ADRENAL CORTICAL TUMOR

+ 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

+ 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

+ 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

+ 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

+ 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

+ 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

+ 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

+ 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

+ 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

+ 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

+ 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)

+ 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

+ 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