CANINE Adrenal Tumors

ADRENAL PHEOCHROMOCYTOMA

PATHOPHYSIOLOGY

+ GENERAL CONSIDERATIONS

● Pheochromocytomas are endocrine tumors of neuroectodermal origin arising from chromaffin cells of the
sympathoadrenal system
● Chromaffin cells are capable of amine precursor uptake and decarboxylation
● Pheochromocytoma is an example of an APUDoma
● Pheochromocytoma is often solitary and located in or adjacent to the adrenal gland
● Pheochromocytoma arising from outside adrenal gland are called either extra-adrenal pheochromocytoma or
paraganglioma
● Pheochromocytomas are functional due to production of epinephrine, norepinephrine ± dopamine
● Pheochromocytoma is a common necropsy finding in 27%-85% dogs
● Clinical signs are caused by either a space-occupying mass or secondary to excretion of catecholamines
● Pattern of secretion is usually paroxysmal but can be constant
● Variety of clinical signs and paroxysmal nature of disease makes clinical recognition of pheochromocytoma difficult

+ ACTION

● Clinical signs in animals with pheochromocytoma are usually due to physiologic effects of catecholamines
● 2 types of catecholamine receptors: α and β (which are subdivided into α-1, α-2, β-1, and β-2)
● Subtypes of receptors differ in their response to epinephrine and norepinephrine
● α-1, α-2, and β-1 receptors respond equally to epinephrine and norepinephrine
● β-2 receptors are more responsive to epinephrine
● Hypertension is a common clinical sign in animals with pheochromocytoma due to increased vascular resistance
mediated by stimulation of α-1 receptors causing vasoconstriction
● Stimulation of β-1 can cause significant tachyarrhythmia which contributes to hypertension
● Prolonged stimulation of catecholamine receptors can result in desensitization (especially α-1 and β-1 receptors)

CLINICAL SIGNS

+ GENERAL CONSIDERATIONS

● Clinical signs due to space-occupying mass or secondary to excretion of excessive amounts of catecholamines
● Clinical signs in cats include polyuria, polydipsia, lethargy, anorexia, seizures, and intermittent vomiting
● Clinical signs in frequency of occurrence in dogs include: weakness, collapse, anorexia, lethargy, vomiting, polypnea,
cough, dyspnea, polyuria, polydipsia, diarrhea, weight loss, pelvic limb edema, abdominal distension, acute blindness,
epistaxis, restlessness, anxiety, pacing, ataxia, seizures, tremors and shaking, cyanosis, and adipsia
● Smaller pheochromocytomas confined to the adrenal medulla may be asymptomatic dogs
● Smaller pheochromocytomas are associated with more clinical signs in humans as large tumors can sequester
catecholamines and store and metabolize catecholamines to metanephrine, normetanephrine, and vanillylmandelic
acid within the tumor, hence decreasing catecholamine secretion
+ PHEOCHROMOCYTOMA CRISIS

● Paroxysm or crisis is a classical manifestation of pheochromocytoma due to catecholamine release and subsequent
stimulation of adrenergic receptors
● Paroxysm can be severe enough to cause acute fulminating signs which are rapidly progressive and potentially fatal
with acute collapse, cardiogenic shock, pulmonary edema, ventricular fibrillation, cyanosis, epistaxis, cerebral
hemorrhage, and seizures

+ PHYSICAL EXAMINATION

● Physical examination findings may be normal due to episodic nature of pheochromocytoma secretion
● Clinical findings attributable to excessive catecholamine release include:
● Abnormal lung sounds due to pulmonary hypertension causing congestion and edema
● Cardiac abnormalities such as tachycardia, arrhythmia, or systolic heart murmur
● Pyrexia and hyperemic mucous membranes
● Ophthalmic findings such as mydriasis, retinal hemorrhage and detachment with associated blindness
● Non-specific neurologic findings include head tilt, nystagmus, strabismus, and seizures
● Focal neurologic deficits have been reported due to cerebrovascular hemorrhage
● Clinical findings attributable to space-occupying mass include:
● Palpable abdominal mass (25%)
● Venous distension, ascites, and peripheral edema of pelvic limbs secondary to invasion of caudal vena cava

DIAGNOSIS

+ GENERAL CONSIDERATIONS

● Routine laboratory tests are rarely helpful in the diagnosis of pheochromocytoma

● Glucose intolerance can be observed in humans due to suppression of insulin release (α-adrenergic stimulation) and
glycogenolysis (β-adrenergic stimulation)
● Blood pressure monitoring is recommended, but hypertension can either be intermittent or constant
● Hypertension is defined as systolic blood pressure > 160 mm Hg and diastolic blood pressure > 100 mm Hg
● Echocardiogram: left ventricular hypertrophy consistent with hypertension
● ECG: sinus tachycardia, arrhythmia, and evidence of cardiac chamber enlargement
● Concurrent neoplasia is common in dogs with pheochromocytoma with 54% (33/61) dogs having tumors such as
adrenocortical adenoma and ADC, thyroid adenoma and ADC, and tumors of lungs, GI, liver, genitourinary and CNS
IMAGING

+ SURVEY RADIOGRAPHS

● Perirenal mass in 30%-56%

● Mineralization of adrenal gland in 10%
● Other radiographic findings include loss of serosal detail due to ascites or hemorrhage, abnormal hepatic contours,
hepatomegaly, and displacement of kidneys
● Thoracic radiographs may reveal cardiac enlargement, pulmonary congestion or edema, and metastatic disease
+ CONTRAST RADIOGRAPHS

Caudal vena cavogram is useful in delineating presence and extent of invasion or tumor thrombus formation

+ ULTRASONOGRAPHY

● Left and right adrenal glands can be identified in 96% and 72% of dogs with abdominal ultrasonography
● Right adrenal gland is more difficult to visualize due to cranial position and overlying pyloric and duodenal gas
● Normal adrenal gland is 0.5-1.4 cm long and 0.3-0.5 cm wide in cats
● Normal adrenal gland is 2.0-3.0 cm long, 1.0 cm wide, and 0.5 cm thick in dogs
● Adrenal glands show considerable variation in size and shape with resultant overlap between ultrasonographic
changes in normal and hyperplastic adrenal glands
● Adrenal mass can be detected in 65%-83% dogs with pheochromocytoma
● Adrenal mass is usually unilateral with adrenomegaly, variable and often heterogenous echogenicity, distortion of
normal architecture and contour ± evidence of vascular invasion or metastatic disease
● Tumor thrombus is 7.55-times more likely to be associated with a pheochromocytoma than an adrenocortical tumor

+ COMPUTED TOMOGRAPHY AND MAGNETIC RESONANCE IMAGING

● CT and MRI can be used to identify presence an adrenal tumor < 1 cm and evidence of vascular invasion and metastatic
disease
● CT preferred in humans with 85%-98% sensitivity and 70% specificity

+ NUCLEAR SCINTIGRAPHY

● Nuclear scintigraphy can be used to localize pheochromocytoma in humans

● Radionucleide agent used is iodine metaiodobenzylguanidine (I-MIBG)

+ DETECTION OF EXCESSIVE CATECHOLAMINES

● Specific diagnostic tests for pheochromocytoma are aimed at identifying elevated circulating levels of catecholamines
or urinary metabolites of catecholamines
● Techniques include:
● Identification of urine metabolites
● Identification of serum catecholamines
● Clonidine suppression test
● Phentolamine suppression test
● Histamine, tyramine, metoclopramide, or glucagon provocative tests
● Uncommon in cats and dogs due to limited availability, expense, lack of reference range, and inconvenience of 24-hour
urine collection

CLINICAL STAGING
SURGICAL MANAGEMENT
+ PREOPERATIVE AND ANESTHETIC MANAGEMENT

● Pheochromocytomas are catecholamine-secreting tumors associated with a high risk of anesthetic complications
● Complications can be reduced if the physiologic consequences of epinephrine and norepinephrine secretion are
addressed prior to anesthesia and surgery, specifically α blockade, blood volume restoration, and treating cardiac
arrhythmias
● Hypertension is treated with α blockers, but therapy needs to be continued for > 10 days for complete α blockade
● Phenoxybenzamine (0.5 mg/kg q 12 hrs in cats and 0.2-2.5 mg/kg q 12 hrs in dogs) is a non-selective and non-
competitive α-1 antagonist with a long duration of action
● Prazosin (0.5-2.0 mg/kg q 8-12 hrs) is a selective and competitive α-1 antagonist which is an alternative to
phenoxybenzamine
● β blockers (i.e., propanolol) can be added to this regime if hypertension, cardiac arrhythmias, or tachycardia persists
● β blockers are only used following α blockade in dogs with pheochromocytomas as a β-blocked heart will not be able to
maintain adequate cardiac output with unopposed α-mediated vasoconstriction resulting in exacerbation of
hypertension due to loss of β-2 vasodilatory effects
● Propanolol: 0.4-1.2 mg/kg q 8 hrs in cats and 0.15-0.5 mg/kg q 8 hrs in dogs
● Esmolol is a short-acting β 1-adrenergic antagonist which is administered in dogs with persistent tachycardia despite
adequate α-adrenergic blockage and vascular volume expansion
● Labetalol is a combined α and β antagonist but does not have an ideal α-to-β ratio with β predominating and resulting in
hypertension

+ ANESTHESIA

● Anesthetic protocol should not stimulate catecholamine release, blunt the sympathetic nervous system response to
anesthesia and surgery, and maintain hemodynamic stability
● Acepromazine is preferred for premedication because of α-blocking actions
● Animal should be well-sedated for placement of intravenous catheters to reduce stress and catecholamine release
● Opioids should be added to acepromazine for preemptive analgesia and additional sedation
● Morphine may cause histamine release and is avoided in animals with pheochromocytomas
● Lidocaine (1-2 mg/kg IV) can be administered 2-3 minutes prior to induction of anesthesia to reduce the induction dose
and protect against catecholamine-induced arrhythmias
● Anesthetic induction agents include etomidate, propofol, or opioid-benzodiazepine combination
● Ketamine increases sympathetic stimulation and is avoided for induction of animals with pheochromocytomas
● Isoflurane and sevoflurane are preferred to halothane for maintenance of general anesthesia as they do not sensitize
the myocardium to catecholamine-induced arrhythmias
● Fentanyl CRI is preferred (1-20 μg/kg/hr) because of superior analgesia and, because of a dose-reduction effect with
inhalation anesthesia, cardiovascular stability
● Epidural analgesia should also be considered for dose-reduction effects and postoperative analgesia
● Non-depolarizing neuromuscular blocking agents should also be considered, particularly for flank approaches,
although atracurium should be avoided because of the potential for histamine release
● Direct arterial blood pressure monitoring is recommended because of risks of hypertension
● Intraoperative hypertension can be treated with:
● Short-acting α-adrenoreceptor blockers (i.e., phentolamine 0.02-0.10 mg/kg IV or 1-2 μg/kg/min)
● Direct vasodilatory agents (i.e., nitroprusside 0.1-8.0 μg/kg/min CRI)
● Hypotension following removal of the adrenal pheochromocytoma is caused by a decrease in vascular tone and is
usually poorly responsive to pharmacologic therapy
● Large volumes of crystalloids should be used ± natural or synthetic colloids
● Ventricular arrhythmia: lidocaine
 ● Ventricular tachycardia: β-blockade with propanolol (0.02-0.10 mg/kg IV)

+ ADRENALECTOMY APPROACHES

● Adrenalectomy can be performed via ventral midline celiotomy, paracostal, or laparoscopic approaches
● Ventral midline celiotomy recommended for exploration of abdominal cavity for metastatic disease and management
of pheochromocytoma invading the caudal vena cava, although adrenalectomy (especially right-side) is more difficult
to perform and postoperative complications (i.e., pancreatitis and wound dehiscence) are more common
● Paracostal approach provides better access to adrenal gland and less likelihood of incisional dehiscence although
exploration of abdominal cavity for metastatic disease is limited
● Laparoscopic approach requires experience although provides excellent access and exploration for metastasis

+ ADRENALECTOMY

● Abdominal exploration to examine for metastatic disease and bilateral adrenal involvement
● Caudal vena cava is examined for tumor thrombus, but should be done with caution to maximize venous return
● Liver, stomach and intestines, spleen, and kidneys are retracted with large hand-held retractors
● Phrenicoabdominal vein is isolated, ligated, and divided, although this may be difficult in large adrenal tumors
● Adrenal gland is bluntly dissected from surrounding tissue
● Hemostatic clips are preferred for ligation because of difficulty hand-ligating deep in the abdominal cavity
● Ipsilateral nephrectomy may be required with adrenal invasion of renal parenchyma or vasculature

+ THROMBECTOMY TECHNIQUES

● Extraction of tumor thrombus may be required with the caval defect repaired primarily or with a patch graft or
segmental reconstruction with autogenous or prosthetic graft material
● Abdominal ultrasonography is 80% sensitive and 90% specific for identifying caval thrombosis
● Tumor thrombus is detected in up to 32% (13/40) of dogs with adrenal tumors, including 21% (6/28) with adrenocortical
tumors and 55% (6/11) with pheochromocytomas
● Majority of tumor thrombi extend beyond the phrenicoabdominal vein and into the prerenal ± intrahepatic and post-
hepatic caudal vena cava with caval thrombus detected in up to 25% (10/40) of dogs with adrenal tumors, including 11%
(3/28) with adrenocortical tumors and 55% (6/11) with pheochromocytomas
● Tumor thrombus arise from left-sided adrenal tumors in 22% (5/23) and right-sided tumors in 40% (8/20)
● Caval thrombus arise from left-sided adrenal tumors in 20% (4/20) and right-sided tumors in 35% (6/17)
● Tumor thrombus is 2.73-times more likely to develop in right-sided adrenal gland tumors and 7.55-times more likely to
be associated with a pheochromocytoma than an adrenocortical tumor
● Tumor thrombi are classified into 3 groups:
● Thrombus confined to the phrenicoabdominal vein
● Thrombus extending into the prehepatic caudal vena cava
● Thrombus extending into the intrahepatic ± post-hepatic caudal vena cava
● Adrenalectomy with tumor thrombus confined to the phrenicoabdominal vein is performed with ligation of the
phrenicoabdominal vein adjacent to the junction of the caudal vena cava and phrenicoabdominal vein
● Thrombectomy techniques in dogs with caval thrombi involves:
● Rumel tourniquets placed cranial and caudal to the adrenal gland tumor
● Cranial Rumel tourniquet immediately caudal to the liver
 ● Caudal Rumel tourniquet cranial to the renal veins or caudal to the right renal vein with a separate Rumel tourniquet
on the right renal vein
● Caudal vena cava is incised around the base of the phrenicoabdominal vein
● Cranial Rumel tourniquet tightened to control hemorrhage after removal of extensive caval thrombus

COMPLICATIONS

+ PULMONARY THROMBOEMBOLISM

● Pulmonary thromboembolism may present with acute dyspnea, respiratory arrest, hypoxia ± jugular pulse
● Diagnosis of pulmonary thromboembolism:
● Normal thoracic radiographs to blunting of pulmonary arteries
● Decreased arterial PaO 2 (< 80 mm Hg) and increased PaCO 2
● Evidence of pulmonary hypertension of echocardiography
● Treatment of pulmonary thromboembolism:
● Oxygen and cage rest
● Heparin therapy to prevent thrombus formation: 200 IU/kg then 10-150 IU/kg q 6 hrs
● Fresh frozen plasma if AT-III low
● Prevention of pulmonary thromboembolism:
● Aspirin 5 mg/kg q 12 hrs for 5 days prior to surgery
● Heparin 10 IU/kg q 6 hrs for 48 hrs following surgery

+ OTHER COMPLICATIONS

● Pancreatitis (common especially with ventral midline celiotomy)

● Others complications in dogs include iatrogenic vascular trauma and hemorrhage, ventricular tachycardia, pneumonia,
renal failure, wound dehiscence, infection, and sepsis

POSTOPERATIVE MANAGEMENT

+SHORT-TERM MANAGEMENT

● Continuous blood pressure monitoring is important as hypotension is the most likely postoperative complication
● Volume expansion
● Blood pressure should normalize within 24-48 hours

+LONG-TERM MANAGEMENT

● Adrenergic antagonist drugs will be required with incomplete resection or metastatic disease:
● Phenoxybenzamine or prazosin
● Propanolol
● α-methyltyrosine can reduce phenoxybenzamine dose and reduce adverse effects of chronic α-blockade
● α-methyltyrosine decreases catecholamine synthesis by inhibiting rate-limiting enzyme tyrosine hydroxylase
● Calcium channel blockers may be useful in controlling hypertension
 ● Chemotherapy has been used with some success in humans and include combinations of dacarbazine,
cyclophosphamide, and vincristine

+PROGNOSIS

● MST 15 months following adrenalectomy with long survival times reported following complete resection (i.e., 18-24
months)
● Neurologic signs, abdominal distension, and weight loss may indicate an advanced stage of disease
● Poor prognostic factors in humans include large tumor size, local tumor extension, DNA ploidy pattern and metastatic
disease
● 25%-52% local invasion
● 11%-24% metastatic rate to regional lymph nodes and distant sites
● Metastatic sites in dogs include lung, liver, spleen, kidney, bone, heart, pancreas, and lymph nodes

ADRENAL CORTICAL TUMOR

GENERAL CONSIDERATIONS

+ ANATOMY & PHYSIOLOGY

● Adrenal gland is composed of the medulla and cortex

● Adrenal medulla secretes epinephrine and norepinephrine
● Adrenal cortex is divided into 3 zones:
• zona glomerulosa: secretes mineralocorticoid and aldosterone
• zona fasciculate: secretes glucocorticoids and androgens
•zona reticularis: secretes glucocorticoids and androgens

+ ADRENAL-DEPENDENT HYPERADRENOCORTICISM

● Adrenal-dependent hyperadrenocorticism accounts for 10%-20% cases

● Adrenal-dependent hyperadrenocorticism is caused by benign or malignant tumors of the adrenal cortex
autonomously secreting excessive quantities of cortisol
● Adrenocortical tumors can produce glucocorticoids, but also mineralocorticoids and adrenal sex hormones
● Contralateral adrenal gland is often atrophied
● Adrenocortical adenoma and ADC occur with equal frequency and are difficult to differentiate with diagnostic tests
and imaging techniques
● Adrenocortical ADC is more likely to invade regional vascular structures (i.e., caudal vena cava and renal and hepatic
veins) (11%-25% cases) and metastasize to lungs, liver, or kidneys
● Metastatic rate variable for adrenocortical ADC: 7%-50%
● Other findings in cats and dogs with adrenal tumors:
○ thrombosis of vessels such as caudal vena cava, iliac, and femoral veins (especially dogs)
○ hypersecretion of sex hormones such as progesterone (especially cats) which may contribute to diabetes
mellitus due to insulin resistance and antagonism
○ bilateral adrenocortical tumors, concurrent adrenocortical tumor and pituitary-dependent
hyperadrenocorticism, concurrent adrenocortical tumor and adrenal pheochromocytoma, and concurrent
pituitary-dependent hyperadrenocorticism and adrenal pheochromocytoma have been reported and may
account for conflicting discriminatory tests and poor response to medical management
CLINICAL SIGNS

+ GENERAL CONSIDERATIONS

● Hyperadrenocorticism is usually an insidious and slowly progressive disease

● Chronic elevation of cortisol results in a broad range of systemic effects due to gluconeogenesis, lipolysis, protein
catabolism, anti-inflammatory effects, and immunosuppression
● Clinical signs in cats and dogs with adrenocortical tumors may be associated with secretion of non-glucocorticoid
substances, such as mineralocorticoids (i.e., hypokalemia and hypertension) and adrenal sex hormones

+ SIGNALMENT

● median age:
● 11.3 years for dogs with adrenal-dependent hyperadrenocorticism
● 10.0 years for cats
● Breeds: Poodle, Dachshund, Terrier, Beagle, GSD, Labrador Retriever, and Boxer are over-represented
● Sex predisposition: female dogs

+ GENERAL APPEARANCE

● Pendulous abdomen with varying degrees of hair loss

● Abdominal distension reported in up to 95% due to redistribution of body fat into the abdomen, hepatomegaly, and
muscle atrophy secondary to catabolic effects of excessive cortisol
● Epatomegaly is caused by accumulation of glycogen and fat

+ SKIN AND HAIR

● Skin and hair changes are frequently observed in feline and canine hyperadrenocorticism
● Skin and hair changes include thinning hair coat, bilaterally symmetrical alopecia, thin skin, comedones,
hyperpigmentation, pyoderma, and calcinosis cutis
● Calcinosis cutis is a raised, cream-coloured plaque surrounded by a zone of erythema and most commonly occurs on
the temporal region of the head

+ POLYURIA AND POLYDIPSIA

● Polyuria and polydipsia are common signs and present in 82% and 97%, respectively
● Nocturia, urinary incontinence, and pollakiuria are common findings secondary to polyuria and polydipsia
● Concurrent diabetes mellitus in 5%-10% of dogs and 76% of cats due to insulin resistance
● UTI common due to increased residual urine volume, dilute urine and immunosuppression

+ PANTING
Excessive panting and reduced exercise tolerance are frequently reported

+ PULMONARY THROMBOEMBOLISM

● Caused by hyperadrenocorticism in 17% dogs

● Should be suspected in hyperadrenocorticoid dogs with respiratory distress
● Due to hypercoagulable condition characterized by impaired fibrinolysis and increased coagulation factors
● Most often seen after initiating medical therapy or following surgery

+ NEUROLOGIC

● Neurologic signs may develop secondary to mass effect of pituitary macroadenoma

● Clinical signs include inappetance, dullness, disorientation, pacing, head pressing, ataxia, loss of learned behaviour,
seizures, visual deficits, anisocoria, and Horner’s syndrome

LABORATORY FINDINGS

+ HEMATOLOGY

Mature leukocytosis with neutrophilia, eosinopenia, and lymphopenia in dogs, but not cat

+ SERUM BIOCHEMISTRY

● Elevated ALP (5-20 times normal), ALT (mild), cholesterol, and glucose
● Hypothyroidism due to excessive cortisol suppressing thyroid-stimulating hormone release

+ URINALYSIS

● Hyposthenuric, but hyperadrenocorticoid dogs can concentrate urine if stressed or deprived of water
● Hyperadrenocorticoid cats are able to maintain USG > 1.020
● Other urinalysis findings include glucosuria (with concurrent diabetes mellitus), bacteruria, and proteinuria

SCREENING TESTS

+ GENERAL CONSIDERATIONS

● Hematology, serum biochemistry, and urinalysis are suggestive of hyperadrenocorticism, but are not diagnostic and do
not differentiate between pituitary-dependent and adrenal-dependent hyperadrenocorticism
● Routine screening tests include ACTH stimulation test, low-dose dexamethasone suppression test, and urine cortisol-
to-creatinine ratio
● However, false-positive results are common in dogs with severe non-adrenal disease with 56% (33/59) having
inadequate cortisol suppression at 8 hours following LDDST, 14% (8/59) having high serum cortisol levels after an ACTH
stimulation test, and 76% (45/59) having a high urine cortisol-to-creatinine ratio
 ● Ultrasound examination can also increase cortisol levels and hence all screening and differentiation tests should not be
performed within 2 hours of abdominal ultrasonography

+ URINARY CORTISOL-TO-CREATININE RATIO

● Excessive urinary concentration of cortisol in dogs with hyperadrenocorticism will increase urine cortisol-to-creatinine
ratio
● Advantages: convenient and inexpensive
● Disadvantages: high sensitivity but poor specificity
● Urine cortisol-to-creatinine ratio can be increased with non-hyperadrenocorticoid diseases such as renal disease,
diabetes mellitus, and neoplasia

+ ACTH STIMULATION TEST

● ACTH stimulation test evaluates ability of adrenal gland to secrete cortisol after maximal stimulation
● ACTH stimulation test is a screening test as it does not differentiate between pituitary- and adrenal-dependent
hyperadrenocorticism, however, it is useful for excluding iatrogenic hyperadrenocorticism
● False negatives (15%-30%) and false positives (in stressed and non-adrenal disease) are common in cats, but up to 70%
of cats will have increased cortisol concentrations after ACTH administration
● Cortisol production following ACTH stimulation remains excessive with both pituitary- and adrenal-dependent
hyperadrenocorticism
● Cortisol production may be normal following ACTH stimulation in dogs with adrenal-dependent hyperadrenocorticism
and hence a normal result does not exclude a diagnosis of hyperadrenocorticism
● Iatrogenic hyperadrenocorticism will have minimal to no response to exogenous ACTH
● 2 ACTH stimulation techniques:
● Serum cortisol collected for baseline and 1 hour after administering 0.25 mg synthetic ACTH IM
● Serum cortisol collected for baseline and 2 hours after administering 2.2 U/kg ACTH gel IM

+ LOW-DOSE DEXAMETHASONE SUPPRESSION TEST

● LDDST is regarded as the most reliable diagnostic test for hyperadrenocorticism

● LDDST is very sensitive but false-positive results are possible
● Low-dose dexamethasone will provide sufficient negative feedback at the pituitary level to down-regulate ACTH
secretion and result in reduced plasma cortisol concentration
● low-dose dexamethasone will not provide negative feedback with pituitary-dependent hyperadrenocorticism resulting
in elevated cortisol levels
● 30%-40% dogs with pituitary-dependent hyperadrenocorticism will suppress cortisol production at 3 hours
● Cortisol secretion is excessive and autonomous with adrenocortical tumors and is not influenced by the normal
pituitary-hypothalamic-adrenal axis and results in persistently high cortisol levels
● Serum cortisol collected for baseline and 3 and 8 hours after administering 0.01 mg/kg dexamethasone IV
● Serum cortisol should be tested more frequently in cats (i.e., 2, 4, 6, and 8 hours) as may escape suppressive effects of
dexamethasone before 8 hours if pituitary-dependent hyperadrenocorticism
● 100% of cats with hyperadrenocorticism do not suppress cortisol at 8 hours

PITUITARY- VERSUS ADRENAL-DEPENDENT HYPERADRENOCORTICISM

+ GENERAL CONSIDERATIONS

Discriminatory tests (i.e., HDDST and endogenous plasma ACTH levels) are used to differentiate pituitary- and adrenal-
dependent hyperadrenocorticism once the diagnosis of hyperadrenocorticism has been confirmed with screening tests

+ HIGH-DOSE DEXAMETHASONE SUPPRESSION TEST

● High-dose dexamethasone will supposedly suppress ACTH secretion in dogs with pituitary-dependent
hyperadrenocorticism but, due to autonomous secretion of cortisol independent of the hypothalamic-pituitary-adrenal
axis, not adrenal-dependent hyperadrenocorticism
● However, 20%-30% of dogs with pituitary-dependent hyperadrenocorticism will not suppress with HDDST
● HDDST can exclude adrenal-dependent hyperadrenocorticism if cortisol production is suppressed but not differentiate
between pituitary- and adrenal-dependent hyperadrenocorticism
● Serum cortisol collected for baseline and 8 hours after administering 0.1 mg/kg dexamethasone IV

+ ENDOGENOUS ACTH CONCENTRATION

● Endogenous ACTH secretion is increased in dogs with pituitary-dependent hyperadrenocorticism

● Pituitary production of ACTH is suppressed in dogs with adrenal-dependent hyperadrenocorticism
● ACTH is very labile and samples must either be immediately centrifuged and frozen or preserved by addition of
protease inhibitor aprotinin
● Combination of endogenous ACTH concentration and ultrasonography correctly differentiated pituitary- and adrenal-
dependent hyperadrenocorticism in 93% (27/29) dogs

IMAGING

+ SURVEY RADIOGRAPHS

● Hepatomegaly, osteoporosis, and soft tissue mineralization are features of hyperadrenocorticism

● Perihilar bronchial mineralization is common in hyperadrenocorticoid dogs
● Adrenal calcification can be observed in normal old dogs, 30% of normal old cats, and dogs with benign and malignant
adrenal neoplasia
● Cranial abdominal mass can be detected in up to 54% of dogs with adrenal tumors

+ CONTRAST RADIOGRAPHS

Caudal Vena Cavogram is useful in delineating presence and extent of invasion or tumor thrombus formation in dogs with
adrenocortical ADC

ULTRASOUND

+ NORMAL ADRENAL GLANDS

● Left and right adrenal glands can be identified in 96% and 72% of dogs with abdominal ultrasonography
 ● Right adrenal gland is more difficult to visualize due to cranial position and overlying pyloric and duodenal gas
● Normal adrenal gland is 0.5-1.4 cm long and 0.3-0.5 cm wide in cats
● Normal adrenal gland is 2.0-3.0 cm long, 1.0 cm wide, and 0.5 cm thick in dogs
● Adrenal glands show considerable variation in size and shape with resultant overlap between ultrasonographic
changes in normal and hyperplastic adrenal glands

+ ADRENAL-DEPENDENT HYPERADRENOCORTICISM

● Dogs with adrenal-dependent hyperadrenocorticism have unilateral adrenomegaly, variable and often heterogenous
echogenicity, distortion of normal architecture and contour, and may have evidence of vascular invasion or metastatic
disease
● Atrophy of contralateral gland is not a consistent finding
● Benign and malignant adrenal neoplasia cannot be differentiated on the basis of ultrasonographic features such as
bilateral involvement, mineralization, and echogenicity
● Malignant tumors tended to have a more rounded appearance and poorly encapsulated (compared to nodular and
well-encapsulated with benign tumors) with evidence of vascular extension or thrombus formation
● Bilateral adrenal tumors and pituitary-dependent hyperadrenocorticism with either adrenocortical tumor or
pheochromocytoma have been reported and must be interpreted with laboratory results
● Combination of endogenous ACTH concentration and ultrasonography correctly differentiated pituitary- and adrenal-
dependent hyperadrenocorticism in 93% (27/29) dogs

+ COMPUTED TOMOGRAPHY AND MAGNETIC RESONANCE IMAGING

CT and MRI can be used to identify pituitary macroadenomas, adrenal tumors, and evidence of vascular invasion and metastatic
disease

MEDICAL MANAGEMENT

+ GENERAL CONSIDERATIONS

● Drugs used for medical management of hyperadrenocorticism include:

● Mitotane (o,p'-DDD)
● Ketaconazole is an anti-fungal agent which inhibits adrenal steroidogenesis with minimal affect on mineralocorticoid
synthesis (5-15 mg/kg/day), but up to 50% dogs fail to respond
● Bromocriptine is a dopamine agonist with limited success
● Selegiline is a monoamine oxidase inhibitor which enhances dopaminergic tone to the hypothalamic-pituitary axis and
inhibits ACTH secretion (1 mg/kg/day)
● Metyrapone is an inhibitor of 11-β-hydroxylase which converts 11-deoxycortisol to cortisol and has shown good short-
term results in cats with hyperadrenocorticism and can be used for preoperative stabilization prior to adrenalectomy
● Aminoglutethimide inhibits conversion of cholesterol to pregnenolone and has been associated with short-term
improvement in 1 cat and suppresses adrenal steroid hormones in normal dogs
● Trilostane

MITOTANE

+ GENERAL CONSIDERATIONS
 ● Mitotane (o,p’-DDD) which is an adrenolytic agent which reduces cortisol secretion through selective necrosis of zona
fasciculata and reticularis (i.e., glucocorticoid-producing portions of the adrenal cortex) and spares the aldosterone-
producing zona glomerulosa
● Adverse effects are common and include glucocorticoid and mineralocorticoid (rare) deficiency during induction
therapy and toxic effects on GI, liver, and CNS (i.e., weakness, disorientation, and ataxia)
● Response rate with adrenal-dependent hyperadrenocorticism is poor with 56% responding to induction therapy
(although better response if no evidence of metastatic disease) with higher doses required for longer duration
● Mitotane has been used in cats although they are traditionally sensitive to chlorinated hydrocarbons, response rate is
less, and incidence of adverse effects higher

+ INDUCTION THERAPY

● Aim: reduce serum cortisol levels to within reference range for both basal and post-ACTH stimulation
● Mitotane: 50 mg/kg/day for 7-10 days or until end-point of induction phase is achieved
● Response to mitotane is variable with adrenal reserves diminished in 5-60 days
● Water intake, appetite, and general health should be closely monitored
● Mitotane is stopped and treatment reassessed if dog becomes listless, inappetant, or develops GI signs
● Success of mitotane induction therapy can be measured directly with ACTH stimulation test or indirectly with an
eosinophil count or reduction in water intake (especially if pre-existing polydipsia)
● 10%-15% dogs will not respond within 7-10 days and will require further induction therapy and repeat ACTH stimulation
test in 7-10 days
● 33% dogs will rebound with subnormal cortisol levels and may require glucocorticoid supplementation until cortisol
levels are within the reference range (usually 2-6 weeks although can be months)

+ MAINTENANCE THERAPY

● Mitotane: 25-50 mg/kg/week divided into 2-3 doses

● Physical examination and ACTH stimulation test should be performed every 3-6 months for monitoring
● Pituitary secretion of ACTH continues despite clinical control of hyperadrenocorticism
● 40%-50% recurrence rate of clinical signs of hyperadrenocorticism within 12 months
● Daily induction therapy restarted for short period followed by maintenance therapy if recurrence

+ PROGNOSIS

MST for dogs with adrenal-dependent hyperadrenocorticism is 11.5 months

ADRENALECTOMY

+ INDICATIONS

Unilateral Adrenalectomy is recommended for treatment of adrenal tumors and some have recommended bilateral
adrenalectomy for management of pituitary-dependent hyperadrenocorticism

+ PREOPERATIVE MANAGEMENT
 ● Glucocorticoid therapy is considered necessary due to functional atrophy of contralateral adrenal gland:
● Dexamethasone: 0.1-0.2 mg/kg bolus or 0.02-0.03 mg/kg/hr CRI for 6 hours
● Prednisolone sodium succinate 1.0-2.0 mg/kg
● Hydrocortisone: 625 µg/kg/hr (glucocorticoid and mineralocorticoid support)
● Coagulation profile important in screening for animals with potential for thromboembolic disease
● Preoperative anticoagulant therapy can be considered although benefit unknown
● ± Heparin (35 U/kg) in plasma to minimize the risk of pulmonary thromboembolism
● Metyrapone inhibits conversion of 11-deoxycortisol to cortisol and has been used in cats for preoperative stabilization
prior to adrenalectomy

+ GENERAL ANESTHESIA

● Anesthetic considerations for animals with hyperadrenocorticism include:

● Fluid and sodium retention
● Hypokalemia
● Hypertension
● Impaired respiratory function due to muscle weakness, hepatomegaly, and excessive fat deposition
● Hypertension occurs in 86% of dogs with untreated hyperadrenocorticism, and treatment does not always correct
hypertension
● Hyperglycemia (± diabetes mellitus) is common
● Pulmonary thromboembolism is a risk during anesthesia and surgery and, although the mechanisms are not fully
understood, include obesity, hypertension, increased red blood cell volume, and hypercoagulability

SURGICAL TECHNIQUE

+ GENERAL CONSIDERATIONS

● Abdominal exploration to examine for metastatic disease and bilateral adrenal involvement
● Caudal vena cava is examined for tumor thrombus, but should be done with caution to maximize venous return
● Liver, stomach and intestines, spleen, and kidneys are retracted with large hand-held retractors
● Phrenicoabdominal vein is isolated, ligated, and divided, although this may be difficult in large adrenal tumors
● Adrenal gland is bluntly dissected from surrounding tissue
● Hemostatic clips are preferred for ligation because of difficulty hand-ligating deep in the abdominal cavity
● Ipsilateral nephrectomy may be required with adrenal invasion of renal parenchyma or vasculature

+ THROMBECTOMY TECHNIQUES

● Extraction of tumor thrombus may be required with the caval defect repaired primarily or with a patch graft or
segmental reconstruction with autogenous or prosthetic graft material
● Abdominal ultrasonography is 80% sensitive and 90% specific for identifying caval thrombosis
● Tumor thrombus is detected in up to 32% (13/40) of dogs with adrenal tumors, including 21% (6/28) with adrenocortical
tumors and 55% (6/11) with pheochromocytomas
● Majority of tumor thrombi extend beyond the phrenicoabdominal vein and into the prerenal ± intrahepatic and post-
hepatic caudal vena cava with caval thrombus detected in up to 25% (10/40) of dogs with adrenal tumors, including 11%
(3/28) with adrenocortical tumors and 55% (6/11) with pheochromocytomas
● Tumor thrombus arise from left-sided adrenal tumors in 22% (5/23) and right-sided tumors in 40% (8/20)
 ● Caval thrombus arise from left-sided adrenal tumors in 20% (4/20) and right-sided tumors in 35% (6/17)
● Tumor thrombus is 2.73-times more likely to develop in right-sided adrenal gland tumors and 7.55-times more likely to
be associated with a pheochromocytoma than an adrenocortical tumor
● Tumor thrombi are classified into 3 groups:
● Thrombus confined to the phrenicoabdominal vein
● Thrombus extending into the prehepatic caudal vena cava
● Thrombus extending into the intrahepatic ± post-hepatic caudal vena cava
● Adrenalectomy with tumor thrombus confined to the phrenicoabdominal vein is performed with ligation of the
phrenicoabdominal vein adjacent to the junction of the caudal vena cava and phrenicoabdominal vein
● Thrombectomy techniques in dogs with caval thrombi involves:
● Rumel tourniquets placed cranial and caudal to the adrenal gland tumor
● Cranial Rumel tourniquet immediately caudal to the liver
● Caudal Rumel tourniquet cranial to the renal veins or caudal to the right renal vein with a separate Rumel tourniquet
on the right renal vein
● Caudal vena cava is incised around the base of the phrenicoabdominal vein
● Cranial Rumel tourniquet tightened to control hemorrhage after removal of extensive caval thrombus

+ POSTOPERATIVE MANAGEMENT

● Monitor systemic blood pressure, oxygenation, serum electrolytes, and other biochemical parameters
● ± Heparin (35 U/kg q 12 hr SC and tapering to 10 U/kg over 3-4 days)

COMPLICATIONS

+ ADRENAL INSUFFICIENCY

● Adrenal insufficiency may occur following unilateral adrenalectomy for adrenal neoplasia and bilateral adrenalectomy
● Prednisone (0.5 mg/kg q 12 hr PO) should be tapered down to 0.2 mg/kg q 12 hr PO within 7-10 days
● ACTH stimulation tests can be used to guide cessation of glucocorticoid therapy
● Mineralocorticoid deficiency can also occur and electrolytes should be monitored
● Mild hyponatremia and hypokalemia has been reported in > 40% dogs after unilateral adrenalectomy
● Mineralocorticoid supplementation: fludrocortisone acetate or desoxycorticosterone pivalate

+ PULMONARY THROMBOEMBOLISM

● Pulmonary thromboembolism may present with acute dyspnea, respiratory arrest, hypoxia ± jugular pulse
● Diagnosis of pulmonary thromboembolism:
● Normal thoracic radiographs to blunting of pulmonary arteries
● Decreased arterial PaO 2 (< 80 mm Hg) and increased PaCO 2
● Evidence of pulmonary hypertension of echocardiography
● Treatment of pulmonary thromboembolism:
● Oxygen and cage rest
● Heparin therapy to prevent thrombus formation: 200 IU/kg then 10-150 IU/kg q 6 hrs
● Fresh frozen plasma if AT-III low
 ● Prevention of pulmonary thromboembolism:
● Aspirin 5 mg/kg q 12 hrs for 5 days prior to surgery
● Heparin 10 IU/kg q 6 hrs for 48 hrs following surgery

+ OTHER COMPLICATIONS

● Pancreatitis (common especially with ventral midline celiotomy)

● Recurrence of clinical signs due to incomplete resection, metastatic disease, or concurrent pituitary-dependent
hyperadrenocorticism in 31% with median time to recurrence 16 months (range, 5-43 months)
● Others complications in dogs include iatrogenic vascular trauma and hemorrhage, ventricular tachycardia, pneumonia,
renal failure, wound dehiscence, infection, and sepsis
● Complications in cats include electrolyte abnormalities, skin lacerations, pancreatitis, hypoglycemia, pneumonia, and
venous thrombosis and pulmonary thromboembolism

PROGNOSIS

+ CATS

82% (9/11) cats responded well to bilateral adrenalectomy and appropriate postoperative management with resolution of clinical
signs and either improvement or resolution of diabetes mellitus

+ DOGS

● 19%-44% perioperative mortality rate

● 14%-50% metastatic rate with metastasis to the liver common
● 12%-31% local tumor recurrence rate
● Resolution of clinical signs in 69%-89% dogs following unilateral adrenalectomy for adrenocortical tumor
● MST for adrenocortical carcinomas: 778 days (range, 1-1,593 days) and 992 days if they survived 14 days
● MST for adrenocortical adenomas: > 730 days (range, 11-730 days)
● No prognostic factors, including presence of tumor thrombus, histopathologic diagnosis, histopathologic features, age,
tumor size, or presence of metastatic disease

+ FERRETS

● Splenomegaly (82%, 46/56) and insulinoma (21%, 12/56) were common concurrent conditions
● Operative mortality < 2 %
● 5% ferrets required mineralocorticoid or glucocorticoid therapy after bilateral adrenalectomy
● 15% recurrence rate with a mean follow-up of 30 months