterization of the clinical syndrome, and (4) increased awareness by veterinary clinicians of its common occurrence in adult to aged cats. In addition, there does appear to be a real increase in the incidence of feline hyperthyroidism over the past 30 years. Potential risk factors that have been reported include a predominantly indoor environment, regular treatment with flea powders, exposures to herbicides and fertilizers, a diet primarily of canned food, and non-Siamese breeds (10 times greater occurrence). It has been suggested that wide variations (excessive to inadequate) in dietary iodine intake over prolonged periods could play a role in the pathogenesis of hyperthyroidism in cats.

The disease in cats is mechanistically different from that of Graves’ disease in human patients in that hyperthyroid cats do not have increased concentrations of circulating thyroid-stimulating immunoglobulins, which are comparable to long-acting thyroid stimulator (LATS) in humans (LATS is an autoantibody that binds to the TSH receptor and activates follicular cells). Purified immunoglobulin G (IgG) prepared from hyperthyroid cats significantly increases ³H-thymidine incorporation into DNA and stimulates thyroid follicular cell proliferation fifteenfold but does not stimulate intracellular cAMP production. The ³H-thymidine incorporation can be completely inhibited by a specific TSH receptor blocking antibody. These data suggest that increased titers of thyroid growth-stimulating immunoglobulins are present in cats with hyperthyroidism and most likely act by the TSH receptor. In cats, the disease most closely resembles toxic nodular goiter in human patients with mutations in genes encoding for either the TSH receptor or the G_sα protein. Mutations in G_sα that correspond to the mutations in humans have been reported in a small group of hyperthyroid cats. G_sα is a G protein that mediates cAMP-dependent TSH signaling. Follicular cell proliferation, differentiation, and secretion of thyroid hormone result from constitutive activation of TSH signaling. In a separate study, all cases of feline follicular hyperplasia and adenomas evaluated by immunohistochemistry demonstrated overexpression of the c-ras oncogene. As was the case for activating G_sα mutations, overexpression of c-ras results in constitutive mitogenesis of thyroid follicular epithelial cells. Hyperplastic and neoplastic thyroid tissue from cats is transplantable into athymic (nude) mice and continues to overproduce T₄ and T₃ in a subcutaneous location.

Follicular cell adenomas, which often develop in a thyroid gland with multinodular hyperplasia, are more common than thyroid carcinomas. Follicles in the rim of thyroid tissue around a functional adenoma are notably enlarged and distended with colloid (colloid involution). The follicular cells are low cuboidal and atrophic with little evidence of endocytic activity in response to the increased concentrations of circulating thyroid hormones. In cats with solitary adenomas, the opposite thyroid lobe should be examined carefully for evidence of nodular hyperplasia or microadenomas. These small foci of multinodular follicular cell hyperplasia can be the cause of hyperthyroidism recurring several months to a year or more after surgical removal of a functional adenoma.

Hyperthyroidism in cats also occurs in association with bilateral multinodular adenomatous hyperplasia (goiter), which usually causes only slight enlargement of the affected lobe(s) (Fig. 12-36). In contrast to adenomas, areas of nodular hyperplasia are not encapsulated and the adjacent thyroid tissue is not compressed. Microscopically, hyperplastic nodules are composed of irregularly shaped, colloid-filled follicles lined by cuboidal follicular cells, and these nodules are considered a preneoplastic lesion as they can coalesce and form a thyroid follicular cell adenoma.

Cats with hyperthyroidism usually have notably increased serum T₄ and T₃ concentrations, but some euthyroid cats have histologic evidence of nodular disease. The serum T₄ concentrations in cats with hyperthyroidism range from 3.4 to 30 µg/dL (normal 1.5 to 5 µg/dL), and serum T₃ concentrations range from 179 to 470 ng/dL (normal 60 to 200 ng/dL). Moderately increased serum enzyme activities, including serum alanine aminotransferase (ALT, SGPT), serum aspartate aminotransferase (AST, SGOT), and especially alkaline phosphatase, occur in hyperthyroid cats.

Hyperthyroid cats often have disturbances of calcium homeostasis and a concomitant diffuse chief cell hyperplasia in the parathyroid glands. Blood ionized calcium and plasma creatinine concentrations are significantly decreased, whereas plasma phosphorus and intact PTH concentrations are increased. Hyperparathyroidism occurs in 77% of hyperthyroid cats, with PTH concentrations elevated up to 19 times that of the upper limit of the reference range. Hyperphosphatemia is present in approximately 40% of hyperthyroid cats. The mechanisms for the development of hyperphosphatemia in feline hyperthyroidism are uncertain but could be related in part to polyphagia, resulting in increased intestinal phosphorus absorption, increased catabolism of muscle proteins, release of phosphorus because of the gluconeogenic effects of the increased thyroid hormone concentrations, and increased bone resorption with release of phosphorus into the blood. Hyperparathyroidism and chief cell hyperplasia appear to be related to the reciprocal decline in amounts of circulating ionized calcium in response to the hyperphosphatemia. Increased blood phosphorus concentrations also could decrease renal 1α-hydroxylase activity and decrease the production of the active form of vitamin D, thereby reducing intestinal calcium absorption. However, circulating concentrations of 1,25-(OH)₂-dihydroxycholecalciferol were not decreased in a limited number of hyperthyroid cats evaluated.

Hyperplasia of Thyroid Follicular Cells (Goiter): Goiter is a clinical term used to describe a nonneoplastic and noninflammatory enlargement of the thyroid gland (Fig. 12-37). It develops in all domestic mammals as a result of hyperplasia of follicular cells. Certain forms of thyroid hyperplasia, especially nodular, are difficult to differentiate from adenomas. The major pathogenetic mechanisms for the development of thyroid hyperplasia include iodine-deficient diets, goitrogenic compounds that interfere with thyroxinogenesis, excess dietary iodide, and genetically determined defects in the enzymes or thyroglobulin that are essential for the biosynthesis of thyroidal hormones. All of these result in inadequate thyroxine synthesis and decreased blood concentrations of T₄ and T_3, which are detected by the hypothalamus. This in turn stimulates the pituitary gland to increase the secretion of TSH, resulting in hypertrophy and hyperplasia of follicular cells.

Diffuse Hyperplastic and Colloid Goiter: Dietary iodine deficiency that resulted in diffuse hyperplastic goiter was common in many areas of the world before the widespread addition of iodized salt to animal diets. Iodine-deficient goiter still occurs worldwide in domestic animals, but cases are sporadic and few animals are affected. Marginally iodine-deficient diets that contain goitrogenic compounds can cause severe thyroid follicular cell hyperplasia and goiter. Goitrogenic substances include glucocorticoids, phenobarbital, sulfonamides, thiocyanate, perchlorate, and a number of plants of the family Brassicaceae. Offspring of females fed iodine-deficient diets are likely to develop severe thyroidal follicular cell hyperplasia and have clinical signs of hypothyroidism. Both lateral lobes of the thyroid gland are uniformly enlarged in young animals as a result of diffuse hypertrophy and hyperplasia of follicular cells (see Fig. 12-9). The enlargements, when extensive, result in palpable or visible swellings in the cranial ventral cervical area. The affected lobes are firm and dark red because an extensive interfollicular capillary network develops under the influence of long-term TSH stimulation.

Colloid goiter represents the involutionary phase of diffuse hyperplastic goiter in both young and adult animals. It develops either after sufficient amounts of iodide have been added to the diet or after the requirements for thyroid hormones have diminished as the animal ages. The notably hyperplastic follicular cells continue to produce colloid, but endocytosis of colloid from the lumen is decreased. This is a consequence of the diminished TSH concentrations produced in response to the return of blood T₄ and T₃ concentrations to normal. Both thyroid lobes are diffusely enlarged but are more translucent and lighter in color than in hyperplastic goiter. These differences in macroscopic appearances are the result of less vascularity in colloid goiter and development of macrofollicles distended with colloid. Follicles are progressively distended (see Fig. 12-10) with densely eosinophilic colloid because of diminished TSH-induced endocytosis. As a result, follicular cells lining the macrofollicles are flattened and atrophic. The interface between the colloid and luminal surface of the follicular cells is smooth, and the cells lack the endocytic vacuoles characteristic of actively secreting thyroid follicular cells. Some involuted follicles in colloid goiter have remnants of the papillary projections on follicular cells extending into their lumens.

The changes in diffuse hyperplastic and colloid goiters are uniform throughout the diffusely enlarged thyroid lobes. Follicles are irregular in size and shape in hyperplastic goiter because they contain varying amounts of colloid, which is lightly eosinophilic and vacuolated. Some follicles collapse because of the lack of colloid. The lining epithelial cells are columnar and have deeply eosinophilic cytoplasm and small hyperchromatic nuclei, which are often situated in the basilar portions of the cells. The follicles are lined by single or multiple layers of hyperplastic follicular cells that in some follicles form papillary projections into the lumens (Fig. 12-38). Similar proliferative changes are present in ectopic thyroid tissue in the neck and mediastinum.

Although seemingly paradoxic, an excess of iodide in the diet also can result in thyroid hyperplasia in animals. Foals of mares fed dry seaweed containing excessive iodide develop thyroid hyperplasia and clinically evident goiter. The thyroid glands of suckling animals are exposed to greater blood iodide concentrations than those of the dam because iodide is concentrated first by the placenta and then by the mammary gland. Increased blood iodide interferes with one or more steps of thyroidal hormone synthesis and secretion, leading to lowered blood T₄ and T₃ concentrations and resulting in a compensatory increase in pituitary TSH secretion. Excess iodine blocks the release of T₃ and T₄ by interfering with proteolysis of colloid by lysosomal enzymes in thyroid follicular cells.

Multifocal Nodular Hyperplasia: Multifocal nodular hyperplasia in thyroid glands occurs in old horses, cats, and dogs and appears as multiple, white-to-tan nodules of variable size (see Fig. 12-36), giving affected lobes a moderately enlarged and irregular contour. Multifocal nodular goiter in most animals except cats is endocrinologically inactive and is an incidental lesion at necropsy. However, functional thyroid adenomas often develop in the thyroid glands of aged cats with hyperthyroidism and multinodular hyperplasia of follicular cells. In contrast to thyroid adenomas, the areas of nodular hyperplasia are not encapsulated and cause minimal to no compression of adjacent parenchyma. Thus nodular goiter consists of multiple foci of hyperplastic follicular cells that are sharply demarcated but not encapsulated from the adjacent thyroid tissue.

The microscopic appearance of nodular hyperplasia often varies. Some hyperplastic follicular cells form small follicles with little or no colloid. Other nodules are composed of larger, irregularly shaped follicles lined by one or more layers of columnar cells that form papillary projections into the lumen. Some of the follicles have undergone colloid involution and are filled with densely eosinophilic colloid. These changes appear to be the result of alternating periods of hyperplasia and colloid involution in the thyroid glands of aged animals.

Follicular Cell Adenomas: Adenomas usually are white-to-tan, small, solid nodules that are well demarcated from the adjacent thyroid parenchyma (Fig. 12-39). The affected thyroid lobe is only moderately enlarged and distorted; usually only a single adenoma is present in a thyroid lobe. A distinct, white, fibrous connective tissue capsule of variable thickness separates the adenoma from the adjacent compressed parenchyma. Some thyroid adenomas are composed of thin-walled cysts filled with a yellow-red fluid. Their external surfaces are smooth and covered by an extensive network of blood vessels. Small masses of neoplastic tissue remain in the wall and form rugose projections into the cyst. Adenomas are histologically classified as follicular and papillary types; the follicular type is more common in the thyroid gland of animals.

Follicular Cell Carcinomas: In dogs, thyroid carcinomas occur more often than adenomas, but in cats adenomas are more common. Boxers develop thyroid carcinomas more frequently than any other breed of dog, but beagles and golden retrievers have a higher risk of developing thyroid carcinomas. Approximately 60% of thyroid carcinomas in dogs are clinically detectable by palpation as a firm mass in the neck and by evidence of respiratory distress caused by tracheal compression. Carcinomas become fixed in position as a result of extensive local invasion of adjacent structures, whereas localized adenomas are freely movable under the skin. Neoplasms of thyroid origin also occur in accessory thyroidal tissue, located anywhere between the base of the tongue and the cranial mediastinum.

Thyroid carcinomas often grow rapidly and invade adjacent structures such as the trachea, esophagus, and larynx (Fig. 12-40). The earliest and most frequent site of metastasis is to lungs because thyroid carcinomas, early in the course of development, invade branches of the thyroid vein. The retropharyngeal and caudal cervical lymph nodes are infrequent sites of metastases.

Thyroid C (Ultimobranchial) Cell Neoplasms: Neoplasms derived from C cells of the thyroid gland occur most frequently in adult to aged bulls, occasionally in horses and dogs, and infrequently in other species. The incidence of C-cell neoplasms increases with advancing age in bulls that also typically have increased vertebral bone density. A high percentage of aged bulls fed calcium-rich diets develop C-cell neoplasms (30%) or hyperplasia of C cells and ultimobranchial derivatives (15% to 20%). The cause of C-cell neoplasms is unknown, but the chronic stimulation of C cells by large concentrations of calcium absorbed from the digestive tract can be responsible for their high incidence. A significant decline in the incidence of C-cell neoplasms occurs when the excessive calcium intake of bulls is reduced. Cows fed similar rations rarely develop proliferative lesions of C cells because of the greater physiologic requirements of pregnancy and lactation for calcium.

C-cell neoplasms in bulls are commonly found in association with other endocrine neoplasms, especially bilateral pheochromocytomas and occasionally pituitary adenomas. There are two distinct forms of the familial cancer syndrome known as multiple endocrine neoplasia (MEN) in humans. MEN1 is due to a disease-causing mutation in the MEN1 gene and is characterized by primary hyperparathyroidism, pancreatic islet cell tumors that are predominantly gastrinomas, and pituitary tumors that are predominantly prolactinomas. Other lesions that can be associated with MEN1 include duodenal gastrinomas, carcinoids, thyroid adenomas, adrenocortical tumors, and lipomas. Mutations in the receptor tyrosine kinase RET result in MEN2. There are two subtypes, MEN2A (also known as Sipple’s syndrome) and MEN2B, both of which are associated with C-cell tumors, primary hyperparathyroidism, and pheochromocytomas. In addition, MEN2B patients frequently have mucosal neuromas and a marfanoid stature. There are increasing reports of MEN in veterinary medicine in cats, dogs, horses, and cattle. However, mutations in MEN1 or RET have never been documented in these cases.

Both C-cell adenomas and carcinomas can contain deposits of amyloid. The source of the localized amyloid deposits in the neoplasms is uncertain, but the amyloid appears to be produced by the neoplastic cells, as amyloid deposits are not present in other organs. Amyloid deposition is consistently documented with medullary thyroid carcinoma in humans, and amyloid has also been reported in certain other endocrine neoplasms. Amyloid in C-cell neoplasms is present between neoplastic cells, around vessels, and in the interstitium. Amyloid has been observed in bulls, horses, and dogs but in amounts varying (minimal to substantial) from case to case. Localized amyloid in C-cell tumors is derived from calcitonin.

Parathyroid (Kürsteiner’s) Cysts: Small cysts within the parenchyma of the parathyroid glands or in the immediate vicinity of the glands occur frequently in dogs but only occasionally in other animal species (Fig. 12-43). Parathyroid gland cysts are usually multiloculated, lined by a cuboidal to columnar, often ciliated epithelium, and filled with a densely eosinophilic proteinaceous material. Parathyroid gland cysts appear to develop from persistent and dilated remnants of the duct that connects the parathyroid and thymic primordia during embryonic development. Parathyroid gland cysts are distinct from midline cysts derived from remnants of the thyroglossal duct. The latter are lined by multilayered thyroidogenic epithelium that often has colloid-containing follicles and are usually located near the midline, from the base of the tongue to the mediastinum.

Lymphocytic Parathyroiditis: Lymphocytic parathyroiditis is characterized by extensive degeneration of chief cells and replacement fibrosis. Mild lesions include infiltrates of lymphocytes and plasma cells and nodular hyperplasia of chief cells. Later, the parathyroid gland is completely replaced by lymphocytes, fibroblasts, and neocapillaries with few remaining viable chief cells (Web Fig. 12-7). Lymphocytic parathyroiditis develops by an immune-mediated mechanism, as evidenced by the production of a similar destruction of parathyroid gland parenchyma and lymphocytic infiltration in dogs injected with emulsions of parathyroid gland in adjuvant.

Primary Hyperparathyroidism: Functional Chief Cell Neoplasms: Adenomas and carcinomas of parathyroid glands often secrete excessive amounts of PTH, resulting in a syndrome of primary hyperparathyroidism. Prolonged increased secretion of PTH accelerates osteolytic and osteoclastic bone resorption. Mineral is removed from the skeleton at an accelerated rate, and bone is replaced by immature fibrous connective tissue. The lesions of fibrous osteodystrophy are generalized throughout the skeleton but are accentuated in certain areas (e.g., maxilla, mandible, and subperiosteal areas of long bones).

Adenomas of parathyroid glands are encountered in older animals, particularly dogs, but parathyroid carcinomas are uncommon. Chief cell adenomas usually cause considerable enlargement of a single parathyroid gland. Parathyroid adenomas are encapsulated and sharply demarcated from the adjacent thyroid gland (Fig. 12-45).

Parathyroid gland adenomas are composed of small, closely packed groups of chief cells delineated by delicate vascular connective tissue septa that have many capillaries (Fig. 12-46). The neoplastic chief cells are round to polyhedral and have pale, expanded eosinophilic cytoplasm in which there are a few electron-dense secretory granules and prominent arrays of endoplasmic reticulum and Golgi complexes (Web Fig. 12-8).

The functional disturbances observed with endocrinologically active chief cell neoplasms are primarily the result of hypercalcemia and weakening of bones by excessive PTH-stimulated resorption of calcium. Cortical bone is thinned as a result of increased resorption by osteoclasts stimulated by the autonomous secretion of PTH (Fig. 12-47). Lameness can result from fractures of long bones that occur after relatively minor physical traumas. Compression fractures occur in vertebral bodies, resulting in pressure on the spinal cord and nerves that leads to motor and/or sensory dysfunction. Facial hyperostosis, caused by extensive osteoblastic proliferation and deposition of poorly mineralized osteoid and loosening or loss of teeth from alveolar sockets has been observed in dogs with primary hyperparathyroidism. Hypercalcemia results in anorexia, vomiting, constipation, depression, polyuria, polydipsia, and generalized muscular weakness because of decreased neuromuscular excitability.

The most practical laboratory test to aid in the diagnosis of primary hyperparathyroidism is quantification of the concentrations of total blood calcium, phosphorus, and circulating PTH (N-terminal or immunoradiometric [IRMA] assay). Dogs with primary hyperparathyroidism have greatly increased blood calcium concentrations (12 to 20 mg/dL or above). Blood phosphorus concentrations are low to normal (4 mg/dL or less) as a result of inhibition of renal tubular phosphorus reabsorption by the autonomous secretion of PTH. The urinary excretion of calcium and phosphorus is increased, which can predispose to the development of nephrocalcinosis and urolithiasis.

Secondary Hyperparathyroidism:

Apocrine Gland Adenocarcinoma: See the section on Disorders of Dogs for a discussion of apocrine gland adenocarcinoma.

Neoplasms Metastatic to Bone: Solid neoplasms that metastasize widely to bone and grow locally can produce hypercalcemia by inducing local bone resorption. This is not common in animals but is an important cause of HHM in humans, particularly patients with metastatic breast and lung carcinomas.

The pathogenesis of enhanced bone resorption is not well understood, but the two primary mechanisms include (1) secretion of cytokines or factors that stimulate local bone resorption and (2) indirect stimulation of bone resorption by tumor-induced cytokine secretion from local immune or bone cells. Cytokines or factors that are secreted by neoplastic cells and stimulate local bone resorption include PTHrP, TGF-α and TGF-β, and prostaglandins, especially prostaglandin E₂.

Lymphoma (Lymphosarcoma): Lymphoma is the most common neoplasm associated with hypercalcemia in dogs and cats. Estimates of the prevalence of hypercalcemia in dogs with lymphoma vary from 20% to 40%. Peripheral lymph node enlargement is present in some cases; cranial mediastinal or visceral nodes usually are involved. The hypercalcemia results from the production of humoral substances by neoplastic cells and/or from physical disruption of trabecular bone by lymphoma in bone marrow. Serum immunoreactive PTH concentrations are subnormal, and plasma prostaglandin E₂ concentrations are not different from those of controls.

Most dogs with lymphoma and HHM have significantly increased circulating PTHrP concentrations, but these concentrations are lower (2 to 15 pmol) than in dogs with carcinomas and HHM; there is no correlation with serum calcium concentration. The latter indicates that PTHrP is an important marker in dogs with HHM and lymphoma but is not the sole humoral factor responsible for the stimulation of osteoclasts and development of hypercalcemia. It is likely that cytokines, such as IL-1 or TNF, function synergistically with PTHrP to induce HHM in dogs with lymphoma. Some dogs with lymphoma and hypercalcemia have increased serum 1,25-dihydroxyvitamin D concentrations that could be responsible for or contribute to the induction of hypercalcemia. PTH (N-terminal) concentrations in dogs with lymphoma and hypercalcemia usually are in the normal range; however, a few dogs have concentrations that are increased slightly above the normal range.

Diabetes Mellitus: Diabetes mellitus is a metabolic disorder that results from a reduction of insulin available for normal function of many cells in the body. In some cases, increased concentrations of glucagon contribute to development of persistent hyperglycemia. Insulin unavailability could be due to degenerative changes in β cells of the pancreatic islets, reduced effectiveness of the hormone because of the formation of antiinsulin antibodies or inactive complexes, damage to β cells from immune-mediated islet cytotoxicity, or inappropriate secretion of hormones by neoplasms in other endocrine organs.

Diabetes mellitus is a common endocrinopathy in dogs and cats. Most cases of spontaneous diabetes occur in mature dogs and in females approximately twice as often as males. An increased incidence of diabetes mellitus has been observed in certain small breeds of dogs, such as miniature poodles, dachshunds, and terriers, but nearly all breeds of dogs can be affected.

Development of diabetes mellitus in young dogs is the result of idiopathic atrophy of the pancreas, acute pancreatitis with necrosis and hemorrhage, and aplasia of pancreatic islets; however, diabetes mellitus can also occur secondary to other endocrine disorders such as acromegaly, Cushing’s syndrome, hyperaldosteronism, hyperthyroidism and various neoplasms. The pancreas with idiopathic atrophy is reduced to a third or less of its size. Hypoplasia of pancreatic islets in which the islets are absent but the pancreatic acini and ducts are present and functional has been a cause of diabetes mellitus in young dogs (2 to 3 months of age).

In the pathogenesis of diabetes mellitus, several factors are responsible for the decreased availability of insulin. Destruction of islets secondary to severe pancreatitis or the selective degeneration of islet cells are the most common causes in animals. In dogs, the pancreatic islets are often destroyed because of inflammation of the exocrine pancreas. Chronic relapsing pancreatitis with progressive loss of both exocrine and endocrine cells and replacement by fibrous connective tissue is a frequent cause of diabetes mellitus. In these dogs, the pancreas becomes firm, multinodular, and has scattered areas of hemorrhage and necrosis after a recent relapse (Fig. 12-49). Later in the course of the disease, all that remains of the pancreas is a thin fibrous band or nodule near the duodenum and stomach (Fig. 12-50).

Histologically, β cells are reduced in number and remaining cells have vacuolated cytoplasm (Fig. 12-51). The cytoplasm of β cells is distended by massive amounts of glycogen particles (Web Fig. 12-9). Hydropic degeneration with glycogen accumulation, especially in cats, appears to develop in β cells in response to long-term overstimulation or exhaustion because of peripheral insulin resistance. When disease is chronic, the islets are difficult to find. Immune-mediated isletitis characterized by a progressive lymphoplasmacytic infiltration and selective destruction of β cells of the islets is another cause of diabetes mellitus (type 1) occasionally in dogs.

Another common pancreatic change in cats with diabetes is the selective deposition of amyloid in islets, resulting in degenerative changes in α cells and β cells (Fig. 12-52). Scattered amyloid deposits in pancreatic islets that increase progressively with age occur in the pancreatic islets of many cats without clinically apparent diabetes mellitus. Islet amyloid polypeptide (IAPP) (37 amino acids) and insulin are both secreted by β cells. The IAPP in cats has a unique amino acid sequence (amino acids 25 to 28: alanine, isoleucine, leucine, and serine), which is predisposed to polymerization and accumulation in pancreatic islets. As the insoluble amyloid fibers progressively accumulate in the islets, they disrupt β cells and surround islet capillaries, leading to the subsequent degeneration of islet cells.

Complete expression of the complex metabolic disturbances in diabetes mellitus appears to be the result of a bihormonal abnormality. Although a relative or absolute deficiency of insulin action in response to a rising extracellular glucose concentration has been long recognized as the sine qua non of diabetes mellitus, the importance of an absolute or relative increase of glucagon secretion in some forms of the disease in certain species has been appreciated only recently. Hyperglucagonemia in diabetic patients can be the result of increased secretion of pancreatic glucagon, enteroglucagon, or both. An increased blood glucagon concentration contributes to the severe endogenous hyperglycemia by mobilizing hepatic stores of glucose and to the development of ketoacidosis by increasing the oxidation of fatty acids by hepatocytes. The major glucoregulatory consequence of insulin deficiency is reduction in the movement of glucose into insulin-sensitive tissues (e.g., liver, adipose tissue, and muscle), with a corresponding increase in hepatic glucose production, resulting in notable endogenous hyperglycemia.

The onset of diabetes mellitus is insidious, and the clinical course is often chronic. Clinically, dogs with diabetes mellitus exhibit polydipsia, polyuria, weight loss in spite of polyphagia, bilateral cataracts, and weakness. The disturbances in water metabolism primarily have an osmotic basis. In dogs with persistent hyperglycemia and glycosuria, the renal tubular epithelium is unable to concentrate the urine effectively against the osmotic attraction of the glucose in the glomerular filtrate.

Diabetic animals have diminished resistance to bacterial and fungal infections, and diseases, such as suppurative cystitis, prostatitis, bronchopneumonia, and dermatitis, often become chronic or recurrent. This increased susceptibility to infection in patients with poorly controlled diabetes can be related in part to impaired chemotactic, phagocytic, and microbicidal functions and decreased adherence of polymorphonuclear leukocytes. The impaired microbicidal function of leukocytes can have a metabolic basis resulting from diminished production of cellular energy from glucose. Radiographic evidence of emphysematous cystitis is strongly suggestive of diabetes mellitus. Infections of the urinary bladder with glucose-fermenting organisms, such as Proteus sp., Aerobacter aerogenes, and Escherichia coli result in gas formation in the wall and lumen. Emphysema also develops in the wall of the gallbladder in some diabetic dogs.

Hepatomegaly occurs as a result of fatty degeneration (see Figs. 1-45 and 8-38). Lipids accumulate in the liver as the result of increased lipid mobilization, and hepatocytes injured by ketonemia have decreased usage of lipids. Individual hepatocytes are greatly enlarged by multiple droplets of lipid (Web Fig. 12-10). If the accumulation of lipids is extensive and long-standing, cirrhosis develops. The liver remains enlarged, and its surface becomes coarsely nodular because of extensive remodeling of hepatic parenchyma (Web Fig. 12-11; also see Fig. 8-21). Individual hepatocytes degenerate and are replaced by regenerative and hyperplastic nodules and interlobular fibrosis. Icterus and bilirubinuria often accompany severe cirrhosis.

Cataracts often develop in dogs with poorly controlled diabetes mellitus. They are stellate or asteroid in shape (Web Fig. 12-12; also see Fig. 20-95) and initially appear along the suture lines of lenticular fibers. Cataract formation in the diabetic patient is related to the unique sorbitol pathway by which glucose is metabolized in the lens. Glucose is first converted to sorbitol by the enzyme aldose reductase and subsequently to fructose by sorbitol dehydrogenase. These sugar alcohols accumulate within the lens and result in an intracellular accumulation of solute and hypertonicity. The initial structural change in the lens consists of swelling and hydropic degeneration of lenticular fibers. In long-standing cases of diabetes mellitus, swelling of lenticular fibers continues until the majority of lenticular fibers are affected. Later, macromolecular aggregation or precipitation of normally translucent lenticular proteins develops, accompanied by disruption of lenticular fibers and formation of interfibrillar clefts. The result is diffuse, often bilateral lens opacity observed in animals with chronic diabetes mellitus.

Other extrapancreatic lesions of diabetes mellitus, such as chronic renal disease, blindness, and gangrene, are the result of microangiopathy characterized by thickening of the capillary basement membrane. Dogs with long-standing, poorly controlled, spontaneous diabetes mellitus develop nodular or diffuse glomerulosclerosis characterized by PAS-positive fibrillar deposits of glycoprotein, which occasionally form spherical nodules in the glomerular capillary tufts. Other renal lesions include accumulation of glycogen within cells of the loop of Henle (intracytoplasmic) and distal convoluted tubule (intranuclear) (Web Fig. 12-13).

β-Cell (Insulin-Secreting) Neoplasms (Insulinomas): The neoplasms most frequently arising in pancreatic islets are adenomas and carcinomas derived from β cells. These neoplasms are often endocrinologically active and produce dramatic functional disturbances. Other pancreatic neoplasms appear to be derived from multipotential ductal epithelial cells that differentiate into one of several other cell types in the pancreatic islets. β-Cell neoplasms are seen most frequently in dogs 5 to 12 years of age (mean 9 years). These neoplasms also occur in older cattle and can cause periodic convulsions. Carcinomas of the pancreatic islets are more common than adenomas in dogs and are commonly found in the duodenal (right) lobe of the pancreas. Carcinomas of the pancreatic islets can be differentiated grossly from adenomas by their larger size, multilobular appearance, extensive invasion of adjacent parenchyma and lymph vessels, and metastases to extrapancreatic sites, such as regional lymph nodes (e.g., duodenal, mesenteric, hepatic, and splenic), liver, mesentery, and omentum.

The clinical alterations observed with functional β-cell neoplasms are the result of excessive insulin secretion and the development of severe hypoglycemia. The clinical signs are not specific for the hyperinsulinism produced by β-cell neoplasms. Initial signs include weakness, fatigue after vigorous exercise, generalized muscular twitching and weakness, ataxia, mental confusion, and changes in temperament. Dogs are easily agitated and have intermittent periods of excitability and restlessness. Periodic convulsive seizures of the tonic-clonic type occur later in the disease and increase progressively in frequency and intensity.

The predominance of clinical signs relating to the CNS demonstrates the primary dependence of the brain on glucose metabolism for energy. The failure to recognize dogs with functional islet cell neoplasms when they have clinical signs suggestive of primary disease of the nervous system has frequently led to the misdiagnoses of idiopathic epilepsy, brain neoplasm, or other organic neurologic disease. Repeated episodes of prolonged and severe hypoglycemia result in neuronal necrosis and permanent neurologic disability with terminal coma and eventually death.

Adenomas of the β cells of the pancreatic islets typically exist as single, yellow to dark red, small (1 to 3 cm), spherical nodules. The neoplasms are of similar consistency to or slightly firmer than that of the surrounding pancreas. Adenomas occur as a single nodule or less often as multiple nodules in one or both lobes and/or body of the pancreas. Islet cell adenomas are sharply delineated and surrounded by a thin capsule of fibrous connective tissue (Fig. 12-53). Small nests of acinar epithelial cells are sometimes present throughout the neoplasm but are more common at the periphery. Numerous connective tissue septa containing small capillaries radiate from the capsule into the neoplasm and subdivide the neoplasm into small lobules or packets. Well-differentiated neoplastic cells are round to polyhedral with distinct cell borders and pale eosinophilic, finely granular cytoplasm.

Islet cell carcinomas are consistently larger than adenomas, are multilobular, and invade into and through the fibrous capsule of the pancreas (Fig. 12-54). The dense bands of fibrous tissue that course through the neoplasm give rise to fine connective tissue septa containing capillaries that subdivide the neoplasm into small cords or lobules. Well-differentiated neoplastic cells in islet cell carcinomas are closely packed but are less uniform in size and shape than the cells in adenomas. They are round to polyhedral and have a granular eosinophilic cytoplasm. Mitotic figures are infrequent. Microscopic evidence of distinct local tissue invasion is the principal criterion for the diagnosis of islet cell carcinoma.

Cells composing functional islet cell neoplasms in dogs usually have histochemical and immunohistochemical characteristics of β cells. Ultrastructurally, the neoplastic β cells are electron dense because of numerous cytoplasmic organelles.

Non-β (Gastrin-Secreting) Islet Cell Neoplasms (Gastrinomas): Gastrin-secreting, non-β islet cell neoplasms of the pancreas have been reported in dogs and cats. The hypersecretion of gastrin in humans results in the well-documented Zollinger-Ellison syndrome, consisting of hypersecretion of gastric acid and recurrent peptic ulceration in the gastrointestinal tract. The non-β islet cell neoplasms derived from ectopic amine precursor uptake decarboxylase (APUD) cells in the pancreas produce an excess of gastrin, which normally is secreted by cells of the antral and duodenal mucosa. The incidence of gastrin-secreting pancreatic neoplasms in dogs and cats is uncertain, but it appears to be uncommon compared with that of insulin-secreting β-cell neoplasms. In the comparatively few canine and feline cases studied, the clinical signs have included anorexia, vomiting of blood-tinged material, intermittent diarrhea, progressive weight loss, and dehydration, the result of the multiple ulcerations of the gastrointestinal mucosa because of gastrin-stimulated gastric acid hypersecretion (Zollinger-Ellison–like syndrome).

Animals with Zollinger-Ellison–like syndrome have single or multiple, variably sized neoplasms in the pancreas. These are firm, have increased amounts of fibrous connective tissue, and although partially encapsulated, the neoplasm usually extends into the surrounding pancreas.

Three histologic patterns of gastrin-secreting islet neoplasms in dogs are recognized: (1) the ribbon or trabecular pattern; (2) solid nests of cells with a delicate, highly vascularized stroma; and (3) an acinar pattern with cuboidal neoplastic cells arranged around a central lumen. The stroma is prominent and hyalinized in some gastrin-secreting neoplasms.

Canine gastrin-secreting islet cell neoplasms invade locally into the adjacent pancreas and often metastasize to regional lymph nodes and to the liver. These dogs have either single or multiple ulcerations of the gastric and/or duodenal mucosa and blood in the gut lumen.

Other non-β islet cell neoplasms reported in animals are those of glucagon-secreting α cells. Glucagonomas have been reported rarely in dogs and are associated with superficial necrolytic dermatitis.

Neoplasms of the Aortic Body: Aortic body neoplasms appear most frequently as a single mass or as multiple nodules near the base of the heart (Fig. 12-55). They vary considerably in size (from 0.5 to 12.5 cm), with carcinomas larger than adenomas. Solitary small adenomas either are attached to the adventitia of the pulmonary artery and ascending aorta or are embedded in the adipose connective tissue between these major vessels. They have a smooth external surface and on cross-section are white and mottled with red-to-brown areas. Larger adenomas are multilobular and can compress and indent the wall of the atria, displace the trachea, and partially surround the major vessels at the base of the heart. Aortic body carcinomas are less frequent than adenomas in dogs. Carcinomas infiltrate the wall of the pulmonary artery and form papillary projections into its lumen or invade through the wall into the lumen of the atria. Although neoplastic cells often invade blood vessels, metastases to the lungs and liver occur infrequently in dogs.

Neoplasms of the aortic bodies in animals are not functional (i.e., they do not secrete excess hormone into the circulation), but as a space-occupying lesion they can produce a variety of functional disturbances. Larger aortic body adenomas and carcinomas put pressure on the atria, vena cava, or both and cause manifestations of cardiac decompensation. A higher percentage of aortic body neoplasms than carotid body neoplasms are benign. Aortic body carcinomas invade locally into the atria, pericardium, and adjacent vessels.

Neoplasms of the Carotid Body: Carotid body neoplasms arise near the bifurcation of the common carotid artery in the cranial cervical area. They are usually unilateral, only rarely bilateral, and are slow growing. Adenomas vary from approximately 1 to 4 cm in diameter, are well encapsulated, and have a smooth external surface. The bifurcation of the common carotid artery is incorporated in the mass, and neoplastic cells are firmly adhered to the tunica adventitia. Adenomas are firm, white with scattered areas of hemorrhage, and are extremely vascular.

Carotid body carcinomas are larger, more coarsely multinodular than adenomas, invade the capsule, and penetrate into the walls of adjacent blood and lymph vessels. The external jugular vein and some cranial nerves can be incorporated into the neoplasm. Metastases of carotid body carcinomas occur in approximately 30% of cases and have been found in the lungs, tracheobronchial and mediastinal lymph nodes, liver, pancreas, and kidneys. Multicentric neoplastic transformation of chemoreceptor tissue (aortic and carotid bodies) occurs frequently in brachycephalic breeds of dogs.

The microscopic features of chemoreceptor neoplasms (“chemodectomas”) are essentially similar, whether they are derived from the carotid or the aortic body. The neoplasm is subdivided into lobules by prominent branching trabeculae of connective tissue, which originate from the fibrous capsule. Neoplasms are further subdivided into smaller nests by fine septa of collagenous and reticulin fibers and small capillaries. Neoplastic cells are commonly aligned along and around small capillaries and are discrete, round to polyhedral, and closely packed, with pale eosinophilic, finely granular, and often vacuolated cytoplasm.

Although the cause of carotid and aortic body neoplasms is unknown, a genetic predisposition aggravated by chronic hypoxia could account for the greater risk of development in certain brachycephalic breeds such as the boxer and Boston terrier. Carotid bodies of several mammalian species, including dogs, have developed hyperplastic foci when the animals were subjected to the chronic hypoxia of high altitude. Humans living at high altitudes have 10 times the frequency of chemodectomas as those residing at sea level.

Heart-Base Neoplasms Derived from Ectopic Thyroid Gland Tissue: Adenomas and carcinomas derived from ectopic thyroid gland account for approximately 5% to 10% of “heart base” neoplasms in dogs. They often compress or invade structures in the cranial mediastinum near the base of the heart (Fig. 12-56). Ectopic thyroid gland neoplasms have a compact cellular (solid) pattern that is difficult to distinguish histologically from that of aortic body neoplasms. Cells of ectopic thyroid gland neoplasms generally are smaller than those of aortic body neoplasms and have more hyperchromatic nuclei and an eosinophilic cytoplasm. Thyroidal neoplasms of follicular cells are not consistently subdivided into small packets by fine strands of connective tissue. Giant cells are infrequent in ectopic thyroid gland neoplasms, and the stroma is not prominent. Usually, primitive follicular structures or colloid-containing follicles can be demonstrated in ectopic thyroid gland neoplasms but not in aortic body neoplasms.