The adrenal glasnds and other abdominal endocrine disorders - 778.pptx

Tumors of adrenal glands

1. The adrenal glands and other abdominal endocrine disorders

2. ADRENAL GLANDS Anatomy : The weight of a normal adrenal gland is approximately 4 g. There are two distrinct components to the gland: the inner adrenal medulla and the outer adrenal cortex. The adrenal glands are situated near the upper poles of the kidneys, in the retroperitoneum , within Gerota’s capsule. The right adrenal gland is located between the right liver lobe and the diaphragm, close to and partly behind the inferior vena cava.

3. The left adrenal gland lies close to the upper pole of the left kidney and the renal pedicle. It is covered by the pancreatic tail and the spleen. The adrenal glands are well supplied by blood vessels. The arterial blood supply branches from the aorta and the diaphragmatic and renal arteries and varies considerably. A large adrenal vein drains on the right side into the vena cava and on the left side into the renal vein.

4. Embryology : The two functional parts, the cortex and the medulla, arise from different blastodermic layers: mesodermal cells form the adrenal cortex and neuroectodermal cells migrate to the cortex from the neural crest during embryogenesis and form the adrenal medulla. Histology : The adrenal cortex is arranged in a zonal configuration. The outer zona glomerulosa contains small, compact cells.

5. The central zona fasciculata can be identified by larger, lipid-rich cells, which are arranged in radial columns. Compact and pigmented cells characterise the inner zona reticularis . The adrenal medulla consists of a thin layer of large chromaffin cells, which synthesise , store and secrete catecholamine. Function of the adrenal glands : The adrenal glands play a pivotal role in the response to stress. Catecholamines are secreted by the adrenal medulla and corticosteroids, aldosterone and cortisol are synthesised in the adrenal cortex.

6. Cells of the adrenal medulla synthesise mainly adrenaline (epinephrine) but also noradrenaline ( norepinephrine ) and dopamine. These catecholamines act as hormones as they are secreted directly in to the circulation. Their effects, which are mediated through α and β receptors on target organs, include the cardiovascular system, resulting in an increase in blood pressure and heart rate; vasoconstriction of vessels in the splanchnic system and vasodilatation of vessels in the muscles; bronchodilatation ; and increased glycogenolysis in liver and muscles: all necessary for the flight/fight response.

7. Cells of the zona glomerulosa produce aldosteone , which regulates sodium-potassium homeostsis . The target organs of aldosterone are the kidneys, the sweat and salivary glands and the intestinal mucosa. Aldosterone promotes sodium retention and potassium excretion. The most important regulators of aldosterone secretion and the renin-angiotensin system and the serum potassium concentration. Renin produced by the juxtaglomerular cells in the kidneys acts on its substrate angiotensinogen to generate angiotensin I.

8. Angiotensin I is converted by angiotensin -converting enzyme (ACE) to the octapeptide angiotensin II, which is modified to angiotensin III. Both stimulate the secretion of aldosterone from the adrenal cortex. A decrease in renal blood flow ( haemorrhage , dehydration, salt depletion, orthostasis , renal artery stenosis ) or hyponatraemia increases renin secretion and leads to sodium retention, potassium excretion and an increase of plasma volume.

9. Cells of the zona fasciculata and zona reticularis synthesise cortisol and the adrenal androgens dehydroepiandrosterone (DHEA) and its sulphate ( dehydroepiandrosterone sulphate (DHEAS). DHEA and DHEAS are precursors of androgens and are converted in peripheral tissues such as fat. Cortisol secretion is regulated by adrenocorticotrophic hormone (ACTH), which is produced by the anterior pituitary gland. The hypothalamus controls ACTH secretion by secreting corticotropin -releasing hormone (CRH). The serum cortisol level inhibits the release of CRH and ACTH via a closed-loop system (negative feedback loop).

10. Cortisol has numerous metabolic and immunological effects. It increases gluconeogenesis and lipolysis , decreases peripheral glucose utilisation , immunological response and muscular mass. It affects fat distribution, wound healing and bone mineralisation ; and alters mood (euphoria or, rarely, depression) and cortical alertness.

11. DISORTERS OF THE ADRENAL CORTEX Incidentaloma : Definition - Incidentaloma is an adrenal mass, detected incidentally by imaging studies conducted for other reasons, not known previously to have been present or causing symptoms. Incidence - The prevalence of adrenal masses in autopsy studies ranges from 1.4 to 8.7 per cent and increases with age. Incidentalomas may be detected on imaging studies on 1 per cent of patients.

12. More than 75 per cent are non-functioning adenomas but Cushing’s adenomas, phaeochromocytomas , metastases, adrenocortical carcinomas and Conn’s tumours can all be found this way. Prevalance of non-functioning and functioning tumours in patients with incidentalomas : Tumour Prevalence (%) Non-functioning adenoma 78 Cushing’s adenoma 7 Adrenocortical carcinoma 4 Phaeochromocytoma 4 Myelolipoma 2 Cyst 2 Metastases 2 Conn’s adenoma 1

13. Diagnosis - When an incidentaloma is identified, a complete history and clinical examination are required. Occasionally, a previously occult endocrine disturbance will come to light. A biochemical work-up for hormone excess is needed and sometimes additional imaging studies are also required. The main goal is to exclude a functioning or malignant adrenal tumour .

14. Hormonal evaluation includes : Morning and midnight plasma cortisol measurements; A 1-mg overnight dexamethasone suppression test; 24-hour urinary cortisol excretion; 12 or 24-hour urinary excretion of metanephrines or plasma-free metanephrines ; Serum potassium, plasma aldosterone and plasma renin activity; Serum DHEAS, testosterone or 17-hydroxyestradiol ( virilising or feminising tumour ).

15. Computed tomography (CT) or magnetic resonance imaging (MRI) should be performed in all patients with adrenal masses. The likelihood of an adrenal mass being an adrenocortical carcinoma increases with the size of the mass (25 per cent >4 cm). Adrenal metastases are likely in patients with a history of cancer elsewhere and the sole indications for biopsy of an adrenal mass is to confirm a suspected metastasis from a distant primary site

16. Summary Adrenal gland biopsy : Never biopsy an adrenal mass until phaeochromocytoma has been biochemically excluded The indication for adrenal gland biopsy is to confirmadrenal gland metastasis

17. Treatment - The treatment of functional adrenal tumours is – Any non-functioning adrenal tumour greater than 4 cm in diameter and smaller tumours that increase in size over time should undergo surgical resection. Non-functioning tumours smaller than 4 cm should be followed-up after 6, 12 and 24 months by imaging (MRI) and hormonal evaluation.

18. Primary hyperaldosteronism – Conn’s syndrome Incidence Primary hyperaldosteronism (PHA) is defined by hypertension, as a result of hypersecretion of aldosterone . In PHA, plasma renin activity is suppressed. Among patients with hypertension the incidence of PHA is approximately 2 per cent. Recent studies have revealed that up to 12 per cent of hypertensive patients have PHA with normal potassium levels, thus potassium levels are an inconsistent diagnostic feature of this disease, and cannot be relied on to confirm or exclude it.

19. Pathology - The most frequent cause of PHA with hypokalaemia is a unilateral adrenocortical adenoma. In 20-40 per cent of cases, bilateral micronodular hyperplasia is present. Rare causes of PHA are bilateral macronodular hyperplasia, glucocorticoid -suppressible hyperaldosteronism o0r adrenocortical carcinoma. In the subset of patients with normokalaemic PHA, 70 per cent have hyperplasia and 30 per cent unilateral adenoma.

20. Clinical features - Most patients are between 30 and 50 years of age with a female predominance. Apart from hypertension, patients complain of non-specific symptoms: headache, muscle weakness, cramps, intermittent paralysis, polyuria , polydypsia and nocturia . Diagnosis – The key feature of the biochemical diagnosis is the assessment of potassium level and the aldosterone to plasma renin activity ratio.

21. Antithypertensive and diuretic therapy, which cause hypokalaemia and influence the renin-angiotensin-aldosterone system, have to be discontinued. Once the biochemical diagnosis is confirmed, MRI or CT should be performed to distinguish unilateral front bilateral disease. Conn’s adenomas usually measure between 1 and 2 cm and are detected by CT with a sensitivity of 80-90 per cent. Micronodular changes and small adenomas are often underdiagnosed . An apparent unilateral mass could be a non-functioning tumour in a patient with bilateral micronodular hyperplasia.

22. Selective adrenal vein catherisation can help before a decision on non-surgical or surgical treatment is made. During selective adrenal vein catheterisation , samples are obtained from the vena cava and from both adrenal veins and the aldosterone to cortisol ratio (ACR) is determined in each sample. A significant difference in the ACR ratio on one side indicates unilateral disease. Treatment The first-line therapy for PHA with bilateral hyperplasia is medical treatment with spironolactone .

23. In most cases supplemental antithypertensive medication is necessary. Unilateral laparoscopic adrenalectomy is an effective therapy in patients with clear evidence of unilateral or asymmetrical bilateral disease. A subtot5al resection can be considered in the case of a typical single Conn’s adenoma. In 10-30 per cent of patients who undergo an adrenalectomy , hypertension persists despite adequate diagnostic work-up and treatment, albeit at a lower level, requiring fewer medications to control it.

24. Cushing’s syndrome Definition – Hypersection of cortisol caused by endogenous production of corticosteroids is known as Cushing’s syndrome. It can be either ACTH-dependent or ACTH-independent in origin. The most common cause (85% ) of ACTH-dependent Cushing’s syndrome is Cushing’s disease resulting from a pituitary adenoma that secretes an excessive amount of ACTH. Ectopic ACTH-producing tumours (small cell lung cancer, foregut carcinoid ) and CRH-producing tumours ( medullary thyroid carcinoma, neuroendocrine pancreatic tumour ) are more infrequent causes of ACTH-dependent Cushing’s syndrome.

25. Excessive or prolonged administration of cortisol -like drugs will produce the same clinical picture. In about 15% of patients, an ACTH-independent Cushing’s syndrome (low ACTH levels) is caused by a unilateral adrenocortical adenoma. Adrenocortical carcinoma and bilateral macronodular or micronodular hyperplasia represent rare causes of hypercortisolism .

26. Clinical symptoms – Clinical features of Cushing’s syndrome Weight gain/central obesity Diabetes Hirsufism Hypertension Skin changes (abdominal striae , facial plethara , ecchymosis , acne) Muscle weakness Menstrual irregularity/ impatence Depression/mania Osteoporosis • Hypokalaemia

27. The typical patient is characterised by a facial plethora, a buffalo hump and a moon face in combination with hypertension, diabetes and central obesity. However, clinical signs can be minimal or absent in patients with subclinical Cushing’s syndrome. Diagnosis Morning and midnight plasma cortisol levels are elevated, possibly with loss of diurnal rhythm. Dexamethasone fails to suppress 24-hour urinary cortisol excretion. Serum ACTH levels discriminate ACTH-dependent from ACTH-independent disease.

28. Elevated or normal ACTH levels provide evidence for an ACTH- producingpituitary tumour (85%) or ectopic ACTH production. Therefore, in patients with elevated ACTH, MRI of the pituitary gland must be performed. If MRI is negative and additional venous sampling from the inferior petrosal sinus has excluded a pituitary microadenoma , a CT scan of the chest and abdomen is warranted to detect an ectopic ACTH-producing tumour . In patients with suppressed ACTH levels, a CT or MRI scan is performed to assess the adrenal glands. Subclinical Cushing’s syndrome is diagnosed if clinical symptoms are absent in the face of abnormal cortisol secretion.

29. Treatment Medical therapy with metyrapone or ketoconazole reduces steroid synthesis and secretion and can be used to prepare patients with severe hypercortisolism preoperatively or if surgery is not possible. ACTH-producing pituitary tumours are treated by trans- sphenoidal resection or radiotherapy. If an ectopic ACTH source is localised , resection will correct hypercortisolism . A unilateral adenoma is treated by adrenalectomy .

30. In cases of bilateral ACTH-independent disease, bilatectopic ACTH-dependent Cushing’s syndrome and an irresectable or unlocalised primary tumour should be considered for bilateral adrenalectomy as this controls hormone excess. Subclinical Cushing’s syndrome caused by unilateral adenoma is treated by unilateral adrenalectomy . Preoperative management Patients with Cushing’s syndrome are at an increased risk of hospital-acquired infection, thromboembolic and myocardial complications. Therefore, prophylactic anticoagulation and the use of prophyhlatic antibiotics are essential.

31. Cushing associated diseases (diabetes, hypertension) must be controlled by medical therapy preoperatively. Postoperative management After unilateral adrenalectomy supplemental cortisol should be given postoperatively because the contralateral gland will be suppressed. In total, 15 mg/hour is required parenterally for the first 12 hours followed by a daily dose of 100 mg for 3 days, which is gradually reduced thereafter. After unilateral adrenalectomy , the contralateral suppressed gland needs up to one year to recover adequate function.

32. In 10% of patients with Cushing’s disease who undergo a bilateral adrenalectomy after failed pituitary surgery, the pituitary adenoma causes Nelson’s syndrome due to continued ACTH secretion at high levels, causing hyperpigmentation as a result of chemical synergies between ACTH and melanocyte -stimulating hormone. Adrenal metastases Adrenal metastases are discovered at autopsy in one-third of patients with malignant disease (less frequently during life). In declining frequency, the most common primary tumours are breast, lung, renal, gastric, pancreatic, ovarian and colorectal cancer.

33. In selected circumstances an adrenalectomy is appropriate, for example if it is the sole site of metastatic disease. Adrenocortical carcinoma Incidence Adrenocortical carcinoma is a rare malignancy with an incidence of 1-2 cases per 1 000 000 population per year and a variable but generally poor prognosis. A slight female predominance is observed (1.5:1). The age distribution is bimodal with a first peak in children and a second between the fourth and fifth decades.

34. Pathology The differentiation between benign and malignant adrenal tumours is challenging, even in the hands of an experienced pathologist. Criteria for malignancy are tumour size, the presence of necrosis or haemorrhage and microscopic features such as capsular or vascular invasion. These should be assessed in terms of a microscopic diagnostic score. Additional information is provided by iommunohistochemistry . The macroscopic features are commonly multinodularity and heterogeneous structure with haemorrhage and necrosis.

35. Clinical presentation Approximately 60% of patients present with evidence of cortisol excess (Cushing’s syndrome). Patients with non-functioning tumours frequently complain of abdominal discomfort or back pain caused by large tumours . However, with increasing use of abdominal imaging, a growing number of adrenocortical carcinomas are detected incidentally. Adrenal tumours secreting more than one hormone in excess, or feminising / masculanising steroids are likely to be malignant.

36. Treatment Complete tumour resection (R0) is associated with favourable survival and should be attempted whenever possible. In order to prevent tumour spillage and implantation metastases, the capsule must not be damaged. En bloc resection with removal of locally involved organs is often required and in case of tumour thrombus in the vena cava chrombectomy is needed. Laparoscopic adrenalectomy is associated with a high incidence of local recurrence and cannot be recommended. Tumour debulking plays a role in functioning tumours to control hormone excess.

37. Patients can be treated postoperatively with mitotance alone or in combination with etoposide , doxorubicin and cisplatin . Adjuvant radiotherapy may reduce the rate of local recurrence. After surgery, restaging every three months is required as the risk of tumour relapse is high. Prognosis depends on the stage of disease and complete removal of the tumour . Patients with stage I or II disease have a five-year survival rate of 25% whereas patients with stage III and stage IV disease have five year survival rates of 6 and 0 per cent, respectively.

38. Congenital adrenal hyperplasia ( adrenogenital syndrome) Virilisation and adrenal insufficiency in children are pathognomonic of congenital adrenal hyperplasia (CAH). This is an autosomal recessive disorder caused by a variety of enzymatic defects in the synthetic pathway of cortisol and other steroids from cholesterol. The most frequent defect (95%) is the 21-hydroxylase deficiency, which has an incidence of 1 in 5000 live births. Excessive ACTH secretion is caused by the loss of cortisol and this leads to an increase in androgenic cortisol precursors and to CAH.

39. CAH may present in girls at birth with ambiguous genitalia or as late onset disease at puberty. Hypertension and short stature, caused by the premature epiphyseal plate closure, are common signs. Affected patients are treated by replacement of cortisol and with fludrocortisone . Large hypoplastic adrenals may need to be removed if symptomatic.

40. Adrenal insufficiency Primary adrenal insufficiency is caused by the loss of function of the adrenal cortex. It was first described by Thomas Addision in 1855. An early diagnosis is a clinical challenge, even today. Symptoms are only evident when about 90% of the adrenal cortex is destroyed. Secondary adrenal insufficiency is defined as a deficiency of pituitary ACTH secretion. Tertiary adrenal deficiency is provoked by a loss of hypothalamic CRH secretion and is caused by therapeutic glucocorticoid administration, brain tumour or irradiation.

41. Acute adrenal insufficiency Acute adrenal insufficiency usually presents as shock in combination with fever, nausea, vomiting, abdominal pain, hypoglycaemia and electrolyte imblance . The Waterhouse- Friderichsen syndrome is a bilateral adrenal infarction associated with meningococcal sepsis and is rapidly fatal unless immediately treated. Because of intestinal symptoms and fever, the so-called Addisionian crisis is often misdiagnosed as an acute abdominal condition.

42. Treatment If a patient displays features of adrenal insufficiency, treatment must immediately be commenced, before awaiting the biochemical diagnosis. Initial blood samples can be used for later determination of ACTH and cortisol levels. In addition to intravenous administration of hydrocortisone, 100 mg every 6 hours, 3 liters of saline is given in 6 hours under careful cardiovascular monitoring. Concomitant infections, which are frequently present, require treatment.

43. Chronic adrenal insufficiency is treated by replacement therapy with dily oral hydrocortisone (10 mg/m 2 body surface area) and fludrocortisone (0.1 mg). Patients must be advised about the need to take lifelong glucocorticoid and mineralocorticoid replacement therapy. To prevent an Addisonian crisis, patients must be aware of the need to increase the dose in case of illness or stress. If patients with adrenal insufficiency are scheduled for surgery, appropriate steroid cover must be administered.

44. DISORDERS OF THE ADRENAL MEDULLA AND NEURAL CREST-DERIVED TISSUE Phaeochromocytoma and paraganglioma Definition These are tumours of the adrenal medulla and sympathetic ganglia which are derived from chromaffin cells and which produce catecholamines . Aetiology The prevalence of phaeochromocytoma in patients with hypertension is 0.1-0.6% with an overall prevalence of 0.05 % in autopsy series.

45. In total, 4% of incidentalomas are phaeochromocytomas . Sporadic phaeochromocytomas occur around the fourth decade whereas patients with hereditary forms are diagnosed earlier. Phaeochromocytoma is known as the ‘10% tumour ’ as 10% are malignant, 10% are extra adrenal, 10% occur in children. With the recent advent of detailed genetic tests, however, the incidence of hereditary phaeochromocytomas has been shown to0 be higher.

46. Hereditary phaeochromocytomas occur in several tumour syndromes: Multiple endocrine neoplasia type 2 (MEN 2): an autosomal dominant inherited disorder that is caused by activating germline mutations of the RET PROTO-ONCOGENE. Familial paraganglioma (PG) syndrome: glomus tumours of the carotid body ajnd extra adrenal paraganglioma are characteristic in this hereditary tumour syndrome, which is caused by germline mutations within the succinate dehydrogenase complex subunit B (SDHB) SDHD and SDHC genes.

47. Von Hippel-Lindau (VHL) syndrome: those affected can develop early-onset bilateral kidney tumours , phaeochromocytomas , cerebellar and spinal haemangioblastoma and pancreatic tumours . Patients have a germline mutation in the VHL gene. Neurofibromatosis (NF) type 1: phaeochromocytomas in combination with fibromas on the skin and mucosa (‘ caffe -au- lait ’ skin spots) are indicative of a germline mutation in the NF 1 gene.

48. Pathology Phaeochomocytomas are greyish -pink on the cut surface and are usually highly vascularised . Areas of haemorrhage or necrosis are often observed. Microscopically, tumour cells are polygonal but the configuration varies considerably. The differentiation between malignant and benign tumours is difficult, except if metastases are present. An increased PASS ( phaeochromocytoma of the adrenal gland scale score), a breached capsule all lean more towards malignant rather than benign.

49. Phaeochomocytomas may also produce calcitonin , ACTH, vasoactive intestinal polypeptide (VIP) and parathyroid hormone related protein ( PTHrP ). In patients with MEN 2, the onset of phaeochromocytoma is preceded by adrenomedullary hyperplasia, sometimes bilateral. Phaeochromocytomas is rarely malignant in MEN 2. Clinical features Symptoms and sign are caused by catecholamine excess and are typically intermittent.

50. In total 90% of patients with the combination of headache, palpations and sweating have a phaeochromocytoma . Paroxysms may be precipitated by physical training, induction of general anaesthesia and numerous drugs and agents (contrast media, tricyclic anti-depressive drugs, metoclopramide and opiates). Hypertension may occur continuously, be intermittent or absent. A subset of patients are asymptomatic. More than 20 per cent of apparently sporadic phaeochromocytomas are caused by germline mutations in the RET, SDHB, SDHC, SDHC and NF1 genes; genetic testing for these genes is therefore recommended, particularly in those aged under 50 years.

51. Clinical signs of phaeochromocytoma Symptoms Prevalance (%) Hypertension 80-90 Paraxysmal 50-60 Continuous 30 Headache 60-90 Sweating 50-70 Palpitation 50-70 Pallor 40-45 Weight loss 20-40 Hyperglycaemia 40 Nausea 20-40 Psychylogical effects 20-40

52. Diagnosis The first step in the diagnosis of a phaeochromocytoma is the determination of adrenaline and noradrenaline breakdown products, metanephrine and normetanephrine level, in a 12- or 24-hours urine collection. Levels that exceed the normal range by 2-40 times will be found in affected patients. Determination of plasma-free metanephrine and normetanephrine levels also has a high sensitivity. Biochemical tests should be performed at least twice. The biochemical diagnosis is followed by the localisation of the phaeochromocytoma .

53. MRI is preferred because contrast media used for CT scans can provoke paroxysms. Classically, phaeochromocytomas show a ‘Swiss cheese’ configuration. 123 I-MIBG ( metaiodobenzylguanidine ) single-photon emission computed tomography (SPECT) will identify about 90% of primary tumours and is essential for the detection of multiple extra adrenal tumours and metastases. PET scanning using FDG PET or DOPA PET is yet more sensitive in detecting metastatic foci.

54. Treatment Laparoscopic resection is now routine in the treatment of phaeochromocytoma . If the tumour is larger than 8-10 cm or radiological signs of malignancy are detected, an open approach should be considered. Preoperative Once a phaeochromocytoma has been diagnosed, an α - adrenoreceptor blocker ( phenoxybenzamine ) is used to block catecholamine excess and its consequences during surgery. With adequate medical pretreatment, the perioperative mortality rare has decreased from 20-45% to less than 3%.

55. A dose of 20 mg of phenoxybenzamine initially should be increased daily by 10 mg until a daily dose of 100-160 mg is achieved and the patient reports symptomatic postural hypotension. Additional β -blockade is required if tachycardia or arrhythmias develop this should not be introduced until the patient is α -blockade. With adequate α -blockade preoperatively, anaesthesia should not be more hazardous than in patients with a non-functioning adrenal tumour ; however, in some patients, dramatic changes in heart rate and blood pressure may occur and require sudden administration of prossor or vasodilator agents.

56. A central venous catheter and invasive arterial monitoring are used. Special attention is required when the adrenal vein is litaged as a sudden drop in blood pressure may occur. The infusion of large volumes of fluid or administration of noradrenaline can be necessary to correct postoperative hypotension in the presence of unopposed α - bloackade . Postoperative Patients should be observed for 24 hours in the intensive care or high dependency unit as hypovolaemia and hypoglycaemia may occur. Lifelong yearly biochemical tests should be performed to identify recurrent, metastatic or metachronous phaeochromocytoma .

57. Phaeochromocytoma Obtain a secure biochemical diagnosis Exclude family history Diagnosis confirmed, treat with α -blockers Plain surgical excision Yearly lifelong follow up Malignant phaeochromocytoma Definition Approximately 10% of phaeochromocytoma are malignant. This rate is higher in extra adrenal tumours ( paragangliomas ). The diagnosis of malignancy implies metastases of chromaffin tissue, most commonly to lymph nodes, bone and liver.

58. Treatment Surgical excision is the only chance for cure. Even in patients with metastatic disease, tumour debulking can be considered to reduce the tumour burden and to control the catecholamine excess. Symptomatic treatment can be obtained with α -blockers. Mitotane should be started as adjuvant or palliative treatment. Treatment with 131 I-MIBG or combination chemotherapy has resulted in a partial response in 30% and an improvement of symptoms in 80% of patients. The natural history is highly variable with a five year survival rate of less than 50%.

59. Phaeochromocytoma in pregnancy Phaeochromocytomas in pregnancy may imitate an amnion infection syndrome or pre- eclampsia . Without adequate α -blockade, mother and unborn child are threatened by hypertensive crisis during delivery. In the first and second trimesters, the patient should be scheduled for laparoscopic adrenalectomy after adequate α -blockade; the risk of a miscarriage during surgery is high. In the third trimester, elective Caesarean with consecutive adrenalectomy should be performed. The maternal mortality rate is 50% when a phaeochromocytoma remains undiagnosed.

60. Neuroblastoma Definition A neuroblastoma is a malignant tumour that is derived from the sympathetic nervous system in the adrenal medulla (38%) or from any site along the sympathetic chain in the paravertebral sites of the abdomen (30%), chest (20%) and, rarely, the neck or pelvis. Pathology Neuroblastomas have a pale and grey surface, are encapsulated and show areas with calcification.

61. With increased tumour size, necrosis and haemorrhage may be detected. They are characterised by the presence of immature cells derived from the neuroectoderm of the sympathetic nervious system. Mature cells are found only in ganglioneuroblastomas . Clinical features Predominantly, newborn infants and young children (<5 years of age) are affected. Symptoms are caused by tumour growth or by bone metastases.

62. Patients present with a mass in the abdomen, neck or chest, proptosis , bone pain, painless bluish skin metastases, weakness or paralysis. Metastatic disease is present in 70% of patients at presentation. Diagnosis Biochemical evaluation should include urinary excretion (24 hrs. urine) of vanillylmandelic acid (VMA), homovanillic acid (HVA), dopamine and noradenaline , as increased levels are present in about 80% of patients. Accurate staging requires CT/MRI of the chest and abdomen, a bone scan, bone marrow aspiration and core biopsies as well as an MIBG scan.

63. Staging is established according to the International Neuroblastoma Staging System (INSS). Treatment Prognosis can be predicted by the tumour stage and the age at diagnosis. Patients are classified as low, intermediate or high risk. Low-risk patients are treated by surgery alone (the addition of 6-12 weeks of chemotherapy is optional) whereas intermediate risk patients are treated by surgery with adjuvant multiagent chemotherapy ( carboplatin , cyclophosphamide , etoposide , doxorubicin).

64. High risk patients receive high dose multiagent chemotherapy followed by surgical resection in responding tumours and myeloablative stem cell rescue. Patients assigned to the low risk, intermediate risk and high risk groups have overall three year survival rates of 90, 70-90 and 30% respectively. Ganglioneuroma Definition A ganglioneuroma is a benign neoplasm that arises from neural crest tissue. Ganglioneuromas can occur in the adrenal medulla and are characterised by mature sympathetic ganglion cells and Schwann cells in a fibrous stroma .

65. Clinical features Ganglioneuroma is found in all age groups but is more common before the age of 60. Ganglioneuromas occur anywhere along the paravertebral sympathetic plexus and in the adrenal medulla (30%). Most often they are identified incidentally by CT or MRI performed for other indications. Treatment Treatment is by surgical excision, laparoscopic when adrenalectomy is indicated.

66. SURGERY OF THE ADRENAL GLANDS Since its introduction in the 1990s, laparoscoopic or retroperitoneoscopic adrenalectomy has become the ‘gold standard’ in the resection of adrenal tumours , except for tumours with signs of malignancy. The more popular approach is the laparoscopic transperitoneal approach, which offers a better view of the adrenal region than open surgery. The advantage of the retroperitoneoscopic approach is the minimal dissection required by this extra abdominal procedure.

67. In the case of small, bilateral tumours or in patients with hereditary tumour syndromes a subtotal resection is warranted, to avoid steroid dependence. The mortality rate ranges from 0 to 2% in the specialised centres . An open approach should be considered if radiological signs, distant metastases, large tumours (<8-10 cm) or a distinct hormonal pattern suggest malignancy. Laparoscopic adrenalectomy Knowledge of the anatomy of the adrenal region is essential as anatomical landmarks guide the surgeon during operation. If these landmarks are respected, injury to the vena cava or renal vein, the pancreatic tail or the spleen can be avoided.

68. Careful haemostasis is essential as small amounts of blood can impatient the surgeon’s view. To prevent tumour spillage, direct grasping of the adrenal tissue/ tumour has to be avoided. Right adrenalectomy Position the patient right side up, with table brake. Use three ports to start. The dissection starts at the level of the periadrenal fat using careful coagulation and the peritoneum should be divided 2 cm below the edge of the liver from medial (inferior vena cava) to the lateral abdominal wall. This flap of peritoneum can then be useful to hold the liver up.

69. Identify the gland and mobilise gently, securing the vein with a clip or using one of the available energy devices, and remove the gland in a plastic catch bag. Left adrenalectomy With the patient positioned on his or her right side, mobilisation of the spleen will displace the pancreatic tail medially. The incision of Gerota’s fascia is followed by identification of the adrenal vein, which runs into the renal vein in the space between the medial aspect of the kidney and the posterior aspect of the pancreatic tail.

70. The resection is completed by mobilising the adrenal gland at the level of the periadrenal fat. Remove the gland in a bag and close the three port sites after infiltrating each with local anaesthesia . Retroperitoneoscopic adrenalectomy The first port is placed at the distal end of the 12 th rib with the patient in the prone position. After a digital dissection into the retroperitoneum , Gerota’s fascia is displaced ventrally. The right adrenal vein is covered by the retrocaval posterior aspect of the adrenal gland.

71. The left adrenal vein is usually located at the medial inferior pole of the adrenal gland. High inflation pressures allow bloodless dissection effectively tamponading the veins. Being outside the abdominal cavity affords an excellent view. Open adrenalectomy An open adrenalectomy is almost exclusively performed when a malignant adrenal tumour is suspected. On the right side, the hepatic flexure of the colon is mobilised and the right liver lobe is cranially retracted to achieve an optimal exposure of the inferior vena cava and the adrenal gland.

72. On the left side, the adrenal gland can be exposed after mobilisation of the splenic flexure of the colon, through the transverse mesocolon or through the gastrocolic ligament. The remaining dissection is the same as in laparoscopic adrenalectomy . A resection of regional lymph nodes is recommended in malignant adrenal tumours and should include resection of the tissue between the renal pedicle and the diaphragm.

73. PANCREATIC ENDOCRINE TUMOURS Introduction Pancreatic endocrine tumours (PET) represent an important subset of pancreatic neoplasms . They account for 5% of all clinically detected pancreatic tumours . They consist of single or multiple, benign or malignant neoplasms and are associated in 10-20% of cases with multiple endocrine neoplasia type 1 (MEN 1). They present as either functional tumours , causing specific hormonal syndromes, or non-functional tumours , with symptomssimilar to those in patients with pancreatic adenocarcinoma .

74. This section focuses on insulinomas , gastrinomas and non-functioning tumours because they represent 90% of all PET. Function of the endocrine pancreas The endocrine cells of the pancreas are grouped in the islets of Langerhans , which constitute approximately 1-2% of the mass of the pancreas. There are about one million islets in a healthy adult human pancreas and their combined weight is 1-1.5 g.

75. There are four main types of cell in the islets of Langerhans , which can be classified according to their secretions: Beta c ells producing insulin (65-80% of the islet cells); Alpha cells producing glucagon (15-20%); Delta cells producing somatostatin (3-10%); Pancreatic polypeptide (PP) cells containing polypeptide (1%) Insulinoma Definition This is an insulin-producing tumour of the pancreas causing the clinical scenario know as Whipple’s triad, i.e., symptoms of hypoglycaemia after fasting or exercise, plasma glucose levels <2.8 mmol /L and relief of symptoms on intravenous administration of glucose.

76. Neuroendocrine tumours of the pancreas Tumour (Syndrome) Incidence (%) Presentation Malignancy (%) Insulinoma 70-80 Weakness, sweating tremor, tachycardia, anxiety, fatigue, dizziness, disorientation, seizures < 10 Gastrinoma 20-25 Intractable or recurrent peptic ulcer disease ( haemorrhage , perforation), complications of peptic ulcer, diarrhoea 60-80 Non-functional tumours 30-50 Obstructive jaundice, pancreatitis, epigastric pain, duodenal obstruction, weight loss, fatigue 60-90 VIPoma 4 Profuse watery diarrhoea , hypotension, abdominal pain 80 Glucagonoma 4 Migratory necrolytic skin rash, glossitis , stomatitis , angular cheilitis , diabetes, severe weight loss, diarrhoea 80 Somatostatinoma <5 Cholelithiasis , diarrhoea , neurofibromatosis 50 Carcinoid <1 Flushing, sweating diarrhoea , oedema 90 ACTHoma <1 Cushing’s syndrome >90 GRFoma < Acromegaly 30

77. Incidence Insulinomas are the most frequent of all the functioning PETs with a reported incidence of 2-4 cases per million population per year. Insulinomas have been diagnosed in all age groups with the highest incidence found in the fourth to the sixth decades. Women seem to be slightly more frequently affected. Pathology The aetiology and pathogenesis of insulinomas are unknown. No risk factors have been associated with these tumours . Virtually all insulinomas are located in the pancreas and tumours are equally distributed within the gland. Approximately 90% are solitary and about 10% are multiple and associated with MEN 1 syndrome.

78. Prognosis and predictive factos No markers are available that reliably predict the biological behaviour of an insulinoma . Approximately 10% are malignant. Insulinomas of <2 cm in diameter without signs of vascular invasion or metastases are considered benign. Clinical features Insulinomas are characterised by fasting hypoglycaemia and neuroglycopenic symptoms. The episodic nature of the hypoglycaemic attacks is caused by intermittent insulin secretion by the tumour .

79. This leads to central nervous system symptoms such as diplopia , blurred vision, confusion, abnormal behaviour and amnesia. Some patients develop loss of consciousness and coma. The release of catecholamines produces symptoms such as sweating, weakness, hunger, tremor, nausea, anxiety and palpitations. Biochemical diagnosis A fasting test that may last for up to 72 hours is regarded as the most sensitive test. Usually, insulin, proinsulin , C-peptide and blood glucose are measured in 1 to 2 hour intervals to demonstrate inappropriately high secretion of insulin in relation to blood glucose.

80. About 80% of insulinomas are diagnosed by this test, most of them in the first 24 hours. Elevated C-peptide levels demonstrate the endogenous secretion of insulin and exclude factitious hypoglycaemia caused by insulin injection. Differential diagnosis The differential diagnosis of hypoglycaemia includes hormonal deficiencies, hepatic insufficiency, medication, drugs and enzyme defects. Occasionally, differentiating insulinoma from other causes of hypoglycaemia can be difficult.

81. Nesidioblastosis is a rare disorder, mainly encountered in children, which is characterised by replacement of normal pancreatic islets by diffuse hyperplasia of islet cells. Medical treatment of insulinoma Medical management is reserved only for patients who are unable or unwilling to undergo surgical treatment or for unresectable metastatic disease. Diazoxide suppresses insulin secretion by direct action on the beta cells and offers reasonably good control of hypoglycaemia in approximately 50% of patients. When surgical options to treat malignant insulinomas cannot be applied, chemotherapeutic options include doxorubicin and streptozotocin .

82. Surgical treatment of insulinoma Indications for operation After a positive fasting test and exclusion of diffuse abdominal meatastases by ultrasound or CT scan, all patients should be advised to undergo surgical excision of insulinoma . Preoperative localisation studies Intraoperative exploration of the pancreas is the best method to use for localisation of insulinoma , yet the operating surgeon will need preoperative localisation ! Insulinomas are detected in about 65% of cases by endoscopic ultrasound (EUS), 33% of cases by CT scan and abdominal ultrasound and 15% of cases by magnetic resonance tomography.

83. Intraoperative ultrasound (IOUS) of the pancreas is a vital tool after mobilisation of the gland. For preoperative localisation of an insulinoma , EUS has the highest sensitivity and should be used if laparoscopic resection is considered. If no lesion is identified and one can rely on the biochemical tests for diagnosis, laparotomy should follow, using IOUS. Benign insulinoma Surgical cure rates in patients with the biochemical diagnosis of insulinoma range from 90-100%. At open surgery an extended Kocher manoeuvre and mobilisation of the head and then the distal pancreas is performed to explore the whole gland.

84. IOUS should then be used to confirm the presence of a tumour , to find non-palpable lesions and also to identify the relation of the tumour to the pancreatic duct. Tumour enucleation is the technique of choice. For superficial tumours , laparoscopic enucleation is undertaken. Tumours located deep in the body or tail of the pancreas and those in close proximity to the pancreatic duct require distal pancreatectomy . Postoperatively, blood sugar levels begin to rise in most patients within the first few hours after removal of the tumour . To preserve pancreatic function and reduce the risk of iatrogenic diabetes mellitus, patients in whom tumour localisation is not successful at operation should not undergo blind resection.

85. Malignant insulinoma Aggressive attempts at resection are recommended as these tumours are much less virulent than adenocarcinomas . Gastrinoma ( Zollinger -Ellison syndrome) Definition Zollinger -Ellison syndrome (ZES) is a condition that includes: (1) fulminating ulcer diathesis in the stomach, duodenum of atypical sites; (2) recurrent ulceration despite ‘adequate’ therapy; and (3) non-beta islet cell tumours of the pancreas ( gastrinoma ).

86. Incidence Gastrinomas account for about 20% of PETs, second in frequency to insulinomas . Approximately 0.1 % of patients with duodenal ulcers have evidence of ZES. The reported incidence is between 0.5 and 4 cases per million population per year. ZES is more common in males than I n females. The mean age at the onset of symptoms is 38 years, and the range is 7-83 years.

87. Pathology The aetiology and pathogenesis of sporadic gastrinomas are unknown. At the time of diagnosis more than 60% of tumours are malignant. Pancreatic gastrinomas are mainly found in sporadic disease; most are found in the head of the pancreas. More than 70% of the gastrinomas in MEN 1 syndrome and most sporadic gastrinomas are located in the first and second part of the duodenum.

88. Therefore, the anatomical area comprising the head of the pancreas, the superior and descending portion of the duodenum and the relevant lymph nodes has been called the ‘ gastrinoma triangle/ because it harbours the vast majority of these tumours . All patients with gastrinomas should be tested in MEN 1 syndrome. Prognosis and predictive factors In general, the progression of gastrinomas is relatively slow with a five year survival rate of 65% and a ten year survival rate of 51%.

89. Patients with complete tumour resection have excellent five and ten year survival rates (90-100%). Patients with pancreatic tumours have a worse prognosis than those with primary tumours in the duodenum. There is no established marker to predict the biological behaviour of gastrinoma . Clinical and biochemical features Over 90% of patients with gastrinomas have peptic ulcer disease, often multiple or in unusual sites. Diarrhoea is another common symptom, caused by the large volume of gastric acid secretion.

90. Abdominal pain from either peptic ulcer disease or gastro- oesophageal reflux disease (GORD) remains the most common symptom, occurring in more than 75% of patients. Biochemical diagnosis If the patient presents with a gastric pH below 2.5 and a serum gastrin concentration above 1000 pg/ml (normal <100 pg/ mL ) then the diagnosis of ZES is confirmed. Unfortunately, the majority of patients have serum gastrin concentrations between 100 and 500 pg/ mL and in these patients a secretin test should be performed.

91. The secretin test is considered positive if an increase in serum gastrin of >200 pg/ mL over the pretreatment value is obtained; this also rules out other causes of hypergastrinaemia (e.g. atrophic gastritis). Differential diagnosis The most common misdiagnoses are idiopathic peptic ulcer disease, chronic idiopathic diarrhoea and GORD. Other reasons for hypergastrinaemia are chronic atrophic gastritis, gastric outlet stenosis and retained antrum after gastric resection.

92. Medical treatement of gastrinoma In the most patients with ZES, gastric hypersecretion can be treated effectively with proton pump inhibititors . Octreotide can also help to control acid hypersecretion . Systemic chemotherapy is utilised in patients with diffuse metastatic gastrinomas . Streptozotocin in combination with 5-fluorouracil or doxorubicin is the first line treatment. Surgical treatment of gastrinoma Indications for operation Surgical exploration should be performed in all patients without diffuse metastases, to remove known malignant gastrinomas or benign ones.

93. Preoperative localisation studies Pancreatic gastrinomas are often larger than 1 cm in diameter whereas gastrinomas of the duodenum are usually smaller. Therefore, it is nearly impossible to identify duodenal gastrinomkas by preoperative imaging. Pancreatic gastrinomas are detected by EUS in about 80-90% of cases, by CT in 39% of cases and by MRI in 46% of cases. In approximately one-third of patients, the results of conventional imaging studies are negative. On the basis of recent studies, either EUS or CT and somatostatin receptor scintigraphy (SRS) should be performed preoperatively for staging.

94. Pancreatic gastrinomas Most pancreatic gastrinomas are solitary, located in the head of the gland or uncinate process, and can be identified at operation. Enucleation with peripancreatic lymph node dissection is the procedure of choice. Rarely, tumours are situated in the body or tail and should be treated by enucleation or distal resection. Even if a tumour is found in the pancreas, duodenotomy is recommended to detect additional tumours , if the patient has MEN 1.

95. Duodenal gastrinomas The duodenum should be opened with a longitudinal incision and the posterior and anterior walls palpated separately. Duodenal tumours smaller than 5 mm can be enucleated with the overlying mucosa; larger tumours are excised with full thickness excision of the duodenal wall. Non-functioning endocrine pancreatic tumours Definition PETs are clinically classified as non-functioning PETs (NF-PETs) when they do not cause a clinical syndrome. Incidence NF-PETs account for 30-50% of all PETs. They are most often diagnosed in the fifth to sixth decades of life.

96. Pathology NF-PETs cannot the differentiated from functional tumours by immunocytochemistry because they may also express hormones such as gastrin , insulin, etc. They usually stain positively for chromogranin A and synaptophysin . The tumours are usually large (<5 cm) and unifocal except in MEN 1 syndrome. They are distributed throughout the pancreas with a head to body to tail ratio of 7:1:1.5.

97. Prognosis and predictive factors About 70% of all NF-PETs are malignant. Overall five and ten year survival rates of 65 and 49%, respectively, have been described. When comparing NF-PETs with functioning PETs, the NF-PEDTs have a worse prognosis. Clinical features Patients usually present late because of the lack of a clinical/hormonal marker of tumour activity. Therefore, in contrast to functioning PETs, patients with NF-PETs present with various non-specific symptoms, including jaundice, abdominal pain, weight loss and pancreatic. In some cases liver metastases are the first presentation.

98. Biochemical diagnosis Increased levels of chromogranin A have been reported in 50-80% of NF-PETs; the level of chromogranin A sometimes correlates with the tumour burden. The combination of elevated chromogranin A and PP measurements increases the sensitivity of diagnosis from 84 to 96% in NF-PETs. Differential diagnosis Differentiation from the more aggressive pancreatic adenocarcinoma is extremely important. Recognition of NF-PETs is imperative because of their resectability and excellent long-term survival compared with their exocrine counterparts.

99. Differences between pancreatic cancer and non-functioning endocrine pancreatic tumours (NF-PETs) Pancreatic cancer NF-PETs Tumour size < 5 cm > 5 cm Computed tomography scan Hypodensity No calcifications Hyperdensity Calcificataions possible Chromogranin A in blood Negative Positive Samatostatin receptor scinitigraphy Negative Positive

100. Medical treatment of non-functioning islet cell tumours When surgical excision is not possible, chemotherapeutic options include streptozotocin , octreoctide and interferon. Surgical treatment of non-functioning islet cell tumours Indications for operation An aggressive surgical approach should be considered in malignant NF-PETs, even in the presence of distant metastases. Preoperativ localistion studies Preoperative ultrasound or CT scan are the procedures of choice as these tumours are relatively large. Also, SRS should be performed to differentiate endocrine from non-endocrine pancreatic tumours .

101. Operative procedures The major goal is a potentially curative resection. This may require partial pancreaticoduodenectomy as well as the synchronous or metachronous resection of liver metastases. Using an aggressive approach, curative resection are possible in up to 62% can be achieved. Repeated resections for resectable recurrnces or metastases are justified to improve survival.

102. NEUROENDOCRINE TUMOURS OF THE STOMACH AND SMALL BOWEL Definition and physiology Neuroendocrine tumours (NET) of the gut and the pancreas arise from the diffuse neuroendocrine cell system, which can be found as single or clustered cells in the mucosa of the bronchi, stomach, gut, biliary tree, urogenital system and in the pancreas. This cell system was first recognised as the ‘clear cell system’ by Feyrter in the 1930s and is identical to the APUD (amine precursor uptake and decarboxylation ) system described by Pearse in 1970.

103. All cells of the system secrete different neuroendocrine markers, such as synaptophysin , chromogranin A and neurone -specific enolase (NSE), and produce peptide hormones that are stored in granules, e.g. serotonin, somatostatin , PP or gastrin . In clinical practice chromogranin A is utilised as a tumour marker. The main functional test for NET of the jejunum and ileum (the NET that are most often encountered) is the measurement of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in urine. Pathology Neuroendocrine cells can form hyperplasia or tumours .

104. In 1907, Oberndorfer coined the term ‘ carcinoids ’ for tumours arising from these cells. Although the term carcinoid continues to be used in clinical practice, these tumours do not always grow in a well-differentiated pattern reflecting the rather benign ‘carcinoma- like’, i.e , ‘ carcinoid ’, tumour . They can show different growth patterns, from benign tumours to high grade undifferentiated carcinomas having a poor prognosis ( neuroendocrine carcinomas). Therefore, they should always be addressed as NET, including a description of their histological pattern (benign, low or high grade malignant) and their anatomical site (e.g. stomach, ileum) according to the World Health Organization classification (2000).

105. Based on embryological principles classifies NET as foregut (lung, stomach, pancreas), midgut (small bowel and appendix) and hindgut (colon and rectum) tumours . Neuroendocrine tumours of the stomach These tumours are rare. They comprise about 5% of all NET of the gastrointestinal tract and have an incidence of approximately 0.2 cases per 100 000 population per year. There are four different types of gastric NET. Types 1 and 2 are small benign tumours that arise from the enterochromaffin -like (ECL) cells in the gastric mucosa and grow in either a linear or a nodular pattern.

106. Hypergastrinaemia may cause symptoms and the treatment of choice is endoscopic resection. Types 3 and 4 are almost always malignant and surgical resection should be undertaken if possible. Site Distribution (%) Lung 10 Stomach 5 Duodenum 2 Small bowel 25 Appendix 40 Colon 6 Rectum 15

107. Pathogenesis, diagnosis and treatment Tye 1 tumours ( ECLomas ) are the most frequent NET of the stomach (approximately 80%); they occur mostly in elderly women. Chronic hypergastrinaemia is the result of chronic atrophic gastritis and achlorhydria , the alkaline pH being the stimulus for hypersecretion of gastrin . They do not cause symptoms and are usually detected during gastroscopy for other reasons. Endoscopic resection is the treatment of choice.

108. The pathogenesis, diagnosis and treatment of type 2 tumours is similar to that of type 1. The only difference is the cause of the hypergastrinaemia , which in type 2 tumours is the result of MEN 1 syndrome, with multiple gastrinomas in the duodenum or, rarely, in the pancreas. Antrectomy and resection of ECLomas should be undertaken only if there is recurrent disease and multiple (more than six) tumours , with at least one measuring >1 cm and infiltration of at least one into the submucosa . Type 3 tumours are, sporadic and solitary tumours of unknown origin.

109. Serum gastrin is normal; upper gastrointestinal bleeding is the usual symptom that leads to endoscopy. Type 3 tumours are usually larger than 2 cm and often have lymph node and liver metastases at the time of diagnosis. Gastrectomy and lymph node dissection and resection of liver metastases is the treatment of choice. Liver metastases can also be treated by chemoembolisation . Type 4 tumours present as large ulcerating malignancies similar to adenocarcinomas and should be treated accordingly. The prognosis of types 3 and 4 is poor.

110. Neuroendocrine tumours of the small bowel Introduction These are the tumours that are most commonly referred to as ‘ carcinoid ’ tumours , as most NET of the gastrointestinal tract are found in the small bowel. They are also called ‘ midgut ’ tumours (together with NET of the appendix and the right colon). These tumours produce serotonin and cause the ‘ carcinoid ’ syndrome, but only in patients who have a large volume of liver metastases or if there is advanced local tumour growth draining into the inferior vena cava and thereby bypassing the liver.

111. NET of the duodenum ( gastrinomas in MEN 1 syndrome, somatostatinomas and others) are very rare and are not discussed further. Pathology NET of the jejunum and ileum arise from a subgroup of cells of the diffuse neuroendocrine system, the enterochromaffin (EC) cells, which secrete serotonin and substance P. They are either solitary or more often multiple, are almost always malignant and metastasise early to the regional lymph nodes and the liver depending on the location of the primary tumour (s).

112. Clinical symptoms Symptoms that lead to the diagnosis are caused by either the primary tumour or its lymph node metastases. Acut5e or chronic, recurrent or persistent abdominal pain, ileus or, rarely, lower gastrointestinal bleeding may occur. Symptoms may be due to liver metastases, such as sudden painful reddening of the face and chest (‘flushing’), diarrhoea or bronchospasm . These symptoms constitute ‘ carcinoid ’ syndrome. About 60% of patients eventually develop cardiac symptoms because of stenosis and insufficiency of the pulmonary and, more rarely, the tricuspid valve, with enlargement and thickening of the wall of the right atrium.

113. The aetiology is unknown but local effects of serotonin and kinins may contribute. Abdominal symptoms are caused either by obstruction of the appendix by an appendiceal NET (leading to appendectomy) or by obstruction of the mesentery or the bowel lumen by growth of lymph node metastases in the mesentery near the bowel. Pain is caused by chronic ischaemic of the bowel, resulting not only from mesenteric lymph node metastases but also from constriction of mesenteric arteries and fibrosis of the mesentery by a so called desmoplastic reaction.

114. Primary tumours in the jejunum and ileum rarely cause symptoms such as bleeding or intussusception as they usually only measure from a few millimetres up to 1 cm or at the most 2 cm in diameter. A polypoid NET of the terminal ileum may, however, cause ileocaecal intussusception . Diagnosis The diagnosis of NET of the small bowel is made by history, physical examination of the abdomen, imaging and an assessment of 5-HIAA in a 24 hour urine sample.

115. It is positive in larger tumours only if metastases are present. Cross sectional imaging, sonograpy , CT scan and MRI may show the primary tumour , mesenteric lymph node and liver metastases. The best method for staging of NET is an octreotide (SRS) scan. This will show all tumour deposits provided that they are large enough and have a high somatostatin receptor density. Surgical procedure Surgery should be undertaken as soon as the diagnosis is made, even in the presence of liver metastases. The main goal is resection of the bowel primary tumour (s) and mesenteric lymph node metastases.

116. This may entail resection of large amounts of bowel (100 cm or more), particularly if stage III or IV lymph node masses are found in the mesentery. In the presence of liver metastases, extrahepatic disease should be resected whenever possible. Metastatic disease in the mesenteric root will lead to long-term pain in the abdomen or back and to a poor quality of life, whereas liver metastases can be treated by chemotherapy or embolisation . Somatostatin and its analogues provide symptomatic treatment of the ‘ carcinoid ’ syndrome caused by a large volume of liver metastases.

117. These drugs may also have an antiproliferative effect. Surgery to remove liver metastases is possible in approximately 10% of patients. In others, embolisation , chemoembolisation , SRS using radioactively labelled octreotide , chemotherapy, biotherapy and also liver transplantation can be performed.

118. MULTIPLE ENDOCRINE NEOPLASIAS Introduction Multiple endocrine neoplasias (MEN) are inherited syndromes characterised by a combination of benign and malignant tumours in different endocrine glands. There are two main types, type 1 (MEN 1) and (MEN 2). The mode of inheritance is autosomal dominant in both. MEN 1 is characterised by the triad of tumours in the anterior pituitary gland, mostly presenting as prolactinomas or nonfunctioning tumours , hyperplasia of the parathyroids causing primary hyperparathyroidism ( pHPT ) and pancreaticoduodenal endocrine tumours .

119. The syndrome was first described by Wermer in 1954 and is therefore also called Wermer’s syndrome. It is caused by germline mutations in the menin gene, located on chromosome 11. MEN 2 is divided into three subtypes: familial medullary thyroid carcinoma (FMTC), MEN2a and MEN 2b. Medullary thyroid carcinoma (MTC) plays the key role in all subtypes. MEN 2 is caused by germline mutations in the RET proto-oncogene, located on chromosome 10. MEN 2a is characterised by the combination of MTC, pHPT and mostly bilateral phaeochromocytomas .

120. MTC combined with phaeochromocytoma alone is called Sipple’s syndrome. FMTC is characterised by distinct mutations in RET and MTC alone as the clinical manifestation. MEN 2b comprises MTC, phaeochromocytoma and characteristic facial and oral mucosal neuromas and intestinal ganglioneuromatosis accompanied by a Marfanoid habitus . The most important difference between MEN 1 and MEN2, besides the different clinical pictures, is that MEN 2 is characterised by a well-understood genotype-phenotype correlation. This means that depending on the particular mutation in the RET proto-oncogene, the phenotypic appearance and the onset of endocrine tumours will be different and can be predicated from the type of mutation.

121. This is not the case in MEN 1 syndrome. Affected organs in multiple endocrine neoplasia type 1: Endocrine gland affected Frequency (%) Hormone Clinical syndrome Parathyroids Pancreas, duodenum (mostly multiple) Gastrinoma Insulinoma Non-functioning tumours VIPoma Glucogonoma Anterior pituitary gland: Prolactinoma Non-functioning odenoma Other manifestations Adrenails NET in lung, thymus, stomach Lipoma 90 50-80 30-60 40-50 3-10 5-10 Gastrin Insulin PP VIP Glucogan Prolactin - Mostly non-functioning - - pHPT Zollinger-Ellision syndrome Hypoglycoemia syndrome - Verner -Morrison syndrome Galactorrhea Non-specific Non-specific - -

122. Multiple endocrine neoplasia type 1 Epidemiology The prevalence of the syndrome is estimated to be around 0.04-0.2 cases per 1000 population per year. The penetrance is high with almost 100% of mutation carries developing the syndrome. The disease is equally distributed between men and women. Clinical presentation The clinical presentation depends on the affected organs. The tumours can occur synchronusly . Most of the mutation carries identified in screening programmes are asymptomatic .

123. Parathyroids In total, 90-100% of patients suffering from MEN 1 develop pHPT and it is usually the first manifestation of the disease. MEN 1 pHPT is characterised by multiglandular disease so that all four parathyroids become hyperplastic in the course of the disease. The clinical presentation of MEN 1 pHPT is similar to that of the sporadic disease. Few patients have asymptomatic disease; most common in symptomatic disease is nephrolithiasis . Diagnosis is established by determination of parathyroid hormone (PTH) and calcium in serum and urine.

124. Endocrine pancreas PETs occur in around 50-60% of MEN 1 patients. In such patients taking part in screening programmes , 70-90% are found to have non-functioning and functioning PETs. This high rate of detection of PETs is the result of the improvement in diagnostic procedures in the last decade, including EUS. MEN 1 PETs are the most common syndrome-associated cause of death. They are mostly multiple and often recur after surgery. Although most patients have multiple tumours , one hormone syndrome is usually dominant.

125. The most common functional tumour is gastrinoma followed by insulinoma . VIPomas , glucagonomas and somatostatinomas are extremely rare. Non-functioning tumours can be asymptomatic for many years. The diagnostic work-up is similar to that for sporadic PETs and includes hormone measurements, e.g. gastrin , insulin, PP, etc., and imaging. Anterior pituitary gland Tumours of the anterior pituitary gland are found in 30-60% of patients with MEN 1. These are mostly microadenomas that present as prolactinomas or non-functioning tumours .

126. Most prolactinomas can be treated with medication, thus avoid operation. Adrenal tumours and other organ manifestations Adrenal involvement is common in MEN 1 patients and affects nearly 40-50% of patients. Mostly non-functioning adenomas are found. Very rarely, adrenocortical carcinomas or phaeochromocytomas may develop. Although very rare, manifestations of MEN 1 include NET of the lung, thymus, stomach, duodenum and small bowel. It is important to check for NETs of the thymus, as they are mostly malignant.

127. Genetic screening Identification of the MEN 1 ( menin ) gene in 1997 formed the basis for direct mutational analysis of the gene and for family screening. After genetic counselling of the index patient, family members can be screened. Mutation carries can then be included in screening programmes that make early detection of endocrine tumours possible. Screeningprogrammes should follow the consensus guidelines published by Brandi et al. in 2001. In cases of apparently sporadic endocrine tumours in patients younger than 40 years, genetic testing for MEN 1 is advised.

128. Operative therapy Parathyroids The indications for surgery in MEN 1 pHPT follow the same criteria as in sporadic disease but the choice of procedure is different. As multiglandular disease is present in all cases, resection follows the same rules as in secondary HPT. Therefore, the most common procedures are total parathyroidectomy , including cervical thymectomy or 3 ½ -gland resect5ion, leaving approximately 50 mg of parathyroid tissue behind, and cervical thymectomy . Selective resection of enlarged glands is obsolete because of the high rates of recurrence.

129. Endocrine pancreas Indications for surgery and its extent are controversial. Most experts agree that MEN 1 gastrinoma and insulinoma have to be operated on to prevent liver metastases and to control hormonal excess, provided that diffuse liver metastases are not present. MEN 1 gastrinomas are more often located in the duodenum as multiple small tumours than in the pancreas. For gastrinomas located in the duodenum or pancreatic head, pylorus-preserving partial pancreaticoduodenectomy is recommended.

130. In rare cases, the gastrinoma is located in the body or tail of the pancreas. In such cases, distal pancreatectomy with excision of tumours in the pancreatic head is the proceudre of choice. In MEN 1 insulinoma the standard operative procedure is distal pancreatectomy with enucleation of tumours in the pancreatic head. Non-functioning PETs are operated on if they reach a size of 1 cm. Careful palpation and IOUS are essential in every pancreatic procedure for MEN 1 PETs.

131. Anterior pituitary gland The indications for surgery in tumours of the anterior pituitary gland are the presence of symptomatic non-functional tumours or if medical therapy of prolactinoma fails. Most procedures can be performed through a trans- sphenoidal approach. Adrenal tumours Functional adrenal tumours in MEN 1 are rare and have to be operated on. Non-functioning tumours should be resected if they reach a size of 4 cm.

132. Pre and perioperative management follows the same rules as in sporadic adrenal tumours ; therefore, phaeochromocytoma has to be ruled out in every patientt . In most cases, a laparoscopic or retroperitoneoscopic approach can be used. If there is evidence for a malignant tumour , open surgery is preferred. Multiple endocrine neoplasia type 2 In most patients with MEN 2a, the disease is caused by mutations of the RET poto-oncogene in codon 634. MTC is almost always the first manifestation of the syndrome.

133. If phaeochromocytoma and pHPT do not occur, one must suspect the presence of the FMTC subtype. Patients with MEN 2b do not develop pHPT and in 95% of cases mutations in codon 918 of the RET proto-oncogene are causative. Medullary thyroid carcinoma MTC is characterised by multicentricity and is often accompanied by C-cell hyperplasia. These characterstics should lead to molecular diagnostic work-up (mutational analysis of the RET proto-oncogene) in patients with apparently ‘sporadic’ MTC.

134. In contrast to sporadic MTC, the diagnosis in families with known mutation of the RET gene is mostly made much earlier, possibly as the result of mutational screening and calcitonin measurements. MTC is most aggressive in MEN 2b. It occurs in early childhood, much earlier than in MEN 2a, with lymph node metastases present in the early stages. Preventative surgery is advised around the age of one year. Primary hyperparathyroidism pHPT in MEN 2a is less common and has a milder clinical course than MEN 1pHPT. It occurs in about 20-30% of patients with MEN 2a

135. Most patients are asymptomatic but all parathyroid glands can become hyperplastic , mostly metachronously . The disease develops after the third decade of life typically. Phaeochromocytoma The frequency of phaeochromocytoma in MEN 2 is arround 10-50% and tumours can be bilateral. This can occur synchronously or metachronously . The tumours are almost always benign. Diagnostic work-up includes measurement of urinary catecholamines , abdominal CT or MRI, and 1311-MIBG scintigraphy .

136. Operative therapy Medullary thyroid carcinoma Operative therapy for MEN 2 MTC in patients detected by genetic screening is a good example of efficient prophylactic surgery, as the likelihood of developing MTC is 100% for most mutations. The mutation carriers can be operated on with no evidence of tumour in the thyroid, protecting them from MTC for the rest of their lives. Different RET mutations are associated with early or late onset of the disease. Risk groups have been defined to determine the appropriate age for thyroidectomy .

137. Prophylatic thyroidectomy for medullary thyroid cancer depending on the site ofmutation of the RET proto-oncogene in multiple endocrine neoplasia type 2 patients with normal calcitonin levels Risk group High Medium Low Codan 883, 918, 922 609, 611, 618, 620, 634 768, 790, 791, 804, 891 Thyroidectomy at age (years) < 1 6 < 20

138. Operative therapy Medullary thyroid carcinoma Operative therapy for MEN 2 MTC in patients detected by genetic screening is a good example of efficient prophylactic surgery, as the likelihood of developing MTC is 100% for most mutations. The mutation carriers can be operated on with no evidence of tumour in the thyroid, protecting them from MTC for the rest of their lives. Different RET mutations are associated with early or late onset of the disease. Risk groups have been defined to determine the appropriate age for thyroidectomy .

139. Phaeochromocytoma The operative approach is laparoscopy or retroperitoneoscopy . Unilateral or bilateral subtotal resection may be feasible, which retains the healthy part of the gland and prevents postoperative dependence on cortisol and mineralocorticoid supplementation. Further phaeos can develop in the remnants that are left so continued surveillance is required. Primary hyperparathyroidism The clinical situation in MEN 2 pHPT is even more difficult than in MEN 1 pHPT because of the association with MTC in MEN 2. During neck surgery for MTC in a eucalcaemic patient, enlarged parathyroid glands should be removed.

140. In cases in which neck surgery has already been performed for MTC, the surgical approach to MEN 2a pHPT syhould be more tailored to the individual patient. For example, in an older patient after thyroidectomy for MTC with mild asymptomatic hypercalcaemia , localisation procedures and a targeted approach may be appropriate.