Claudia E. Reusch, DECVIM-CA
Adrenal tumours may be functional or non-functional. Functional tumours may arise from all zones of the adrenal cortex or the adrenal medulla and oversecrete cortisol, aldosterone, cortisol and aldosterone precursors, sex-hormones and catecholamines.
Glucocorticoid-secreting Adrenocortical Tumour
They are the most common adrenal tumours in dogs. For many years, it was assumed that ATs produce large amounts of hormone, more than the hyperplastic adrenal glands of dogs with PDH. However, it appears the opposite is true; in many dogs with AT, the hormone excess and subsequent clinical signs are only moderate. Thus, despite the fact that ATs usually greatly exceed the size of the normal adrenal gland, the tumour tissue is only moderately active, and the neoplastic transformation results in a decreased function per unit of volume. It is also possible that the cortisol synthesis pathway in dogs with AT is not intact. In humans, adrenal carcinomas tend to produce large amounts of precursors of cortisol, and a partial or complete deficiency of 11β-hydroxylase is common. In dogs, the existence of a similar phenomenon has recently been suggested. In dogs with AT, the right and left adrenal glands are affected with about equal frequency. Usually there is a unilateral solitary adrenal mass, although in approximately 10 per cent of cases, bilateral tumours are found.
Adenomas and carcinomas probably occur with equal frequency. Similar to other endocrine tumours, it is difficult to distinguish between adrenal adenomas and carcinomas. Even differentiation between AT and pheochromocytoma may require a pathologist with experience in special immunohistochemical staining techniques. Sometimes ATs that were initially diagnosed as benign turn out to be malignant when metastases are found later. Histological differentiation between benign and malignant tumours is only straightforward when there is capsular or vascular invasion by the tumour.
It is not uncommon for AT to be associated with pheochromocytoma; another interesting phenomenon is the co-existence of pituitary tumours and AT. Both situations may pose a difficult diagnostic and therapeutic challenge.
In humans bilateral nodular hyperplasia with HAC has been identified as a sequel to several pathophysiological conditions. Long-standing ACTH hypersecretion may result in nodular enlargement of the adrenal gland. Over time, these nodules may become autonomous or semiautonomous. Another type of nodular hyperplasia has been termed macronodular adrenal hyperplasia. It is ACTH-independent and characterized by bilateral nodules secreting excessive amounts of cortisol. Recent studies indicate that receptors for various hormones may be abnormally expressed by the adrenal glands; an example is ectopic expression of the gastric inhibitory polypeptide receptor. It is likely that adrenocortical nodular hyperplasia also exists in dogs, up till now one case has been described.
Dogs with AT are usually > 6 years of age; breeds most commonly involved are poodles, German shepherd dogs, Dachshunds, Labrador retrievers and various terrier breeds. Approximately 45 to 50% of dogs with AT weigh more than 20 kg i.e., belong to medium-sized and large breeds.
Clinical signs and clinicopathological findings are similar in dogs with AT and PDH. Typical symptoms include pu/pd, polyphagia, truncal obesity or abdominal enlargement (due to hepatomegaly, muscle wasting and/or intra-abdominal fat accumulation), thin haircoat, failure to regrow shaved hair, alopecia (may or may not be bilaterally symmetric, usually sparing head and extremities), thin skin, pyoderma, panting, muscle weakness, muscle atrophy and lethargy. Less common signs are heat intolerance, seborrhoea, comedones, hyperpigmentation, calcinosis cutis, bruising, testicular atrophy, failure to cycle, clitoral hypertrophy and facial paralysis. Rupture of an AT with intraabdominal or retroperitoneal haemorrhage is a rare complication, leading to acute severe lethargy, weakness and pale mucous membranes. Most frequent laboratory findings are increase in ALP, ALT, cholesterol, iso- or hyposthenuria, proteinuria and positive bacterial culture of urine.
The further diagnostic work up is a two step procedure. The first step is to confirm the diagnosis of HAC, the second to differentiate between PDH and AT. Routinely used screening tests include the urine cortisol:creatinine ratio (UCC) and the low dose dexamethasone test (LDDS test). With regard to the LDDS test it has long been thought that all dogs with AT show dexamethasone resistance (elevated cortisol concentration 4 and 8 hours after dexamethasone administration). However, it has now been described by us and others that a substantial percentage of dogs with AT may show suppression of cortisol 4 hours after dexamethasone which has originally been thought to be typical for PDH. Some dogs with AT even have normal cortisol concentrations after 4 and 8 hours. It is therefore advisable to perform additional tests with a higher sensitivity, such as UCC and to use ultrasonography and cATCH to differentiate between AT and PDH. Surgical removal is the treatment of choice. Patients must be assessed preoperatively for metastases or invasion of the tumour into surrounding tissues. Adrenalectomy is technically challenging and should be performed by a skilled surgeon. Approximately 50 per cent of patients develop postoperative complications, which may be severe and life-threatening and include pancreatitis, pneumonia, pulmonary thromboembolism, acute renal failure, sepsis and hypoadrenocorticism. The reported death rate after adrenalectomy varies between 10 and 34% and certainly depends on factors such as state of disease, skills of the surgeon, quality of perioperative management. It is not known whether dogs with AT that undergo long-term medical treatment before adrenalectomy have fewer postoperative complications and higher survival rates. Recurrence of HAC weeks to months after surgery or persistence of clinical signs occurs in dogs in which tumour removal was incomplete.
Autonomous cortisol secretion results in atrophy of the cells of the zona fasciculata and zona reticularis; in a few dogs aldosterone-producing cells of the zona glomerulosa may also be atrophied. Thus glucocorticoid substitution intraoperatively and postoperatively is necessary. Mineralocorticoid treatment is instituted when required.
For inoperable AT we currently use mitotane according to a protocol aiming for complete adrenal destruction. In some dogs, this treatment regime results in complete tumour remission and even disappearance of metastases.
Pheochromocytoma (Pheo) is the second most common adrenal tumour in dogs. It is of neuroectodermal origin arising from chromaffin cells of the sympathoadrenal system. Clinical signs result from excretion of excessive amounts of catecholamines and rarely from the direct presence and space occupying nature of the tumour. Pheo is identified most commonly in older dogs (> 7 years). There does not seem to be a sex or breed predilection. Symptoms are subtle, episodic and often complicated by concurrent disease. The most common clinical signs are generalized weakness and episodic collapse. Further symptoms include intermittent agitation, pacing, excessive panting, pu/pd. Systemic hypertension may occur leading to retinal detachment or retinal haemorrhage or hemorrhage into the retroperitoneal space, the abdominal cavity or the CNS. Vomiting, diarrhea, inappetence, weight loss, tender abdomen and cardiac arrhythmias may also be seen. Signs related to a space-occupying process are a palpable mass, enlarged abdomen, ascites and rear limb edema. Collapse and death from a sudden, massive and sustained release of the catecholamines and massive haemorrhage due to sudden increase in blood pressure or rupture of the tumour is possible. Many of the clinical signs caused by pheo are unspecific and vague and may be associated with a variety of more frequent diseases. There are no consistent abnormalities on haematology, serum biochemistry and urinalysis which would raise the suspicion of pheo. Up till recently the majority of cases were therefore only diagnosed at necropsy and were not suspected antemortem. However, due to the fact that abdominal ultrasonography including adrenal imaging is increasingly used as part of a diagnostic work-up, the situation has started to improve. Often, pheo is only considered after an adrenal mass is identified on abdominal ultrasonography. Although normal sized adrenal glands do not rule out pheo, there seems to be a relationship between tumour size and severity of clinical signs. In most dogs with obvious clinical signs the tumour is easily detectable. Different to the situation in human medicine the majority of pheos in dogs are malignant. Ultrasonography can provide information regarding local invasion to surrounding tissue and vessels, tumour thrombi and metastasis to other abdominal organs. In more than 50% of dogs with pheo tumour thrombi and/or metastasis are present at the time of diagnosis.
Pheo and AT can occur simultaneously, and since clinical signs may be similar it is important to rule out HAC in questionable cases. Determination of blood pressure is indicated in any dog with suspected pheo and demonstration of hypertension would be supportive of the disease. However, catecholamine secretion by the tumour and thus hypertension tends to be episodic. Hypertension has been documented in only 40-50% of dogs with pheo in which blood pressure had been measured.
In human medicine, measurement of urinary catecholamines, their metabolites metanephrine and normetanephrine, and vanillylmandelic acid in urine collected over 24 hours constitutes the traditional approach to the biochemical diagnosis of pheo. Alternatively to 24 hours urine sampling ratios to creatinine (in particular metanephrine:creatinine ratios) from spot urine samples can be used. In veterinary medicine biochemical testing has infrequently been performed due to limited availability of techniques, lack of established reference ranges and the problems of 24-hour urine collection. We recently established reference ranges for urine epinephrine-, norepinephrine-, metanephrine- and normetanephrine:creatinine ratios in dogs. From preliminary data from dogs with confirmed pheo we assume that the normetanephrine:creatinine ratio may be the most sensitive parameter.
The treatment of choice is surgical removal after a 2-3 weeks period of medical therapy to reverse the effects of catecholamine excess. For the latter phenoxybenzamine, an a-adrenergic antagonist can be used. Initial dose is 0.25 mg/kg BID, followed by gradual increase every few days until the dog shows clinical improvement or signs of hypotension. Maximum dosages is around 1.5-2.0 mg/kg BID. Prognosis is guarded due to the malignant nature of the tumour. Reported survival times range between 1-36 months.
Sex Hormone Producing Tumour
In humans with adrenocortical tumours aberrant synthesis pathways are well characterised.
Those tumours may be deficient in the enzymes involved in normal steroidogenic pathways, such as 21β-hydroxylase or 11β-hydroxylase, leading to an accumulation of steroid precursors proximal to the blockade. These precursors may either cause clinical signs similar to those seen with cortisol excess or they may be shunted into other metabolic pathways, and cause signs of androgen excess.
In veterinary medicine knowledge on abnormal steroidogenic pathways is scarce and matter of controversial discussions. A small number of dogs with sex-hormone producing tumours have been described. They had clinical signs consistent with HAC, and cortisol levels measured during screening-tests were negative. Further endocrine testing revealed that various precursors resp. sex-hormones such as progesterone, 17-hydroxyprogesterone, DHEAS, androstenedione, testosterone and estrogen were elevated. A lot more work is required to determine the frequency of these tumours and to characterize the specific enzyme-defects.
Aldosterone-producing tumours are increasingly reported in cats. In dogs, however, the disease appears to be rare. One dog has recently been described, which was presented with pu/pd. Further work-up revealed hypokalaemia, hypophosphataemia and alkalosis. Diagnosis was made by demonstrating high aldosterone levels and low renin activity and a nodule in one adrenal gland by CT. The dog made a complete recovery after adrenalectomy.
Adrenal tumours may not only oversecrete aldosterone, but also its precursors. A high index of suspicion and access to precursor measurements are necessary to make the diagnosis. A deoxycorticosterone-secreting adrenal tumour was demonstrated recently in a dog. Clinical signs were those of mineralocorticoid excess, however, aldosterone levels were undetectable. Deoxycorticosterone which has mineralocorticoid activity and acts as the same receptor as aldosterone was elevated. In another dog with signs consistent with mineralocorticoid excess oversecretion of aldosterone as well as of deoxycorticosterone was shown.
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