Tumours of the adrenal medulla

Tumours of the adrenal medulla are classified as follows:

neoplasms of the sympathetic neurons:

     ganglioneuroma,

     neuroblastoma (sympatheticoblastoma);

neoplasm of chromaffin cells: phaeochromocytoma.  

Those occurring at any age

 A ganglioneuroma is relatively benign. This neoplasm is symptomless, grows to a large size and constitutes one of the varieties of retroperitoneal ~sarcoma’ (Chapter 56). Only 15 per cent involve the adrenal, the remainder occurring in any position along the sympathetic chain. If removed completely at a comparatively early stage, a cure may be expected.

 Those occurring in infants and children

 Neuroblastoma

 Neuroblastoma is a malignant tumour of neural crest origin arising from sympathetic nervous tissue from the orbit to the pelvis. Three-quarters arise in the abdomen and half of these from the adrenal gland. It is the most common solid tumour of infancy and childhood, and by far the most common in the newborn. The incidence is approximately 1 per 10 000 live births. Ninety per cent of cases of neuroblastoma occur under the age of 8; over half occur in children under 2 years.

Clinical features. Three-quarters of patients present with an abdominal mass. Metastatic spread, via lymphatics and bloodstream, occurs at an early stage, and approximately 70 per cent of cases have metastases at the time of initial diagnosis (Fig. 45.12). Weight loss, failure to thrive, abdomi­nal pain and distension, fever and anaemia may be present. Excessive catecholamine production may cause hypertension, flushing, sweating and general irritability. Some of these tumours produce VIP, which results in watery diarrhoea and hypokalaemia. Acute cerebellar ataxia characterised by opsomyoclonus and chaotic nystagmus or the ‘dancing eye syndrome is an unusual manifestation of neuroblastoma of unknown cause.

Diagnosis. Over 80 per cent of patients excrete cate­cholamine metabolites in the urine. The most common by­products assayed in the urine are vanillylmandelic acid (VMA) and homovanillic acid (HVA), and such measure­ments may be useful in monitoring the course of the disease.

Plain radiography shows fine, stippled calcification in 50 per cent of cases. Abdominal ultrasound examination shows the anatomical margins and extent of the disease, and is particularly helpful in evaluating the results of treatment.

CT demonstrates calcium in 80 per cent of cases and accurately evaluates intraspinal extension as well as hepatic and renal metastatic disease. MRI is a promising technique which may supersede CT in many patients. It will also evaluate bone marrow metastases.

Meta-iodobenzyl-guanidine (MIBG, see below) is metabolised by neuroblastoma cells and may be used for imaging, especially in small residual tumours not evident on other conventional imaging studies.

Bone-seeking isotope (technerium-99m), as well as demonstrating bone involvement, is also concentrated by 60 per cent of adrenal lesions.

Treatment. Although surgical excision is the mainstay of cure in localised disease, widespread disease at presentation often makes surgery inappropriate as the primary form of treatment. Multi drug chemotherapy and radiotherapy are instituted in advanced disease. Surgical excision is appropriate in disease confined to one side of the midline, or as a delayed treatment following control by chemotherapy and radiotherapy. However, the cure rare remains low with an overall survival rare of 30—35 per cent. Age has an important favourable influence on prognosis — the younger the patient the better the prognosis, and children in the first year of life have a long-term survival rare of 70 per cent.

 Phaeochromocytoma

 Phaeochromocytoma has been called the ‘10 per cent tumour’ because approximately 10 per cent are bilateral, malignant, extra-adrenal, multiple, familial and occur in children. Although 90 per cent of phaeochromocytoma arise in the adrenal medulla, they may be found anywhere along the paraganglionic system. The most common extra-adrenal site is the organ of Zuckerkandl at the aortic bifurcation and less common sires are the urinary bladder, renal hilum, chest and neck. Extra-adrenal tumours have a higher incidence of malignancy of 25—40 per cent. A phaeochromocytoma is a soft, vascular tumour usually less than 5 cm in diameter but occasionally very much larger. It is usually pink-tan in colour and is composed of large, differentiated, sympathetic gan­glion cells and a few fibres, enclosed in a delicate capsule. It owes its name to the presence of chromaffin granules. This tumour occurs in both sexes, usually during early adult life or middle age. It produces, either intermittently or continu­ously, an excess of adrenaline, and especially of nor-adrenaline: the ratio of the latter to the former often being as high as 20:1 causing hypertension which is either paroxysmal or persistent. The latter predominates statistically and probably indicates a late stage of the disease. Consequently all patients under 60 years of age who suffer from sustained arterial hypertension deserve routine tests to confirm or exclude a phaeochromocytoma. Although not more than 0.5 per cent of cases of hypertension are caused by a phaeochromocyroma, at the Mayo Clinic2, where routine diagnostic procedures are undertaken to confirm or exclude the presence of this tumour in all cases of hypertension, the percentage has been stated to be nearly 3 per cent. Untreated, it progresses to a fatal termination from cardiac dysrhythmia or cerebral haemorrhage.

The importance of phaeochromocytoma as a component of the multiple endocrine neoplasia syndromes MEN IIa and MEN IIb should be remembered (see earlier and Chapter 44).

Clinical features. A typical complaint is that of fear — ‘I thought I was going to die’. The most common symptoms, in order of frequency, are: headache (55 per cent), palpitation, vomiting, swearing, dyspnoea, weakness and pallor — i.e. the symptoms of adrenal overdosage. The paroxysmal attack may vary from a few minutes to some hours. The blood pressure may be very high and hyperglycaemia present. The symptoms may be mistaken for hyperthyroidism, hypo­calcaemia, an acute anxiety state, paroxysmal atrial tachycardia and carcinoid syndrome. The main obstacle to the diagnosis of a phaeochromocytoma is the failure to think of it as a cause of the observed symptoms.

 Diagnostic tests

 The basis of the laboratory diagnosis is measurement of elevated catecholamines and their metabolites in urine and blood.

  Urine studies. Confirmation of the diagnosis is usually readily made by measurement of free catecholamines, VMA and metadrenalines (metanephrines) in 24-hour collections of - urine. Patients with phaeochrornocytoma usually excrete free catecholamines in excess of 100 ag/24 hours, VMA in excess of 7 mg/24 hours and metadrenalines in excess of 1.3 mg/24 hours. Laboratories vary in the reliance they place on these various estimations; at the Mayo Clinic, for example, most reliance is placed on urinary metadrenalines. False-positive elevations of metadrenaline excretion may occur in patients taking monoamine oxidase-inhihiting drugs, and in those who have recently had angiographic contrast studies.

Plasma catecholamines. Sensitive assays are now available for plasma catecholamines and patients with phaeochrornocytoma usually have total plasma catecholamines in excess of 1000 pg/rn1. Such assays may be highly accurate in confirming the diagnosis, but plasma catecholamines may not be continuously elevated and many factors, including exercise, severe illness and the drug methyldopa, may influence the levels.

 Localisation tests

  Computerised tomography (Fig. 45.13) is the method of choice for localisation with an accuracy of 90—95 per cent and has largely replaced more invasive and hazardous techniques such as arterio­graphy and selective venous sampling. Because of their size, most adrenal phaeochromocytomas are also visible on ultrasound scanning.

       Radionuclide imaging. The development of a specific radionuclide for catecholamine precursors, iodine-labelled MIBG, has been a significant recent advance in the localisation of adrenal and ectopic phaeochromocytomas. Only abnormal areas of adrenergic tissue show uptake of MIBG and normal adrenals do not visualise. MIBG scanning may be particularly valuable in locating an ectopic phaeochromocytoma when CT shows normal adrenals (Fig. 45.14).

 Preoperative preparation

 Catecholamine-secreting tumours are a challenge to both the surgeon and anaesthetist. A patient with phaeochromocytoma is hypovolaemic because of the contraction of the vascular bed by excess circulating catecholamines. During surgery handling of the tumour may increase circulating catecholamine levels up to 600-fold causing large swings in blood pressure and cardiac arrhythmias. Severe hypotension may follow removal of the tumour. These dangers may be minimised by careful preoperative preparation. Effective blockade of the effects of high circulating catecholamines has significantly reduced the operative mortality and is mandatory. The alpha-adrenergic blocking drug phenoxybenzamine in an initial dose of 20—40 mg/day is increased until hypertension is controlled and mild orthostatic hypotension induced. Such preparation takes 1—3 weeks. In most centres a beta-blocking drug such as propranolol is added for 3~7 days before operation to control tachycardia and arrythmias. Extra fluids should be given iv. to occupy the sudden expansion of the vascular bed when the tumour is removed, and a preoperative fluid ‘overload’ is advisable.

 Operation

 During surgery, intravenous infusions of alpha- and beta-blocking drugs are given, if required, as determined by the blood pressure, pulse rate and central venous pressure. The hazardous phases in the operation are during the induction of anesthesia, positioning of the patient on the operating table, when the tumour is manipulated, and immediately after removal of the tumour. Sodium nitroprusside, a direct peripheral vasodilator, is the drug of choice for the management of significant intraoperative hypertension.

Even though preoperative localisation is highly accurate, the possible multiplicity of tumours (intra- and extra-adrenal) and the need to avoid excessive tumour manipulation necessitate a generous transabdominal approach. The tumour should be manipulated as little as possible and the main adrenal vein ligated as a first step. Inadvertent rupture of the tumour should be avoided as this may result in local spread and recurrence of even apparently benign tumours.