Veterinary Society of
Surgical Oncology

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

General Considerations

  • 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
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