A pheochromocytoma originates from the adrenal medulla.

Behaviour

Most pheochromocytomas are benign and are located in one adrenal gland, although they can occur in both adrenal glands. These tumours range in size from a few millimeters to 15 centimeters and large pheochromocytomas often invade blood vessels and adjacent tissues. Local invasion into adjacent blood vessels is observed in up to 56% of dogs and this behaviour is often related to malignancy. However, based on the latest definition of the WHO, pheochromocytomas are only considered malignant when distant metastases are present. In approximately 20% of dogs with pheochromocytoma, metastases are described in regional lymph nodes, liver, spleen, pancreas, lung, heart, central nervous system, kidney, and bone.

Approximately 50% of dogs with pheochromocytoma also have another endocrine tumour. These are tumours that involve endocrine glands, such as adrenal or pituitary tumours causing Cushing’s syndrome (most common), followed by parathyroid tumours, thyroid tumours, and insulinomas.

Prevalence

Pheochromocytoma is usually diagnosed in older dogs and is uncommon. Currently it is estimated that pheochromocytoma accounts for 0.01% to 0.1% of all canine tumours. This prevalence might be an underestimation because the diagnosis of pheochromocytoma via bloodwork has only recently become possible; the diagnosis can now be made faster and easier than before.

Breed predisposition

There is no obvious apparent sex or breed predisposition, although brachycephalic dog breeds (such as Bulldog, Pug) seem to be predisposed to develop a pheochromocytoma.

Symptoms

Pheochromocytomas are characterized by the overproduction of catecholamines (hormones) such as epinephrine and norepinephrine.

Clinical signs are usually related to the direct actions of secreted catecholamines and/or the space‐occupying or invasive nature of the adrenal mass. Hormone secretion from the tumour is unpredictable and episodic and consequently, the clinical picture varies considerably. Episodes of increased catecholamine release may occur several times per day or only at intervals of weeks to months. The triggers for catecholamine secretion in dogs are unknown. Pheochromocytoma should be considered a potentially life-threatening disease that can result in collapse and sudden death due to massive catecholamine release or tumour rupture.

The clinical manifestations of catecholamine excess are often non‐specific and may resemble other disorders that are more common than pheochromocytoma. General symptoms may include weakness, abdominal pain, anorexia, and discomfort. Other symptoms (related to the cardiorespiratory system) can include panting, a very fast heartbeat, an irregular heartbeat, and fainting. Systemic hypertension, one of the hallmarks of pheochromocytoma, is present in approximately 50% of affected dogs at the time of initial examination. The neuromuscular system may be affected by catecholamine‐induced spasm of blood vessels, haemorrhage within the central nervous system, or brain metastases. As a consequence, dogs may present with pacing, disorientation, anxiety, and seizures. Paresis (partial paralysis), lameness, and pain have been reported as a result of metastases to the vertebral canal or bone. Amongst the miscellaneous clinical signs of pheochromocytoma, drinking and urinating more are common.

The veterinarian can suspect a pheochromocytoma based on the dog’s clinical signs and/or an incidental finding of an adrenal mass via diagnostic imaging. Confirmation requires demonstration of both excessive catecholamine production and an abnormal adrenal gland on diagnostic imaging.

Blood or urine analysis

The preferred first step to diagnose a pheochromocytoma is the measurement of certain catecholamine metabolites (metanephrines). Metanephrines can be measured in the urine or plasma and include normetanephrine (NMN) and metanephrine (MN). The measurement of NMN is more indicative for a diagnosis of a pheochromocytoma than MN (in case of an pheochromocytoma, NMN is increased and MN can still be normal).

Imaging

Ultrasound

Another option to diagnose a pheochromocytoma than via blood or urine is via an ultrasound-guided fine-needle aspiration biopsy. Although fine-needle biopsy of an adrenal mass is considered relatively safe, complications can occur and involve haemorrhage, a very fast heartbeat, and respiratory distress. Therefore, making a diagnosis of phaeochromocytoma by NMN and MN measurement via blood or urine analysis is a preferred option.

CT scan

Imaging with a CT scan should be performed to evaluate the size of the adrenal mass and to screen for possible metastasis.

Surgery

Surgery (adrenalectomy) is currently the only curative treatment option for a pheochromocytoma.

Removal of the tumour will reverse the clinical signs associated with excessive catecholamine release and avoid the complications of uncontrolled tumour growth. Complications occurring during surgery are mainly catecholamine‐induced effects, which may be serious and potentially life‐threatening. To prevent these effects, treatment with an alpha-blocker should be initiated at least 2 weeks before adrenalectomy.

During treatment with an alpha-blocker, blood pressure should regularly be monitored to avoid hypotension. Often, the dose of the medication is adjusted based on owner feedback. If the dog shows signs of hypotension, such as lethargy and weakness, the dose of the alpha-blocker should be decreased. The literature shows that the mortality rate after adrenalectomy was significantly lower in dogs pre-treated with alpha-blockers than in untreated dogs.

Prerequisites for a successful outcome are appropriate preoperative medical treatment, an experienced anaesthetist, a skilled surgeon, and adequate facilities for post‐operative intensive care.

Targeted treatment

When a pheochromocytoma is not amenable to surgical removal or surgery is prevented by concurrent disorders, metastasis, or for other reasons, medical treatment with tyrosine kinase inhibitors (TKI) toceranib phosphate (Palladia®) is an option. The principal effect of this treatment is stabilisation of tumour growth; shrinking of the tumour has thus far not been achieved. The TKI is given every 48h and the dose should be adjusted based on regular assessments by the veterinarian during the first 6 weeks and approximately every 6 weeks, thereafter. After two weeks, blood and urine examination are required to evaluate the safety of the drug. After six weeks, this is combined with diagnostic imaging. The treatment is continued as long as no progression of the tumour growth has been detected.

Treatment may be associated with adverse reactions, such as diarrhoea, decreased appetite, lameness and muscle weakness. Dose interruptions and dose reductions may be needed during the treatment course depending upon the severity of clinical signs.

The prognosis for pheochromocytomas is worse in case of a large tumour, endocrine activity, vascular invasion, and the presence of metastases. Additional negative prognostic factors are old(er) age, bad general health, and the presence of concurrent disease. Most dogs with pheochromocytoma die because of complications caused by catecholamine excess, tumour thrombosis, tumour invasion into surrounding tissues, tumour rupture, or metastases. Dogs that undergo successful adrenalectomy can live for several years, the peri-operative mortality rate is 15-37%.

Survival times of dogs receiving medical treatment only are not known so far. The effect of Palladia® in dogs with pheochromocytoma is described in only one retrospective study involving five dogs. In this study, there were three dogs without metastases and two with metastases. In the dogs without metastases, no further tumour growth occurred during treatment with Palladia® for 28 weeks for dog 1, 36 weeks for dog 2 and 61 weeks for dog 3. The two dogs with metastases survived for 11 and 18 weeks while undergoing Palladia® therapy. This treatment can be safely combined with an alpha blocker if necessary.