Tumors of the Endocrine System

Pathogenesis

Hypercortisolism (HC), also termed hyperadrenocorticism or Cushing’s syndrome, is a common endocrine disease of middle-aged and older dogs.¹⁷ It is uncommon in cats. This clinical syndrome results from chronic exposure to excessive blood levels of glucocorticoids. Naturally occurring canine and feline HC are almost always either pituitary-dependent or a result of excessive glucocorticoid secretion from an adrenocortical tumor.^17,18

HC in human medicine is differentiated into ACTH-dependent and ACTH-independent disease.¹⁹ ACTH-dependent disease most commonly results from excessive ACTH secretion from a pituitary tumor but may also be caused by ectopic secretion of ACTH from an extrapituitary tumor or very rarely by ectopic secretion of corticotrophin-releasing hormone (CRH). There is only one clearly documented report of ectopic ACTH secretion in the dog,²⁰ which may reflect the fact that it is very difficult to prove this diagnosis.

Pituitary-dependent hypercortisolism (PDH) is the most common form of spontaneous HC in dogs and cats, accounting for 80% to 85% of cases in these species.^17,18,21,22 This disorder is a consequence of autonomous synthesis and secretion of ACTH from a pituitary tumor. The secretion of ACTH from the pituitary tumor is chronically excessive, leading to bilateral adrenal cortical hyperplasia and hypercortisolemia. The pituitary tumor is relatively insensitive to negative feedback by cortisol and there is also a loss of hypothalamic control over ACTH release because CRH secretion is suppressed by the chronic hypercortisolemia.¹⁸

Pituitary tumors that secrete ACTH are derived from pituitary corticotroph cells. Expression of several proteins and their receptors thought to be involved in the etiology of human pituitary tumors responsible for ACTH hypersecretion has been studied. Leukemia inhibitory factor and its receptor are expressed in canine pituitary adenoma samples, although no mutations were identified in the receptor that might account for autonomous ACTH production.^23,24 Dopamine and somatostatin receptor subtype expressions were evaluated in normal canine pituitary tissue and compared to adenomatous tissue. The type 2 dopamine receptor and somatostatin type 2 (SST2) receptor were most prevalent in canine pituitary tumors but expressed at low levels.

Pituitary tumors may be described as macrotumors or microtumors.¹⁸ The latter distinction is derived from human medicine: microtumors are less than 1 cm in diameter and macrotumors are 1 cm or larger in diameter. The use of this size-based classification is controversial in veterinary medicine, at least partly due to variability in patient size and conformation.¹² Pituitary tumors may also be classified as noninvasive adenomas, invasive adenomas, or adenocarcinomas. The latter term is reserved for tumors in which there is demonstrated evidence of metastatic disease. Canine pituitary adenocarcinomas are uncommon. A recent study of 33 dogs with pituitary tumors, all of which underwent necropsy evaluation after brain imaging, revealed that 61% had a pituitary adenoma, 33% had an invasive adenoma, and 6% had an adenocarcinoma.¹¹

ACTH-independent HC refers to disease of the adrenal cortex, including neoplasia, dysplasia, or hyperplasia. This will be referred to as adrenal-dependent hypercortisolism (ADH) in this chapter and will be discussed in the section on adrenal gland tumors.

Clinical Findings and Diagnostic Evaluation in Dogs

The majority of dogs with PDH are older than 9 years of age, and female dogs are slightly overrepresented. Breed predispositions have been noted in Dachshunds, terrier breeds, German shepherd dogs, and poodle breeds.^17,18 The onset of canine Cushing’s syndrome is often slow, and the signs may progress slowly. Affected dogs are often not considered by their owners to be sick; they have a good appetite and do not show signs such as vomiting, diarrhea, coughing, or weight loss. Because spontaneous HC typically affects elderly dogs, the signs may initially be attributed to normal aging. The progress of the disorder is generally insidious, but eventually the owners of affected dogs seek veterinary care due to the frustration associated with signs such as polyuria, polydipsia, panting, and exercise intolerance.

The most common signs of canine HC are polyuria, polydipsia, polyphagia, abdominal enlargement, lethargy, panting, exercise intolerance, muscle weakness, alopecia, calcinosis cutis, thinning of the skin, and reproductive abnormalities.^17,18 These clinical signs are the result of the gluconeogenic, catabolic, immunosuppressive, and antiinflammatory effects of excessive circulating glucocorticoids. Glucose intolerance and insulin resistance have been shown to be common in dogs with HC,²⁵ and overt diabetes mellitus may develop in as many as 10% of these patients.²⁶ The catabolic effects of glucocorticoids result in thinning of the skin, poor wound healing, muscle wasting, and decreased bone density.²⁷ The antiinflammatory and immunosuppressive properties of glucocorticoids are responsible for the increased susceptibility to infections in dogs with hypercortisolemia.¹⁷ This most often manifests as an increased incidence of urinary tract infections in canine patients. In one study, 46% of dogs with HC were found to have a urinary tract infection.²⁸

More serious disorders associated with canine HC include hypertension and proteinuria.^17,29 These are particularly insidious because they may not initially be associated with overt clinical signs. If untreated, hypertension can damage end organs such as the eye, brain, and kidneys, leading to complications that may include blindness or glomerular disease. Over 80% of dogs with canine Cushing’s syndrome were reported to be hypertensive in one case series.³⁰ Although uncommon, pulmonary thromboembolism is another potentially life-threatening complication of HC.^26,31

Spontaneous HC is suspected when typical clinical signs are detected in a middle-aged or older dog that is not receiving exogenous glucocorticoid therapy. The diagnosis is further investigated when initial laboratory tests reveal classic abnormalities, including neutrophilia, monocytosis, lymphopenia, eosinopenia, thrombocytosis, elevated serum alkaline phosphatase levels, a mild increase in alanine aminotransferase, and elevated cholesterol. Urinalysis may demonstrate minimally concentrated, isosthenuric, or hyposthenuric urine. Ancillary tests recommended in dogs suspected to have HC include urine culture, blood pressure measurement, thoracic radiographs, and abdominal ultrasonography.^17,18,32

The tests that are most commonly used to screen for the presence of spontaneous HC are the urine cortisol : creatinine ratio, the ACTH stimulation test, and the low-dose dexamethasone suppression test (LDDST). These tests should be reserved for patients in which there is clinical suspicion of HC. Due to space considerations, readers are directed to several excellent references for more in-depth discussion of the comparative aspects of these tests.^17,18,32,33 The urine cortisol : creatinine ratio is very sensitive, but specificity is low and it should not be used in patients with concurrent illnesses. The ACTH stimulation test has a lower sensitivity and higher specificity in comparison to the LDDST. The LDDST is highly sensitive and therefore less likely to give false-negative results. An additional advantage of this test is that it is capable of distinguishing between PDH and ADH in some cases.¹⁷ For patients with typical clinical signs of HC and positive results on the ACTH stimulation test, further testing is generally performed to differentiate between pituitary and adrenal-dependent disease. These further tests are also necessary after positive results on the LDDST for those patients in which this test does not additionally confirm the presence of PDH. Differentiation tests that are commonly used include the high-dose dexamethasone suppression test (HDDST) and the measurement of endogenous ACTH levels.^17,32 In dogs with ADH, it is expected that endogenous ACTH levels will be low due to feedback inhibition of pituitary ACTH release by chronic hypercortisolemia. Patients with PDH would be expected to have elevated endogenous ACTH levels.^34-36

The results of imaging studies, including ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI), may assist in differentiating between PDH and ADH.^17,18 Abdominal ultrasonography should not be used as a screening test for HC, and it should also not be used as the sole mechanism for discriminating between PDH and ADH; however, it can provide useful information.^35,37-40 The adrenals of patients with PDH are often bilaterally enlarged with increased thickness, and they typically maintain a normal shape and are homogeneous in echogenicity.³⁷ However, there can be overlap between adrenal gland measurements in normal dogs, dogs with nonadrenal disease, and dogs with HC. Adrenal gland asymmetry may also be detected in dogs with PDH due to nodular hyperplasia. In some cases, this appearance can be confused with adrenal neoplasia. To further complicate the diagnostic accuracy of abdominal ultrasonography, a small percentage of patients with HC may have concurrent PDH and ADH.⁴¹ Bilateral adrenal tumors may also occur, including both functional or nonfunctional adrenocortical tumors and pheochromocytomas.^39,42-45 Thus ultrasound findings must always be interpreted concurrently with clinical findings and endocrine test results. Abdominal CT is used less commonly than ultrasonography to evaluate the adrenals, but CT findings may also assist in the discrimination between PDH and ADH.^46,47 This technique also demonstrates overlap between adrenal volume in dogs with PDH and dogs with nonadrenal disease and also confirms that dogs with PDH can have nodular adrenal lesions.⁴⁷

Although 80% to 85% of dogs with spontaneous HC have PDH and almost all cases of PDH are due to the presence of a pituitary tumor, canine patients do not often show clinical signs directly referable to the local effects of the tumor.¹⁷ The vast majority of cases are initially presented for veterinary care due to the typical clinical signs of HC, as described previously. Pituitary tumors may be detected by CT,^12,14 dynamic CT,^48,49 MRI,^12,14,50-53 or dynamic MRI⁵⁴; however, these techniques are not routinely performed in all dogs that are diagnosed with PDH.¹² In most cases, the diagnosis is based on the presence of typical clinical signs and clinicopathologic changes of hypercortisolemia, together with the results of endocrine testing.¹⁷

As noted previously, brain imaging is not performed in the great majority of dogs with PDH, and most receive treatment to address adrenal hyperfunction rather than the pituitary tumor itself. This is most likely due to the fact that brain imaging and pituitary surgery or radiation therapy (RT) are not affordable or accessible to many clients. Although medical therapy for PDH (see later) has a long history of successful use, it is important to note that the pituitary lesion in dogs with PDH will progress over time. In a study of 13 dogs that underwent MRI evaluation of the brain at the time of diagnosis of PDH and before medical therapy was instituted, 8 of the dogs had a visible pituitary mass and none of the dogs had clinical signs of neurologic disease.⁵³ Four of the dogs showed enlargement of the pituitary tumor on MRI 1 year later, and a pituitary tumor was also detected in two dogs that did not have a visible mass on the initial MRI. Two of the 13 dogs had developed neurologic signs at the time of the 1-year follow-up MRI. A recent study evaluated diagnostic imaging findings in 157 dogs with PDH with and without neurologic signs.¹⁴ Central nervous system (CNS)-specific signs such as circling, seizures, or ataxia were neither sensitive nor specific for predicting the presence of a pituitary macrotumor. However, signs such as lethargy, mental dullness, and decreased appetite were highly specific for detection of a pituitary macrotumor but not highly sensitive. Other studies have also documented that mentation and appetite changes are the most common signs associated with pituitary tumors.^13,55

When considering brain imaging in dogs with PDH, several factors should be taken into account: 40% to 50% of dogs with PDH have tumors that are not visible on CT or MRI, and these dogs are unlikely to develop neurologic signs associated with the tumor; 15% to 25% of dogs with PDH are at risk for the development of neurologic signs due to the presence of an enlarging tumor, and these signs typically develop within 6 to 18 months of the diagnosis of PDH; brain imaging may be helpful in predicting dogs likely to develop neurologic signs in patients with PDH that initially have no signs directly attributable to the tumor¹⁷; and if RT is being considered, early treatment will likely improve prognosis.^13,56 It is also possible that measurement of plasma ACTH precursor concentrations could help in the selection of patients for brain imaging because it has been shown that pro-opiomelanocortin/pro-ACTH levels in plasma are correlated with pituitary tumor size in dogs with PDH.^57,58 However, plasma cortisol concentrations at baseline and 4 or 8 hours after administration of a low dose of dexamethasone do not appear to correlate with the development of neurologic signs.¹⁴

Treatment of Canine Pituitary-Dependent Hypercortisolism

Options for management of canine PDH include medical therapies that address adrenocortical hyperfunction, as well as direct treatment of the pituitary lesion through surgery or RT. The decision to treat patients with PDH should be guided by the patient’s quality of life, the owner’s wishes, and consideration of the risks of serious or life-threatening complications of the disease, such as neurologic signs, hypertension, recurrent infections, or thromboembolic disease. Some dogs with PDH have mild clinical signs and a good quality of life when initially diagnosed. There is no clear evidence that early treatment of these patients is necessary to improve long-term survival. Treatment of PDH is rarely an emergency, and more serious concurrent illnesses should be addressed first.

Feline Pituitary-Dependent Hypercortisolism

As noted previously, approximately 80% to 85% of cases of HC in the cat are due to pituitary disease.^17,21,22 However, Cushing’s syndrome is considerably less common in cats than in dogs. The mean age of cats with PDH is reported to be around 10 years.²¹ Feline HC is often associated with insulin-resistant diabetes mellitus, with signs of polyuria, polydipsia, polyphagia, and weight loss. Cats with HC often have a potbellied appearance due to hepatomegaly and muscle weakness, and they frequently have thin fragile skin that tears and bruises easily. Additional signs include lethargy, generalized muscle atrophy, weakness, alopecia, and an unkempt haircoat (Figure 25-1). On routine laboratory testing, elevated alkaline phosphatase is much less frequently detected in cats with HC compared to dogs. Cats may have elevated alanine aminotransferase, hypercholesterolemia, azotemia, and minimally concentrated urine. Hyperglycemia and glycosuria are expected in cats with concurrent diabetes mellitus. No consistent complete blood count (CBC) changes have been reported in cats with HC.^21,22

Tests used to screen for spontaneous HC in cats include the urine cortisol : creatinine ratio, the ACTH stimulation test, and the LDDST. It is important to note that the details of these protocols differ between dogs and cats, and readers are directed to more complete references for further information.^21,22 The HDDST, endogenous ACTH levels, and abdominal ultrasound examination may be used to assist in differentiation of PDH from ADH in the cat.

Because PDH is relatively uncommon in the cat, there are few case series and case reports on which to base treatment recommendations.^76,77 Direct treatment of the pituitary tumor has been reported, with either surgical hypophysectomy or RT.^59,78-80 Surgical bilateral adrenalectomy has also been described and was considered the treatment of choice for some time.⁸¹ However, these cats are often poor surgical candidates, they have poor healing ability, and complications are common. Laparoscopic adrenalectomy is potentially a better option for these patients because the incisions are much smaller and more likely to heal; however, this has not yet been reported in cats with PDH. Medical therapy with trilostane may be a reasonable option for these cats, based on the authors’ experience and a small number of published cases.^82,83 This drug could be used as the sole therapy or to prepare cats for surgery or RT.

Adrenocortical Tumors

Functional cortisol-secreting tumors of the adrenal cortex are responsible for 15% to 20% of canine and feline cases of naturally occurring HC, with PDH accounting for 80% to 85%.^17,18,21,22 In the necropsy and surgical biopsy data from UC Davis, adrenocortical adenomas were almost 4 times more common than carcinomas¹¹³; however, the functionality of these tumors was not assessed. A review of case reports of functional adrenocortical tumors in dogs suggests that approximately 60% of surgically removed tumors are carcinomas.* Adenomas are typically smaller, with tumors larger than 2 cm more likely to be carcinomas.¹³² However, adenomas up to 6 cm have been reported.¹⁷ On histopathologic examination, adenocarcinomas appear more likely to exhibit a trabecular growth pattern, peripheral fibrosis, capsular invasion, necrosis, and/or hemorrhage.¹³² They are less likely to exhibit cytoplasmic vacuolization, extramedullary hematopoiesis, or fibrin thrombi. Approximately 20% of adrenocortical carcinomas locally invade into the phrenicoabdominal vein, with extension into the renal vein and/or caudal vena cava.^42,131 Intravascular invasion has the potential to cause severe and life-threatening intraabdominal or retroperitoneal hemorrhage.^45,133 Metastasis was identified in approximately 50% of dogs with adrenocortical carcinomas.^131,132 Although involvement of the liver and lungs is most common, other organs reported to be affected with metastases include the kidney, ovary, mesenteric lymph nodes, peritoneal cavity, and thyroid gland. In the absence of evidence of tumor invasion or metastasis, there are no consistent clinical, biochemical, or imaging findings that reliably distinguish between functional adrenocortical adenomas and carcinomas in dogs and cats. The cellular and molecular events underlying the development of canine adrenocortical tumors are unknown. Recent studies have demonstrated downregulation of ACTH receptors in cortisol-secreting adrenocortical carcinomas and ectopic expression of gastric-inhibitory polypeptide and vasopressin (2) receptor proteins in neoplastic zona fasciculata tissue from canine adrenocortical tumors.^134,135 The significance of these findings in tumorigenesis remains to be elucidated.

Dogs with PDH and dogs with ADH are similar in age, but almost 50% of dogs with ADH weigh more than 20 kg, compared to approximately 25% of dogs with PDH.³⁴ The historic features, physical changes, clinical signs, and basic laboratory findings in canine Cushing’s syndrome are essentially the same in dogs with PDH and dogs with ADH and are described in the earlier section on Pituitary Corticotroph Tumors. Similar screening tests are used to confirm the diagnosis of HC; however, the sensitivity of the ACTH stimulation test for the diagnosis of ADH is only around 60%.³² Thus the LDDST is a better screening test when ADH is suspected. Dogs with ADH fail to show suppression on the LDDST or the HDDST, and differentiation from PDH is generally determined by imaging studies, particularly abdominal ultrasound examination,³³ and measurement of endogenous ACTH levels.³⁴ Excessive secretion of glucocorticoids by a functional adrenocortical adenoma or adenocarcinoma occurs independent of pituitary control, with secondary atrophy of the normal adrenocortical cells in both the affected and contralateral adrenal glands. Unfortunately the functional atrophy of the contralateral adrenal gland is not always easily detected on abdominal ultrasonography.³⁹ This finding, termed equivocal adrenal asymmetry, is also observed in some dogs with PDH, associated with asymmetric hyperplasia of the glands.³⁷ The results of a recent ultrasound study of dogs with equivocal adrenal asymmetry suggested that a maximal dorsoventral thickness of the smaller gland of less than 5.00 mm was consistent with a diagnosis of ADH.⁴⁰

Surgical adrenalectomy is the treatment of choice for dogs with ADH,* and surgical management is further addressed later. An early case series of dogs undergoing surgical removal of adrenocortical tumors revealed that 60% of patients were euthanized during surgery or died within 2 weeks.¹³¹ In a more recent case series, the perioperative mortality has ranged from 19% to 28%.^17,42,43,136 In one series of 144 dogs undergoing surgical removal of a functional adrenocortical tumor, the prognosis was described as excellent for patients that survived 4 weeks postoperatively, with an average life expectancy of 3 years. Nine of 144 dogs were euthanized at the time of surgery, and 29 dogs died during surgery or immediately postoperatively.¹⁷ Median survival times of 230 to 778 days have been reported for dogs undergoing adrenalectomy for adrenal carcinomas,^42,114,115 compared to a MST of 687.5 days for dogs with adenomas.¹¹⁴ Laparoscopic adrenalectomy has been described for noninvasive adrenocortical carcinomas in a small number of dogs; further studies are needed to determine if this technique can reduce the postoperative complications associated with conventional surgery.¹³⁷

Medical therapy for ADH should be used when surgery is not a good option for the patient or client, or it may be used prior to adrenalectomy in patients that are significantly debilitated by HC. The primary options for medical therapy are mitotane and trilostane. Treatment with mitotane as an alternative to surgical adrenalectomy utilizes the drug as a true cytotoxic agent. Detailed protocols are readily available,¹³⁸ and clinicians should be aware that this approach typically requires higher doses of mitotane than those used in PDH¹³⁹ and that relapses are common. However, this treatment can be effective, with a mean survival of 16.4 months reported in a series of 32 dogs. Dogs without evidence of metastatic disease may show a better response to mitotane therapy.¹⁴⁰ Trilostane is not a cytotoxic drug, but it has been used to successfully manage patients with ADH,^68,69,141 including a small number of dogs with metastatic disease.¹⁴² A recent retrospective study comparing trilostane and mitotane in dogs with ADH reported a median survival of 353 days with trilostane therapy compared to 102 days for mitotane. These survival times were not significantly different; however, this study did further confirm that survival times are significantly decreased in the presence of metastatic disease.¹⁴³

Functional adrenocortical tumors in dogs and cats can also secrete one or more sex hormones, including androstenedione, progesterone, 17-hydroxyprogesterone, testosterone, and estradiol. These tumors may or may not secrete glucocorticoids, and some patients have been reported to show signs of HC in the absence of elevated cortisol levels on typical screening tests.^144-149 Signs of sex hormone excess appear uncommon in dogs with sex-hormone–secreting adrenal tumors but have been reported in a small number of cats.^150,151

Aldosterone-secreting adrenocortical tumors have rarely been reported in dogs,^152-154 but there is increasing evidence that primary hyperaldosteronism (also termed primary aldosteronism or Conn’s syndrome) may be an underrecognized condition in cats. In fact, it has been suggested to be the most common adrenocortical disorder in this species.¹⁵⁵ Affected cats are middle-aged or older, and the most common clinical sign is muscle weakness due to hypokalemia. Arterial hypertension is frequently detected in these patients and may be associated with ocular changes. Routine laboratory testing often reveals hypokalemia, but hypernatremia is uncommon, presumably due to intact water balance mechanisms in these patients. Some cats may also have evidence of concurrent renal disease. Plasma aldosterone can be measured in cats, and normal or elevated levels in the face of hypokalemia would be regarded as inappropriate. However, definitive diagnosis using aldosterone levels is difficult without the measurement of plasma renin activity and the calculation of an aldosterone : renin ratio.¹⁵⁶ Unfortunately, a plasma renin activity assay is not readily available to most clinicians. An oral fludrocortisone suppression test has recently been suggested to be a useful diagnostic test for feline hyperaldosteronism,¹⁵⁷ but the use of this tool has not yet been widely reported. Imaging of the adrenal glands is often performed in the evaluation of these patients,^158,159 and this may distinguish between unilateral and bilateral lesions and also reveal the presence of vascular invasion or metastatic disease. Most cats with hyperaldosteronism have an adrenal adenoma or carcinoma.¹⁶⁰ Bilateral adenomas have been reported,¹⁶⁰ and some cats have adrenal hyperplasia.¹⁵⁶ Adrenalectomy is the treatment of choice for cats with unilateral disease, and good outcomes have been reported for both adenomas and carcinomas, as well as for tumors associated with vena cava thrombosis.^160-163 Medical management with potassium supplementation, antihypertensive drugs, and the aldosterone antagonist spironolactone can give reasonable survival times in patients that are not surgical candidates.^156,160,161

Adrenal Medullary Tumors

Chromaffin cells are part of the sympathetic nervous system and are present in the adrenal medulla and other locations throughout the body. Neoplastic chromaffin cells in the adrenal medulla give rise to pheochromocytomas, which are tumors that predominantly secrete catecholamines. Chromaffin cell tumors (termed paragangliomas or extraadrenal pheochromocytomas) can arise in other parts of the body, but these are rare in veterinary medicine. Pheochromocytomas are uncommon in dogs and rare in cats.^164,165 In past decades, the diagnosis of pheochromocytoma was most often made incidentally at necropsy,^166,167 but these tumors are now likely to be detected antemortem because advanced abdominal imaging techniques are routinely used in small animal patients. Pheochromocytomas are generally considered to be malignant tumors in dogs.¹⁶⁴ Metastasis is reported in up to 40% of affected dogs; sites include liver, spleen, lung, regional lymph nodes, bone, and CNS.^166-168 Vascular invasion by the tumor has been reported in as many as 82% of cases.^43,45,169 This finding is not specific for pheochromocytoma because vascular invasion can also occur with adrenocortical tumors.

Pheochromocytoma is usually diagnosed in older dogs,^164,167 and males may be overrepresented.¹⁶⁹ Catecholamine release by pheochromocytomas is typically episodic, and thus clinical signs may be intermittent and often absent at the time of physical examination. Signs may include weakness, episodic collapse, panting, anxiety, restlessness, exercise intolerance, decreased appetite, weight loss, polyuria, and polydipsia. Physical examination of dogs with pheochromocytoma may be normal due to the episodic nature of catecholamine release or may reveal tachypnea, panting, tachycardia, weakness, pallor, cardiac arrhythmias, or hypertension.^164,166,167 Some dogs have signs referable to an abdominal mass, and acute collapse may occur secondary to tumor rupture with abdominal or retroperitoneal bleeding.¹³³ There are no consistent abnormalities on the CBC, serum biochemistry profile, or urinalysis in dogs with pheochromocytomas.

Diagnostic imaging, particularly abdominal ultrasound examination, is central to the evaluation of patients with pheochromocytoma. In many dogs, evaluation for pheochromocytoma occurs after an adrenal mass is found when abdominal ultrasonography is performed for other reasons. In addition to revealing the presence of an adrenal tumor, abdominal ultrasonography may reveal metastatic disease and is sensitive and specific for detecting vascular invasion by adrenal tumors.^43,45 CT and MRI are the imaging modalities of choice for humans with pheochromocytomas, and early experience in canine patients has been encouraging.^170-172 Abdominal radiographs may reveal the presence of a large adrenal mass^166,170 but are generally less informative than ultrasound examination. Thoracic radiographs are recommended to evaluate the cardiovascular system and for detection of pulmonary metastases in any patient with a suspected adrenal tumor. There are rare reports of PET or nuclear scintigraphy imaging in dogs with pheochromocytomas.^173,174 Immunohistochemical staining for chromogranin A can distinguish pheochromocytomas from adrenocortical tumors on tissue obtained at surgery or necropsy.¹⁷⁵

Plasma and urinary concentrations of catecholamines and their metabolites are routinely measured in humans for the diagnosis of pheochromocytoma.¹⁶⁴ Recent reports have suggested that urinary catecholamine and metanephrine to creatinine ratios hold promise as a diagnostic tool in dogs.^176-178 Plasma-free metanephrine and normetanephrines have also been evaluated in cats and dogs, with encouraging preliminary results.^165,179

Surgery is the only definitive treatment for pheochromocytoma.^{43,164,166,167,169} This should be performed by an experienced surgical and anesthesiology team because potentially life-threatening complications, including hypertension, hypotension, cardiac arrhythmias and hemorrage,¹⁶⁹ may occur during anesthetic induction and handling of the tumor. It has been shown that dogs receiving phenoxybenzamine, a noncompetitive α-adrenergic antagonist, prior to surgery are significantly more likely to survive adrenalectomy. Specifically, dogs that received this medication at doses ranging from 0.1 to 2.5 mg/kg every 12 hours, for a median period of 20 days, had a 13% mortality rate, compared to a mortality rate of 48% in dogs that did not receive this therapy.¹⁶⁹ Chemotherapy and RT have not been evaluated in dogs with pheochromocytoma. RT using ¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG) was recently reported in one case.¹⁸⁰

The prognosis for dogs with pheochromocytoma is affected by tumor size, presence of metastases, and local invasion. A MST of 374 days has been reported after surgical treatment of pheochromocytoma,¹¹⁴ and some dogs may survive for as long as 2 to 3 years.^167,181 Dogs without metastatic disease that survive the perioperative period appear to have a good prognosis.¹⁶⁴

Surgical Management of Adrenal Tumors

Prior to adrenalectomy, every attempt should be made to determine whether an adrenal tumor is functional, whether there is evidence of metastatic disease, and whether there is vascular invasion. Patients suspected to have a pheochromocytoma should be treated preoperatively with phenoxybenzamine. If tachyarrhythmias are present, a β-blocker such as propranolol or atenolol may also be administered but should only be started after α-adrenergic blockade has been initiated to prevent unopposed α-adrenergic stimulation and severe hypertension.¹⁶⁴ Patients with HC due to ADH may be medically managed with trilostane or mitotane prior to surgery if they are significantly debilitated by their disease, although this is rarely necessary. The potential for intraoperative and postoperative complications associated with adrenalectomy is significant¹⁸²; these cases are best managed by an experienced team, including a surgeon, anesthesiologist, internist, and critical care specialist. Particular concerns with pheochromocytomas include cardiovascular complications and hemorrhage, as noted previously. Patients with functional adrenocortical tumors are at risk for adrenocortical insufficiency, pulmonary thromboembolism, pancreatitis, renal failure, and wound dehiscence.* Protocols are available to guide the perioperative management of adrenalectomy patients.¹⁷ At CSU, patients with pheochromocytoma are treated preoperatively with phenoxybenzamine as described earlier. Patients with functional adrenocortical tumors receive heparin and corticosteroid therapy during and after surgery. Postoperatively, an ACTH stimulation test is performed 24 to 48 hours after surgery, and electrolytes and blood glucose are measured frequently. The duration of prednisolone therapy and the necessity for mineralocorticoid supplementation are each determined on an individual case basis. For patients with adrenal tumors of unknown origin, preoperative phenoxybenzamine is recommended, and the protocol for functional adrenocortical tumors is followed, until postoperative ACTH stimulation test results and histopathology results are available to guide further management.

The overall perioperative mortality rate for dogs undergoing adrenalectomy for all adrenal tumors is around 10% to 20%,^{43,45,114,115} and MSTs of 690 to 953 days have been reported.^114,115 A number of investigators have evaluated prognostic factors and predictors of outcome in these patients. In two studies, the presence of caval tumor thrombus did not affect perioperative morbidity and mortality, although the long-term prognosis for dogs with an adrenocortical tumor may be poorer in the presence of a thrombus.⁴³ In contrast, a more recent study suggested that vein thrombosis was associated with a poorer prognosis.¹¹⁵ In the latter study, vein thrombosis was associated with tumors with major axis length of 5 cm or larger, and the presence of metastases or tumor size of 5 cm or larger were both associated with a poorer prognosis.¹¹⁵ Large tumors were also associated with increased perioperative mortality in a series of dogs undergoing elective or emergency adrenalectomy. The dogs in this report that had emergency surgery for acute adrenal bleeding experienced a 50% perioperative mortality rate.⁴⁵

Incidental Adrenal Masses

Advances in abdominal imaging have led to the diagnostic dilemma of the incidental adrenal mass (“incidentaloma”) in both human and veterinary medicine. When an incidental adrenal mass is identified in a dog or cat, a thorough history and physical examination, including blood pressure measurement and fundic examination, are indicated. Endocrinologic testing should be pursued to rule out a functional adrenocortical tumor. Given the high incidence of metastatic lesions in canine and feline adrenal glands, imaging of the thorax and abdomen should be performed to rule out another primary tumor. Aspiration cytology and ultrasound- or CT-guided biopsies are not routinely recommended for incidentalomas because of the high risk of complications and the inability to reliably differentiate benign and malignant lesions.^38,112 Adrenalectomy should be considered for masses that are functional, locally invasive, or larger than 2.5 cm in maximum dimension. Masses smaller than 2 cm with no evidence of hormonal activity should be monitored with abdominal ultrasonography. A suggested interval is to repeat the sonogram 1 month after the initial study and then after 2, 4, and 6 months, with further intervals determined by the appearance of the mass and the clinical status of the patient.¹⁶⁴

Beta-Cell Tumors in Dogs

The cellular and molecular events causing beta-cell tumors in dogs are unknown. Canine insulinomas have been shown to express somatostatin receptors, which may have implications for both diagnosis and therapy (see later).³⁴⁵ Local production of GH and IGF-1 have also been demonstrated in canine insulinomas, with a higher level of expression of GH and IGF-1 mRNA in metastases compared to primary tumors.^338,346 It has been suggested that the locally produced hormones may have autocrine or paracrine effects on cell proliferation, and tumor growth and progression. Furthermore, it is speculated that locally produced somatostatin has inhibitory effects on insulinomas within the pancreas, but that these effects are decreased in metastases, leading to increased GH production.³⁴⁶ The World Health Organization (WHO) recommendations have been used to stage canine pancreatic tumors.³⁴¹ Thus clinical stage I tumors involve only the pancreas with no evidence of local or distant lymph node involvement and no distant metastasis (T1N0M0). Stage II tumors have lymph node involvement (T1N1M0), and stage III tumors have distant metastasis (T1N1M1 or T1N0M1). A recent study evaluated several clinicopathologic and morphologic criteria of canine insulinomas with the goal of establishing prognostic biomarkers for this tumor.³³⁹ It was found that tumor size was predictive for disease-free interval (DFI) in a multivariate analysis, and Ki67 index, a marker of proliferation, was predictive for both DFI and survival time.

Canine insulinomas are most commonly reported in medium- and large-breed dogs, particularly Labrador retrievers, Golden retrievers, German shepherd dogs, German pointers, Irish setters, Boxers, and mixed breed dogs. Small-breed dogs can also be affected; West Highland white terriers appear overrepresented in some reports. Depending on the case series, the median reported age is 9 to 10 years, with a range of 3 to 15 years, and no sex predilection.^{337,340-342,346,347}

The clinical signs of insulinoma result from the effects of hypoglycemia on the nervous system, which is termed neuroglycopenia, and these signs include weakness, ataxia, collapse, disorientation, behavioral changes, and seizures. Catecholamine release stimulated by low blood glucose levels may also cause muscle tremors, shaking, anxiety, and hunger. Clinical signs may be present for days to months and are often intermittent or episodic. They may be precipitated by fasting, exercise, excitement, or eating. Signs may be less pronounced with more chronic hypoglycemia, and patients may be clinically normal with significantly low blood glucose levels. Physical examination findings are usually otherwise unremarkable in these patients. A paraneoplastic peripheral neuropathy has been described in dogs with insulinoma. This appears to be rare, although subclinical neuropathies may be present and undetected.^348-352 Brain lesions associated with hypoglycemia have also been reported in rare cases.^353,354

The diagnosis of insulinoma is confirmed by documenting hypoglycemia (blood glucose <60 mg/dL) with a concurrent normal or elevated serum insulin concentration. In some cases, it may be necessary to fast the patient, with careful monitoring, and repeat blood glucose measurements every 30 to 60 minutes. Once the blood glucose is less than 60 mg/dL, a serum sample should be submitted for concurrent insulin measurement. The presence of normal or high serum insulin concentration in the face of hypoglycemia is inappropriate and generally sufficient to confirm the diagnosis of insulinoma. This insulin-glucose pair should be performed more than once if the initial sample provides equivocal results.³⁵⁵ The use of insulin : glucose or glucose : insulin ratios is not recommended because these do not improve diagnostic accuracy. Provocative testing is also rarely used in veterinary medicine because of risks, expense, and poor sensitivity.³⁴² Serum fructosamine and glycosylated hemoglobin concentrations can also be measured in dogs to support a suspicion of insulinoma.^356-359 Concentrations of these glycosylated proteins would be expected to be lower than normal in dogs with chronic hypoglycemia, although this is not necessarily pathognomonic for insulinoma.

Imaging studies are often used in the evaluation of insulinoma patients, particularly in preparation for surgical management. Thoracic and abdominal radiographs are usually unremarkable but are often obtained to investigate other potential causes of hypoglycemia. Abdominal ultrasonography is commonly performed but has been reported to clearly identify and localize a pancreatic mass in less than 50% of cases.^{344,347,360,361} Abdominal ultrasonography is also used to identify metastatic lesions in dogs with insulinoma but has low sensitivity and specificity for this purpose. Thus, although abdominal ultrasonography is widely available and often used in the evaluation of patients with hypoglycemia, it cannot be used to rule in or rule out a diagnosis of insulinoma. In human medicine, endoscopic and intraoperative ultrasonography are used to identify small pancreatic tumors, but these techniques have yet to be reported in canine patients.³⁶²

CT findings have been reported in a small number of dogs with insulinoma.^361,363,364 In a study comparing ultrasound, CT, and single-photon emission CT (SPECT), CT was found to be the most sensitive technique, identifying 10 of 14 confirmed primary insulinomas. However, CT also identified a significant number of false-positive metastatic lesions.³⁶¹ The results of SPECT with ¹¹¹In-DTPA-D-Phe¹-octreotide have been reported in a total of 19 dogs with insulinoma, with an overall sensitivity of 50% for detection and correct localization of the primary tumor.^345,361 Enhanced CT techniques such as dynamic CT or dual-phase CT angiography hold promise for greater sensitivity of detection of insulinomas in dogs, but large-scale studies have yet to be reported in the veterinary literature.^363,364 Somatostatin receptor scintigraphy (SRS) is an important imaging modality in humans with pancreatic endocrine tumors, including insulinomas. Indium In-111 pentetreotide SRS has been reported in a total of six dogs with insulinoma, with positive results reported in five cases, although an accurate anatomic localization was only obtained in one case.^365,366 PET has been used in human patients to localize insulinomas when CT, MRI, and ultrasound are negative.³⁶⁷ This modality has yet to be explored in canine insulinoma patients.

Therapy for canine insulinoma involves acute and chronic treatment of hypoglycemia and long-term management of the tumor. Acute treatment of hypoglycemia is accomplished through administration of intravenous dextrose, often as a slow bolus, followed by continuous rate infusion (CRI). This should be given with caution because this treatment can stimulate further unregulated insulin secretion and worsened hypoglycemia. A CRI of glucagon has also been used in the management of hyperinsulinemic-hypoglycemic crisis in a dog.³⁶⁸

Exploratory laparotomy is indicated in dogs with hypoglycemia and inappropriately elevated serum insulin concentrations, regardless of the results of abdominal imaging studies.^{340-342,344,347} Blood glucose levels should be stabilized before surgery and monitored throughout the procedure. Surgery allows confirmation of the diagnosis of insulinoma, resection of primary and metastatic neoplasia, and staging of the disease. Details of the technique of partial pancreatectomy are described elsewhere.¹⁸² The majority of canine insulinomas are visible or palpable at surgery, and tumors are identified in both lobes of the pancreas with equal frequency. Suspected metastatic lesions should be resected whenever possible, and the liver and regional lymph nodes should always be biopsied. Potential postoperative complications include pancreatitis, persistent hypoglycemia, transient hyperglycemia or diabetes mellitus, and exocrine pancreatic insufficiency.^187,331,342

Medical treatment of insulinoma is used to stabilize patients preoperatively, as an alternate therapy if surgery is not possible, and in conjunction with surgical management. Medical therapies are primarily used to control hypoglycemia, but cytotoxic agents have also been used to destroy pancreatic beta-cells. Streptozocin (streptozotocin) is the chemotherapeutic drug that has been used most often, albeit infrequently, in dogs. Its use in dogs was historically limited by its nephrotoxicity,³³¹ but more recent reports suggest that the risk of nephrotoxicity is significantly reduced if the drug is given in combination with intensive saline diuresis.^369,370 Other side effects of this drug include vomiting during administration, diabetes mellitus, hypoglycemia, and mild hematologic changes.^369,370 The administration of streptozocin does not significantly increase the duration of normoglycemia in dogs with insulinoma compared with control dogs treated medically or surgically.³⁶⁹ Although individual dogs have demonstrated reductions in tumor size or resolution of paraneoplastic neuropathy with streptozocin, it is still unclear if the risks of therapy outweigh the benefits of this treatment for dogs with insulinoma.

Strategies used to control hypoglycemia consist of dietary modification and medical therapy with prednisone, diazoxide, or octreotide. Excitement should be avoided in these patients, and exercise limited. Diets high in fat, protein, and complex carbohydrates should be fed in small, frequent meals, and simple sugars avoided.³³¹ Prednisone is used for its insulin-antagonizing, gluconeogenic, and glycogenolytic effects.³³¹ A starting dose of 0.25 mg/kg by mouth (PO) twice daily is recommended, with gradual dose increases as needed to control hypoglycemia.^331,342 Typical glucocorticoid side effects should be anticipated. Diazoxide is a nondiuretic benzothiadiazine that suppresses insulin release from beta-cells. It also stimulates hepatic gluconeogenesis and glycogenolysis and inhibits cellular uptake of glucose. Diazoxide is not cytotoxic and does not inhibit insulin synthesis. A starting dose of 5 mg/kg PO twice daily is recommended, and the dose can be gradually increased to 30 mg/kg PO twice daily if necessary.^331,342 Approximately 70% of canine insulinoma patients respond to diazoxide therapy.^331,340 Side effects are uncommon but may include ptyalism, vomiting, anorexia, and diarrhea.^331,342,371 The use of diazoxide has been limited by its cost and inconsistent availability. Octreotide is a somatostatin receptor ligand that inhibits synthesis and secretion of insulin by pancreatic beta-cells. It has been reported to alleviate hypoglycemia in up to 50% of dogs with insulinoma, although some may become refractory to treatment.^331,345 The suggested dose is 10 to 50 µg SQ 2 to 3 times daily, and side effects appear to be rare. In a more recent study, a single 50 µg dose of octreotide was administered to 12 dogs with insulinoma. Plasma insulin concentrations decreased significantly after administration of octreotide in dogs with insulinoma, but GH, ACTH, cortisol, and glucagon levels did not change and glucose levels increased.³⁷² These findings suggest that the use of octreotide warrants further investigation in canine patients with insulinoma, although the cost of the medication may be a significant impediment.

The prognosis for dogs with insulinomas is good in the short term but guarded to poor in the long term. Patients that undergo surgery followed by medical management are more likely to become euglycemic, remain euglycemic for longer periods, and have longer survival times compared to patients that receive only medical therapy.^344,347 MSTs following partial pancreatectomy range from 12 to 14 months over several different studies.³⁷¹ The prognosis following surgery depends on the clinical stage of the disease. Dogs in stage I have a longer DFI compared to dogs in stages II and III, with 50% of dogs in stage I free of hypoglycemia 14 months after surgery compared to less than 20% of dogs in stages II and III being free of hypoglycemia at this time.³⁴¹ Dogs in clinical stage III have a significantly shorter survival time than dogs in stages I and II, with approximately 50% of dogs with metastasis dead by 6 months.³⁴¹ A more recent retrospective study showed improved survival in dogs with insulinoma compared to earlier reports.³⁴⁷ The authors reported a MST of 785 days for 19 dogs undergoing partial pancreatectomy, with a median DFI of 496 days. The subset of nine dogs that received surgery followed by medical therapy with prednisolone had a MST of 1316 days. For eight dogs receiving medical therapy alone, the MST was 196 days. When all the dogs that received medical therapy were considered as a group, the MST after institution of the medical treatment was 452 days.³⁴⁷ These results lend strong support to the use of medical therapy in canine patients with insulinoma, particularly when clinical signs recur after surgery.

Beta-Cell Tumors in Cats

Compared to dogs, there are significantly fewer reports of insulinomas in cats. History, clinical signs, and biologic behavior in this species appear to be similar to those in the dog, and concurrent measurements of blood glucose and serum insulin concentrations are used to confirm the diagnosis. However, it is important to use an insulin assay that has been validated in cats. Siamese cats may be overrepresented,³⁷¹ but because the disease is rarely reported, firm conclusions on breed predisposition should not be drawn. Surgical management has been reported in feline patients, with survival times ranging from 1 to 32 months.^331,373-377 Medical therapy with dietary management and prednisolone have also been used in cats. Octreotide may also be considered, although there is little evidence to support its use, and no evidence to support the use of diazoxide or streptozotocin in this species.³³¹

Gastrinoma

Gastrinomas are neuroendocrine tumors that secrete excessive amounts of gastrin. Zollinger-Ellison syndrome refers to the triad of a non–beta-cell neuroendocrine tumor in the pancreas, hypergastrinemia, and gastrointestinal ulceration. Gastrinomas are rare in dogs and very rare in cats.^378,379 Almost all reported gastrinomas in these species were identified in the pancreas, although there is one report of a duodenal gastrinoma in a dog.³⁸⁰ In contrast, the majority of gastrinomas in humans arise in the duodenum, with fewer detected in the pancreas.¹⁰ Although gastrin-producing G cells normally exist in the duodenum and gastric antrum, they are not present in the pancreas. The cell of origin for primary pancreatic gastrinomas is not known, but D cells (which secrete gastrin in the fetus and neonate) are the most likely candidates.^378,379 Gastrinomas are highly metastatic, with involvement of the liver, regional lymph nodes, spleen, peritoneum, small intestine, omentum, or mesentery identified in 85% of dogs and cats at the time of initial diagnosis.^{378,379,381-383}

Gastrinomas are typically reported in middle-aged dogs and older cats.^378,379 No obvious breed or sex predilections have been identified. Clinical signs result from gastric acid hypersecretion and gastric mucosal hyperplasia.^{378,379,381-389} The most common signs are vomiting and weight loss. Melena, abdominal pain, anorexia, hematemesis, hematochezia, and diarrhea may also occur. Physical examination findings range from unremarkable to a patient in hypovolemic shock due to perforation of an ulcer. Serum biochemistry profile, CBC, and urinalysis may demonstrate changes associated with protein loss and bleeding due to gastrointestinal ulceration or may reflect the consequences of severe or persistent vomiting or the presence of hepatic metastases. One case of common bile duct obstruction due to a duodenal gastrinoma has been reported in a dog.³⁸⁰ Abdominal radiographs may be unremarkable unless gastrointestinal perforation has occurred. Contrast radiographs and abdominal ultrasound examination may show evidence of gastrointestinal ulceration and thickened pyloric antrum and gastric wall. Ultrasound examination may also reveal metastatic lesions in the liver or regional lymph nodes; however, the primary tumor in the pancreas is usually too small to be detected with this modality.³⁸³ The results of techniques such as CT and MRI have not been widely reported in dogs and cats with gastrinomas. Endoscopy may reveal esophagitis with ulceration, gastric and duodenal ulceration, thickened gastric rugae, and hypertrophy of the pyloric antrum. The diagnosis may be supported by measuring basal serum gastrin levels or levels after provocative testing or by scintigraphy using radiolabeled pentetreotide.³⁹⁰ Basal gastrin levels have been significantly elevated in dogs and cats with gastrinoma; however, gastrin levels can also be elevated in renal, hepatic, or gastric disease, and after therapy with antacids such as H₂-receptor antagonists and proton pump inhibitors.³⁹¹ Provocative testing has rarely been reported in veterinary medicine.^187,378,379

Exploratory laparotomy is recommended for dogs and cats suspected to have a gastrinoma. Even though the majority of dogs and cats have visible metastasis at the time of initial diagnosis, surgical debulking will reduce gastrin secretory capacity and enhance the efficacy of medical therapy.³⁷⁹ In addition, deep or perforated gastrointestinal ulcers can be identified and excised. Long-term medical management includes the use of proton pump inhibitors, H₂-receptor antagonists, and sucralfate.^384,388 Octreotide has been used in two dogs with success.^390,392 Survival times for dogs and cats with gastrinoma have ranged from 1 week to 26 months.^378,379,388

Glucagonoma

Glucagonomas are rare in dogs and humans, and there are no case reports in cats.^10,378,379 These tumors are associated with a crusting dermatologic condition referred to as superficial necrolytic dermatitis, diabetic dermatopathy, hepatocutaneous syndrome, or necrolytic migratory erythema (NME). Other associated problems include hyperglycemia or overt diabetes mellitus, hypoaminoacidemia, and increased liver enzyme values. Lesions associated with NME include hyperkeratosis, crusting, ulceration and erosions of the footpads, mucocutaneous junctions, external genitalia, distal extremities, pressure points, and ventral abdomen.^{187,378,379,393-397} Glucagonomas arise from alpha-cells in the pancreas and are sometimes detected on abdominal ultrasound examination or CT.^379,395,397 Plasma glucagon levels may be measured, and amino acid concentrations have also been evaluated in a small number of patients,^394-396 but the sensitivity and specificity of these diagnostic tests is unknown. Surgical resection or debulking is the treatment of choice for canine glucagonoma, but metastasis is common at the time of surgery, and prognosis is generally poor.^{187,378,379,395} There are rare reports of the use of somatostatin analogs.^396,397 The dermatologic lesions of NME may improve after surgery or medical therapy, and lesions may also respond to treatment with amino acid infusions, oral protein supplementation (with protein powders or egg yolks), zinc, or essential fatty acids.³⁷⁹ When NME is suspected, it is important to rule out liver disease because this is a more common cause of this dermatologic condition in dogs.

Intestinal Carcinoid

Intestinal carcinoid tumors are rare in dogs and cats. They arise from enterochromaffin cells that are found in a variety of locations; hence these tumors have been reported in several sites throughout the gastrointestinal tract, liver, gallbladder, and pancreas.^{378,379,398-403} Clinical signs are generally associated with the anatomic location of the tumor; the physiologic effects of vasoactive substances released from the tumor were suspected in one dog with an intestinal carcinoid.⁴⁰² In general, the prognosis for these tumors is guarded because metastasis is common at the time of diagnosis.³⁷⁹ Surgical removal is recommended,³⁷⁸ and there is a single case report describing adjuvant chemotherapy in a canine patient.⁴⁰⁴

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