One consequence of increasing subspecialization is that few surgeons now require a detailed knowledge of the disorders of the adrenal gland. Adrenal pathology is not only relatively uncommon but also tends to present with functional abnormalities due to excess or insufficient hormone secretion for which, most often, a physician will be consulted initially. Surgical involvement is usually limited to the management of conditions such as adrenocortical neoplasia or phaeochromocytomas at a stage when much of the diagnostic work-up has been completed. With this background in mind, this section has been written to provide core knowledge for the surgeon in training and a useful reference for the surgeon who may occasionally be called upon to manage the various disorders of the adrenals.

The adrenal glands are paired structures located medial to the upper pole of each kidney. Normally each weighs between 4 and 5 g but after a prolonged illness they may increase substantially as a result of adrenocorticotrophic hormone (ACTH) stimulation. Rarely adrenal tissue may develop at an ectopic site which bears an embryological relationship to the urogenital ridge and its derivatives. Ectopic tissue has most frequently been documented in the testis or spermatic cord but it may be located anywhere in the retroperitoneum from the diaphragm to the pelvis; in most cases it consists almost entirely of cortex, but it can include medulla, especially when it is located in the region of the coeliac ganglion. The importance of ectopic adrenal tissue is that it may undergo hyperplasia in Cushing's disease or rarely it may undergo neoplastic change.

The adrenal cortex and medulla are anatomically and functionally discrete units. The steroid-secreting cortex originates from the mesoderm of the urogenital ridge and gains a distinctive yellow colour from its content of steroid precursors which include free and esterified cholesterol, triglycerides, and phospholipids. The catecholamine-secreting medulla on the other hand is derived from the neural crest and is thus closely related to the sympathetic nervous system and the extra-adrenal paraganglia. Primitive medullary cells develop along two lineages: the chromaffin cells which become phaeochromocytes and neuroblasts which mature into ganglion cells.

At birth the cortex consists predominantly of a wide fetal zone but after several months three clearly defined cortical zones can be identified. The subcapsular zona glomerulosa, which accounts for 10 to 15 per cent of the adult cortex, is the source of mineralocorticoids, the most important of which is aldosterone. The intermediate zona fasiculata which accounts for about 80 per cent of the adult cortex and the inner zona reticularis (5–10 per cent) produce glucocorticoids (predominantly from the zona fasiculata), the most active of which is cortisol, androgens (of which testosterone is the most significant), and small quantities of oestrogens. Cortisol and testosterone secretion is regulated by ACTH whereas aldosterone secretion by the zona glomerulosa is primarily regulated by the renin–angiotensin system and is largely independent of ACTH.

The adrenal medulla is extremely vascular and consists largely of a reticular network of catecholamine-secreting chromaffin cells with a closely related plexus of venous sinusoids intertwined amongst them that facilitates the release of catecholamines into the circulation. The gland has a rich nerve supply derived mainly from the coeliac and renal plexuses. The nerve endings terminate directly on the chromaffin cells which contain numerous electron-dense granules that have a role in the synthesis and storage of catecholamines. The predominant catecholamine produced and stored in the adrenal medulla is, as its name suggests, adrenaline but smaller quantities of noradrenaline are also produced.

Clinical disorders resulting from abnormal adrenocortical function can be considered to be of four types (Table 1) 260. Hypofunction is most often a consequence of iatrogenic suppression or autoimmune destruction of the gland. Hyperfunction results from excessive production of adrenal hormones secondary to a functioning adrenal tumour or more commonly to overproduction of ACTH. Inborn errors of steroid synthesis may produce a mixed clinical picture of hyper- and hypofunction. Finally, non-functioning adrenal masses may present as an incidental finding or with symptoms unrelated to adrenal function.

In this section the various clinical syndromes associated with these disorders will be considered followed by an account of the diagnosis and management of adrenocortical tumours and the management of adrenal masses discovered incidentally during investigation of an unrelated condition.

Congenital adrenal hypoplasia is a rare developmental anomaly which presents in the neonatal period. Two forms are recognized. The anencephalic type is associated with other serious congenital anomalies, usually including anencephaly, and these infants are usually stillborn or do not survive for more than a few days. The cytomegalic type may be genetically determined with a recessive pattern of inheritance and if recognized and treated appropriately with steroid replacement therapy long-term survival may result.

In later life adrenocortical hypofunction can be split into three categories: primary chronic adrenal insufficiency, primary acute adrenal insufficiency, and secondary adrenal insufficiency.

To the surgeon, secondary insufficiency is probably of greatest importance, or at least that most likely to be encountered. It is most frequently due to adrenal suppression resulting from chronic steroid therapy for a variety of conditions including autoimmune diseases or in the recipients of organ transplants. Alternatively it may be encountered following treatment of Cushing's syndrome by adrenalectomy or following removal of a functional adrenal adenoma. Secondary adrenal insufficiency may present with an ‘adrenal crisis’ especially during times of stress such as acute illness or following major surgery, unless adequate precautions are taken to prevent its occurrence (see below).

Primary chronic adrenal insufficiency (Addison's disease) is an uncommon condition which today is usually the result of autoimmune destruction of the adrenal cortex (previously tuberculosis was the most common cause). It is more common in women than men (M : F ratio approximately 3 : 1) and antiadrenocortical antibodies are demonstrable in the majority of cases, particularly in women. It may be associated with other autoimmune conditions and antibodies against the thyroid, parietal cells, or intrinsic factor are commonly found in these patients.

Primary acute hypoadrenalism may occur on a background of chronic adrenal insufficiency, for instance during ‘adrenal crises’ of addisonian patients or following too rapid withdrawal of steroids from patients with suppressed adrenals, or failure to increase replacement steroids in times of stress. More rarely it may be due to massive haemorrhagic adrenal infarction. In neonates, in whom the adrenal is relatively large, this may follow birth trauma and/or hypoxia. In adults, when it is known as Waterhouse-Friederichsen syndrome, it is often related to acute bacteraemic infection, most commonly with the meningococcus, but it may also occur during pneumococcal, staphylococcal, or Haemophilus influenzae infections. It may also occur as a preterminal, agonal, event.

The symptoms and signs of primary and secondary adrenal insufficiency are similar except that primary chronic insufficiency may be associated with abnormal pigmentation, especially in the skin creases, scars, and inside the lips and cheeks. This is a consequence of chronic stimulation of the pituitary and overproduction of ACTH and &bgr;–melanocyte stimulating hormone which stimulate increased pigmentation.

Chronic cortisol deficiency commonly results in weight loss which is often associated with episodes of colicky non-specific abdominal pain, vomiting and diarrhoea, general malaise, and lack of energy and there may be marked postural hypotension. The features of ‘adrenal crises’ due to acute cortisol insufficiency include hypotension, shock, and hyponatraemia often associated with muscle cramps, myalgia, or unexplained fever.

The biochemical characteristics of hypoadrenalism are hyponatraemia, hyperkalaemia, and an elevated blood urea (8–15 mmol/l) all of which may occur in either primary adrenal insufficiency, in which both cortisol and aldosterone are deficient, or secondary insufficiency, where cortisol alone is deficient. These abnormalities tend to be most marked during acute adrenal crises. Proof of the diagnosis is not always easy since normal urinary cortisol excretion may be below the limits of detection and some urinary cortisol may be detected in hypoadrenalism. Likewise plasma cortisol levels in adrenal insufficiency are often in the low-normal range. A high plasma cortisol, however, especially during acute illness, effectively eliminates the diagnosis. Definitive proof of hypoadrenalism usually requires demonstration that the plasma ACTH is disproportionately high compared to plasma cortisol levels or that the adrenal fails to produce a normal secretory response following a challenge with exogenously administered ACTH.

The hypotensive patient with acute adrenal insufficiency requires immediate volume replacement with normal saline solution and steroid replacement, for example hydrocortisone 100 mg intramuscularly or intravenously, which should be administered prior to confirmation of the presumed diagnosis. Improvement should occur within 4 to 6 h if the diagnosis is correct. The patient should then receive regular steroid parenterally, for example hydrocortisone 100 mg intramuscularly or intravenously every 6 h for 2 or 3 days, and may subsequently require oral maintenance steroid replacement.

In primary chronic adrenal insufficiency both cortisol and aldosterone require replacement. This requires the equivalent of about 30 mg of cortisol per day (two-thirds administered in the morning and one-third in the evening) and the mineralocorticoid (for example fludrocortisone) dosage adjusted according to blood pressure and plasma renin. In secondary adrenal insufficiency only cortisol needs to be replaced. Patients should be advised to double the daily glucocorticoid dose during intercurrent illness, for example fever above 38°C, systemic infection, or trauma, and if vomiting occurs for more than 24 h parenteral replacement should be given. Prior to surgery patients should receive replacement therapy as for acute adrenal insufficiency, commencing 1 h before anaesthesia and converting to oral replacement therapy once reliable oral intake has been re-established.

Cushing's syndrome encompasses a group of disorders presenting with the symptoms and signs of exposure to excess glucocorticoids. Since the onset of symptom is usually insidious and the typical picture of the patient with all the features of the syndrome develops slowly, a relatively late clinical diagnosis is common.

Some features are more important than others diagnostically. These include skin atrophy producing skin which is palpably thin and the development of spontaneous purpura due to capillary fragility. Wasting affecting the proximal muscles, especially those of the pelvic girdle, and weakness which may be aggravated by hypokalaemia are also particularly characteristic. Osteoporosis, mainly affecting the axial skeleton and leading to spontaneous fractures of the ribs or vertebrae, and growth arrest in children are also important diagnostic clues. Other features of the syndrome which tend to be of less diagnostic value include central obesity, which predominantly affects the face (‘facial mooning’), neck, and trunk and may contribute to the classical ‘buffalo hump’ appearance (Fig. 1) 791, purple striae, poor wound healing and paper thin scars, facial hirsuitism, acne and plethora, oedema, moderate hypertension, glucose intolerance, amenorrhoea, and psychiatric manifestations such as depressive psychosis.

Any of several underlying conditions of diverse aetiology may lead to Cushing's syndrome. Probably the most common cause today is iatrogenic Cushing's syndrome due to chronic administration of glucocorticoids to organ transplant recipients or patients with immune disorders. Cushing's syndrome due to primary adrenal disease or excessive exposure to ACTH is less common but collectively these conditions are of great importance because of the diagnostic challenge they pose and the potential for curative surgical intervention. Of these cases between 65 and 75 per cent are attributable to an ACTH-secreting pituitary microadenoma which is often referred to as Cushing's disease as a tribute to Harvey Cushing who first described the condition in 1932. A further 10 to 15 per cent are due to ectopic sources of ACTH such as carcinoma of the lung (particularly small cell carcinoma), malignant pancreatic tumours, benign or malignant thymomas or (less commonly) carcinoids, phaeochromocytomas, medullary carcinoma of the thyroid, and rarely other primary carcinomas. Primary adrenal disease such as adenoma, adenocarcinoma, or micronodular adrenal hyperplasia account for the remaining 10 to 20 per cent.

Certain clinical features may give some indication as to the aetiology of Cushing's syndrome. Ectopic ACTH production by a rapidly growing malignant primary tends to produce very high levels of cortisol secretion with rapid development of a Cushing's syndrome in which features such as hypokalaemia and oedema predominate in addition to the clinical features of the primary disease. Cushing's syndrome resulting from ACTH secretion by benign tumours tends to have a more indolent course with gradual development of the clinical manifestations. Malignant tumours of the adrenal cortex may synthesize cortisol inefficiently and this may lead to excessive production of androgen precursors which in turn may produce hirsuitism and virilization, neither of which tends to be features of Cushing's syndrome induced by adrenal adenomas.

Investigation of patients suspected of having Cushing's syndrome is conducted in two phases: confirmatory screening or diagnostic tests followed by investigations to determine the underlying aetiology (Table 2) 261. Probably the most useful screening test for hypercortisolism is the 24-h urinary free (unconjugated) cortisol excretion (the sensitivity and specificity of this investigation are approximately 95 per cent) but raised cortisol excretion may also be seen in obesity, during periods of stress, during pregnancy, or if oral contraceptives are being taken. The level of steroid over-production may also give some guidance to the aetiology. Levels of more than 5000 nmol/day are commonly found in Cushing's syndrome due to ectopic ACTH or adrenal carcinoma but only rarely in other cases. Urinary 17-hydroxysteroid and 17-ketosteroid excretion reflects basal cortisol production but is less discriminating than free cortisol excretion and there is greater overlap with normal subjects. Plasma cortisol levels are more difficult to interpret because under normal circumstances there is great variability. However, loss of the normal diurnal variation with failure of the plasma cortisol level to fall at night is a useful and constant feature of Cushing's syndrome. Elevation of the midnight plasma cortisol is a sensitive test but it may also occur during pregnancy, stress, or in subjects taking oral contraceptives. A somewhat more definitive test for Cushing's syndrome depends upon the relative resistance to suppression by exogenous steroids. Dexamethasone is a potent steroid which normally suppresses pituitary derived ACTH and thus lowers plasma cortisol but in subjects with Cushing's syndrome suppression of cortisol secretion is resistant to low doses of dexamethasone and urinary excretion of 17-hydroxysteroids remains elevated. The single dose (overnight) dexamethasone suppression test, in which the morning plasma cortisol is measured after administration of 1 to 2 mg of dexamethasone at midnight, is associated with a low false-negative rate but a false-positive result may occur in the obese patient, in subjects taking oestrogens or phenytoin, or in the chronically ill. The so-called low-dose dexamethasone suppression test in which 24-h urinary 17-hydroxysteroids are measured during administration of 0.5 mg of dexamethasone 6-hourly may be more reliable.

The high-dose dexamethasone suppression test, in which 2 mg of dexamethasone is administered 6-hourly for 2 days and the 24 h urinary 17-hydroxysteroid excretion is measured during the second day, has been used to determine the underlying aetiology of Cushing's syndrome. In nearly all patients with Cushing's disease the 17-hydroxysteroid excretion is suppressed to less than 40 per cent of the baseline measurements but nearly all patients with adrenal tumours, most with adrenal hyperplasia and all with an ectopic ACTH source fail to show suppression. However, since suppressibility with dexamethasone is a matter of degree and subject to errors induced by natural biological variability, other, more reliable, diagnostic tests have tended to supersede the dexamethasone suppression tests. Determination of the plasma ACTH by radioimmunoassay of blood samples taken in the morning, when ACTH is usually detectable in normal subjects, is the most useful investigation for determining the cause of Cushing's syndrome. In primary adrenal disease the levels are undetectable (except occasionally in patients with micronodular adrenal hyperplasia in whom ACTH may be normal) whereas in Cushing's syndrome due to pituitary ACTH production the level is almost always elevated or normal. In cases of ectopic ACTH secretion plasma ACTH levels are always elevated and levels greater than 200 pg/l are virtually diagnostic. Note however that following adrenal ablation ACTH levels may be grossly elevated and this may be associated with Nelson's syndrome (see below).

Metyrapone is also useful in the determination of the aetiology of Cushing's syndrome. Metyrapone inhibits adrenal 11&bgr;-hydroxylation of 11-deoxycortisol to cortisol and thus leads to reduced cortisol secretion and a rise in ACTH and production and excretion of cortisol precursors. In cases due to primary adrenal adenoma, adrenal carcinoma, or ectopic ACTH production the pituitary is suppressed and no rise in ACTH or cortisol precursors occurs following administration of metyrapone but in 90 per cent of cases of Cushing's disease the pituitary does respond by increasing ACTH production.

Diagnostic imaging and treatment of pituitary microadenomas is dealt with in detail elsewhere and will therefore be considered only briefly here. Untreated Cushing's disease commonly leads to death due to the complications of excessive exposure to cortisol including hypertension, stroke, and ischaemic heart disease. Although spontaneous remission has been documented this is an exception rather than the rule and therefore surgical treatment is generally recommended.

In the past permanent relief of hypercortisolism was achieved by total adrenalectomy but this was associated with a high operative morbidity and mortality, mainly as a consequence of chronic excessive exposure to steroids, and left the individual dependent upon life-long replacement therapy. Furthermore many patients developed very high ACTH levels, enlarged pituitary glands, and hyperpigmentation (Nelson's syndrome) often necessitating pituitary ablation. Today total adrenalectomy is reserved for the occasional patient in whom the pituitary lesion cannot be treated directly by surgical removal or irradiation.

In Cushing's syndrome secondary to ectopic ACTH secretion the ACTH secreting tumour should be sought and if possible removed. In the case of benign tumours, for example thymomas and some carcinoids, this may effect a surgical cure. When it is not possible to remove the source of the ACTH excessive cortisol secretion can usually be controlled with adrenolytic drugs such as metyrapone or aminoglutethimide which inhibits the conversion of cholesterol to &Dgr;5-pregnenolone, thereby inhibiting production of cortisol, mineralocorticoids, and androgens. Occasionally surgical adrenalectomy may be considered if the ACTH source cannot be removed and the patient would otherwise have a good prognosis following relief of the hypercortisolism.

Primary aldosteronism most commonly results from excessive and autonomous secretion of aldosterone by an adenoma of the adrenal cortex (Fig. 2) 792 but less commonly may be due to bilateral micronodular hyperplasia involving the zona glomerulosa. Although the aetiology of the latter is unknown it has been suggested that it may represent tertiary aldosteronism, in which excessive renin secretion (subsequently suppressed) was the original stimulus, but this remains entirely hypothetical.

In 1955 Conn was the first to describe a patient with hypertension, neuromuscular symptoms, and renal potassium wastage which was associated with elevated aldosterone secretion and an adrenocortical adenoma. Excessive secretion of aldosterone produces hypertension, predominantly as a result of intravascular volume expansion secondary to aldosterone-induced salt and water retention, but as a primary cause of hypertension it is rare, and accounts for less than 0.5 per cent of cases. Primary aldosteronism is most commonly suspected when hypokalaemia is associated with alkalosis in the presence of hypertension but it must be distinguished from other (more common) causes of hypokalaemia associated with hypertension, particularly that induced by loop or thiazide diuretics, and by renin-induced secondary hyperaldosteronism. The latter is seen in hypertension due to renovascular disease and in severe essential hypertension. Primary aldosteronism without hypokalaemia is uncommon. Patients presenting with hypertension in whom studies to exclude Conn's syndrome should be undertaken include those with spontaneous hypokalaemia (<3.5 mmol/l), moderately severe hypokalaemia (<3.0 mmol/l) while taking diuretics or difficulty maintaining a normal potassium despite oral supplements or potassium sparing diuretics, and patients with hypertension refractory to treatment with no specific evidence of a secondary cause.

Confirmation of suspected primary aldosteronism can sometimes be difficult but most often the diagnosis is easily established by demonstrating elevated plasma aldosterone, or increased urinary excretion of aldosterone, despite adequate salt loading (confirmed by measurement of urinary sodium excretion) over several days. Hypokalaemia, inappropriate kaliuresis, and depressed plasma renin activity that fails to rise in response to salt and water depletion or the upright posture are supportive features but their absence does not exclude the diagnosis. In primary aldosteronism the plasma sodium is usually normal or elevated whereas, in contrast, hyponatraemia is often a feature of secondary aldosteronism. If the diagnostic tests are equivocal multiple measurements of aldosterone during salt loading may be needed.

It is important to distinguish between adrenal hyperplasia and an adenoma since the treatment of each condition differs. An adenoma is said to produce more pronounced biochemical abnormalities (higher aldosterone, and lower renin and potassium) than does hyperplasia but this is of little value in distinguishing the two and diagnostic imaging is required. Large adenomas (greater than 1 cm in diameter) may be detected reliably by computed tomography (CT) (Fig. 3) 793 or magnetic resonance imaging (MRI) but since these investigations provide little or no information regarding the function of any abnormal tissue detected radionuclide imaging or selective venous sampling may be required to distinguish an adenoma from hyperplasia. Selective adrenal sampling for aldosterone and cortisol levels is an extremely valuable test in confirming the diagnosis and localizing a tumour. The cortisol levels allow the validity of the adrenal vein sampling to be established in comparison with peripheral samples (see adrenocortical tumours below).

Primary aldosteronism due to an adenoma is treated by surgical excision (adrenalectomy) once the hypertension and hypokalaemia have been corrected with spironolactone or amiloride. Surgical treatment of micronodular hyperplasia is much less satisfactory and the treatment of choice is long-term control with spironolactone or amiloride.

In children, virilizing tumours may present with precocious puberty, phallic enlargement, and development of secondary hair growth on the face, axillae, and pubes and the differential diagnosis includes congenital adrenal hyperplasia (see below), idiopathic hirsuitism, and other causes of precocious puberty. In the adult female, virilizing tumours present with deepening of the voice, hirsuitism, amenorrhoea, enlargement of the clitoris, increase in muscle bulk, and increased libido whereas, in the adult male, they may be relatively silent and may only be recognized as an incidental finding or, if malignant, by the development of metastases.

Virilizing adrenal tumours are most commonly diagnosed by finding an enlarged adrenal or adrenal mass on CT scan in association with appropriate biochemical abnormalities. Both adrenal and gonadal causes of virilization produce increased plasma androgens but elevated dehydroepiandrosterone (DHEA) which is secreted almost exclusively by the adrenal gland, suggests an adrenal cause for virilization. DHEA may also be elevated in some cases of idiopathic hirsuitism but this may be distinguished from an adrenal tumour biochemically by the dexamethasone suppression test: 17-ketosteroid secretion is not normally suppressed in cases due to adrenal tumours. In adrenocortical carcinoma producing virilization plasma DHEA and 17-ketosteroid levels tend to be very high.

Feminizing tumours are very rare and are almost always malignant. In men they may present with gynaecomastia and impotence before they have metastasized and curative resection may be possible but in women they tend to be advanced when first detected.

This is a family of genetically controlled congenital disorders which have in common a complete or partial defect in the control of steroid biosynthesis producing elevated ACTH, excessive production of androgens and/or mineralocorticoids, and striking enlargement of the adrenals which reach 10 to 20 times their normal weight. Inheritance is by recessive genes with variable penetrance and the incidence is between 1 : 10 000 and 1 : 50 000 live births. Any one of several enzyme defects may be responsible but the most common is 21-hydroxylase deficiency in which cortisol and aldosterone production is defective and excessive secretion of pituitary ACTH results in high levels of adrenal androgen production that may produce virilization at birth or sexual precocity in males. Less commonly an 11&bgr;-hydroxylase deficit produces excess 11-deoxycortisol, a cortisol precursor with mineralocorticoid activity, which may produce hypertension in addition to increased androgen secretion. Other, less common, defects include 17-hydroxylase deficiency, 18-hydroxylase deficiency, and 3&bgr;-hydroxysteroid dehydrogenase deficiency.

There is a wide spectrum of clinical presentations but the diagnosis should be suspected in babies or children with abnormal genitalia (for example cryptorchidism, hypospadias, or ambiguous genitalia), clitoromegaly with or without pubic hair development in the female, or precocious puberty in the male or in children with hypertension. A family history of neonatal deaths, or siblings with hirsuitism or congenital adrenal hyperplasia helps to identify individuals with a relatively high risk.

The diagnosis is confirmed by laboratory investigations including 24-h urinary oxogenic- and oxosteroids and plasma cortisol (which maybe normal), ACTH, testosterone, and 17&agr;-hydroxyprogesterone. Treatment is directed at correcting metabolic abnormalities (for example salt deficiency) followed by replacement of mineralocorticoid and cortisol, to suppress ACTH and reduce androgen overproduction. This should allow for emergence of normal gonadotriphic function at puberty and permit normal growth. Surgery for cryptorchidism or genital abnormalities may be required, often as staged procedures, and the perioperative period should be covered with increased steroid replacement as for adrenal insufficiency.

Clinically detected adrenocortical neoplasms are roughly equally divided between benign and malignant. Most benign tumours secrete either glucocorticoids, mineralocorticoids, androgens, or oestrogens but, in contrast, carcinomas of the adrenal secrete large amounts of various biologically active and inactive steroids such that about half of them produce clinical features attributable to steroid secretion. Cushing's syndrome is the most common clinical presentation of adrenocortical tumours but they may also present with aldosteronism, virilization, or very rarely feminization. A mixed picture is characteristic of adrenocortical carcinoma and reflects the spectrum of steroids and biologically active steroid precursors produced by the tumour.

Following biochemical confirmation of a clinically suspected functional adrenal tumour localization and staging is required before planning surgical intervention. CT, the most commonly used imaging modality in the assessment of adrenal pathology, can identify almost all lesions greater than 1 cm in diameter and it has largely replaced investigations such as intravenous pyelography, retroperitoneal pneumography, nephrotomography, selective arteriography, or selective venography. Although CT is sensitive it is not specific and cannot, for instance, distinguish between adenoma, carcinoma, lymphoma, or haematoma. A CT scan may detect evidence of local invasion of the kidney or other adjacent structures and it may also demonstrate lymph node or liver metastases. Tumours more than 6 cm in diameter as assessed by CT should be suspected of malignancy and in these cases selective arteriography or venography may be useful to determine the degree to which local structures have been invaded, information which may be crucial in determining whether or not the tumour is operable. MRI is as sensitive as CT for detecting adrenal lesions but, in addition, it has been claimed that MRI may be capable of distinguishing an adrenal metastasis, carcinoma, or phaeochromocytoma from an adenoma, lipoma, or myelolipoma on the basis of tissue imaging characteristics but it remains unclear whether this claim can be substantiated. MRI does, however, demonstrate the relationship of adrenal pathology to adjacent vascular structures more clearly than CT and has therefore proved to be useful in the assessment of the local extent of suspected malignant tumours. CT and MRI should be treated as complementary investigations.

Isotope scans provide both anatomical and functional information and may be a useful adjunct to CT or MRI. In Cushing's syndrome the pattern of uptake of ¹³¹I–6&bgr;-iodomethyl–19-norcholesterol (NP59) is dependent upon the underlying aetiology. Four distinct patterns are recognized. Lateralized increased uptake with non-visualization of the other side is virtually pathognomonic of an adrenocortical adenoma. However, there have been several reports of well differentiated cortisol secreting adrenocortical carcinomas which demonstrated intense uptake of NP59 and were initially thought to be benign on the basis of the NP59 scan. Adrenocortical carcinomas are usually unable to incorporate enough NP59 to be visualized by NP59 scintigraphy because of inefficient production of cortisol, and since pituitary ACTH is suppressed by the excessive cortisol production the contralateral gland is also suppressed, resulting in bilateral non-visualization. Thus, bilateral non-visualization in the presence of Cushing's syndrome is considered to be diagnostic of carcinoma. Androgen or oestrogen secreting tumours do not usually suppress ACTH and in these cases the pattern is one of bilateral uptake with marked asymmetry since the tumour itself is not visualized but the remainder of the ipsilateral gland and the entire contralateral gland are. In contrast, in Cushing's syndrome due to pituitary or ectopic ACTH the uptake is increased bilaterally and symmetrically. Micronodular hyperplasia of the adrenal may produce asymmetric bilateral increased uptake.

In primary aldosteronism radionuclide imaging, using radiolabelled cholesterol during dexamethasone suppression of cortisol secretion, can be used to detect functional tissue and may detect tumours as small as 5 mm in diameter. Selective adrenal vein catheterization and measurement of aldosterone on each side should reveal unilateral increased secretion with suppression of the other side if a functional adenoma is present but bilaterally increased secretion if aldosteronism is due to hyperplasia or is secondary to increased renin secretion. When radionuclide imaging is combined with selective adrenal vein catheterization a clear distinction between adenoma and hyperplasia should be achieved in most cases. Occasionally, however, a case for diagnostic surgical exploration can be made.

The preferred treatment for a functioning adrenocortical adenoma is surgical excision because the results of surgery are generally good and often produce a complete cure. Most adenomas coming to surgery are less than 4 cm in diameter and in selected cases it may be possible to preserve uninvolved adrenal tissue. Operations to resect adrenal adenomas causing Cushing's syndrome usually have excellent results but in the long term many patients remain obese and hypertensive. Surgical intervention in this group is, however, associated with a relatively high morbidity because of chronic exposure to excess glucocorticoids specifically resulting in poor wound healing, increased risk of infection, and a relatively high risk of pulmonary thromboembolism. Perioperative glucocorticoid supplementation is required because of chronic suppression of the contralateral gland and this must be continued, with graduated dosage reduction, for several months.

Following surgical removal of an aldosterone-producing adenoma the hypertension is cured in 70 to 80 per cent of cases and in the remainder surgery usually renders the hypertension more responsive to medical therapy. Several weeks before operation hypertension and metabolic abnormalities should be corrected medically. The hypertension is salt and water dependent and is best treated by sodium deprivation and potassium sparing diuretics. Postoperatively there may be a sodium diuresis and retention of potassium and close monitoring of plasma electrolytes is required in the first week. In some cases suppression of the contralateral gland results in postoperative aldosterone deficiency which may produce hyponatraemia with hyperkalaemia necessitating mineralocorticoid replacement until the remaining gland recovers.

Carcinoma of the adrenal cortex is usually highly aggressive and has a poor prognosis. Fortunately it is a rare tumour with an incidence of about 1 per 1.5 × 10&sup6; population per year. It can occur in all age groups but most commonly presents in the fifth to seventh decades and it occurs roughly equally in both sexes.

The tumour may attain a very large size (>20 cm) and overall the median size at presentation is about 10 to 12 cm but relatively few (<10 per cent) are less than 6 cm at presentation. Traditionally adrenocortical carcinomas are classified as functioning or non-functioning. Non-functioning tumours fail to produce clinical evidence of steroid synthesis but in most cases detailed studies indicate that these tumours do produce precursor steroids with little or no biological activity. The non-functioning tumours, which account for about 50 per cent of all carcinomas, often attain a very large size before detection and frequently present as an abdominal mass or with abdominal pain, weight loss, or fatigue. In some cases haemorrhagic necrosis of a large tumour may result in severe pain, fever, and even shock.

Functioning tumours may also be large at presentation because of inefficient steroid production by the malignant tissue and therefore relatively late development of endocrine manifestations. Commonly they present with symptoms and signs of cortisol, androgen, or oestrogen excess, often with a mixed picture, but clinical evidence of aldosterone excess is rarely a presenting feature and exclusive production of aldosterone by the tumour is very rare. Metastases to the local lymph nodes, liver, lungs, or less commonly bone are found in 70 to 75 per cent of patients at presentation and these may produce the initial manifestations of the disease.

Adrenocortical carcinomas usually appear lobulated and encapsulated and they frequently erode through their capsule and invade local structures such as the pancreas, kidney, and bowel. On cutting, areas of haemorrhagic necrosis are commonly found. Histologically it can be difficult to distinguish between a benign adenoma and a well differentiated carcinoma on the basis of cellular characteristics alone and it is often necessary to fall back upon the presence of local invasion and metastases as hallmarks of malignancy to make the diagnosis. The cellular DNA content may be useful diagnostically in that at least one study suggests that aneuploid tumours metastasize whereas euploid tumours do not. As CT-guided percutaneous fine-needle aspiration cytology is used more frequently in the assessment of adrenal masses, incorporating measurement of the DNA content may prove to be a powerful diagnostic approach.

Surgical eradication of the tumour offers the only chance of cure but even if complete resection is not possible because of invasion of vital structures, debulking of the tumour is important for palliation especially if the tumour is functional. In patients without demonstrable remote metastases a radical approach is generally advocated. Adrenocortical carcinomas are approached by a transabdominal or thoracoabdominal route and the tumour and adjacent involved organs are excised en bloc. In some cases even involvement of the inferior vena cava may not prevent complete resection provided the facilities for cardiopulmonary bypass are available. Lymph node metastases are excised with the tumour and liver metastases accessible for wedge resection should be removed. The operation must be covered with perioperative steroid replacement but in the case of non-functioning tumours this can be tapered relatively quickly over the first 1 to 2 weeks after the operation.

Chemotherapy may be used for inoperable or recurrent carcinomas or as an adjuvant to maintain remission following apparently complete excision. The agent with which there is the greatest accumulated experience in the treatment of these tumours is mitotane (o,p'-DDD), a derivative of DDT which produces selective necrosis of the zona fasiculata and zona reticularis. The effectiveness of mitotane is dependent upon the bulk of the tumour present and it is therefore important that surgical debulking is followed by early postoperative chemotherapy. Cortisol replacement therapy is invariably required and in some patients mineralocorticoid deficiency may also require treatment.

The clinical response to mitotane is rather variable and the side-effects (nausea, anorexia, neurotoxicity, ataxia, papilloedema, skin rashes, and cystitis) may lead to poor patient acceptance. However, the alternatives are limited as there is relatively little experience with other agents even though short-term responses to alkylating agents and doxorubicin have been reported. Treatments to reduce steroid production with aminoglutethimide or metyrapone may afford significant palliation but they do not produce tumour regression. Radiotherapy has not been systematically examined in the treatment of adrenocortical carcinoma but it has never been shown to be effective as a primary treatment or as an adjuvant for residual disease. However, it does appear to be effective for the relief of pain from bony metastases.

The prognosis correlates with the size of the tumour and the functional status, but overall the outlook is poor. Patients presenting with anaplastic tumours without laboratory evidence of steroid production have a median survival of about 6 months and the response to therapy is very poor. Differentiated carcinomas with hormone production are associated with a greater median survival (about 2 years) and in about 50 per cent there is objective evidence of a response to chemotherapy. Even in cases where surgical excision has been apparently curative long-term follow-up is required because late recurrence may occur.

With wide application of sensitive non-invasive imaging of the abdomen the detection of an adrenal mass as an incidental finding during investigation for an unrelated condition has become an increasingly common clinical problem. For example, it has been estimated that approximately 1 per cent of upper abdominal CT scans performed for a variety of reasons will detect a clinically silent adrenal lesion. Although most solid lesions will be found to be non-functioning cortical adenomas they all require careful evaluation directed towards ruling out malignancy and detecting functional tumours which require excision. Other conditions such as myelolipoma may remain clinically silent, producing neither symptoms nor signs, but occasionally complications, such as bleeding into a cyst, may bring them to clinical attention.

The CT appearance may be diagnostic. Simple cysts, myelolipomas, and adrenal haematomas can usually be identified and managed appropriately on the basis of the CT image alone. Most cystic masses are benign endothelial-lined (lymphangiomatous or angiomatous) cysts or pseudocysts secondary to haemorrhage into a normal adrenal. Occasionally, however, cortical adenomas, adenocarcinomas, or phaeochromocytomas may undergo cystic degeneration. Following biochemical evaluation cystic masses should be aspirated, under ultrasonic or CT guidance, and the aspirate sent for cytological evaluation to confirm their benign nature. Suspicion of malignancy is an indication for operation. Adrenal haemorrhage may result from bleeding into an adrenal tumour and it should therefore be followed by a repeat CT scan.

Rarely the CT appearances will be diagnostic of primary adrenal carcinoma on the basis of size, lack of homogeneity, irregular borders, local infiltration, and evidence of metastases. Primary adrenal carcinomas are rarely found to be less than 6 cm in diameter and it has been estimated that in the absence of CT characteristics suggestive of malignancy fewer than 1 in 10 000 incidentally discovered lesions below 6 cm in diameter will be adrenocortical carcinomas. The likelihood that solid lesions 6 cm or more in diameter will be malignant is more difficult to estimate but it is probably in excess of 30 per cent. Metastatic carcinoma of the adrenal is also very uncommon but in the presence of a known primary malignancy elsewhere this becomes the most likely explanation for an incidentally detected solid adrenal lesion.

Careful clinical assessment is required to detect evidence of clinical or subclinical function but it is debated whether extensive biochemical evaluation is required in all cases. According to Ross and Aron, in the absence of certain clinical features of a functional tumour, biochemical exclusion of the diagnosis is unnecessary. For instance, virtually all patients with primary hyperaldosteronism have hypertension and in its absence biochemical exclusion is not required. Furthermore in hypertensive patients with an incidentally discovered adrenal mass the absence of spontaneous hypokalaemia has a 95 per cent negative predictive value for an aldosterone-producing adenoma and further biochemical exclusion is therefore not required. It is reasonable then to limit the initial studies directed towards the exclusion of function to plasma potassium, and 24-h urinary cortisol, catecholamine, and vanillylmandelic acid (VMA) excretion unless specific clinical evidence of function is present. In doubtful cases isotope scans such as NP59 and ¹³¹I-MIBG * 4 scans may also help to distinguish truly non-functional tumours from those with subclinical function. Evidence of hormone hypersecretion is an indication for operation.

The management of solid masses is controversial. It seems generally agreed that tumours 6 cm or more in diameter should be resected because they carry a high risk of malignancy and most surgeons would also agree that tumours less then 3 cm in diameter without biochemical evidence of function or any identifiable features of malignancy may be observed by CT. Evidence of growth should be an indication for operation but if they remain unchanged after repeated studies they are most likely to be benign, since carcinomas proliferate rapidly, and further studies are unnecessary. For tumours between 3 and 6 cm some surgeons advocate routine resection or selective resection based upon patient age (<60 years for example) and operative risk but this policy involves high morbidity and expense with few patients benefiting from an earlier diagnosis of malignancy and it has not found general acceptance. Others routinely observe by repeated CT scans since the risk of malignancy is low and adenomas are not known to become malignant. MRI may help to distinguish adrenal metastases, phaeochromocytomas, and carcinomas from adrenal adenomas, lipomas, and cysts depending upon differences in signal intensities and may thus be helpful in determining whether operation should be advised. There is little evidence that MRI substantially improves diagnostic accuracy but it does increase the costs of investigation. One scheme for the management of ‘incidentalomas’ is presented in Fig. 4 794.

The clinically important disorders of the adrenal medulla are tumours; the most important of these are neuroblastomas and phaeochromocytomas.

Neuroblastomas occur almost exclusively in children and are the most common malignant tumours in neonates and infants less than 1 year old. The overall incidence is approximately 8 per million population per year with 50 per cent presenting within the first 2 years of life and about 75 per cent in the first 5 years. They arise from the neuroblasts of the adrenal medulla in roughly 50 per cent of cases or from the prevertebral or paravertebral ganglia from the neck to the pelvis.

The tumours have a variable appearance and may be irregular or nodular and range in size from 3 to 4 cm to massive retroperitoneal masses. They are very vascular, friable tumours and areas of haemorrhage, necrosis, and calcification are commonly found in larger examples. They tend to invade their capsule early and then infiltrate along tissue planes and perineural pathways. Frequently, however, the plane between an adrenal neuroblastoma and the kidney parenchyma remains intact and although structures such as the ureters, major vessels, and gut are often surrounded by tumour the lumen is rarely invaded. Neuroblastomas metastasize early to the prevertebral lymph nodes and by haematogenous spread to bone, bone marrow, and liver but pulmonary metastases are relatively rare. A peculiarity is that the bony orbit is frequently involved and this may produce proptosis and ‘bruising’ around the orbit.

A neuroblastoma may present with a wide range of symptoms and signs related to the varied sites of the primary and metastases. Abdominal pain may be a presenting symptom but it is often vague and difficult to assess in children. Sudden recognition of an abdominal mass, which is usually firm to hard, knobbly and irregular, and not particularly tender, is probably the most common mode of presentation. Some tumours produce biologically active peptides, for example VIP, which produce specific symptom clusters. The so called ‘dumbbell’ tumours may produce paralysis or other neurological signs in the lower limbs as a result of spinal cord compression or invasion. Metastases are present in over 50 per cent of cases at presentation and may produce symptoms including bone pain, or respiratory distress secondary to massive hepatomegaly.

Most tumours produce catecholamines and in 85 to 90 per cent of cases abnormal levels of urinary catecholamines or their metabolites may be detected. It should be noted however that benign ganglioneuromas can also raise the urinary catecholamine excretion. There are several serum tumour markers of neuroblastoma which may be particularly useful for monitoring disease activity. Neurone-specific enolase (NSE) is elevated in 95 per cent of cases with metastatic disease but only rarely so if the disease is localized, and high serum levels of the ganglioside Gd&sub2;, which is expressed by virtually all neuroblastomas, are associated with active and advanced disease.

In investigation and staging of the tumour the minimum set of investigations should include liver and renal function tests, a chest radiograph and skeletal survey with orbital views, a bone scan, CT of the abdomen and pelvis, and a bone marrow aspirate. CT is highly sensitive for abdominal masses and demonstration of lymph node involvement. MRI defines vessel encasement better than CT and provides superior imaging of the vertebral canal in the assessment of ‘dumbbell’ tumours. ¹³¹I-MIBG scanning is also highly sensitive and is especially useful in the demonstration of metastases or recurrent tumour.

The prognosis in this condition is well known to be related to age and stage at presentation but other prognostic variables related to tumour biology have also been identified (Table 3) 262. Tumours presenting in infancy have a relatively good prognosis even if they are relatively advanced and it is well documented that small tumours presenting during the first year of life have a fairly high incidence of spontaneous regression or maturation into a benign ganglioneuroma. Several staging systems have been used and that proposed by Evans in 1971 is perhaps the most widely used. However, this does not take into account the feasibility of surgical excision and more recently an international staging system for neuroblastoma (INSS) has been proposed which combines the Evans staging system and the results of surgical excision (Table 4) 263. At all ages, stages I and II have a good prognosis and in infancy even stage III or IV disease is relatively favourable.

It is now recognized that up to 80 per cent of these tumours are associated with chromosomal abnormalities which have a bearing on the prognosis. Abnormalities of chromosome 1p are relatively common and associated with a relatively poor outcome. A single copy of the oncogene N- myc is normally present on the short arm of chromosome 2 but in many patients with a poor prognosis the N- myc gene appears to have been translocated to chromosome 1 and amplified resulting in the observed chromosome 1 abnormalities and high levels of the proteins encoded by N- myc. N- myc amplification and/or overexpression is found in more than 50 per cent of patients with advanced disease but rarely in those with stage I or II disease or special stage IV (stage IVs). In contrast to other tumours, in which an abnormal cellular DNA content is often associated with a poor outcome, in neuroblastomas hyperploidy is a favourable marker. Poorly differentiated tumours, especially those said to be stroma-poor and those with abnormal nuclear morphology, have a poor prognosis as do those with evidence of immature catecholamine synthesis as indicated by a high urinary homovanillic acid (HVA) to VMA ratio.

Treatment of a neuroblastoma usually requires a combined approach by surgeons and oncologists which is well planned and co-ordinated. Total surgical removal of localized disease is the most favourable outcome but when incomplete removal only is possible the tumour must be controlled with chemotherapy or radiotherapy. In disseminated disease surgery may initially be limited to establishing the diagnosis through biopsy of the primary and or metastases, although this may also be achieved by needle core biopsy. Delayed surgery may then be undertaken to assess the effectiveness of chemotherapy or radiotherapy and to excise residual tumour.

Chemotherapy seems to have made little impact upon advanced disease in older children even though cyclophosphamide, cis-platinum, doxorubicin, and tenopside have each been shown to produce complete or partial response rates of 35 to 45 per cent and some multidrug regimens have been curative in some patients with non-resectable localized disease. This is particularly disappointing given the dramatic results in the treatment of nephroblastoma and other tumours of childhood.

The use of radiotherapy has declined in recent times and currently it is used as primary therapy in combination with chemotherapy treatment of regional lymph nodes in infants or it may be used for bone marrow ablation in preparation for autologous bone marrow transplantation. In disseminated disease radiotherapy is effective for pain control, particularly that from bony metastases, and for reducing the size of troublesome metastases.

Overall more than 90 per cent of patients who fall into the good prognostic group (stages I and II and, if in infancy, stage III) can be cured whether or not there is residual disease following surgery or lymph node involvement. In groups with an intermediate prognosis (infants with stage IV, or older children with stage III disease) about 75 per cent respond to combined surgery, chemotherapy, and radiotherapy and more than 50 per cent survive disease free. Children over the age of 1 year with stage IV disease have a less than 20 per cent chance of survival despite multimodality therapy.

Phaeochromocytomas are uncommon tumours of the chromaffin cells that secrete excessive quantities of catecholamines into the circulation. They are named from the Greek phaeos (dusky) and chromos (colour) for the dark brown staining of the tumour cells with chromium salts. Their incidence is approximately 1.5 to 2 per million population per year and although most commonly presenting between the ages of 20 and 50 years they may present at any age and they occur with roughly equal frequency in both sexes. Their importance, apart from the risk of malignancy, is that they cause secondary hypertension which if diagnosed early may be cured by surgery but if left untreated may produce serious and sometimes lethal complications. Unfortunately, up to one-third of cases are not diagnosed during life and in many of these cases death is associated with general anaesthesia for an unrelated procedure.

Phaeochromocytomas may be found anywhere from the neck to the pelvis, in the distribution of the neural crest-derived sympathetic/adrenal system. However, 80 to 90 per cent arise in the adrenal medulla and most extra-adrenal tumours (also known as paragangliomas) are intra-abdominal and arise in the region of the aortic bifurcation from the organ of Zuckerkandl. Overall only about 3 per cent of phaeochromocytomas are extra-abdominal and most of these are found in the paravertebral region in the chest but very rarely they may arise in the neck from the cervical ganglia.

The tumour may range in size from a few millimetres to a large cystic mass weighing approximately 3 kg but most tumours weigh less than 100 g, are between 3 and 5 cm in diameter, and are roughly spherical in shape. About 10 to 20 per cent are bilateral and this is more common in the familial varieties. Overall, 5 to 10 per cent are malignant and this is also more likely in familial phaeochromocytomas. In children phaeochromocytomas are less frequently malignant but a greater proportion are extra-adrenal, more are bilateral or multiple, and there is a greater chance of familial disease or an association with multiple endocrine neoplasia (MEN) syndromes.

Overall, between 10 and 20 per cent of phaeochromocytomas are familial and may be associated with some well known syndromes. These cases are more likely to present in childhood and are frequently (>50 per cent) multiple, or bilateral. In some, there is just a simple familial predisposition with an autosomal dominant pattern of inheritance without other associations. Others are associated with Sipple's syndrome also known as MEN type IIa (phaeochromocytoma, medullary carcinoma of the thyroid and C cell hyperplasia, and parathyroid hyperplasia or adenoma) or with MEN type IIb (phaeochromocytoma, medullary carcinoma of the thyroid and C cell hyperplasia, mucosal neuromata, and marfanoid features) both of which have an autosomal dominant pattern of inheritance. Approximately 5 per cent of patients with phaeochromocytoma have neurofibromatosis (von Recklinghausen's syndrome) that may be familial or sporadic but relatively few patients (approximately 1 per cent) with neurofibromatosis develop a phaeochromocytoma.

Phaeochromocytomas can present in many ways and this, combined with their relative rarity, explains why the diagnosis is often missed. Hypertension, which is commonly episodic, is the most consistent feature and is present in more than 90 per cent of cases. Two patterns are recognized: sustained hypertension with or without episodic rises which occurs in about 50 per cent of adults with phaeochromocytoma and paroxysmal attacks with normal blood pressure during the intervals. Most commonly both the systolic and diastolic pressures are elevated but if adrenaline is the major secretory product systolic hypertension and tachycardia may be associated with a normal or low diastolic pressure. A consistently normal blood pressure in the presence of a functioning tumour occurs in approximately 10 per cent of cases. It is not cost effective to screen all patients with hypertension since less than 1 per cent will have a phaeochromocytoma but hypertension in association with one or more of the other clinical features of phaeochromocytoma, or hypertension in children or young adults, should lead to appropriate screening tests.

The triad of headache, often sudden in onset and described as pounding, sweating, and tachycardia in a patient with hypertension is said to have high sensitivity and specificity (each in excess of 90 per cent) for phaeochromocytoma. Tremor, palpitations, and feelings of apprehension or anxiety are also common and the episodes may be associated with facial pallor or a mottled appearance to the skin. Attacks may occur several times per day or as infrequently as once a week. Most are short lived, lasting from 15 min to 1 h, and may be followed by feelings of exhaustion, weakness, and muscle aches. Various precipitating factors have been described which are often associated with a change in pressure on the tumour. In the case of abdominal phaeochromocytomas, straining at stool, lying in a particular position, bending over, or abdominal palpation have all been described as precipitating factors. Some drugs, for example metoclopramide, tricyclic antidepressants, or naloxone may precipitate dangerous hypertensive crises.

Other cardiovascular abnormalities are common and may be the first manifestation of a phaeochromocytoma. Patients may present with symptoms and signs of acute myocardial infarction, with myocarditis, with pulmonary oedema, or with arrhythmias that may be precipitated by anaesthesia, for unrelated surgery. Cardiovascular crises under anaesthesia especially, unexplained hypertension, tachycardia, oedema, or shock, should lead to performance of screening tests for phaeochromocytoma.

Neurological or psychiatric symptoms may also be presenting features as may strokes or seizures due to hypertension. Diabetes, due to the anti-insulin effect of catecholamines, and other endocrine abnormalities may occasionally dominate the clinical picture. Some phaeochromocytomas secrete parathyroid hormone, ACTH, or other biologically active peptides (for example VIP) each of which may produce an appropriate cluster of symptoms and signs. Some patients present with acute abdominal pain which is thought to be due to bowel ischaemia. Occasionally, however, abdominal pain may be due to haemorrhagic necrosis of the tumour which may precipitate marked hypertension followed by hypotension, shock, and even death as a consequence of sudden withdrawal of catecholamines resulting in arterial and venous dilatation in the presence of a shrunken intravascular volume.

Physical signs of phaeochromocytoma other than hypertension are relatively uncommon. In approximately 50 per cent of cases, hypertension is associated with postural hypotension that is probably a consequence of impaired orthostatic autonomic reflexes resulting from chronic overexposure to catecholamines. A large phaeochromocytoma may be palpable as an abdominal mass. Café-au-lait patches and neurofibromata may be associated with phaeochromocytoma and the thyroid should be examined for carcinoma.

The most useful diagnostic tests for phaeochromocytoma are measurement of 24-h urinary excretion of noradrenaline, adrenaline, and their metabolites (normetadrenaline, metadrenaline and vanillylmandelic acid). Noradrenaline is generally the major secretory product but occasionally adrenaline, and rarely dopamine, may predominate. Although it has been suggested that adrenaline secretion may indicate an adrenal tumour it is clear that extra-adrenal phaeochromocytomas can also secrete adrenaline and thus the spectrum of catecholamine secretion is not a reliable guide to the site. In most cases excessive excretion of at least one catecholamine or metabolite will be detected but the pattern of abnormality is quite variable and assays of any one of them (for example vanillylmandelic acid) to the exclusion of the others may be misleading. In some cases repeated assays may be required to make the diagnosis especially when the symptoms are sporadic or if clinical suspicion is high in the presence of a negative or equivocal result. Ideally the urine collection should be begun immediately after an attack.

The place of assays for plasma catecholamines is disputed but there is evidence that small tumours may release predominantly unmetabolized catecholamines into the circulation and may be best diagnosed by direct measurement of circulating catecholamines. Overall, assays for plasma catecholamines, urinary metadrenaline and normetadrenaline, or urinary vanillylmandelic acid each have a very high positive predictive value but combinations of tests give the greatest diagnostic accuracy. False-positive results may occur in patients taking certain drugs (phenothiazines, methyldopa, or monoamine oxidase inhibitors, for example) or with excessive intakes of tea, coffee, or chocolate and rebound hypertension with high levels of circulating and urinary catecholamines may occur following withdrawal of clonidine.

Occasionally it may be necessary to distinguish between patients with a phaeochromocytoma and equivocally elevated plasma or urinary catecholamines and patients without a phaeochromocytoma who have excessive activity of the sympathetic nervous system. If clinical suspicion is high provocation or suppression tests may be performed but provocation tests must be undertaken with considerable caution because dangerous hypertensive crises may be precipitated. In the glucagon stimulation test, which is relatively free of adverse effects, a positive result is indicated by a clear increase in plasma catecholamines 1 to 3 min after administration of the drug. The clonidine suppression test relies upon the capacity of clonidine to inhibit neurogenically mediated catecholamine release. In patients with a phaeochromocytoma clonidine fails to suppress plasma catecholamine levels but the test should be administered with caution since clonidine suppression may result in hypotension and it should not be undertaken on patients with volume depletion or those already treated with &bgr;-blockers.

After the diagnosis has been established biochemically, localization of the tumour is important in order to confirm the diagnosis and to assist in the planning of the surgical approach. Modern non-invasive imaging can safely detect and localize virtually all tumours. CT of the abdomen and pelvis is the preferred modality since it will detect the majority of tumours. Whether it is positive or negative, however, a ¹³¹I-MIBG scan provides useful additional anatomical and functional information and may locate occult second tumours or metastases to bone, liver, or lung. Preoperative CT and ¹³¹I-MIBG together will locate more than 95 per cent of tumours. The place of MRI is less clear but it does have certain advantages over CT scan in relation to in-vivo tissue characterization. Phaeochromocytomas produce a high T&sub2;-weighted signal intensity unlike other tumours in which the signal intensity is low and it may be possible to distinguish a phaeochromocytoma from other adrenal masses. Unfortunately malignant and benign phaeochromocytomas have the same MRI signal and cannot be distinguished. MRI can, however, distinguish tumour from surrounding vascular structures without the need for the administration of contrast and since there is no exposure to X-rays MRI is the investigation of choice in pregnancy. Older methods of localization, such as intravenous pyelography or venous catheterization and selective sampling at sites along the inferior and superior vena cavae, are rarely used today. Both are invasive and can provoke release of catecholamine and development of dangerous hypertensive crises. Occasionally venous sampling is used in subjects in whom clinical and biochemical tests strongly suggest phaeochromocytoma but radiological studies fail to identify the tumour. Several days before embarking upon this investigation adequate &agr;- and &bgr;-adrenergic receptor blockade should be established.

In most cases the appropriate treatment for phaeochromocytoma is surgery following medical therapy to prevent cardiovascular complications and reduce the risks of operative intervention. The medical preparation and anaesthesia is a critical aspect of surgery for phaeochromocytoma and is discussed in detail in Section 11.4 87.

The results of surgery are generally good with 75 to 90 per cent of patients cured of their hypertension and free of the risk of recurrent disease. However, the surgery is risky and close attention to management in the perioperative period is essential. In skilled centres the operative mortality is about 3 per cent. Several postoperative complications require special mention. Hypotension may result from marked arterial and venous dilatation following the sudden withdrawal of catecholamines and may be compounded by inadequate volume loading. The primary treatment here should be volume replacement rather than pressor agents. Hypoglycaemia may occur as a result of withdrawal of the anti-insulin effect of catecholamines and this may manifest as postoperative hypotension resistant to volume replacement and vasopressors. Finally if the arterial blood pressure does not return to normal within about 2 weeks of surgery evidence of residual phaeochromocytoma or metastases should be sought by checking urinary or plasma catecholamines. Persistent hypertension may be due to hypertensive vascular disease or coexistent essential hypertension and if the catecholamine levels remain elevated the clonidine suppression test should distinguish those cases in which the hypertension is under neurogenic control. Patients should generally be followed for life with annual blood pressure checks and catecholamine studies.

The diagnosis of malignancy depends upon clinical or macroscopic pathological evidence of local invasion or the presence of metastases (usually in the liver, lung, or bone) rather than on histological criteria. Histology may be misleading because the usual features of malignancy (nuclear pleiomorphism, giant cells, frequent mitotic figures, and capsular invasion) may all occur in tumours that subsequently follow a benign course. DNA ploidy, however, may prove to be a useful discriminatory test since it has been reported that benign phaeochromocytomas tend to have diploid DNA content whereas malignant tumours are hyperdiploid. High plasma or urinary dopamine levels are suggestive, but not diagnostic, of malignancy.

Malignant phaeochromocytomas tend to be slow growing tumours and evidence of recurrence, or of malignancy following excision of an apparently benign tumour, may occur many years after surgery. Following excision some patients survive for more than 20 years but the overall 5-year survival is about 45 per cent.

Whenever possible surgical excision or debulking of the tumour should be attempted. Some patients will be cured, and debulking facilitates the medical control of symptoms since the level of catecholamine secretion is proportional to the size of the tumour. If there is residual catecholamine secretion then medical therapy aims to control the effects of circulating catecholamines by &agr;- and &bgr;-adrenergic receptor blockade, often supplemented with calcium channel blockade, and to inhibit the synthesis of catecholamines using &agr;-methyltyrosine. This ‘false’ catecholamine precursor inhibits tyrosine hydroxylase which is the rate limiting enzyme for catecholamine synthesis.

Although malignant phaeochromocytomas respond poorly to chemotherapy or radiotherapy combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine may produce temporary control in some patients and administration of ¹³¹I-MIBG to ablate residual primary or secondary deposits has produced short-term remission or palliation in some cases but evidence of a significant long-lasting benefit is lacking.

The history of adrenal surgery begins in 1889 when Thornton resected a large adrenal tumour en bloc with the kidney in a young woman with hirsuitism. In 1914 Sargent performed the first planned operation to remove an adrenal tumour causing Cushing's syndrome and in 1926 César Roux in Lausanne and Charles Mayo in Rochester independently removed phaeochromocytomas. In the 1950s after the discovery of cortisone subtotal or total bilateral adrenalectomy was performed for adrenal hyperplasia and for pituitary dependent Cushing's syndrome. However, this procedure was associated with high surgical morbidity, 2 to 5 per cent operative mortality, and the need for life-long replacement therapy and has now been largely abandoned. Occasionally surgical ablation of the adrenals is still used in Cushing's disease or in the treatment of hormonally dependent tumours such as breast carcinoma.

Today the indications for adrenalectomy are largely restricted to resection of the various adrenal neoplasia. With modern imaging exploratory operations have become virtually obsolete and a carefully planned approach to adrenal surgery is almost always possible. There are several operative approaches to the adrenal glands and each has its own particular indications. The choice of approach depends upon the adrenal pathology and indications for operation, the size and shape of the patient, and the experience and familiarity of the surgeon with the various options.

The posterior extraperitoneal approach was first described over 50 years ago and is still used for selected patients. The original ‘hockey stick’ incision, however, is now rarely used and an oblique incision through the bed of the 11th or 12th rib is usually employed. The advantages of this approach are that it is direct, and relatively atraumatic, which minimizes postoperative pain, and both glands can be exposed simultaneously. The main disadvantage is that the operative field is relatively restricted which limits its usefulness to resection of small lesions such as adenomas less than 5 cm in diameter. It is not suitable for removal of large adrenal lesions (>5 cm) or potentially malignant tumours. Retroperitoneal exposure of the adrenal through the flank is rarely indicated but it may be the preferred route in obese patients with Cushing's syndrome in whom only one gland needs to be explored.

The transabdominal approach, by an extended subcostal or bilateral subcostal incision, provides excellent exposure of both glands, if necessary, as well as the abdominal organs and the retroperitoneum. This approach is indicated for large lesions or potentially malignant tumours and it is mandatory for the resection of a phaeochromocytoma since it allows for early vascular control and for the possibility of bilateral, multiple, or extra-adrenal tumours. A midline approach may be used for extra-adrenal tumours in the organ of Zuckerkandl or the pelvis.

A thoracoabdominal approach provides outstanding exposure of the adrenal, but exposure of the contralateral gland is more difficult than by the anterior transabdominal route, and it is generally reserved for very large tumours that cannot be removed by the anterior approach.

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