Blood supply and lymphatic drainage

The blood supply is derived from branches of three vessels, the inferior phrenic artery, the ipsilateral renal artery and the aorta. These branches often subdivide into a leash of vessels, before entering the gland. Venous return is via a single adrenal vein that drains into the renal vein on the left and directly into the inferior vena cava on the right.¹ The right vein is short and an important landmark for the surgeon. The veins drain from the medulla and therefore the venous return from the cortex flows through the medulla. This is relevant as glucocorticoid hormones secreted by the cortex activate phenylethanolamine N-methyltransferase (PNMT), an enzyme involved in the synthesis of catecholamines. Medullary and subcapsular lymphatic plexuses drain into lymphatics that follow the arterial supply to the para-aortic lymph nodes.

Nerve supply

The adrenal cortex receives a few vasomotor fibres, but the medulla is richly supplied with fibres derived from the splanchnic nerves (T5–9) and should be regarded as a modified sympathetic ganglion in which the axon has been replaced by secretory cells, called phaeochromocytes or chromaffin cells, filled with granules containing catecholamines.

Microscopic anatomy

The adrenal medulla accounts for 15% of the volume of the adrenal gland and consists of vascular spaces and eosinophilic phaeochromocytes of variable size containing polymorphic nuclei. Phaeochromocytes are characterised histologically by their uptake of dichromate salts and hence are referred to as chromaffin cells.

The adrenal cortex is divided into three layers: the outer zona glomerulosa, the zona fasciculata and the innermost zona reticularis. The zona glomerulosa produces mineralocorticoids. It consists of columnar cells, with relatively little cytoplasm compared with their nuclei, organised into clusters. The zona fasciculata is the largest of the cortical zones, occupying approximately 75% of the cortex, that contains poorly staining, polyhedral cells organised in radial columns and is primarily responsible for the production of glucocorticoids. The innermost zona reticularis is characterised by rounded branching cords of cells and produces sex hormones, particularly dehydroepiandrosterone sulphate (DHEAS).²

Embryology

The cortex and medulla have different embryological origins. The adrenal cortex is mesodermal in origin and starts to appear in the fifth week of gestation as two clefts on either side of the embryonic dorsal mesentery that enlarge to form the primitive or foetal cortex. This is surrounded at the seventh week by a second wave of mesothelial cells to form the secondary cortex that eventually becomes the adult adrenal cortex. Concordantly, cells migrating from the neural crest invade the developing adrenal gland to form the adrenal medulla, which is therefore neuroectodermal in origin. The adrenal glands are large at birth, but reduce in size thereafter due to regression of the primary cortex, and do not regain their original size until puberty. The zona glomerulosa starts to appear before delivery, followed by the zona fasciculata and finally the zona reticularis a few months after birth. Neural crest cells, outside the adrenal medulla, are widely present in the embryo, but regress after birth.³

Adrenal medulla

Adrenal cortex

The zones of the adrenal cortex synthesise steroid hormones from cholesterol via a common pathway illustrated in Fig. 3.3.

Case study 1

Consider the management of a 65-year-old woman who has an incidental 3-cm right adrenal adenoma on unenhanced computed tomography (CT) scan (see Fig. 3.4) performed following a fall in which she suffers a femoral shaft fracture. There is a recent history of hypertension. After surgery for her fracture a bone mineral density scan shows severe osteoporosis. Biochemical evaluation including 24-hour urinary free cortisol, plasma free metanephrines, plasma aldosterone and renin actitivity are unremarkable, but plasma cortisol fails to suppress after an overnight low-dose dexamethasone test and plasma ACTH is suppressed.

Definition and incidence

Incidentalomas are tumours identified inadvertently during investigation of an unrelated condition. Overall adrenal incidentalomas are present on 4% of abdominal CT scans,⁵ though their incidence increases with age from < 1% in the third decade to 7% in the eighth decade of life.⁶ The current widespread use of cross-sectional abdominal imaging has created the clinical dilemma of how to manage these incidentalomas. The objective is to identify those that are potentially malignant, or harmful due to excessive hormonal secretion.

Aetiology

The majority of adrenal incidentalomas are benign non-functioning adenomas. The incidence of clinically significant adrenal incidentaloma varies between studies, but about 15% are found to secrete excess hormones.⁷ Adrenocortical carcinoma and phaeochromocytoma each account for 5–10%.⁸ Excluding studies of oncology patients, metastases account for a small (2.5%) proportion of incidentalomas. Lung, breast, ovary, kidney and melanoma are the most common primary tumours that metastasise to the adrenal gland.⁹ The remaining incidentalomas are due to myleolipoma, haemorrhage, adrenal cortical cyst, ganglioneuroma, neuroblastoma, lymphoma, congenital adrenal hyperplasia, haemangioma, granulomatous disease and other rare diagnoses.⁷

Investigation

Initial assessment of a patient with an incidentaloma should start with the patient and not by focusing on the imaging. Reflex biopsy and unconsidered investigation of coincidentally found adrenal masses can lead to disasters. A past medical history of malignant disease or family history of endocrine disease should be sought. History and clinical examination should be carefully undertaken, looking for evidence of hormone excess such as obesity, hypertension, diabetes, osteoporosis, virilisation or feminisation. Features of pituitary–adrenal axis imbalance may suggest Cushing’s syndrome, and hypokalaemia in hypertensive patients suggests primary hyperaldosteronism.

Biochemistry

Biochemical investigation needs to exclude phaeochromocytoma by measuring fractionated urinary metanephranes or plasma free metanephranes. The diagnosis of Cushing’s syndrome is more difficult to exclude as more subtle forms, so-called subclinical Cushing’s syndrome, occur and 24-hour urinary free cortisol, low-dose (1 mg) overnight dexamethasone suppression test and midnight salivary cortisol may all be required to confirm or exclude the diagnosis. Primary hyperaldosteronism is suggested in hypertensive patients with elevated plasma aldosterone:renin activity ratio >20. Hypokalaemia is present in only half the patients with primary hyperaldosteronism. Serum DHEAS and 17-hydroxyprogesterone are measured to exclude adrenal androgen hypersecretion that occurs in some adrenocortical carcinomas or, when bilateral adrenal masses are present, congenital adrenal hyperplasia.¹⁰

Biopsy

Adrenal biopsy is generally unhelpful, as differentiating between benign and malignant primary adrenocortical lesions is rarely possible, and biopsy may precipitate a ‘phaeochromocytoma crisis’ in unblocked phaeochromocytoma.

Imaging

Adrenal cysts, myelolipoma and haemorrhage have characteristic features on CT enabling diagnosis; differentiating adrenal adenoma from malignant tumours, phaeochromocytoma and other causes of incidentaloma can be more problematic, as some overlap occurs in the appearance of these lesions on cross-sectional imaging.⁷

Most adrenal adenomas are lipid rich and appear as low-density (or attenuation) masses on unenhanced CT. They are characteristically homogeneous with a regular outline, and adrenal incidentaloma <4 cm in size with these features, and an attenuation value of <10 Hounsfield units on unenhanced CT require no further diagnostic imaging.¹²

Malignant lesions, phaeochromocytoma and up to 30% of adenomas are lipid poor and have high attenuation on unenhanced CT. Other features that increase the risk of malignancy include heterogeneity, irregular outline and size >4 cm.¹³ CT with contrast enhancement and washout characterise these lesions. Both adrenocortical carcinomas and medullary tumours show rapid contrast enhancement but adenomas have a rapid washout of contrast, resulting in an attenuation value of <30 Hounsfield units at 10 minutes, in contrast to malignant adrenocortical tumours and phaeochromocytoma where contrast is retained.¹⁴

Magnetic resonance imaging (MRI) can distinguish between benign and malignant tumours in 90% of cases. Malignant tumours usually have a higher fluid content than lipid-rich adenomas, which results in high signal intensity on T2-weighted MRI. Loss of signal intensity on out-of-phase MRI with chemical shift imaging, also due to the high lipid content of adenomas, can be used to distinguish benign from malignant tumours.¹⁵ Homogeneous enhancement following intravenous gadolinium-enhanced MRI is characteristic of adrenal adenoma.

[¹⁸F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with CT is highly accurate at differentiating benign from malignant incidentalomas and is helpful in lesions with an indeterminate appearance on CT or MRI.²⁰ Malignant tumours characteristically have high [¹⁸F]FDG uptake compared to adenomas.

Management

The evidence base for the management of incidentalomas is based on expert opinion due to the lack of prospective studies. Potentially malignant and functional adrenal incidentaloma should generally be excised.

Size is the major determinant of malignant potential, as less than 2% of tumours <4 cm will be adrenocortical carcinoma (ACC), whereas 25% of tumours >6 cm are ACC.

The natural history of adrenal incidentalomas is unknown. Although approximately a quarter of incidentalomas increase in size with time, the risk of malignant change is thought to be low. Annual surveillance imaging is often performed though there is limited evidence to recommend the optimum length or frequency of radiological follow-up. To avoid excessive radiation exposure that in itself may be tumour inducing, MRI is the preferred method for serial surveillance. Secretory hyperfunction may also develop during follow-up in up to 9% of incidentalomas, though further data are needed to establish the benefit, length and frequency of follow-up hormonal evaluation.^17,18

Although clinically evident Cushing’s syndrome is rare in patients presenting with incidentalomas, more subtle elevations of cortisol secretion, termed ‘subclinical’ Cushing’s syndrome, are detected in 5–20%.¹⁹ These patients may exhibit some signs of glucocorticoid excess such as obesity, hypertension, diabetes mellitus or osteoporosis, but lack the characteristic features of the full-blown syndrome. Often one or more of the biochemical tests for Cushing’s syndrome are normal in patients with subclinical Cushing’s syndrome, commonly the urinary free cortisol. The low-dose overnight dexamathasone test or late-night salivary cortisol are more sensitive tests, and progression to full-blown Cushing’s syndrome is unpredictable.^17,18,19,21

Efforts to establish evidence-based management of subclinical Cushing’s syndrome are hampered by any agreed diagnostic criteria and the lack of randomised studies comparing medical to surgical management. Uncontrolled surgical series have reported improvements in hypertension, obesity and diabetes mellitus following adrenalectomy in patients with subclinical Cushing’s syndrome, though these studies did not compare surgery with best medical management.¹⁰

Case study 1 (discussion)

This patient has subclinical Cushing’s disease with hypertension and osteoporosis that may be due to glucocorticoid excess. The size and imaging characteristics of the incidentaloma do not merit surgery alone, as these suggest a benign adrenal adenoma. If conservative management is pursued then medical management of hypertension and osteoporosis should be undertaken, with surveillance to (a) exclude enlargement of the adrenal tumour or development of malignant features, (b) monitor continued hormone excess and (c) detect any deterioration in bone mineral density. It is very reasonable to offer adrenalectomy; the laparoscopic transabdominal or retroperitoneal approaches are both suitable. Age and medical comorbidities influence the decision to operate in these circumstances. Perioperative steroids should be given to prevent an Addisonian crisis postoperatively.

Case study 2

Consider the management of a 50-year-old man who on investigation for abdominal discomfort is found to have a large non-functioning adrenal mass (see Fig. 3.5).What is the differential diagnosis? Staging investigations are negative. What is the surgical approach and which adjuvant therapy is indicated?

Incidence and aetiology

Adrenocortical carcinoma (ACC) is one of the most lethal endocrine tumours but fortunately is rare, with an incidence of 1–2 per million per year. Most ACC is sporadic in origin but it may be associated with a number of rare syndromes, including: multiple endocrine neoplasia type 1 due to mutation in a gene on chromosome 11 encoding the protein menin; Beckwith–Wiedemann syndrome (exophthalmos, macroglossia and nephromegaly) in childhood due to mutation of two genes on chromosome 11 leading to overproduction of insulin-like growth factor (IGF) 2; and Li–Fraumeni syndrome (breast carcinomas, osteosarcomas and brain tumours) due to inactivating mutations of tumour suppressor gene p53 on chromosome 17.²²

Clinical features

The majority of ACCs are hormonally functional and present with Cushing’s syndrome, primary hyperaldosteronism, virilisation or feminisation. Secretion of multiple hormones is characteristic of ACC. In our own series, in which the frequency of clinical presentation was quite typical, 57% of ACCs were functioning, 48% presented with Cushing’s syndrome (18% secreted multiple hormones – Cushing’s syndrome and virilisation), 6% presented with pure virilisation and 3% feminisation; 43% were non-functioning, of which 34% had symptoms (abdominal discomfort) and 9% were found incidentally.²³

Biochemistry

Biochemical evaluation to establish the steroid secretory profile of ACC should be undertaken as described elsewhere in this chapter. Certain biochemical findings are characteristic of ACC: excess secretion of multiple steroid hormones, particularly glucocortocoids and androgens, elevated DHEAS, raised oestradiol in men and postmenopausal women, and as enzyme function is often defective in ACC, accumulation of steroid precursors such as 17α-hydroxyprogesterone and androstenedione.²⁴ Phaeochromocytoma should also be excluded biochemically, as this is not possible on imaging alone.

Imaging

ACCs typically appear as large (usually >5 cm), heterogeneous lesions with an irregular margin on unenhanced CT. They are denser than lipid-rich adenomas so they have attenuation >10 Hounsfield units on unenhanced CT and display delayed washout of contrast. Local invasion or distant metastases may be apparent on CT. The incidence of malignancy, which increases with size, is 2% in adrenal masses < 4 cm, 6% for those 4–6 cm and 25% in lesions >6 cm.^13,25

MRI can be helpful as ACCs have high signal intensity on T2-weighted images, heterogeneous enhancement and delayed washout with gadolinium contrast, and do not exhibit loss of signal intensity on out-of-phase chemical shift imaging seen with lipid-rich adenomas.¹⁵ MRI, in addition to an inferior vena cava (IVC) contrast study, is useful if vascular invasion or tumour thrombosis is suspected.

When adrenal tumours cannot be characterised on conventional cross-sectional imaging, [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG-PET) with CT has a sensitivity of 100% and specificity of 88% in differentiating malignant from benign lesions. FDG-PET may also be useful to detect recurrent or metastatic disease not seen on CT.^13,20

Diagnosis and staging

Percutaneous biopsy is not recommended for the work-up of ACC due to the difficulty in differentiating primary malignant from benign adrenal disease, and the risk of seeding tumour cells along the biopsy track. The only absolute criterion for the diagnosis of ACC is presence of extensive invasion of local structures or metastases. The most widely used algorithm for the diagnosis of ACC was described by Weiss and is based on nine histological features, the presence of three or more indicating malignant potential.²⁶ Ki67 immunohistochemistry may also help differentiate benign from malignant adrenocortical tumours.²⁴

The 2004 International Union Against Cancer TNM stages ACC according to size, presence of lymph node metastases, local invasion and distant metastases, and is based on the original staging system described by MacFarlane in 1958²⁷ and Sullivan et al. in 1978.²⁸ The European Network for the Study of Adrenal Tumours (ENSAT) has recently proposed further refinements of this staging system, which is the basis for prognostic and treatment stratification in ACC, as well as enabling comparison of outcomes between treatment centres.²⁹

Treatment

Prognosis

The reported overall 5-year survival for ACC varies between 16% and 38% depending on the stage at diagnosis. Median survival following non-curative surgery or diagnosis of metastatic disease is less than 12 months.²⁴

Case study 2 (discussion)

The CT scan shows an ACC. Phaeochromocytoma or neuroblastoma may give a similar appearance but these diagnoses can be excluded on the basis of negative urinary or plasma metanephrines. As staging was negative open surgery is indicated. The patient should be warned of the possible need to resect adjacent organs; in this case the left kidney was excised en bloc with the adrenal tumour. Histopathology showed a 2.3-kg ACC. Tumour thrombus was present in the renal vein. Postoperative mitotane and chemotherapy were given in this case.

Case study 3

Consider the management of a 60-year-old hypertensive woman investigated for symptoms of palpitations. Twenty-four-hour electrocardiogram and echocardiography are unremarkable and she is commenced on beta-blockers. Subsequently overnight urinary fractionated metanephrines and normetanephrines are found to be markedly elevated. Anatomical and functional localisation studies show a right adrenal phaeochromocytoma (see Fig. 3.9).

Incidence and aetiology

Phaeochromocytoma and extra-adrenal paraganglioma are tumours derived from catecholamine-producing chromaffin cells of neural crest origin arising in either the adrenal medulla (phaeochromocytoma) or extra-adrenal autonomic ganglia (paraganglioma). Phaeochromocytoma has an incidence of 3–8 per million per year and usually presents in middle age, though hereditary forms occur at a younger age. Phaeochromocytoma is very rare in children. Studies suggest 0.05% of all autopsies harbour an undiagnosed phaeochromocytoma and it is probable that this rare tumour is under-recognised in life.³⁹ Traditionally termed the ‘10% tumour’ (10% bilateral, extra-adrenal, familial or malignant), this description has now been challenged by recent advances in genetics and diagnosis.⁴⁰

The majority of extra-adrenal sympathetic paragangliomas occur in the abdomen, either arising from sympathetic ganglia in the organ of Zuckerkandl, which is situated along the lower abdominal aorta and its bifurcation, or around the renal hilum (Fig. 3.6). Less common sites for paraganglioma include the urinary bladder or the mediastinum, where they may even arise in the nerves supplying the myocardium (see Fig. 3.7). One-quarter of phaoechromocytomas managed in our unit are extra-adrenal, and a similar high proportion of extra-adrenal tumours are reported from other endocrine surgical centres, though this may reflect referral bias.⁴¹ In contrast to sympathetic paraganglioma, those arising from parasympathetic ganglia occur mostly in the head and neck (see Fig 3.8), and rarely produce catecholamines.

Although the majority of phaeocytochromas are sporadic, it is now thought that up to one-third of patients with phaeocytochromas carry germ-line mutations in predisposing genes, three of which are well known: RET (multiple endocrine neoplasia types 2A and 2B), VHL (von Hippel–Lindau syndrome) and NF1 (neurofibromatosis type 1). The remaining mutations occur in genes (SDHB and C) encoding subunits of the succinate dehydrogenase (SDH) enzyme responsible for the ‘paraganglioma–phaeocytochroma syndrome’.⁴²

The diagnosis of phaeochromocytoma may be the presenting episode of a hereditary syndrome; therefore, a careful medical and family history should be taken and examination performed to identify related features of a predisposing syndrome.

Phaeochromocytomas occur in approximately half of patients with multiple endocrine neoplasia type 2 (depending on the codon mutation), in association with medullary thyroid carcinoma (MTC) and hyperparathyroidism in multiple endocrine neoplasia type 2A (MEN2A) and multiple mucosal ganglioneuromas, megacolon and marfanoid habitus in MEN2B. Germ-line mutations in VHL, a tumour suppressor gene that regulates the accumulation of hypoxia-induced proteins and angiogenesis, lead to the rare VHL syndrome, characterised by central nervous system haemangioblastomas, renal cell cancer, cysts of kidney, testis and pancreas, and phaeochromocytoma (in up to a third). The clinical features of NF1 (also known as von Recklinghausen’s disease) include multiple neurofibromas, café-au-lait spots, skin-fold freckling and iris hamartomas. Phaeochromocytoma occurs in < 5% of NF1 patients.⁴³

Hereditary mutations in the SDH genes lead to failure of oxidative phosphorylation, the process by which adenosine triphosphate (ATP) is produced in mitochondria via the citric acid (Kreb’s) cycle. The SDH genes encode succinate dehydrogenase, a key component of aerobic glycolysis, ‘oxidative stress’ and accumulation of pro-oxidants leading to DNA damage. This is thought to underlie the pathogenesis of phaeochromocytoma and paragangliomas.⁴ Well-recognised genotype–phenotype correlations are seen with SDH mutations and, in contrast to RET, VHL and NF1, patients with mutations in the SDH genes commonly present with paragangliomas. SDHB carriers characteristically present at a young age with solitary malignant abdominal paraganglioma, whereas SDHD carriers are more likely to present with multiple paragangliomas in the head and neck, abdomen and adrenal gland.⁴⁴

Clinical presentation

The clinical symptoms and signs of phaeochromocytomas are numerous and are due to the paroxysmal excessive secretion of catecholamines. The classic symptoms are headaches, palpitations and sweating, but pallor, nausea, weight loss, tiredness and anxiety commonly occur. The characteristic feature of all presenting symptoms is that they are intermittent or paroxysmal in nature, which makes diagnosis difficult as the patient may be perfectly well between symptomatic episodes. Postural changes, exercise and anxiety often provoke symptoms. Hypertension is the commonest sign, along with diabetes mellitus. ‘Phaeochromocytoma crisis’ due to massive secretion of catecholamines into the circulation may present with sudden death, arrhythmia, heart failure, multi-organ failure or cerebrovascular accident. Anaesthesia, trauma, biopsy, haemorrhage or tumour manipulation during surgery may precipitate these crises. Phaeochromocytoma may also be found incidentally on cross-sectional imaging – approximately 5% of adrenal incidentalomas are phaeochromocytomas. Typically the diagnosis of phaeochromocytoma is delayed by several years as the symptoms overlap many common endocrine, cardiovascular or neurological disorders. The key to diagnosis is staying alert to the possibility of the disease.⁴³

Biochemical diagnosis

Phaeochromocytomas are rare tumours yet the consequences of missing the diagnosis may be catastrophic, so any screening test must be highly sensitive to minimise false-negative results. Plasma catecholamines are not a good diagnostic test as levels vary episodically in phaeochromocytoma, and may be elevated due to stress or medication in normal individuals. Measuring 24-hour or overnight urinary catecholamines improves diagnostic accuracy.

Metanephrines, produced continuously by the action of catechol-O-methyltransferase on catecholamines within tumour cells, leak into the circulation where their concentrations have been shown to accurately reflect tumour mass. When measuring plasma metanephrines, blood samples should be taken after 20 minutes of supine rest in order to avoid false-positive results. The sensitivity and specificity of plasma free metanephrines for the diagnosis of phaeochromocytoma are 96–100% and 80–100%, respectively. Twenty-four-hour or overnight urinary fractionated metanephrines have a similar diagnostic accuracy to plasma free metanephrines.

Imaging

Localisation should only be performed once the biochemical diagnosisis is confidently established. The high sensitivity of CT (85–94%) and MRI (93–100%) for the diagnosis of phaeochromocytoma enables accurate anatomical localisation.⁴⁹ Phaeochromocytomas usually appear as a homogeneous mass with a soft-tissue density of 40–50 Hounsfield units (HU) on unenhanced CT, though larger tumours may appear heterogeneous due to haemorrhage, necrosis, calcification or cyst formation. Concerns about provoking a phaeochromocytoma crisis with ionic contrast medium, necessitating α-adrenergic receptor blockade prior to contrast-enhanced CT, have been addressed as it has been demonstrated that non-ionic contrast does not provoke catecholamine secretion.⁵⁰

Phaeochromocytomas have similar signal intensity to the liver on T1-weighted MRI and a characteristically high signal intensity on T2-weighted MRI due to high vascularity. MRI offers excellent assessment

of the relationship to surrounding vessels (see Fig. 3.9) and may be preferred for phaeochromocytoma in the para-aortic and mediastinal regions to assess vessel invasion. MRI is also used to image phaeochromocytoma in children and pregnant women.⁴⁹

[¹⁸F]Fluorodihydoxyphenylanaline (DOPA) and [¹⁸F]fluorodopamine (DA) with PET have advantages over MIBG such as immediate scanning, reduced radiation exposure and tomographic rather than planar images (though [¹³¹I]MIBG may be combined with single positron emission computed tomography (SPECT) to give tomographic images).

The cost and availability of [¹⁸F]DA and [¹⁸F]DOPA currently limit their widespread use. Occasionally rapidly growing de-differentiated malignant or metastatic phaeochromocytomas fail to take up any of these radiopharmaceuticals and in these circumstances somatostatin receptor scintigraphy (Octreoscan) or [¹⁸ F]fluorodeoxy-D-glucose (FDG) with PET may localise the tumour.^39,48,49

Medical management

Once the biochemical diagnosis of phaeochromocytoma is established, pharmacological control of the adverse effects of circulating catecholamines should take priority over localisation studies. Phenoxybenzamine, a long-acting non-competitive and non-selective α-adrenergic receptor antagonist, is the agent most frequently used. Phenoxybenzamine is commenced at a dose of 20 mg twice daily, increased by 10-mg increments with monitoring of arterial blood pressure until postural hypotension occurs. This can usually be accomplished as an outpatient over a 2- to 4-week period. Side-effects of phenoxybenzamine include headache, nasal stuffiness, somnolence and reflex tachycardia.⁵¹ Alternatives to phenoxybenzamine have their proponents and include the selective, competitive α₁-adrenergic receptor agonists doxazosin⁵² and urapidil,⁵³ as well as the calcium channel blocker nicardipine.⁵⁴ Beta-blocking drugs may also be required to counteract tachycardia and arrhythmia, but should not be started until alpha blockade is complete to avoid unopposed α-adrenergic receptor stimulation that may cause hypertensive crisis or pulmonary oedema. The period of preoperative blockade allows intravascular volume expansion to occur and cardiomyopathy secondary to chronic hypertension to resolve. A cautious approach to optimising the patient’s condition for surgery is advised and rapid blockade programmes, although advocated by some, are seldom necessary.⁵¹

Prior to operation placement of intra-arterial and central venous catheters is essential to detect and correct potential hypertensive episodes perioperatively. Careful liaison between surgeon and anaesthetist is essential and undue handling of the tumour is to be avoided. Intravenous administration of either the short-acting vasodilator sodium nitroprusside, calcium channel blocker nicardipine or α-adrenergic receptor anatagonist phentolamine are required for intraoperative hypertensive episodes as well as beta-blockers for tachycardia and arrhythmia.⁵¹

Once the tumour is devascularised a significant fall in catecholamines will occur, potentially resulting in hypotension; thus, significant volume replacement and/or inotropes may be required preoperatively, and in the high-dependency or intensive care unit postoperatively. In addition, regular monitoring of the blood glucose is advised as the metabolic consequences of removing a phaeochromocytoma include hypoglycaemia due to sudden withdrawal of the lipolytic, glycolytic and glycogenolytic effects of catecholamines that were induced by the phaeochromocytoma.⁵¹

Surgical management

Laparoscopic excision of abdominal extra-adrenal paragangliomas is undertaken in our unit, though paragangliomas situated in the para-aortic region are usually approached by open surgery, as they may be intimately related to or invade the aorta. Subtotal adrenalectomy may have a role to avoid the need for lifelong steroid dependence in patients with multiple, bilateral hereditary phaeochromocytomas.⁵⁷

If an undiagnosed phaeochromocytoma is encountered during laparotomy for an unrelated condition, surges in blood pressure, pulse rate or arrythmias during induction of anaesthesia or tumour manipulation suggest the diagnosis. In this scenario the tumour should be handled as little as possible and not removed. The primary disease for which the laparotomy was indicated should be treated providing the patient is stable, and immediate blockade, work-up and subsequent elective removal of the phaeochromocytoma should be planned.

Case study 4

Investigation of abdominal and leg pain in a 60-year-old woman identified a pre-aortic mass (see Fig. 3.10). What is the differential diagnosis based on imaging? Biochemical work-up established the diagnosis of an abdominal paraganglioma. Functional localisation and cross-sectional imaging identify a left femoral metastasis (see Figs 3. 11 and 3.12). What would your management be?

Malignant phaeochromocytoma

The incidence of malignancy is higher in large phaeochromocytomas and extra-adrenal paraganglioma, and SDHB mutation carriers have a particularly high risk of malignancy. There are no histopathological features that reliably distinguish benign from malignant phaeochromocytoma and so malignancy is based on the confirmation of metastatic disease, which usually occurs in lymph nodes, liver, lung or bone.⁵⁸

Histological scoring systems such as the Phaeochromocytoma of the Adrenal gland Scoring Scale (PASS) have been devised in order to predict malignancy. Ki67 proliferation index may be elevated in malignant phaeochromocytoma.⁵⁸ Recently, a panel of genes identified by genome-wide expression profiling has been identified that may distinguish benign from malignant tumours, though these results need further validation.⁵⁹

There are a number of treatment options for metastatic disease, though none is curative. Symptom relief can be achieved by tumour debulking, inhibition of catecholamine synthesis, and α- and β-adrenergic receptor blockade. External beam radiotherapy, chemotherapy, radiofrequency ablation and transcatheter arterial embolisation may have a role. Therapeutic doses of [¹³¹I]MIBG can produce symptomatic and hormonal improvement as well as tumour regression or stabilisation.³⁹

Phaeochromocytoma in pregnancy

Phaeochromocytoma in pregnancy is rare, but dangerous, and carries a significant mortality both for the infant and mother.

Case study 3 (discussion)

The first priority in this patient is to stop beta-blockers, which are potentially dangerous in this scenario. Alpha blockade should then be instituted – phenoxybenzamine is used in our unit. Localisation is undertaken in this case with a combination of MRI and [¹²³I]MIBG. Although the tumour is large, it is amenable to laparoscopic surgery. Anaesthesia is undertaken with full cardiovascular monitoring by an anaesthetist with experience in phaeochromocytoma and the patient is admitted to the high-dependency unit postperatively. In the absence of any family history or features to suggest a hereditary predisposition, genetic screening is unnecessary in this case. Follow-up fractionated urinary metanephrines are measured and repeated annually for life to exclude recurrence or further new disease.

Case study 4 (discussion)

Differential diagnosis based on CT abdomen at initial presentation includes paraganglioma lymphadenopathy (benign or malignant, primary or secondary) or sarcoma. Localisation studies indicate metastases to the femoral shaft consistent with malignant paraganglioma. The first priority is to achieve alpha blockade. Tumour debulking may improve symptom control and the primary tumour is amenable to surgical excision in this case. The open surgical approach is recommended due to the proximity of the tumour to the aorta. Palliative treatment options for the metastatic disease include therapeutic doses of [¹³¹I]MIBG, external beam radiotherapy and chemotherapy. The former two options were chosen with good improvement in symptoms, radiological regression of the metastasis and hormonal control.

Case study 5

A 40-year-old woman presents with classic features of Cushing’s syndrome. Biochemical work-up confirms Cushing’s disease and MRI shows a pituitary adenoma (see Fig. 3.15). Trans-sphenoidal surgery to the pituitary fossa is undertaken but the disease persists. Repeat biochemical work-up, including inferior petrosal sinus sampling and MRI, shows an incompletely excised functioning pituitary adenoma. Further trans-sphenoidal surgery still does not control the disease. Consider the further management.

Definition and aetiology

Cushing’s syndrome is a rare disorder with an incidence of 1–2 per 10⁶ per year, characterised by a number of symptoms and signs due to the long-term effects of inappropriately elevated levels of glucocorticoids. Some of the features of Cushing’s syndrome, such as obesity, diabetes mellitus, hypertension and osteoporosis, are also common in the general population, and more subtle forms of Cushing’s syndrome, referred to as ‘subclinical’, are increasingly being diagnosed in this context.

The most common cause of hypercortisolism is exogenous administration of steroids. Endogenous Cushing’s syndrome is more common in women than men and the majority (80%) is ACTH dependent, due to either pituitary (70%) or ectopic (10%) origin; ACTH-independent (or adrenal) Cushing’s is usually due to adrenocortical adenoma or carcinoma and rarely to ACTH-independent macronodular adrenal hyperplasia (AIMAH) or primary pigmented nodular adrenocortical disease (PPNAD).⁶⁰

Clinical features

The classic features of florid Cushing’s syndrome include centripetal obesity, buffalo hump, moon faces, facial plethora, red–purple striae, hirsutism, loss of libido, menstrual irregularity, depression or psychosis, proximal myopathy and easy bruising (see Figs 3.13 and 3.14). Myopathy, plethora, striae and easy bruising in particular suggest the diagnosis of Cushing’s syndrome.

Biochemical diagnosis

False-positive and -negative results may also occur due to critical illness, alcoholism, depression, drugs (including phenytoin, carbemazepine, fluoxetine, diltiazem, cimetidine, oestrogens), renal failure, pregnancy and psychological stress.

ACTH-dependent Cushing’s syndrome

The majority of ACTH-dependent Cushing’s syndrome is pituitary in origin and was first described by Harvey Cushing in 1932, now referred to as Cushing’s disease. Ectopic ACTH production may be due to carcinoid tumours (particularly bronchial), medullary thyroid carcinoma, small-cell lung cancer, neuroendocrine tumours and phaeochromocytoma.⁶⁴

Differentiating pituitary from ectopic ACTH-dependent Cushing’s syndrome is challenging and is best conducted in specialist endocrinology centres. History and examination may suggest the aetiology. Tumour markers such as urinary 5-hydroxyindoleacetic acid (5-HIAA), serum calcitonin, chromagranin A and gastrointestinal neuroendocrine hormones may be helpful in suspected ectopic ACTH secretion. The high-dose dexamethasone suppression test, corticotropin-releasing hormone test, pituitaryMRI and inferior petrosal sinus sampling may establish the cause of ACTH-dependent disease.^60,62

Imaging

Pituitary MRI is the cross-sectional study of choice for Cushing’s disease (see Fig. 3.15), though an adenoma is found in only 50–60% of patients with the disease as microadenomas are not visible on cross-sectional imaging.⁶⁶ Furthermore, non-functioning pituitary incidentalomas are present in up to 10% of the population, so interpretation of cross-sectional imaging must be done carefully in conjunction with biochemical tests.⁶⁷

Cross-sectional imaging of the neck, chest, abdomen and pelvis should be used to look for a cause when ectopic ACTH secretion is suspected. If the primary is not found on CT or MRI then somatostatin receptor scintigraphy (Octreoscan) may have a role, though often the causative lesion remains occult.⁶⁸

ACTH-independent Cushing’s syndrome

ACTH-independent Cushing’s syndrome is due to adrenal disease, and cross-sectional imaging with CT or MRI scan will usually identify an adrenal lesion. There is an overlap in the appearances of adrenal adenoma and carcinoma on CT imaging, though the risk of malignancy is increased in adrenal lesions that have high attenuation, irregular outline, delayed washout of contrast, are heterogeneous or >4 cm in size.^13,14 The higher water content of adrenal carcinoma is exploited in MRI using gadolinium enhancement or chemical shift imaging to differentiate benign from malignant lesions.¹⁵ Cushing’s syndrome due to adrenal carcinomas is often characterised by co-secretion of multiple hormones, particularly androgens.

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is an uncommon cause of Cushing’s syndrome characterised by bilateral nodular adrenal hyperplasia that is usually apparent on cross-sectional imaging. A similar appearance is seen in chronic Cushing’s disease when prolonged stimulation of the adrenal glands by high levels of circulating ACTH occurs. Primary pigmented nodular adrenocortical disease (PPNAD) is a rare condition that may be associated with other symptoms of Carney’s complex (see Chapter 4) such as myxomas, blue naevi and pigmented lentigines. The adrenal glands may appear normal on cross-sectional imaging in PPNAD.⁶³

Management

Case study 5 (discussion)

In this case the cause of Cushing’s was confirmed on the basis of pituitary MRI and IPSS, hence ectopic ACTH, which was one potential reason for treatment failure, was excluded. Following failed TSS for Cushing’s disease, laparoscopic bilateral adrenalectomy is effective at curing the disease. Perioperative steroids need to be given and the patient warned of the need for lifelong steroid replacement. Following adrenal surgery, this patient underwent radiotherapy to the pituitary to prevent Nelson’s syndrome.

Case study 6

A 30-year-old man with a strong family history of ischaemic heart disease is investigated for hypertension and found to have an elevated plasma aldosterone and suppressed renin activity off antihypertensive medication. CT scan of the abdomen shows a 1.2-cm left adrenal lesion (see Fig. 3.16). Plan the management of this patient.

Definition and aetiology

Primary hyperaldosteronism is the commonest cause of secondary hypertension and is due to inappropriate, excessive and autonomous adrenal secretion of aldosterone. Secondary hyperaldosteronism is due to activation of the renin–angiotensin mechanism in conditions such as liver failure, cardiac failure and nephrotic syndrome.

In 1954 Jerome Conn first described an aldosterone-producing adrenocortical adenoma in a young woman with hypertension; this has since been referred to as Conn’s syndrome. Primary hyperaldosteronism was considered to be uncommon, but is now recognised to occur in 5–13% of hypertensive patients.⁷² Bilateral adrenal hyperplasia and aldosterone-producing adrenocortical adenoma account for the majority of cases; other rare causes include aldosterone-secreting adrenocortical carcinoma, unilateral adrenal hyperplasia and familial glucocorticoid-suppressible aldosteronism.⁷³

Biochemical diagnosis

Primary hyperaldosteronism should be considered in all hypertensive patients presenting with hypokalaemia, severe or treatment-resistant disease, patients aged < 40 years or those with adrenal incidentaloma.⁷³ Hypertension is usually the only clinical sign. Hypokalaemia is absent in the majority of patients with primary aldosteronism but when present may lead to muscle weakness, cramps, palpitations and polyuria.

Plasma aldosterone concentration (PAC) and plasma renin activity (PRA) should be measured simultaneously in an ambulatory patient suspected of primary aldosteronism. An elevated PAC, suppressed PRA and PAC:PRA ratio >20–30 are consistent with the diagnosis,⁷³ though it is important to note that several drugs that affect the renin–angiotenson–aldosterone axis, including aldosterone antagonists, beta-blockers, calcium-channel blockers and angiotensin-converting enzyme inhibitors, can interfere with the results and so may need to be discontinued prior to biochemical tests.⁷⁴ Confirmatory tests with the fludrocortisone suppression test or by oral/intravenous saline loading to demonstrate that aldosterone secretion is inappropriate and non-suppressible may be required in borderline cases.⁷²

Imaging

Following biochemical confirmation, localisation with CT scan (or MRI) is undertaken. Aldosterone-producing adrenocortical adenomas are characteristically solitary, homogeneous and < 2 cm in size. Adrenocortical carcinoma usually appears as heterogeneous lesions >4 cm.⁹ CT in adrenal hyperplasia may be normal or show nodularity. Primary hyperaldosteronism may also be falsely attributed to non-functioning adrenal incidentaloma, which are common in older patients, or to a solitary dominant adrenal nodule seen in patients with bilateral adrenal hyperplasia.⁶

Aldosterone and cortisol are measured in blood taken from a catheter placed under radiological guidance into the adrenal vein via the inferior vena cava. The side of aldosterone hypersecretion can be established by AVS with a sensitivity of 95% and specificity of 100%. In cases of bilateral adrenal hyperplasia this will also allow the dominant side to be identified.⁷³

Management

When unilateral disease is confirmed on preoperative investigations, minimally invasive surgery is the preferred option for benign tumours, either transperitoneal or retroperitoneal.⁷⁷ Hypertension and hypokalaemia should be corrected prior to surgery. Postoperatively, hypertension improves in the majority but only resolves completely in about 50%. A family history of hypertension, need for multiple antihypertensive medications, age >50 years and long duration of hypertension predict postoperative antihypertensive requirement.⁷⁸

Medical management with aldosterone antagonists such as spironolactone or eplerenone can be an effective alternative in those patients who are unfit or decline surgery.⁷⁹ Spironolactone has a number of side-effects including gynaecomastia, loss of libido, menstrual irregularity and erectile dysfunction that limit its use, though these do not occur with eplerenone.⁷² The risks of malignancy need to be considered before advocating primary medical management for unilateral disease and the long-term cost of medication is higher than surgery.⁸⁰ Bilateral adrenal hyperplasia should be managed medically as surgery is unlikely to be curative. Patients with glucocorticoid-remediable aldosteronism should be treated with steroids to suppress ACTH secretion from the pituitary.⁷²

Case study 6 (discussion)

CT shows a 1.2-cm adrenal mass characteristic of Conn’s syndrome. This is very amenable to minimally invasive surgery, which is the preferred option in this case. Given the low incidence of adrenal incidentaloma in this age group it would be acceptable to perform surgery, without AVS. Alternatively, the patient can opt for a trial of treatment with lifelong mineralocorticoid antagonists. This is the more expensive option; side-effects may be debilitating and long-term surveillance will be needed.

Open adrenalectomy

Following the first successful adrenalectomy for phaeochromocytoma in 1927 by Charles Mayo, open surgery was the standard approach to the adrenal gland, but it has now been superseded by laparoscopic adrenalectomy for most adrenal tumours.⁷⁷ Open adrenalectomy, if necessary by a thoraco-abdominal incision, remains the approach of choice for malignant adrenal lesions, as it gives excellent access to enable control of major vessels and en bloc resection of adjacent organs, and minimises the risk of recurrence due to tumour disruption and spillage.

Laparoscopic adrenalectomy

Since laparoscopic adrenalectomy was first described by Michel Gagner in 1992,⁸⁴ it has become widely adopted by surgeons, anaesthetists and patients, and should now be considered the standard technique for adrenalectomy.

Several factors influence the choice of approach for minimally invasive surgery. The lateral (transabdominal) approach is the most popular as it provides a large working space, easy identification of anatomical landmarks, gravity facilitates mobilisation of surrounding organs (such as the spleen) and, in the event of conversion to an open procedure (which occurs in 5%), there is no need to reposition the patient. The lateral (transabdominal) approach is therefore particularly suitable for larger adrenal tumours, which are technically more difficult to dissect.⁸⁵

The posterior retroperitoneal approach gives direct access to the adrenal glands, avoiding the need to mobilise intra-abdominal viscera to allow access, so potentially reducing operating time, and avoids the need to reposition the patient with bilateral disease. However, the working space is smaller, access may be compromised in obese patients, anatomical landmarks are less easily seen and vascular control, if required, is more difficult.

The posterior retroperitoneal approach lends itself to smaller, particularly bilateral tumours, and when intra-abdominal adhesions from previous surgery make the transperitoneal approach difficult.⁸⁶

Although the laparoscopic approach is preferable for most benign adrenal pathologies, an upper size limit of 10–12 cm is generally advised, due to the technical difficulties of dissecting large tumours and their higher risk of malignancy. Laparoscopy has been advocated for large, potentially malignant adrenal tumours, though increased risk of recurrence has been cited as an indication for open surgery in these circumstances.30–33

Robotic adrenalectomy

Since the first robotic adrenalectomy was performed over a decade ago,⁸⁷ several centres have now reported their results. The subjective advantages of robotic surgery for the surgeon include the greater range of movement, more degrees of freedom and better visualisation, though it has not been shown whether these translate into better outcomes for the patient. Prospective randomised trials have shown similar outcomes to laparoscopic adrenalectomy but with higher costs and longer operating times for robotic adrenalectomy,⁸⁸ though operating time may decrease with progression along the learning curve.

Summary

Surgical preference and experience therefore dictate which technique is used in practice, as no single minimally invasive approach has been demonstrated to be superior.

1. McMinn, R.M.H., Last, R.J. Last’s anatomy: regional and applied, 9th ed. Edinburgh: Churchill Livingstone; 1994. [p. vi].

2. Ross, M.H., Reith, E.J., Romrell, L.J. Histology: a text and atlas, 2nd ed. Baltimore: Williams & Wilkins; 1989.

3. Sadler, T.W., Langman, J., Leland, J., et al. Langman’s medical embryology, 7th ed. Baltimore: Williams & Wilkins; 1995. [p. xi].

4. Pacak, K., Phaeochromocytoma: a catecholamine and oxidative stress disorder. Endocr Regul. 2011;45(2):65–90. 21615192

5. Bovio, S., Cataldi, A., Reimondo, G., et al, Prevalence of adrenal incidentaloma in a contemporary computerized tomography series. J Endocrinol Invest. 2006;29(4):298–302. 16699294

6. Kloos, R.T., Gross, M.D., Francis, I.R., et al, Incidentally discovered adrenal masses. Endocr Rev. 1995;16(4):460–484. 8521790

7. Mantero, F., Terzolo, M., Arnaldi, G., et al, A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab. 2000;85(2):637–644. 10690869

8. Terzolo, M., Bovio, S., Pia, A., et al, Management of adrenal incidentaloma. Best Pract Res Clin Endocrinol Metab. 2009;23(2):233–243. 19500766

9. Young, W.F., Jr., Clinical practice. The incidentally discovered adrenal mass. N Engl J Med. 2007;356(6):601–610. 17287480

10. Nieman, L.K., Approach to the patient with an adrenal incidentaloma. J Clin Endocrinol Metab. 2010;95(9):4106–4113. 20823463

11. Mazzaglia, P.J., Monchik, J.M., Limited value of adrenal biopsy in the evaluation of adrenal neoplasm: a decade of experience. Arch Surg. 2009;144(5):465–470. 19451490 This retrospective review of 163 adrenal biopsies demonstrated that only 16% of these showed malignancy in patients with isolated adrenal incidentalomas, compared to 70% of those in patients with a history of non-adrenal primary malignancy. The low negative predictive value and sensitivity of adrenal biopsy limited its value in the work-up of adrenal incidentalomas.

12. Dunnick, N.R., Korobkin, M., Imaging of adrenal incidentalomas: current status. AJR Am J Roentgenol. 2002;179(3):559–568. 12185019

13. Boland, G.W., Lee, M.J., Gazelle, G.S., et al, Characterization of adrenal masses using unenhanced CT: an analysis of the CT literature. AJR Am J Roentgenol. 1998;171(1):201–204. 9648789

14. Pena, C.S., Boland, G.W., Hahn, P.F., et al, Characterization of indeterminate (lipid-poor) adrenal masses: use of washout characteristics at contrast-enhanced CT. Radiology. 2000;217(3):798–802. 11110946

15. Israel, G.M., Korobkin, M., Wang, C., et al, Comparison of unenhanced CT and chemical shift MRI in evaluating lipid-rich adrenaladenomas. AJR Am J Roentgenol. 2004;183(1):215–219. 15208141

16. Grumbach, M.M., Biller, B.M., Braunstein, G.D., et al, Management of the clinically inapparent adrenal mass (“incidentaloma”). Ann Intern Med. 2003;138(5):424–429. 12614096 This summary from an expert panel convened by the National Institutes of Health sets out current recommendations for the management of adrenal incidentalomas.

17. Barzon, L., Scaroni, C., Sonino, N., et al, Risk factors and long-term follow-up of adrenal incidentalomas. J Clin Endocrinol Metab. 1999;84(2):520–526. 10022410 This study of 75 patients with adrenal incidentaloma followed up for a median of 4 years showed a risk of mass enlargement or hormonal hyperfunction of 18% and 9.5% at 5 years, though none developed malignancy.

18. Bernini, G.P., Moretti, A., Oriandini, C., et al, Long-term morphological and hormonal follow-up in a single unit on 115 patients with adrenal incidentalomas. Br J Cancer. 2005;92(6):1104–1109. 15770213

19. Terzolo, M., Bovio, S., Reimondo, G., et al, Subclinical Cushing’s syndrome in adrenal incidentalomas. Endocrinol Metab Clin North Am. 2005;34(2):423–439. 15850851

20. Groussin, L., Bonardel, G., Silvera, S., et al, ¹⁸F-Fluorodeoxyglucose positron emission tomography for the diagnosis of adrenocortical tumors: a prospective study in 77 operated patients. J Clin Endocrinol Metab. 2009;94(5):1713–1722. 19190108

21. Toniato, A., Merante-Boschin, I., Opocher, G., et al, Surgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study. Ann Surg. 2009;249(3):388–391. 19247023 Over a 15-year period, 45 patients with subclinical Cushing’s syndrome were randomised to surgery or conservative management. After mean follow-up of 7 years, greater improvements in diabetes, hypertension, hyperlipidaemia and obesity were observed in the surgical group.

22. Dackiw, A.P., Lee, J.E., Gagel, R.F., et al, Adrenal cortical carcinoma. World J Surg. 2001;25(7):914–926. 11572033

23. Aspinall, S.R., Imisairi, A.H., Bliss, R.D., et al, How is adrenocortical cancer being managed in the UK? Ann R Coll Surg Engl. 2009;91(6):489–493. 19558758

24. Allolio, B., Fassnacht, M., Clinical review. Adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab. 2006;91(6):2027–2037. 16551738

25. Schteingart, D.E., Doherty, G.M., Gauger, P.G., et al, Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocr Relat Cancer. 2005;12(3):667–680. 16172199

26. Weiss, L.M., Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol. 1984;8(3):163–169. 6703192

27. MacFarlane, D.A., Cancer of the adrenal cortex; the natural history, prognosis and treatment in a study of fifty-five cases. Ann R Coll Surg Engl. 1958;23(3):155–186. 13571886

28. Sullivan, M., Boileau, M., Hodges, C.V., Adrenal cortical carcinoma. J Urol. 1978;120(6):660–665. 731800

29. Fassnacht, M., Johanssen, S., Quinkler, M., et al, Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer. 2009;115(2):243–250. 19025987

30. Miller, B.S., Ammori, J.B., Gauger, P.G., et al, Laparoscopic resection is inappropriate in patients with known or suspected adrenocortical carcinoma. World J Surg. 2010;34(6):1380–1385. 20372905 This retrospective review of 88 patients who underwent laparoscopic or open surgery for ACC advised against laparoscopy for ACC based on a higher incidence of positive surgical margins and shorter time to recurrence in the laparoscopic group.

31. Palazzo, F.F., Sebag, F., Sierra, M., et al, Long-term outcome following laparoscopic adrenalectomy for large solid adrenal cortex tumors. World J Surg. 2006;30(5):893–898. 16680605

32. Brix, D., Allolio, B., Fenske, W., et al, Laparoscopic versus open adrenalectomy for adrenocortical carcinoma: surgical and oncologic outcome in 152 patients. Eur Urol. 2010;58(4):609–615. 20580485

33. Gonzalez, R.J., Shapiro, S., Sarlis, N., et al, Laparoscopic resection of adrenal cortical carcinoma: a cautionary note. Surgery. 2005;138(6):1078–1086. 16360394

34. Terzolo, M., Angeli, A., Fassnacht, M., et al, Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med. 2007;356(23):2372–2380. 17554118 This multicentre retrospective analysis demonstrated significantly longer recurrence-free survival in 47 patients who received adjuvant mitotane following radical surgery for ACC compared to 122 patients who did not (median time to recurrence 42 months vs. 10–25 months, respectively).

35. Berruti, A., Fassnacht, M., Baudin, E., et al, Adjuvant therapy in patients with adrenocortical carcinoma: a position of an international panel. J Clin Oncol. 2010;28(23):e401–e402 author reply e403. 20567001

36. Fassnacht, M., Hahner, S., Polat, B., et al, Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma. J Clin Endocrinol Metab. 2006;91(11):4501–4504. 16895957

37. Berruti, A., Terzolo, M., Sperone, P., et al, Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer. 2005;12(3):657–666. 16172198

38. Berruti, A., Ferrero, A., Sperone, P., et al, Emerging drugs for adrenocortical carcinoma. Expert Opin Emerg Drugs. 2008;13(3):497–509. 18764725

39. Eisenhofer, G., Bornstein, S.R., Brouwers, F.M., et al, Malignant pheochromocytoma: current status and initiatives for future progress. Endocr Relat Cancer. 2004;11(3):423–436. 15369446

40. Elder, E.E., Elder, G., Larsson, C., Pheochromocytoma and functional paraganglioma syndrome: no longer the 10% tumor. J Surg Oncol. 2005;89(3):193–201. 15719371

41. Madani, R., Al-Hashmi, M., Bliss, R., et al, Ectopic pheochromocytoma: does the rule often apply? World J Surg. 2007;31(4):849–854. 17372668

42. Gimenez-Roqueplo, A.P., Lehnert, H., Mannelli, M., et al, Phaeochromocytoma, new genes and screening strategies. Clin Endocrinol (Oxf). 2006;65(6):699–705. 17121518

43. Lenders, J.W., Eisenhofer, G., Mannelli, M., et al, Phaeochromocytoma. Lancet. 2005;366(9486):665–675. 16112304

44. Chetty, R., Familial paraganglioma syndromes. J Clin Pathol. 2010;63(6):488–491. 20498024

45. Jimenez, C., Cote, G., Arnold, A., et al, Review: Should patients with apparently sporadic pheochromocytomas or paragangliomas be screened for hereditary syndromes? J Clin Endocrinol Metab. 2006;91(8):2851–2858. 16735498 This literature review summarises the evidence for genetic testing in patients with sporadic phaeochromocytoma and recommends that this should be undertaken in those presenting < 20 years, or < 50 years with multiple phaeochromocytomas, sympathetic paraganglioma, or with clinical findings or family history suspicious of hereditary disease.

46. Grossman, A., Pacak, K., Sawka, A., et al, Biochemical diagnosis and localization of pheochromocytoma: can we reach a consensus? Ann N Y Acad Sci 2006; 1073:332–347. 17102103 This report summarises the recommendations of an expert panel on the biochemical diagnosis and localisation of phaeochromocytoma from the First International Symposium on Phaeochromocytoma in 2005.

47. Lenders, J.W., Pacak, K., Walther, M.M., et al, Biochemical diagnosis of pheochromocytoma: which test is best? JAMA. 2002;287(11):1427–1434. 11903030

48. Pacak, K., Eisenhofer, G., Ahlman, H., et al, Pheochromocytoma: recommendations for clinical practice from the First International Symposium, October 2005. Nat Clin Pract Endocrinol Metab. 2007;3(2):92–102. 17237836

49. Ilias, I., Pacak, K., Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab. 2004;89(2):479–491. 14764749

50. Mukherjee, J.J., Peppercorn, P.D., Reznek, R.H., et al, Pheochromocytoma: effect of nonionic contrast medium in CT on circulating catecholamine levels. Radiology. 1997;202(1):227–231. 8988215

51. Kinney, M.A., Narr, B.J., Warner, M.A., Perioperative management of pheochromocytoma. J Cardiothorac Vasc Anesth. 2002;16(3):359–369. 12073213

52. Prys-Roberts, C., Farndon, J.R., Efficacy and safety of doxazosin for perioperative management of patients with pheochromocytoma. World J Surg. 2002;26(8):1037–1042. 12192533

53. Tauzin-Fin, P., Sesay, M., Gosse, P., et al, Effects of perioperative alpha1 block on haemodynamic control during laparoscopic surgery for phaeochromocytoma. Br J Anaesth. 2004;92(4):512–517. 14766711

54. Lebuffe, G., Dosseh, E.D., Tek, G., et al, The effect of calcium channel blockers on outcome following the surgical treatment of phaeochromocytomas and paragangliomas. Anaesthesia. 2005;60(5):439–444. 15819762

55. Parnaby, C.N., Serpell, M.G., Connell, J.M., et al, Perioperative haemodynamic changes in patients undergoing laparoscopic adrenalectomy for phaeochromocytomas and other adrenal tumours. Surgeon. 2010;8(1):9–14. 20222397

56. Shen, W.T., Sturgeon, C., Clark, O.H., et al, Should pheochromocytoma size influence surgical approach? A comparison of 90 malignant and 60 benign pheochromocytomas. Surgery. 2004;136(6):1129–1137. 15657566 In this retrospective study, 90 malignant and 60 benign phaeochromocytomas were compared to determine whether tumour size affected the surgical approach. Laparoscopic adrenalectomy was considered safe in the majority, as tumour size did not discriminate benign from malignant phaeochromocytomas provided there was no evidence of local invasion or metastases.

57. Yip, L., Lee, J.E., Shapiro, S.E., et al, Surgical management of hereditary pheochromocytoma. J Am Coll Surg. 2004;198(4):525–535. 15051000

58. McNicol, A.M., Update on tumours of the adrenal cortex, phaeochromocytoma and extra-adrenal paraganglioma. Histopathology. 2011;58(2):155–168. 20718871

59. Suh, I., Shibru, D., Eisenhofer, G., et al, Candidate genes associated with malignant pheochromocytomas by genome-wide expression profiling. Ann Surg. 2009;250(6):983–990. 19661783

60. Newell-Price, J., Bertagna, X., Grossman, A.B., et al, Cushing’s syndrome. Lancet. 2006;367(9522):1605–1617. 16698415

61. Nieman, L.K., Biller, B.M., Findling, J.W., et al, The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;93(5):1526–1540. 18334580

62. Arnaldi, G., Angeli, A., Atkinson, A.B., et al, Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2003;88(12):5593–5602. 14671138

63. Porterfield, J.R., Thompson, G.B., Young, W.F., Jr., et al, Surgery for Cushing’s syndrome: an historical review and recent ten-year experience. World J Surg. 2008;32(5):659–677. 18196319

64. Aniszewski, J.P., Young, W.F., Jr., Thompson, G.B., et al, Cushing syndrome due to ectopic adrenocorticotropic hormone secretion. World J Surg. 2001;25(7):934–940. 11572035

65. Oldfield, E.H., Doppman, J.L., Nieman, L.K., et al, Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome. N Engl J Med. 1991;325(13):897–905. 1652686

66. Invitti, C., Pecori Giraldi, F., de Martin, M., et al, Diagnosis and management of Cushing’s syndrome: results of an Italian multicentre study. Study Group of the Italian Society of Endocrinology on the Pathophysiology of the Hypothalamic–Pituitary–Adrenal Axis. J Clin Endocrinol Metab. 1999;84(2):440–448. 10022398

67. Hall, W.A., Luciano, M.G., Doppman, J.L., et al, Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population. Ann Intern Med. 1994;120(10):817–820. 8154641

68. Ilias, I., Torpy, D.J., Pacak, K., et al, Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. J Clin Endocrinol Metab. 2005;90(8):4955–4962. 15914534

69. Chow, J.T., Thompson, G.B., Grant, C.S., et al, Bilateral laparoscopic adrenalectomy for corticotrophin- dependent Cushing’s syndrome: a review of the Mayo Clinic experience. Clin Endocrinol (Oxf). 2008;68(4):513–519. 17970770

70. Thompson, S.K., Hayman, A.V., Ludlam, W.H., et al, Improved quality of life after bilateral laparoscopic adrenalectomy for Cushing’s disease: a 10-year experience. Ann Surg. 2007;245(5):790–794. 17457173

71. Gil-Cardenas, A., Herrera, M.F., Diaz-Polanco, A., et al, Nelson’s syndrome after bilateral adrenalectomy for Cushing’s disease. Surgery. 2007;141(2):147–151. 17263968

72. Young, W.F., Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol (Oxf). 2007;66(5):607–618. 17492946

73. Funder, J.W., Carey, R.M., Fardella, C., et al, Case detection, diagnosis, and treatment of patients with primary aldosteronism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2008;93(9):3266–3281. 18552288

74. Seifarth, C., Trenkel, S., Schobel, H., et al, Influence of antihypertensive medication on aldosterone and renin concentration in the differential diagnosis of essential hypertension and primary aldosteronism. Clin Endocrinol (Oxf). 2002;57(4):457–465. 12354127

75. Nwariaku, F.E., Miller, B.S., Auchus, R., et al, Primary hyperaldosteronism: effect of adrenal vein sampling on surgical outcome. Arch Surg. 2006;141(5):497–503. 16702522 This retrospective study compared the results of adrenal venous sampling and CT in 39 patients with primary hyperaldosteronism and found the results to be concordant in only 54% of cases. It was concluded that CT was unreliable in lateralising the abnormal adrenal gland in primary hyperaldosteronism.

76. Tan, Y.Y., Ogilvie, J.B., Triponez, F., et al, Selective use of adrenal venous sampling in the lateralization of aldosterone-producing adenomas. World J Surg. 2006;30(5):879–887. 16680603

77. Assalia, A., Gagner, M., Laparoscopic adrenalectomy. Br J Surg. 2004;91(10):1259–1274. 15376201 This systematic review sets out the evidence comparing laparoscopic with open adrenalectomy and demonstrates that laparoscopic adrenalectomy is consistently associated with faster recovery and lower morbidity than the open approach.

78. Sawka, A.M., Young, W.F., Thompson, G.B., et al, Primary aldosteronism: factors associated with normalization of blood pressure after surgery. Ann Intern Med. 2001;135(4):258–261. 11511140

79. Ghose, R.P., Hall, P.M., Bravo, E.L., Medical management of aldosterone-producing adenomas. Ann Intern Med. 1999;131(2):105–108. 10419425

80. Sywak, M., Pasieka, J.L., Long-term follow-up and cost benefit of adrenalectomy in patients with primary hyperaldosteronism. Br J Surg. 2002;89(12):1587–1593. 12445071

81. VanWyk, J.J., Ritzen, E.M., The role of bilateral adrenalectomy in the treatment of congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2003;88(7):2993–2998. 12843131

82. Maris, J.M., Recent advances in neuroblastoma. N Engl J Med. 2010;362(23):2202–2211. 20558371

83. Hardy, R., Lennard, T.W., Subtotal adrenalectomy. Br J Surg. 2008;95(9):1075–1076. 18690616

84. Gagner, M., Lacroix, A., Bolte, E., Laparoscopic adrenalectomy in Cushing’s syndrome and pheochromocytoma. N Engl J Med. 1992;327(14):1033. 1387700

85. Lal, G., Duh, Q.Y., Laparoscopic adrenalectomy – indications and technique. Surg Oncol. 2003;12(2):105–123. 12946482

86. Walz, M.K., Alesina, P.F., Wenger, F.A., et al, Posterior retroperitoneoscopic adrenalectomy – results of 560 procedures in 520 patients. Surgery. 2006;140(6):943–950. 17188142

87. Horgan, S., Vanuno, D., Robots in laparoscopic surgery. J Laparoendosc Adv Surg Tech A. 2001;11(6):415–419. 11814134

88. Morino, M., Beninca, G., Giraudo, G., et al, Robot-assisted vs laparoscopic adrenalectomy: a prospective randomized controlled trial. Surg Endosc. 2004;18(12):1742–1746. 15809781

89. Berber, E., Tellioglu, G., Harvey, A., et al, Comparison of laparoscopic transabdominal lateral versus posterior retroperitoneal adrenalectomy. Surgery. 2009;146(4):621–626. 19789020 This retrospective study found similar perioperative outcomes in 159 patients who underwent lateral laparoscopic transabdominal adrenalectomy or posterior endoscopic retroperitoneal adrenalectomy when selected on the basis of previous abdominal surgery, body mass index, tumour size and bilaterality.

90. Naya, Y., Nagata, M., Ichikawa, T., et al, Laparoscopic adrenalectomy: comparison of transperitoneal and retroperitoneal approaches. BJU Int. 2002;90(3):199–204. 12133053

91. Schreinemakers, J.M., Kiela, G.J., Valk, G.D., et al, Retroperitoneal endoscopic adrenalectomy is safe and effective. Br J Surg. 2010;97(11):1667–1672. 20665481

92. Gagner, M., Pomp, A., Heniford, B.T., et al, Laparoscopic adrenalectomy: lessons learned from 100 consecutive procedures. Ann Surg. 1997;226(3):238–247. 9339930

93. Henry, J.F., Defechereux, T., Raffaelli, M., et al, Complications of laparoscopic adrenalectomy: results of 169 consecutive procedures. World J Surg. 2000;24(11):1342–1346. 11038204