16 Michael Stechman and David Scott Coombes Department of Endocrine Surgery, University Hospital of Wales, Cardiff, UK Managing patients with adrenal disease requires a detailed knowledge of endocrinology, pathology, radiology as well as both laparoscopic and major resectional surgery. It is important that patients are managed in a multidisciplinary setting. The principle tenets of adrenal surgery are to establish the presence or absence of endocrine dysfunction, determine the likelihood of adrenal malignancy, and assess the requirement for medical stability in the preoperative period. Laparoscopic surgery is the gold standard approach for benign tumours. Open surgery is mandatory for adrenocortical carcinoma. Keywords: adrenal; cortex; medulla; Conn syndrome; Cushing syndrome; pheochromocytoma; adrenalectomy Management of patients with adrenal disease should be conducted within a multidisciplinary team. This team should involve an endocrinologist, a surgeon, a radiologist, a pathologist, a biochemist, an intensivist, and at times, access to a geneticist and an oncologist. Patients presenting with adrenal disease should be managed according to the five principles of adrenal surgery: The adrenal glands are paired and lie superior to the kidneys, historically known as supra renal glands (Figure 16.1). The adrenal has two distinct parts: (i) the cortex, a busy endocrine gland subordinate to the pituitary, and (ii) the medulla, a specialised part of the sympathetic nervous system. Each adrenal measures about 5 × 1 cm and weighs about 5 g. They are not symmetrical. However, each adrenal gland is shaped like a cocked hat. Its cross‐section resembles a triple sandwich: the outermost layer is the yellow zona glomerulosa, next the zona fasciculata, and third, the brown zona reticularis. Finally, there is a vascular filling – the medulla. (Figure 16.2). The triple layer of cortex is only a few millimetres thick – hence the term ‘suprarenal capsule’. Figure 16.1 Surgical relations of the adrenal glands. Figure 16.2 The sandwich structure of the adrenal: zona glomerulosa (aldosterone); zona fasciculata (cortisol); zona reticularis (androgens); and medulla (adrenalin and noradrenalin). Each of the three layers of the cortex has a different function. The foamy cells of the outermost zona glomerulosa form aldosterone. The zona fasciculata – so called because its cells are lined up in orderly bundles – produces glucocorticoids, mainly cortisol. The zona reticularis produces androgens. The medulla is made of pheochromocytes surrounded by spongy vascular spaces, rich in sympathetic ganglion cells. The pheochromocytes make the catecholamines adrenalin and noradrenalin. Because these turn brown when oxidised, this is called the ‘chromaffin reaction’. Above each adrenal lies the diaphragm; medially are the aorta or the vena cava; laterally is the abdominal wall; inferiorly is the kidney to which the adrenal is so firmly attached that pulling down the kidney is a useful way of bringing the adrenal into a surgical incision. In front are the duodenum and colon: behind the diaphragm, 12th rib, and the pleural recess. The right gland has a pyramidal shape and lies between the inferior vena cava and the right crus of the diaphragm. Its upper part lies in contact with the bare area of the liver, whilst its lower half has a peritoneal covering. The left gland is more crescentic in shape and lies on the medial border of the left kidney above the hilum, sandwiched between tail of pancreas and left crus of diaphragm. The adrenal is supplied by small branches of the phrenic, renal, and lumbar arteries. Blood leaves the hilum through a single vein which flows into the renal vein on the left side and the inferior vena cava on the right. These adrenal veins are easily torn; on the right, such a tear may lead to daunting haemorrhage from the vena cava. The adrenal medulla has a rich splanchnic nerve supply which is stimulated by sympathetic pre‐ganglionic nerves of the aortic and renal sympathetic plexuses. There are three distinct zones within the cortex (Figure 16.2), but they all synthesise and secrete steroid hormones derived from cholesterol. The cells of the zona glomerulosa make aldosterone – the 18‐aldehyde of corticosterone, which is released under the action of angiotensin II, and by retaining water and salt in the distal tubules helps to sustain a rise in blood pressure by increasing blood volume. The zonae fasciculata and reticularis are controlled by adrenocorticotrophic hormone (ACTH) from the anterior pituitary, which in turn responds to ACTH‐releasing hormone of the hypothalamus. The zona fasciculata forms the glucocorticoids cortisol and corticosterone, and the mineralocorticoid deoxycorticosterone. The glucocorticoids – all 17‐hydroxycorticosteroids – can be measured in the urine. Cortisol can be measured in the plasma where it rises and falls according to the time of day, usually being lowest in the morning and highest in the evening. Glucocorticoids are so named because they increase the production of glucose. Many synthetic glucocorticoids are available (e.g. prednisone, prednisolone, betamethasone, and dexamethasone), which all vary in the relative strength of their effects on inflammation and sodium retention. The zona reticularis forms a little testosterone, and more of the androgen precursors dehydroepiandrosterone and androstenedione, which are converted into testosterone in tissue. The metabolic end product of all these androgens appears in the urine as the 17‐ketosteroids. The androgens stimulate growth and the appearance of male secondary sexual hair. The adrenal medulla secretes the catecholamines adrenaline (80%) and noradrenaline (20%) and small amounts of dopamine (Figure 16.3). Unlike other adrenergic neurons, those of the medulla express phenylethanolamine‐N‐methyltransferase (PNMT) which catalyses the conversion of noradrenaline to adrenaline. Which are metabolised to normetanephrin and metanephrin. Their common metabolic end result in the urine is vanillyl mandelic acid (VMA). The effects of catecholamine excess include increased liver and skeletal muscle glycogenolysis, increased metabolic and respiratory rate, and greater force and rate of myocardial contraction. Noradrenalin raises the blood pressure by increasing peripheral resistance (by driving vasoconstriction) without changing the cardiac output. Adrenalin increases cardiac output by raising pulse rate and systolic pressure, without increasing peripheral vascular resistance (drives dilation of blood vessels in the liver and muscle). These effects are mediated by alpha‐adrenergic receptors that bind both catecholamines and beta adrenergic receptors that preferentially bind adrenaline; it is the expression of alpha and beta receptors by different tissues that permits differing effects of both hormones when they are released simultaneously. Figure 16.3 Hormonal control of the layers of the adrenal: the zona glomerulosa secrete aldosterone under the influence of angiotensin II. The hypothalamus secretes corticotropin‐releasing hormone (CRH), which stimulates the anterior pituitary to secrete adrenocorticotropic hormone (ACTH), which stimulates the zona fasciculata to secrete the corticosteroids, and the zona reticularis to secrete androgens. Adrenal tumours are classified not only according to neoplasia but also regarding their endocrine function (Table 16.1). Table 16.1 Classification of pathology of the adrenal gland. Loss of adrenal function will result in electrolyte disturbance, hypoglycaemia, and circulatory collapse. In the chronic variety serum ACTH levels are high, and the patient may become pigmented due to excess circulating melanocyte stimulating hormone (MSH). This occurs because ACTH and MSH are components of a common prohormone, pro‐opiomelanocortin (POMC), and when ACTH is cleaved from POMC, MSH is also released. There are a number of different scenarios for how this event might arise. The most common cause is from primary disease of the adrenal itself. This is an autoimmune disease resulting in lymphocytic infiltration of the gland. Other causes include bilateral metastases, tuberculosis, sarcoidosis, and amyloid deposition. This arises from failure of the hypothalamic pituitary axis. It might result from pituitary surgery, irradiation, tumour expansion, or infarction. Three conditions result from overproduction of steroids. ACTH‐dependent hypercortisolism from an anterior pituitary tumour is defined as Cushing disease. Cushing syndrome arises from ACTH‐independent hypersecretion of cortisol from tumours of the zona fasciculata, of which half are benign and half are malignant. Cushing disease accounts for 80% of all Cushing pathology and causes bilateral adrenal hyperplasia. This typically affects young (30–40 years) women (4 : 1). The excess corticosteroid leads to proteolysis and glycogen deposition resulting in the ‘lemon‐on‐sticks’ appearance (Figure 16.4), buffalo humps, and moon face (Figure 16.5). Patients are affected with hypertension, thin skin, bruising, and depression. Other symptoms include hirsutism, myopathy, and oligomenorrhoea or impotence. Osteoporosis may be severe. Subclinically, Cushing syndrome refers to patients with mild autonomous cortisol excess in the absence of any clinical signs. Figure 16.4 Patient with Cushing syndrome with typical ‘lemon‐on‐stick’ body habitus. Figure 16.5 Caricature showing the principal clinical features of Cushing syndrome. Endocrinology Hypercortisolism is confirmed by demonstrating a nonsuppressible 8 a.m. serum cortisol following administration of 1 mg oral dexamethasone the night before (low‐dose overnight dexamethasone suppression test) or the finding of raised salivary and urinary‐free cortisol levels. Measuring the ACTH should distinguish pituitary and primary adrenal disease. Radiology Cushing disease is imaged with pituitary magnetic resonance imaging (MRI) and bilateral inferior petrosal sinus venous sampling. ACTH‐independent disease is investigated with an adrenal cross‐sectional imaging (Figure 16.6). In addition to localising the tumour, features of malignancy should be carefully considered (see Sections 16.4.3.1 and 16.4.6). Figure 16.6 Unenhanced computed tomography (CT) scan showing primary cortical tumour of the right adrenal causing Cushing syndrome. Cushing disease is best managed with hypophysectomy. Adrenal surgery is only considered when pituitary surgery fails and the Cushing disease becomes severe. At that point, bilateral adrenalectomy is the operation of choice. Cushing syndrome is managed with adrenal surgery. In the absence of suspicion for carcinoma, the laparoscopic approach is preferred. Preoperatively, optimisation of hypertension, diabetes, and muscle strength should be achieved. Severe hypercortisolism is best controlled medically (e.g. with ketoconazole or metyrapone; in severe cases, etomidate infusion may be necessary, but this requires intubation and ventilation in a critical care environment). The contralateral adrenal will be suppressed and adjuvant steroid supplementation must be prescribed pre‐ and postoperatively in liaison with the endocrinologist. These patients have delicate skin and brittle bones and so patients should be handled with the upmost care. Furthermore, surgery is associated with an increased risk of infection and thromboembolic disease, therefore, thromboprophylaxis is given. Subclinically, Cushing syndrome may be associated with hypertension and impaired glucose tolerance, but the optimal treatment remains unclear. Typically identified as part of the investigation of an adrenal incidentaloma and may be an indication for adrenalectomy, but long‐term follow‐up data is scanty [1]. Clinical Features PA is a disorder with autonomous hypersecretion of aldosterone which leads to sodium and fluid retention, thereby causing hypertension (Figure 16.7). Hypokalaemia may be present, especially in severe and long‐standing cases. Plasma renin is suppressed leading to a high plasma aldosterone to renin ratio (PARR). It is estimated that PA may account for between 5 and 18% of the general hypertensive population [2]. There are two major subtypes of PA. Bilateral adrenal hyperplasia (BAH) accounts for 50–70% [3]. Patients with BAH are generally older, have milder hypertension, and are more often normokalaemic. Aldosterone‐producing adenoma (APA, also known as Conn adenoma) is unilateral and should be considered in younger patients with more severe disease. Adrenocortical carcinoma (ACC) accounts for about 1% of cases of PA. Figure 16.7 Principal features of Conn syndrome. Patients present with hypertension, which is often refractory to treatment (requiring three or more drugs). Fatigue, muscle cramps or weakness, thirst, and polyuria are secondary to hypokalaemia, but half of patients are normokalaemic. Endocrinology The established screening test is the PARR. In most patients, the renin is suppressed the plasma aldosterone concentration is raised and a ratio of >800 is diagnostic. Several antihypertensive agents interfere with the renin‐angiotensin system and may affect the PARR. Beta‐blockers and spironolactone should be stopped two weeks before testing. It is also advised to use a second confirmatory test (fludrocortisone suppression test) and the involvement of an endocrinologist is essential. Localisation Once PA has been biochemically proven, it is essential to determine if this is unilateral or bilateral as it determines whether surgery is indicated. Conn tumours are nicknamed ‘canary tumours’ because they are small and yellow. In fact APAs may be as small as a few millimetres and beyond the resolution of available cross‐sectional imaging. CT should be performed in all patients; however, normal CT does not exclude Conn tumours and the discovery of a tumour does not prove unilateral disease because it may be a nonfunctioning incidentaloma. Current guidelines recommend adrenalectomy without other localising tests in younger patients (<40 years) with an adrenal mass > 10 mm on CT [4]. In all other patients, a functional test should be undertaken. Adrenal Venous Sampling This is the gold standard. Each adrenal vein is catheterized via the femoral vein (Figure 16.8). Samples are drawn from the adrenal veins, the inferior vena cava (IVC) and the periphery. Assay for cortisol confirms the accurate placement of the catheter within the adrenal vein. Samples are taken for aldosterone and the aldosterone‐to‐cortisol ratios between adrenals are compared. A ratio greater than two confirms laterality (or a ratio of 4 : 1 if synacthen is given). Figure 16.8 Selective adrenal venous sampling demonstrating the catheters in each adrenal vein. Patients with BAH should be treated medically with a mineralocorticoid receptor antagonist; spironolactone, or eplenerone. Laparoscopic adrenalectomy should be offered in cases of unilateral PA [5]. Hypertension may be cured in up to one‐third of patients, but for the remainder, it becomes easier to control. The preoperative response to hypertension control by spironolactone is a good predictor for those whose hypertension will be cured [6]. These are rare accounting for four cases per million of population. Up to 30% are malignant. Patients present with hirsutism, acne, and an enlarged laryngeal prominence (Figure 16.9). Figure 16.9 Acne and hirsutism in a 24‐year‐old woman with a benign androgen‐secreting tumour. The diagnosis is confirmed by measuring serum testosterone and its precursors androstenedione and dehydroepiandrosterone‐sulphate (DHEAS). Elevation of DHEAS is observed in 80% of adrenocortical cancers. Either MRI or CT scanning will localise the tumour and identify risks for malignancy such as size, local invasion, and presence of metastases. Adrenalectomy will aim to cure the patient. In circumstances when malignancy is suspected, an open approach should be adopted (see Section 16.4.6.). An adrenal mass discovered incidentally during an imaging investigation for a nonadrenal disorder. Autopsy studies estimate the prevalence of adrenal tumours to be 6% [7], and so as imaging resolution improves the prevalence of adrenal incidentalomas on cross‐sectional abdominal imaging nears 6% [8]. Most (80%) patients are entirely asymptomatic when they have a nonfunctioning adenoma [9], but subclinically, Cushing syndrome (5%), pheochromocytoma (5%), and Conn tumours (1%) feature in the differential diagnosis. The differential diagnosis of an adrenal mass is shown in Table 16.2. The purposes of investigations are to identify functioning tumours or those that could be malignant. Patients are therefore screened for Conn tumours, Cushing syndrome, and pheochromocytoma. Factors that raise suspicion for malignancy include virilisation, rapid growth, certain radiological features on MRI/CT, and positive uptake on a positron emission tomography (PET) scan. The MRI/CT features to suggest malignancy include a large size (>6 cm), heterogeneous uptake of contrast, an irregular outline, and especially the presence of local invasion or metastases (Figure 16.10). The best modalities to predict malignancy are MRI and PET scan [10]. Biopsy should never be undertaken for a pheochromocytoma. Biopsy should not be undertaken for adrenocortical cancer as the histology report will be uncertain and biopsy risks tumour seeding. Biopsy might be considered when there is a known extra‐adrenal primary malignancy as an investigation to diagnose metastasis. Table 16.2 Differential diagnosis of an adrenal mass on imaging. Figure 16.10 Coronal section of enhanced computed tomography (CT) scan. A left adreno‐cortical carcinoma is large with a heterogeneous pattern of uptake of contrast with an irregular outline and suspicion of local invasion of the upper pole of the kidney. Surgery is indicated for functional tumours, primary adrenal malignancy, and metastasectomy, if the disease is isolated. The risk of primary malignancy in unselected incidentaloma cases is 0.1% [9]. The risk of malignancy rises as the tumour size gets bigger (>4 cm: 10%, vs. >6 cm: 25–90%) [11]. But there is no benefit to excising all incidentalomas because it does not lead to an increase in the incidence of excising small cancers [12]. Surgery is recommended for tumours equal to or greater than 4 cm in maximum diameter. For the majority of patients found to have a smaller (<4 cm) nonfunctioning tumour, it is recommended that they undergo a further adrenal scan at a 3–6 months interval to exclude early growth. There is no consensus about follow‐up beyond that period. However, there is evidence that a tumour greater than 3 cm has an increased risk of developing hyperfunction over time [13]. Cysts in the adrenal may be so large as to be palpable. They rarely occur in infants [14]. They displace the kidney and are easily imaged by ultrasound and CT scanning. True cysts may be lymphangiomatous with milky fluid; pseudocysts are reported from degeneration or haemorrhage in a normal gland or tumour [15]. In adults, they are usually detected by chance, but occasionally become infected or give rise to retroperitoneal haemorrhage [16]. In the tropics they may occasionally be hydatid cysts [17]. Imaging by CT scan is usually diagnostic. Cysts have a smooth outline, are isodense, and appear fluid filled. Long‐standing cysts may show calcification in the wall. Cysts of the adrenal can usually be left alone unless they are causing discomfort by pressure on adjacent organs when they can be aspirated under radiological guidance. Recurrent cysts following aspiration can be considered for laparoscopic resection [18] or fenestration. These are rare benign tumours composed of mature adipose and haematopoietic tissue. They can arise from either the adrenal cortex or medulla. Their size varies from millimetres to more than 20 cm. Typically, they are discovered as incidental findings during abdominal imaging (ultrasound, CT, etc.). They account for 3–5% of all adrenal tumours and are commonest in the sixth decade of life. They are hormonally inactive but may coexist with functioning adrenal tumours. They are usually asymptomatic. Myelolipomas appear as well‐delineated heterogeneous masses with low‐density mature fat (less than −30 HU) interspersed with more dense myeloid tissue (Figure 16.11). Fine‐needle aspiration cytology should be considered when CT scanning is non‐diagnostic. Figure 16.11 Enhanced computed tomography (CT) scan of myelolipoma of the right adrenal gland with a very low Hounsfield unit (HU) density (−54). Most of these tumours can be left alone. Surgery is only indicated when there is evidence of endocrine function or if the surgeon is convinced that a larger tumour (>70 mm) is the cause of local symptoms [19]. This is a rare aggressive tumour with a poor prognosis. It affects about one to three people per million of population. Nonfunctioning tumours will either present as an incidentaloma or with symptoms and signs of an abdominal mass. Functioning tumours will manifest with rapid onset of symptoms and signs of Cushing syndrome. Virilisation is highly suggestive of malignancy. Endocrinology Patients must be screened for Cushing syndrome and pheochromocytoma. If negative, in the presence of hypertension, Conn tumours but should be considered (very rare). Plasma androstenedione, testosterone, and DHEAS should be measured. Analysis of urine from patients with ACC (urinary metabolomics) has demonstrated that there is a specific ‘signature’ for malignancy, whereby patients with malignant tumours exhibit increased urinary excretion of steroid precursors compared with patients with benign disease [20]. Radiology CT scanning will identify the hallmarks for malignancy – a large irregular mass with delayed washout of contrast (<50% at 10 minutes), uneven enhancement, possible local invasion, and distant metastases. PET scanning is effective at assessing metastatic disease. Surgery offers the best chance of survival. There is no role for laparoscopic surgery in most cases, and even for small tumours that might be resectable via a laparoscopic approach, its use is controversial. The philosophy is to perform an R0 (clear margins) en‐bloc resection. Traditionally invasion of the IVC (on the right) and superior mesenteric artery (SMA) (on the left) determined whether the tumour could be resected. Nowadays this surgery should be undertaken in specialist surgical centres with input from endocrine, hepatic (possibly transplant) and vascular surgeons. Even if R0 is not feasible, there may be merit in debulking the disease prior to chemotherapy. The multidisciplinary team should discuss adjuvant chemotherapy with mitotane by an oncologist familiar with this treatment and it should be considered in tumours with a Ki67 proliferation index >10% or those with incomplete resection or metastases. There is no conclusive evidence of benefit in those with complete resection and no known metastatic disease (Table 16.3) [21]. It is important to establish plasma levels within a defined therapeutic range. Mitotane can induce adrenal insufficiency necessitating steroid replacement. Table 16.3 Adjuvant therapy according to World Health Organisation stage in adrenocortical carcinoma. UICC, Union Internationale contre le Cancer. T1: Tumour<5 cm; T2: >5 cm, T3: tumour infiltration into surrounding tissue, T4: Tumour invading adjacent organs. N0: no lymph node metastases; N1: lymph node metastases. M1: distant metastases. The adrenal glands are the most common deposit for metastases. Common primary cancers that metastasise to the adrenal include lung, kidney, colon, prostate and breast. Synchronous metastases are defined as those with a disease‐free survival of <6 m. Metastases diagnosed after 6 m are termed ‘metachronous’. The diagnosis usually starts with staging tests for a known carcinoma. PET scanning is useful in selecting those with an isolated metastasis (Figure 16.12). Biopsy should only be considered when imaging is equivocal. Figure 16.12 Fluorodeoxyglucose (FDG) sagittal, coronal, and cross‐sectional fused positron emission tomography‐computed tomography (PET‐CT) scan demonstrating high uptake in a right adrenal tumour (metastasis). Adrenalectomy is considered in the rare circumstance when the metastasis is isolated without evidence of other spread. There is a paucity of data regarding the merits of this operation, but the evidence suggests that there is greater benefit for metachronous disease [22]. Laparoscopic adrenalectomy is the preferred approach, with open surgery being reserved for the presence of local invasion. In circumstances when a patient develops a second isolated adrenal metastasis, adrenal surgery will render the patient (who is possibly receiving chemotherapy) steroid dependent. Renal cell cancer is the most common scenario and the decision to operate should be judged on its individual merits by the multidisciplinary team. There is anecdotal evidence suggest that increasing size is associated with more difficult laparoscopic removal and greater risk of involved margins; therefore, if removal is contemplated, it should be carried out sooner rather than later. Patients who undergo a bilateral adrenalectomy do not suffer from any consequences of loss of the adrenal medulla. This malignant tumour originates from primitive nerve cells (neuroblasts) of the sympathetic nervous system, so they can be found anywhere along this system. It is the most common solid tumour of infancy, making up half of all tumours in this age group. Most occur younger than the age of five and half younger than the age of two. More than half arise in the neural crest tissues of the abdomen, 25% of them in the adrenal, the rest arise anywhere in association with the sympathetic trunk, thorax, and neck. Clinically, 75% of neuroblastomas present as a large fixed nodular lump, usually on the left. Most (80%) present before the age of five years. The child presents with weight loss and poor health. One in three younger than the age of two years already have metastases causing ‘joint pains’ and fever, prompting the misdiagnosis of rheumatic fever. Retro‐orbital metastases cause malignant proptosis. If the tumour occurs in utero, it may cause hypertension in the mother. Bleeding into the tumour causes anaemia. Urinary catecholamines are elevated. Marrow aspiration may show infiltration by tumour. Alpha‐fetoprotein and carcinoembryonic antigen are raised – the latter being a useful marker of response to chemotherapy. Ultrasound and CT confirms the mass (Figure 16.13). Figure 16.13 Enhanced computed tomography (CT) scan showing huge mass occupying the entire left side of the retroperitoneum. This neuroblastoma displaces the left kidney inferiorly and invades the renal pedicle. The International Neuroblastoma Staging System has identified distinct prognostic stages [23]. Patients can be assigned to low‐, intermediate‐, or high‐risk groups. Patients with a low risk can be cured with surgery or just observed. Patients with an intermediate risk require surgery and chemotherapy. Patients with a high‐risk require surgery, radiation therapy, intensive chemotherapy, bone marrow, or haematopoietic stem cell transplantation. Newer types of treatment include agents that target factors that have a role in proliferation and cell survival [24]. The tumours are uncommon with an incidence of two to eight per million of population. Tumours that arise from the neuroectodermal tissue of the adrenal medulla are termed pheochromocytomas (PHAEO) and those arising from the extra‐adrenal parasympathetic and sympathetic ganglia are termed paragangliomas (PGL). PHAEO and sympathetic PGL are predominantly intra‐abdominal, functioning tumours that secrete catecholamines and their metabolites. PGLs derived from parasympathetic ganglia of the head and neck PGL tend to be non‐functioning. M : F preponderance is equal and median age at diagnosis is 55 years. About 70% of PHAEO and PGL are sporadic with the rest occurring as part of inherited endocrine tumour syndromes, including multiple endocrine neoplasia type 2 (MEN2), von Hippel‐Lindau disease (VHL), neurofibromatosis type 1 (NF1), and the inherited paraganglioma syndrome types 1, 3, and 4. About 10% are bilateral, 10% are extra‐adrenal and less than 1% are malignant. Outside the adrenal these chromaffinomas occur in the retroperitoneum near the adrenals, mediastinum, carotid body, organ of Zuckerkandl (at the origin of the inferior mesenteric artery), and bladder, where paroxysmal hypertension occurs with micturition. Most patients present with one or all of the classical triad of sweating, palpitations, and episodic headache. These can be brought on by smoking, sexual intercourse, defaecation, pressure on the abdomen, pregnancy, and drugs such as morphine, ACTH, and parenteral methyldopa. Hypertension is observed in just more than two‐thirds of patients and 2% of those with hypertension will have a PHAEO. Tumours may also present due to mass effect (abdominal pain, distension), as an incidental finding on imaging studies performed for other reasons, or as part of biochemical screening for familial disease. Most patients with symptoms will have increased levels of urinary or plasma fractionated catecholamines (i.e. adrenaline, noradrenaline, and dopamine) or metanephrines (i.e. metadrenaline, normetadrenaline, and 3‐methoxytyramine). Metanephrines are produced as a result of intratumour conversion of catecholamines by the enzyme catecholamine‐O‐methyl‐transferase (COMT), and measurement of plasma and urinary metanephrines (99 and 97% sensitive) is more sensitive than plasma and urinary catecholamine measurement (86 and 84% sensitive) [25]. Measurements of one or more of these substances, that are four times greater than the upper limit of the reference range is 100% diagnostic. Equivocal urinary biochemistry should prompt the use of an alternative test (e.g. plasma metanephrines) and because the results of metanephrine estimation may be affected by certain drugs (e.g. monoamine oxidase inhibitors, paracetamol, tricyclic antidepressants, sympathomimetics such as ephedrine and phenylephedrine, amphetamines, and levodopa), these should be discontinued prior to testing [26]. Tumours may exhibit characteristic biochemical profiles, classified as either noradrenergic or adrenergic. PGLs and PHAEOs arising in association with VHL disease are noradrenergic and predominantly secrete noradrenaline and normetadrenaline. Conversely, adrenergic PHAEOs secrete a mixture of adrenaline/metadrenaline and noradrenaline/normetadrenaline and may be sporadic or due to MEN2 or NF1. Positive biochemistry should be followed by imaging studies to determine tumour localisation. Abdomino‐pelvic CT and MRI are most commonly used (sensitivity 90–100%, specificity 70–80%) [27] and will detect the majority of tumours particularly if they are symptomatic; however, they may lack the sensitivity to localise early screen‐detected tumours (e.g. lesions <1 cm) (Figure 16.14). Contrast CT is quicker and often more readily available but requires exposure to radiation. Ionic contrast has been reported to precipitate catecholamine release from PHAEO, leading to ‘PHAEO crisis’, but non‐ionic contrast media have been shown to be safe. MRI avoids radiation and can distinguish PHAEO (which appear hyperintense on T2‐weighted images) from other types of adrenal mass (usually hypointense). Tumours appear vascular and frequently possess cystic areas or central necrosis. Figure 16.14 Enhanced computed tomography (CT), magnetic resonance image (MRI), meta‐iodobenzylguanidine (123I‐MIBG) scan, and positron emission tomography (PET) scans show pheochromocytoma of a small renal mass. Extra‐adrenal PGL may occur in the head and neck (5%), along the sympathetic chain in the thorax (10%) and abdomen (75%), above (juxtarenal) or below the origin of the inferior mesenteric artery (organ of Zuckercandl) and the bladder (10%). If initial imaging is negative or reveals extra‐adrenal disease, functional investigation with meta‐iodobenzylguanidine (123I‐MIBG) – 80–90% sensitive) or 111In‐octretide scanning (50–70% sensitive) Routine use is not advocated in well‐localised adrenal lesions. More recently, 6‐[18F]fluorodopamine positron emission tomography‐CT (PET‐CT) scanning (Figure 16.15) have shown promise particularly in the setting of extra‐adrenal PGLs, where conventional imaging and MIBG scanning are negative [28]. PET‐CT is a nuclear medical scan combined with an x‐ray CT scanner. It acquires sequential images from both devices in the same session, which are superposed (Figure 16.15). Thus, functional imaging depicts the spatial distribution of metabolic or biochemical activity in the body. Selective adrenal vein sampling has proved misleading in the case of PHAEO and is probably of very limited use. Figure 16.15 Positron emission tomography‐computed tomography (PET‐CT) showing ‘hot’ area of pheochromocytoma. Biochemical diagnosis and localisation of PHAEO or PGL should be followed by medical preparation to control blood pressure and prompt surgical excision. Surgery in the presence of undiagnosed PHAEO is associated with a mortality of between 25 and 100%; therefore, preoperative preparation to protect against catecholamine excess and triggers of secretion such as induction of anaesthesia is essential for a successful outcome. Although practice varies, alpha‐adrenergic blockade with or without the addition of beta‐adrenergic blockade is most commonly used. Supervised initiation of alpha blockade using oral phenoxybenzamine to control blood pressure is the first step. Once alpha blockade has been established (good blood pressure control with a postural drop >10 mm Hg and nasal stuffiness) beta blockade to control tachycardia may be commenced (e.g. propranolol). This order is important to avoid dangerous elevations in blood pressure that occur if beta blockade is commenced without blockade of alpha‐induced vasoconstriction. Pharmacological treatment reduces blood pressure, allows restoration of depleted circulating volume, and takes two to four weeks. In the week prior to surgery, admission, and supervised blood pressure monitoring allows further optimisation of alpha and beta blockade to ensure normal blood pressure with a postural drop and abolition of compensatory tachycardia. Other regimens have been described, for example alpha blockade with doxazosin or prazosin, with and without beta blockade, using calcium channel blockers alone, and using the catecholamine synthesis blocker, metyrosine in the setting of cardiac failure. However, familiarity and experience with a particular pharmacological regime are probably more important than the regime itself. At this point surgery is safe to proceed. PHAEO and intra‐abdominal PGL account for 95% of tumours and can be dealt with by laparotomy or laparoscopic surgery. Laparoscopic adrenalectomy is the ideal management for all PHAEOs up to 10–12 cm. In large tumours (>10–12 cm) make a transverse or vertical abdominal incision. Display the right adrenal by mobilising the colon and duodenum and retracting the liver and gallbladder upwards (Figure 16.16). On the left side, mobilise the splenic flexure and duodenum downwards and medially (Figure 16.17). For a very large left tumour a thoracoabdominal approach is used. Figure 16.16 Exposure of the right adrenal in pheochromocytoma. The liver is retracted upwards and the colon and duodenum mobilised medially. Figure 16.17 Exposure of the left adrenal for pheochromocytoma. After taking down the splenic flexure, (a) the colon and (b) the duodenum and retracted medially. In common with ACC, diagnosis of malignancy requires the presence of direct invasion or metastases on preoperative imaging; if there is direct invasion, laparotomy, and en bloc excision of involved adjacent organs offers the best chance of cure. In the presence of metastases, excision of the primary tumour is still recommended to improve symptom control and improve the sensitivity of adjuvant radio‐labelled MIBG and octreotide therapy. Tumours along the sympathetic chain can be technically challenging due to their posterior relationship to the great vessels and visceral arterial branches, which may hide smaller lesions. Furthermore, Type 4 hereditary PGL are associated with increased risk of local recurrence. For this reason, minimally invasive surgery may not be feasible, open surgery is the preferred option. As previously described, patients with functioning tumours should be managed in a multidisciplinary setting to prepare the patient for a safe operation. This team should include endocrinologist, anaesthetist, and surgeon and in some circumstances an intensivist and biochemist. The surgeon should be skilled in both the open and laparoscopic approaches and should maintain a prospective audit of outcomes. The anaesthetists should have experience in managing patients with functioning adrenal tumours. When appropriate patients should be consented about invasive monitoring and bladder catheterization. Consideration should be given to thromboprophylaxis, prophylactic antibiotics and the probability of blood transfusion. In patients with Cushing syndrome should receive steroid supplementation. The gold standard for adrenalectomy is laparoscopic surgery because of the advantages of smaller incisions, less pain, shorter hospital stay, and improved cosmesis [29]. There are two approaches – transperitoneal and retroperitoneal. Most surgeons favour the transperitoneal route because the surgeon is familiar with the peritoneal cavity. The retroperitoneal approach is technically more challenging, but this approach has advantages for patients with bilateral adrenal tumours and in the presence of previous extensive intra‐abdominal surgery. Primary adrenocortical cancer is an absolute contraindication to either minimally invasive approach. Relative contraindications include a large size and previous abdominal surgery. Tumours greater than 5 cm are difficult to extract via the retroperitoneal route whereas the cut‐off for the transperitoneal approach is around 8–10 cm. Monitoring: in addition to the standard observations, there are specific issues to consider. After removal of a pheochromocytoma the blood glucose may fall precipitously. Patients with Cushing syndrome require steroid support (either intravenous or oral). A synacthen test should be done to test the function of the contralateral gland. In Conn tumours and pheochromocytoma all antihypertensives should be stopped in the postoperative period and the blood pressure monitored. Patients with Cushing syndrome are vulnerable to most complications including haematoma, bruising, infection, and peptic ulcer formation and complications. Haemorrhage into the adrenals on one or both sides may follow a difficult labour or childbirth asphyxia. The diagnosis is usually made postmortem, the child having died of exsanguination and hypoadrenalism. Sometimes Gerota fascia will tamponade the bleeding and control it, and the child then survives with a mass which displaces the kidney downwards and may calcify later on. There may be late adrenal insufficiency The adrenal is often torn during nephrectomy, when there may be bleeding from the venous sinuses of the medulla, which may need suture ligature. Spontaneous haemorrhage into the adrenals occurs in the Waterhouse–Friderichsen syndrome in septicaemic shock. Calcification in the adrenals from old tuberculosis was in former times an important cause of Addison disease – hypoadrenalism.
The Adrenal Glands
Abstract
16.1 Principles of Endocrine Surgery
16.2 Anatomy
16.2.1 Surgical Relations
16.2.2 Arterial Supply
16.2.3 Nerve Supply
16.3 Physiology
16.3.1 Cortex
16.3.2 Medulla
16.4 Pathology
Neoplasm
Endocrine status
Cortex
Medulla
Benign
Functioning
Hyperaldosteronism
Cushing’ syndrome
Virilisation syndrome
Phaeochromocytoma
Non‐functioning
Cyst
Myelolipoma
Malignant (primary)
Functioning
Hyperaldosteronism
Cushing syndrome
Virilisation syndrome
Pheochromocytoma
Non‐functioning
Adrenocortical carcinoma
Malignant
(secondary)
Non‐functioning
Adrenal metastases
16.4.1 Pathology of the Adrenal Cortex
16.4.1.1 Hypofunction
16.4.1.1.1 Acute
16.4.1.1.2 Addison Disease (Primary Chronic Adrenal Insufficiency)
16.4.1.1.3 Secondary Chronic Adrenal Insufficiency
16.4.1.2 Hyperfunction
16.4.1.2.1 Cushing Syndrome (Hypercortisolism)
Clinical Features
Investigations
Treatment
16.4.1.2.2 Primary Hyperaldosteronism (PA)
Investigations
Treatment
16.4.1.2.3 Virilising Tumours
Clinical Features
Diagnostic Tests
Treatment
16.4.1.3 Nonfunctioning Pathology
16.4.1.3.1 Incidentaloma
Definition
Clinical Features
Diagnostic Tests
Adenoma
Nodular hyperplasia
Carcinoma
Ganglioneuroma
Pheochromocytoma
Angiomyolipoma
Abscess
Amyloidosis
Cyst
Fibroma
Granulomatosis
Hamartoma
Haematoma
Lipoma
Liposarcoma
Myelolipoma
Teratoma
Pseudocyst 
Treatment
16.4.1.3.2 Cyst
Clinical Features
Investigation
Treatment
16.4.1.3.3 Myelolipoma
Clinical Features
Investigations
Treatment
16.4.1.3.4 Adrenocortical Carcinoma (ACC)
Clinical Features
Diagnostic Tests
Treatment
Stage
UICC/WHO
Adjuvant therapy
I
T1, N0, M0
Minimal benefit in R0 resection unless Ki67 > 10% in which case consider Mitotanea therapy
II
T2, N0, M0
Minimal benefit if R0, consider Mitotanea if Ki67 > 10%
III
T3, N0, M0
Mitotanea therapy probably beneficial
T1–2, N1, M0
IV
T4, N0–1, M0
Consider Mitotanea in combination with cisplatin or
Any M1
etopiside chemotherapy
16.4.1.3.5 Adrenal Metastases
Clinical Features
Diagnostic Tests (Endocrinology and Imaging)
Treatment
16.5 Pathology of the Adrenal Medulla
16.5.1 Hypofunction
16.5.2 Non‐function
16.5.2.1 Adrenal Neuroblastoma
16.5.2.1.1 Clinical Features
16.5.2.1.2 Investigations
16.5.2.1.3 Treatment
16.5.3 Hyperfunction
16.5.3.1 Pheochromocytoma and Paraganglioma
16.5.3.1.1 Clinical Features
16.5.3.1.2 Investigations
16.5.4 Imaging and Localisation
16.5.4.1 CT and MRI
16.5.4.2 Management
16.5.4.2.1 Preoperative Control of Blood Pressure
16.5.4.3 Treatment
16.5.4.3.1 Adrenalectomy for PHAEO
16.5.4.3.2 Surgery for PGL
16.5.4.3.3 Adrenal Surgery
Preoperative Preparation
Surgery
Postoperative Care
16.6 Congenital Disorders of the Adrenals
16.7 Trauma
16.8 Inflammation
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