Adrenal gland tumours are uncommon in dogs and cats, representing 1% to 2% of all canine tumours (Lunn 2013). However, due to the widespread use of abdominal ultrasonography, the identification of adrenal neoplasia has increased in recent years. In fact, advances in abdominal imaging have led to the diagnostic dilemma of incidental adrenal mass findings (so-called adrenal incidentaloma) in patients with unrelated clinical signs. In cats primary hyperaldosteronism (PHA) or Conn’s syndrome is currently considered the most common adrenocortical disease (Djajadiningrat-Laanen et al. 2011). PHA is characterised by excessive and autonomous secretion of mineralocorticoids, mainly aldosterone, by either bilateral nodular hyperplasia or a tumour of the zona glomerulosa of the adrenal gland(s) (Galac et al. 2010). In dogs adrenal neoplasia can be either functional or non-functional and most commonly, functional adrenal tumours secrete excessive amounts of cortisol or catecholamines.
ADRENAL GLANDS NEOPLASIA
Among the canine primary adrenal gland tumours, the most common are adrenocortical neoplasias, such as adenomas, carcinomas, and pheochromocytomas. Primary tumours of different origins and metastatic involvement of the adrenal glands have also been reported (Lunn 2013).
Functional adrenocortical cortisol-secreting adenomas and carcinomas may lead to clinical signs of hyperadrenocorticism (HAC) and are responsible for 15% to 20% of cases of naturally occurring HAC (Melián et al. 2010).
The classical clinical findings include polyuria/polydipsia (PU/PD), polyphagia and alopecia, and basic laboratory findings of HAC (such as a stress leukogram, increased alkaline phosphatase, increased alanine aminotransferase, hyperlipidaemia, decreased urinary specific gravity or proteinuria). These are similar for dogs with Pituitary Dependent Hyperadrenocorticism (PDH) or Functional Adrenocortical Tumours (FATs) (Melián et al. 2010).
Abdominal ultrasonography can help to guide differentiation between PDH and adrenal-dependent HAC, as contralateral atrophy is more common with the latter. It can also allow identification of metastatic lesions and loco-regional invasion by the tumour. Tumours bigger than 20 mm in diameter are more likely to be carcinomas, although adenomas up to 60 mm have been described (Labelle et al. 2004, Cook 2014).
Between 11-16% of adrenocortical carcinomas invade into the phrenicoabdominal vein, with extension into the renal vein and/or caudal vena cava in some cases (Adin and Nelson 2012). Metastases occur in approximately 50% of cases, the liver and lungs being the most common locations (Lunn 2013).
Pheochromocytomas are catecholamine-secreting neuroendocrine tumours arising from neoplastic chromaffin cells in the medulla of the adrenal glands. Clinical signs are related to the release of catecholamines and include generalised weakness, episodic collapse, restlessness, exercise intolerance, decreased appetite, weight loss and PU/PD. Some dogs present signs referable to the presence of a space-occupying abdominal mass, and acute collapse can occur secondary to tumour rupture and haemoabdomen.
Physical examination might be normal due to episodic nature of catecholamine secretion or might reveal tachypnoea, panting, tachycardia, cardiac arrhythmias or weakness. Systemic hypertension secondary to catecholamine release is a common feature of pheochromocytomas and may cause retinal haemorrhage and retinal detachment.
There are no specific abnormalities in routine blood work or urinalysis. A recent study (Gostelow et al. 2013) has shown that the measurement of plasma-free normetanephrine has an excellent sensitivity and specificity for the diagnosis of pheochromocytoma in dogs.
Metastasis to local lymph nodes and distant organs are reported in approximately 40% of cases. Vascular invasion is common in this tumour type, being described in 35-82 % of dogs with pheochromocytomas (Herrera et al. 2008, Adin and Nelson 2012, Lunn 2013).
PHA in cats is mainly caused by either an adrenocortical adenoma or carcinoma. Unilateral carcinoma occurs slightly more often than unilateral adenoma (Lo et al. 2014, Djajadiningrat-Laanen et al. 2011).
Aldosterone secretion is normally regulated by the renin-angiotensin-aldosterone system (RAAS) and extracellular potassium concentration, with a small amount of secretion stimulated by ACTH (Galac et al. 2010). Aldosterone increases renal secretion of potassium and hydrogen and resorption of sodium and chloride in the distal convoluted tubules of the kidney, which leads to an expansion of plasma and extracellular fluid volume, increased sodium retention and decreased extracellular, and eventually intracellular, potassium concentration. Cats with PHA secrete excessive amounts of aldosterone independent of the RAAS or extracellular concentration of potassium. The increased aldosterone concentration will result in an increased sodium and water retention and increased renal potassium excretion that may eventually lead to systemic hypertension and/or hypokalaemia.
Clinical signs are typical of hypokalaemic polymyopathy and include the characteristic cervical ventroflexion (Fig. 1), plantigrade stance of the hindlimbs and/or difficulties jumping. In some cases, there is a progression of the clinical signs to flaccid paresis, muscle hypotonia, respiratory failure and collapse. Some cats with PHA present initially with ocular signs of systemic arterial hypertension such as acute onset of blindness due to retinal detachment and/or intraocular haemorrhage.
Cats with PHA may have concurrent diseases due to their age (e.g. chronic kidney disease or hyperthyroidism) that can mimic the clinical signs of PHA and therefore hinder the diagnosis.
PRE-OPERATIVE DIAGNOSTIC WORK-UP
Dogs and cats undergoing adrenal surgery should have a full health assessment prior to surgery to identify any comorbidity, given that they are often older patients. Furthermore, they should be fully staged in order to determine if they are good surgical candidates and allow accurate surgical planning.
Adrenal tumours can invade the associated phrenicoabdominal vein, which has to be excised en bloc together with the adrenal mass. Invasion of the caudal vena cava or renal vein through the vascular lumen, or less frequently by direct invasion of the vascular wall, can also be seen (Figs. 2a & 2b). Caval invasion occurs more commonly associated with right-sided adrenal tumours due to their anatomic proximity.
A recent study (Davis et al. 2012) reported abdominal ultrasonography to be 100% sensitive and 96% specific in identifying the presence of a tumour in the caudal vena cava (Fig. 3). However, ultrasound identification of tumour thrombi is very dependent on the patient, equipment, and operators experience.
Abdominal ultrasonography is very helpful to identify also feline adrenal masses (Fig. 4). In all reported cases of PHA due to a unilateral adrenal mass where abdominal ultrasonography was performed, evidence of adrenal enlargement was always found in ultrasonography with diameters ranging from 10 to 46mm (Harvey & Refsal 2013).
In a recent report (Lo et al. 2014), vascular invasion was observed intraoperatively in seven out of ten cats with unilateral adrenal tumours but only one adrenal tumour was reported as invasive before surgery using CT and none using ultrasonography.
Advanced imaging such as Computer Tomography (CT) and Magnetic Resonance Imaging (MRI) is recommended to evaluate the invasiveness of the tumour, to identify distant metastases, and for a better surgical planning. Moreover, CT imaging allows oncologic staging of the patient.
PRE- & PERI-OPERATIVE MANAGEMENT
Significant blood loss can occur during surgery and blood-typing and cross-matching in preparation for a possible blood transfusion is recommended for patients undergoing adrenalectomy.
Removal of cortisol-secreting adrenal tumours normally leads to acute temporary hypoadrenocorticism (secondary to the effects of inhibitory feed-back from excessive cortisol on the contra-lateral adrenal gland) until the remaining gland starts compensating. Intravenous glucocorticoid therapy with dexamethasone 0.05-0.1 mg/kg IV, given over 6 hours as a constant rate infusion and mixed with crystalloids, should be started as soon as the tumour is excised and then continued at 12-hour intervals.
Dogs with pheochromocytomas are at risk of systemic hypertension, therefore blood pressure should be measured and hypertension addressed appropriately. The use of phenoxybenzamine pre-operatively has been associated with improved post-operative survival in dogs with pheochromocytomas (Herrera 2008). The starting dosage is 0.5mg/kg q12h, with increases every two to three days until normotension is achieved or side effects such as vomiting are observed. Phenoxybenzamine maximum dosage should not exceed 2.5 mg/kg q12h. Surgery is recommended 1-2 weeks after normotension or a maximum dosage is achieved.
Electrocardiography should be performed because abnormalities of the cardiac rhythm such as tachyarrhythmias are often observed in patients with suspected pheochromocytomas. If persistent tachycardia is present, a β-blocker (e.g. propanolol, 0.2-1 mg/kg/PO/ q8h or atenolol, 0.2-1 mg/kg/PO/ q12-24h) should be given. This treatment should be started only if therapy with phenoxybenzamine has already been given and systemic blood pressure is adequate.
In order to control intraoperative tachyarrythmias, β-blockade can be attempted using propanolol (0.3-1 mg/kg IV) or esmolol (0.05-0.25 mg/kg IV). The latter is preferred because of its short-acting effect and because it can be given as a bolus or via constant rate infusion (CRI). Intraoperative episodes of arterial hypertension, pathologic ventricular arrhythmias and bradycardia are not uncommon (Fig. 5). Although a short-acting α-antagonist such as phentolamine (1-2 μg/kg/min) might be effective, a direct vasodilator like nitroprusside (0.1-0.8 μg/kg/min) might be necessary (Fossum 2013).
Adrenalectomy is the treatment of choice for long-term management of the Conn’s syndrome. Medical stabilization aimed to correct hypokalaemia and hypertension are recommended prior to surgery. Hypokalaemia should be treated with oral potassium gluconate (2-6 mmol PO q12h), although some severely hypokalaemic cases will require intravenous potassium chloride supplementation as well. The calcium channel blocker amlodipine besylate (0.625-1.25 mg per cat PO q24h) is the recommended treatment for systemic arterial hypertension.
SURGICAL APPROACH
Adrenalectomy can be performed via a ventral midline, paracostal or laparoscopic approach. A ventral midline approach allows exploration of the abdomen for evidence of metastasis and provides better exposure of the caudal vena cava. A combined ventral midline and paracostal approach provides better adrenal gland visualisation but is more invasive and is only rarely performed. Laparoscopic adrenalectomy has been described with small adrenal tumours with no loco-regional invasion with few significant intra-operative complications (Naan et al. 2013, Jiménez Peláez et al. 2008).
Surgical Technique. Good exposure of the adrenal glands is essential to facilitate surgery; because of their location in the dorsal abdomen self-retaining abdominal retractors as well as manual retraction of tissues by a scrubbed assistant is advisable (Fig. 6). Once the surrounding organs have been retracted to expose the adrenal tumour, the vascular supply and ureter of the ipsilateral kidney should be identified and protected during dissection . The phrenicoabdominal vein and artery are ligated and removed en bloc with the excised adrenal gland (Fig. 7).
The adrenal gland is carefully dissected from surrounding tissue using a combination of sharp and blunt dissection and retracted medially, exposing several small vessels entering the gland dorsally. A small stay suture or atraumatic instruments may be helpful at grasping the adrenal gland. Adrenal glands have a relatively extensive blood supply, even in the healthy state, which is usually significantly increased by tumour neovascularisation complicating the dissection in many cases. Haemostasis of these vessels is facilitated by use of the combination of bipolar electrocautery, haemoclips, and vessel sealing devices rather than ligation with suture material. Once the gland has been freed from its lateral and dorsal attachments dissection between the caudal pole of the gland and the renal vessels should follow. The adrenal tumour is contained within a capsule that should not be damaged to avoid neoplastic seeding within the abdominal cavity. Malignant tumours may invade the kidney or body wall and ipsilateral ureteronephrectomy and/or partial body wall resection en bloc with the adrenalectomy may be sometimes required. In cats, if nephrectomy is to be considered, it is important to consider the effects on overall renal function and glomerular filtration rate, given the close association between PHA and chronic kidney disease. Finally, the phrenicoabdominal vein is ligated at its entry into the vena cava, and medial attachments of the adrenal gland to the vena cava or aorta are bluntly dissected.
Thrombi extending from the phrenicoabdominal vein into the caudal vena cava are generally peduncolated. Consequently, surgical removal of the caval thrombus involves a venotomy around the insertion site of the phrenicoabdominal vein.
The adrenal mass is dissected from the surrounding tissue until the only remaining attachment is the thrombus extending through the phrenicoabdominal vein into the vena cava. Roumel tourniquets using umbilical tape are placed around the vena cava cranial and caudal to the thrombus (cranial and caudal to the junction of the phrenicoabdominal vein) to temporarily occlude the caudal vena cava. Consequently, the Roumel tourniquets are tightened and the vena cava incised around the phrenicoabdominal vein and the venotomy extended cranially and/or caudally until the thrombus can be removed without tearing the wall of the vein. The thrombus is removed, and also the compromised wall of the vena cava if direct tumour invasion is observed. Vascular forceps can be placed parallel to the long axis of the caudal vena cava to partially occlude the venotomy in order to allow easier closure of the caval incision minimising the risk of bleeding. The caudal tourniquet is first released followed by the cranial tourniquet to avoid air embolism. Then, the venotomy incision is closed using vascular suture in a simple continuous pattern and finally the vascular forceps are released.
The venotomy is closed with 4-0 or 5-0 suture in a continuous pattern. In an effort to minimise the risk of air embolism, the vascular clamp is removed before tightening the final suture closure to allow restoration of blood flow into the isolated section. Air is forced out through the incision along with a small volume of blood and the final suture is tightened (Adin and Nelson 2012).
HAC/PHA impairs wound healing; therefore, abdominal closure should be performed with, monofilament, slowly absorbable (e.g. polydioxanone) or non nonabasorbable (e.g. nylon) suture material.
POST-OPERATIVE CARE
Perioperative complications are not uncommon in animals undergoing adrenalectomy. Therefore, owners must be fully aware about the possible complications of this surgery. Acute haemorrhage from the caudal vena cava is the most common and severe complication reported.
In dogs that undergo removal of cortisol-secreting adrenal tumours, dexamethasone dose is tapered by 0.02mg/kg q24 h but administration should be continued at 12-hour intervals until the dog can safely receive oral medication. Dexamethasone can at this point be replaced with oral prednisolone (0.2-0.5 mg/kg q12 h). Once the dog is reliably eating and drinking, which may take 2-3 days after surgery, the dose of prednisolone can be given once a day. The prednisolone dose should be progressively decreased over 2 to 3 months and eventually discontinued. At this stage an ACTH stimulation test should be performed to confirm that the remaining adrenal gland is functioning appropriately (Kyles 2003).
Common postoperative complications include arterial hypotension, pulmonary thromboembolism, hypoadrenocorticism, haemoabdomen, acute renal failure, acute pancreatitis, arrhythmias, coagulopathies, sepsis, hypoglycaemia, and delayed wound healing. Pulmonary thromboembolism can be a complication after adrenalectomy in dogs with cortisol-secreting adrenocortical tumours (Adin and Nelson 2012). There have been no controlled studies reporting a decrease incidence of postoperative thromboembolism with the perioperative use of anticoagulant therapy. However, the use of heparin after surgery is usually recommended in an effort to prevent thromboembolism. Heparin at 35 U/kg is given subcutaneously twice after surgery at 8-hour intervals and then tapered doses for an additional 2-3 days (e.g. day 2, 25 U/kg/injection q8hr; day 3, 15 U/kg/injection q8hr) (Adin and Nelson 2012). Some authors also administer heparinised plasma (35 U/kg added to 10 mL/kg of canine plasma) intravenously during surgery as a source of antithrombin III (Adin and Nelson 2012).
In order to promote blood flow and decrease the risk of thromboembolism, the anaesthetic protocol should allow dogs to be ambulatory within 4-6 hours of the surgery to be able to go out often for short walks.
Fluid therapy should continue until the dog is able to maintain hydration. Heart rate, heart rhythm, pulse quality, respiratory rate, membranes mucous, capillary refill time and blood pressure should be monitored closely for 24-36 hours after surgery.
Long-term medical management is not necessary in most cats after complete unilateral adrenalectomy. It has been suggested by some authors (Djajadiningrat-Laanen et al. 2011), to increase the administration of dietary sodium during the first weeks after surgery in order to avoid hyperkalaemia and hyponatraemia resulting from atrophy of the contralateral adrenal gland. However, while electrolyte monitoring is recommended postoperatively, adrenal insufficiency has not been reported after removal of aldosterone-secreting tumours.
PROGNOSIS
Historically, the perioperative mortality of dogs undergoing adrenalectomy was very high (Adin and Nelson 2012). However, peri-operative mortality rates between 10% and 20% have been reported in recent studies suggesting that improvements in the pre- and post- operative management, anaesthetic protocols and monitoring and surgical techniques have led to a decrease in mortality (Lunn, 2013).
Tumour size, the presence of metastatic disease, and acute adrenal haemorrhage have been associated with decreased survival in different studies (Massari et al. 2011).
Thrombosis of the caudal vena cava does not appear to increase peri-operative mortality unless the thrombus is very extensive or associated with tumours with a major axis length of 50 mm or larger (Kyles et al. 2003, Massari et al. 2008).
Shorter survival times have been reported for dogs with pre-operative weakness and lethargy, thrombocytopenia, increased BUN, aPTT, AST, hypokalaemia, concomitant nephrectomy and postoperative pancreatitis or acute renal failure (Schwartz et al. 2008).
Long-term prognosis of dogs surviving the peri-operative period is generally good with median survival times up to 953 days reported (Massari et al. 2008).
The prognosis for cats with unilateral neoplasia after complete adrenalectomy is usually excellent if they survive the immediate postoperative period.
References
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