Tumours of the adrenal gland

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Introduction

The adrenal glands lie superomedial to the upper poles of both kidneys. Each adrenal gland comprises a medulla and a cortex, and each component has a distinct embryological origin. The adrenal cortex is of mesodermal origin, whereas the adrenal medulla arises from neural crest cells along with the sympathetic ganglia. The adrenal medulla produces catecholamines, including adrenaline, noradrenaline and dopamine and is under the control of the sympathetic nervous system. The adrenal cortex produces glucocorticoids (cortisol, corticosterone), mineralocorticoids (aldosterone) and sex steroids (oestrogen, testosterone, dihydroepiandrosterone). The adrenal cortex is under the control of adrenocorticotropic hormone (ACTH), a hormone produced by the pituitary gland.

Adrenal and neural crest tumours

Adrenal masses are common, affecting 3–7% of the population. Tumours can arise from both the adrenal cortex and the adrenal medulla as well as from neural crest structures. Tumours of either origin may be benign or malignant, functioning or non-functioning, and solitary or multiple. Adrenal tumours can be considered in the following groups:

  • Tumours of the adrenal medulla/neural crest (phaeochromocytomas and paragangliomas)
  • Adrenocortical tumours
  • Adrenal incidentalomas

The clinical features and investigation of adrenal tumours are summarised in Clinical features and investigations for adrenal tumours.

Table 36. Clinical features and investigations for adrenal tumours
Syndrome or tumour Hormones secreted Symptoms
Adrenal medullary or neural crest tumours Phaeochromocytoma Adrenaline Sweating, palpitations, hypertension (intermittent or sustained)
Paraganglioma Noradrenaline
Dopamine
Adrenocortical tumours Cushing's syndrome Glucocorticoids Central obesity, buffalo hump, abdominal striae, hypertension, peripheral weakness, plethoric facies
Conn's syndrome Aldosterone Hypertension, hypokalaemia
Virilising/feminising tumours Sex steroids Virilisation in females, feminisation in males
Adrenal incidentaloma Benign adrenocortical adenomas Non-secreting Asymptomatic (picked up on incidental CT scan or ultrasound)
Adrenal cysts
Adrenal lymphomas
Schwannomas
Myelolipomas
Metastases

Phaeochromocytoma and paraganglioma

Pathology

Phaeochromocytoma and paraganglioma are tumours arising from the adrenal medulla or neural crest. Although the classification has been confusing in the past, a consensus is now emerging (Classification of adrenal medullary and neural crest tumours). All such tumours are thought to ultimately be of neural crest origin. Adrenal phaeochromocytomas are of sympathetic origin. Extra-adrenal tumours may be of sympathetic origin and are located anywhere from the cervical ganglia to the urinary bladder. They are classified as extra-adrenal phaeochromocytoma, although they have also been labelled as paraganglioma in the past. Extra-adrenal tumours may also be of parasympathetic origin, comprising mainly head and neck tumours such as carotid body tumours.

Table 37. Classification of adrenal medullary and neural crest tumours
Origin Origin Tumour site Pathology
Sympathetic tissue Adrenal gland Adrenal phaeochromocytoma
Extra-adrenal Extra-adrenal phaeochromocytoma
• Zuckerkandl remnant
• Filum terminal tumour
• Urinary bladder tumour
• Thoracic paravertebral tumour
• Cervical ganglia tumour
Parasympathetic tissue Extra-adrenal Paraganglioma
• Carotid body tumour
• Vagal paraganglioma
• Jugulotympanic paraganglioma
• Laryngeal paranganglioma
• Aorticopulmonary paraganglioma

The majority of adrenal phaeochromocytomas are benign and functioning, but between 10 and 20% are malignant. This diagnosis may be difficult to make on histological examination, as with most endocrine tumours, and may not become apparent until the appearance of distant metastases during follow-up. Such tumours have a tendency to grow along the adrenal and renal veins and may extend into the inferior vena cava. Approximately 10% of phaeochromocytomas are bilateral within the adrenal glands.

The majority of extra-adrenal phaeochromocytoma are also functioning, but a greater percentage are malignant compared to adrenal tumours. True paragangliomas only rarely function, and the rate of malignancy is very low.

Phaeochromocytomas and paragangliomas may occur sporadically, or in association with a familial disorder such as multiple endocrine neoplasia IIA (MEN IIA - medullary carcinoma of the thyroid, phaeochromocytoma and hyperparathyroidism) or von Hippel-Lindau syndrome (retinal, cerebellar, spinal and medullary hemangioblastomas, renal cysts and carcinoma, pancreatic cysts, phaeochromocytoma and papillary cystadenoma of the epididymis).

Clinical presentation

Phaeochromocytomas present a rare but curable cause of hypertension, with varying combinations of paroxysmal or sustained hypertension (0.5% of patients with hypertension have a phaeochromocytoma), headache, sweating and palpitations. Loss of weight is a common symptom. Up to one third of cases may be asymptomatic.

Investigation

The clinical diagnosis of phaeochromocytoma is confirmed on the basis of elevated catecholamine levels (adrenaline, noradrenaline, dopamine) in the plasma or urine. Once a biochemical diagnosis is established, the tumour can usually be localised with by CT scan, or by MRI. A nuclear medicine scan performed with metaiodo-benzyl-guanidine (MIBG) is useful to confirm the functional status of a tumour, and may detect an extra-adrenal phaeochromocytoma, or demonstrate small lesions within the adrenal gland that are not apparent on other forms of imaging.

Treatment

Phaeochromocytoma and paraganglioma are treated by surgical excision. Careful pre-operative preparation is required in order to prevent an intra-operative hypertensive crisis, due to the massive release of catecholamine with tumour handling, or profound post-operative hypotension and massive fluid requirements resulting from the fluid shifts that follow catecholamine control. Pre-operative preparation is best undertaken with administration of alpha-adrenergic blocking agents, such as phenoxybenzamine.

Adrenocortical tumours

Pathology

These tumours may be non-functioning, or may secrete glucocorticoids, aldosterone or the sex steroids. They may occur sporadically, or as part of an hereditary syndrome such as Li-Fraumeni syndrome, Beckwith-Weidmann syndrome, Carney's complex or MEN I. The majority of glucocorticoid-producing adrenocortical tumours are benign but up to 20% may be malignant. As with other endocrine tumours, a diagnosis of adrenocortical carcinoma is based on the finding of capsular or vascular invasion, but again may not be made until the later appearance of distant metastases. These tumours may reach a very large size before diagnosis, and as the size increases the risk of malignancy also rises.

Mineralocorticoid-producing adrenal tumours are almost always small (<1 cm) and virtually always benign. Bilateral nodular hyperplasia may be difficult to distinguish from a single aldosterone-producing adenoma. The majority of sex steroid-producing tumours are malignant at presentation. Adrenocortical carcinomas are rare and 70% are associated with hormonal hypersecretion.

Clinical presentation

GLUCOCORTICOID-PRODUCING TUMOURS

Most patients present with features of glucocorticoid excess (Cushing's syndrome), which includes central obesity, peripheral weakness, abdominal striae, buffalo hump, hirsutism, plethoric facies and hypertension. Most patients present with features of glucocorticoid excess (Cushing's syndrome), which includes central obesity, peripheral weakness, abdominal striae, buffalo hump, hirsutism, plethoric facies and hypertension. Occasionally a large tumour may present with local symptoms, such as pain or fullness in the flank. A number of hormone-secreting tumours are diagnosed incidentally, on the basis of a CT or ultrasound scan, (adrenal incidentaloma), although many such tumours have now been shown to be associated with subclinical Cushing's syndrome (pre-Cushing's syndrome). This syndrome is associated with hypertension, diabetes, obesity and osteoporosis but without the full biochemical manifestations of Cushing's syndrome. Often all that is demonstrated on investigation is loss of the diurnal rhythm of cortisol secretion and suppression of function of the contralateral gland.

ALDOSTERONE-PRODUCING ADENOMAS (CONN'S SYNDROME)

Most of these tumours present during the investigation of hypertension but may be suggested by symptoms such as polyuria, polydipsia and muscle weakness due to the associated hypokalaemia. While hypokalaemia has been used as a screening test for Conn's syndrome in the past, there is increasing evidence that up to 50% of mineralocorticoid-producing tumours may be associated with normal levels of serum potassium.

SEX STEROID-PRODUCING TUMOURS

Clinical features will be specific to the type of hormone produced, with either virilisation in females or feminisation in males. Many of these patients also have palpable masses and 50% have metastatic tumour at the time of presentation.

Investigations

The initial test used to diagnose Cushing's syndrome is measurement of serum cortisol and 24-hour urinary free cortisol levels. A dexamethasone suppression test may be required to confirm true glucocorticoid excess. The presence of an adrenal tumour as the cause of the glucocorticoid excess, rather than a pituitary tumour or an ectopic ACTH-secreting tumour, can generally be made by measuring plasma ACTH levels and performing an abdominal CT scan. Bilateral nodular hyperplasia may occasionally be difficult to differentiate from a single small adrenal tumour.

A low serum potassium level will often suggest the possibility of an aldosterone-secreting tumour although more than 50% of patients are now known to be normokalaemic. Measurement of the ratio of plasma renin and plasma aldosterone (PRA ratio) will confirm the diagnosis of hyperaldosteronism, as primary hyperaldosteronism is characterised by low plasma renin activity. A CT scan may detect an adrenal tumour but, because many of these tumours are very small, selective adrenal vein sampling for aldosterone may be required to localise the tumour.

Measurement of the sex hormones as well as the 17-ketosteroids will confirm the diagnosis of a sex steroid-producing tumour. These tumours are often large and should be detected on CT scanning.

Treatment

Surgical excision (adrenalectomy) is the only treatment for an adrenocortical tumour. For large or potentially malignant tumours, wide local excision and local lymph node dissection may be required.

Adrenal incidentalomas

Pathology

Any tumour arising in the adrenal gland can present as an adrenal incidentaloma, including adrenocortical tumours, adrenal medullary tumours, Schwannomas, myelolipomas, adrenal cysts, adrenal lymphomas and adrenal metastases from other malignancies, particularly breast cancer. Incidental benign adrenocortical adenomas are very common and can be found at postmortem in up to 10% of the normal population.

Clinical presentation

By definition, an adrenal incidentaloma will present as an incidental finding, usually on a CT scan or ultrasound. They will not be associated with local symptoms, nor with any of the syndromes of hormonal excess.

Investigation

The tumour will already have been demonstrated by imaging. Hormonal secretion must be excluded by measurement of 24-hour urinary free cortisol, PRA ratio, adrenal sex steroids and urinary catecholamines. A nuclear medicine scan using seleno-cholesterol may help to determine whether the tumour is arising from the adrenal cortex, and whether or not there is suppression of hormone secretion from the contralateral side.

Treatment

Incidental adrenal tumours that do not secrete hormones are not associated with local symptoms and are less than 4–5 cm in diameter, can be treated conservatively, although there are increasing data to suggest that the potential risk for malignancy may require that cutoff to be lower, for example 3 cm. A follow-up CT scan should be performed after 6 months to make sure there is not a progressive increase in size, which would suggest malignancy. Large tumours, or those that demonstrate an increase in size, should be removed surgically because of the increased risk of malignancy.

Operative management: adrenalectomy

Adrenalectomy can be performed either as an open procedure, as a laparoscopic procedure with hand assist devices, or solely as a laparoscopic procedure. Increasingly, the accepted philosophy is to tailor the surgical approach to the tumour size and clinical situation. The open approach to the adrenal gland is either anteriorly through the peritoneal cavity (now used only for large and probably malignant lesions), or via an extraperitoneal approach, either posteriorly through the bed of the 12th rib or postero-laterally, or combined as a thoraco-abdominal procedure. These procedures should be used for very large tumours, or those known to be malignant.

Laparoscopic adrenalectomy is associated with reduced post-operative pain, and allows the patient to leave hospital after 2 or 3 days. The procedure is ideally suited to small benign adrenal tumours, such as those commonly found in Conn's syndrome, but is also indicated for phaeochromocytoma, including bilateral tumours.

Complications of adrenalectomy include all the general complications of any open abdominal adrenal operation or laparoscopic procedure such as bleeding, wound infection and ileus. The particular anaesthetic complications of phaeochromocytoma surgery have already been discussed. Surgery for glucocorticoidsecreting tumours, and occasionally for incidentalomas with sub-clinical hormone secretion, may be associated with post-operative Addisonian crisis, because of suppression of the contralateral adrenal gland. This will require steroid administration until the remaining gland recovers, which may take 4–6 weeks.
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