NEUROENDOCRINE TUMORS AND THE CARCINOID SYNDROME
Neuroendocrine tumours are cancers that arise from enterochromaffin cells found throughout the body. A “carcinoid tumour” implies a well-differentiated neuroendocrine tumour and excludes high-grade or poorly differentiated neuroendocrine tumours. Although several classification systems for neuroendocrine tumours currently exist, there has been a shift away from the term carcinoid tumour in favour of the term well-differentiated neuroendocrine tumour.
Well-differentiated neuroendocrine tumours, or carcinoids, occur most often in the lung (30% of all carcinoid tumours), small intestine (25%), rectum (15%), appendix (10%), and stomach (5%) but may be seen in many other organs. Typical well-differentiated neuroendocrine tumours demonstrate a histologic pattern of dense nests of cells of uniform size and nuclear appearance that contain secretory granules. The neurosecretory granules contain various amines such as 5-hydroxytryptamine (serotonin), peptides, tachykinins, and prostaglandins. Low-grade neuroendocrine tumours have a low mutation rate compared to most neoplasms. Mutations in key oncogenic pathways, such as the PI3K/AKT/mTOR pathway, have been identified. The incidence of carcinoid tumours (2 to 5 per 100,000 population) has been increasing over the past 20 years. Because carcinoid tumours are relatively slow growing, their prevalence is actually greater than that of oesophageal, gastric, or pancreatic cancers. Carcinoid tumours may be associated with multiple endocrine neoplasia type 1 (MEN 1) syndrome. Thymic carcinoid tumours present in patients with MEN 1 portend a worse prognosis.
Patients with neuroendocrine tumours present either with symptoms related to tumour mass or symptoms resulting from the release of biologically active peptides into blood. Abdominal pain from a tumour mass or bowel obstruction related to the desmoplastic reaction in the surrounding mesentery is a common presenting symptom. The desmoplastic reaction is believed to develop in response to the secretion of growth factors such as platelet-derived growth factor, insulin-like growth factor, epidermal growth factor, and transforming growth factor-β. Infrequently, primary tumours cause haemoptysis or gastrointestinal bleeding. Hepatomegaly may be noted at diagnosis. Other patients may present with symptoms related to the systemic release of peptides from tumour cells, referred to as the carcinoid syndrome.
The term carcinoid syndrome refers to the systemic signs and symptoms resulting from the release of neuroendocrine mediators by some carcinoid tumours. Cutaneous flushing, diarrhoea, and cardiac valvular lesions are the most common manifestations of the carcinoid syndrome. Only 8 to 10% of all neuroendocrine tumours are associated with the carcinoid syndrome, usually ileal carcinoids with hepatic metastases. Carcinoids from different primary sites possess unique clinical characteristics. Carcinoid tumours arising from organs of the embryonic foregut (e.g., bronchus, stomach, pancreas, and thyroid) are infrequently associated with the carcinoid syndrome; carcinoids from the distal large intestine may metastasize but do not exhibit endocrine effects.
The carcinoid syndrome results from the production of a variety of biologically active substances by the neuroendocrine tumour cells, including serotonin, tachykinins, histamine, and prostaglandins. Most low-grade neuroendocrine tumours contain the enzyme tryptophan hydroxylase, which catalyses the formation of 5-hydroxytryptophan (5-HTP) from tryptophan. The typical ileal carcinoid tumour also contains aromatic l -amino-acid decarboxylase, which catalyses the conversion of 5-HTP to 5-hydroxytryptamine (5-HT or serotonin). Following its release, serotonin is oxidized to 5-hydroxyindoleacetaldehyde and rapidly converted to 5-hydroxyindoleacetic acid (5-HIAA) by aldehyde dehydrogenase. This acid is excreted into the urine, and almost all circulating serotonin can be accounted for as urinary 5-HIAA. Tachykinins are also stored in neuroendocrine tumours. Of these, neuropeptide K, neurokinins A and B, and substance P have been identified in tumours and blood from patients with the carcinoid syndrome. Some carcinoid tumours, particularly those of gastric origin, release excessive amounts of histamine. Secretion of a variety of prostaglandins by carcinoids has also been demonstrated. Neuroendocrine tumours, particularly of the thymus and lung, have been associated with ectopic production of adrenocorticotropic hormone and growth hormone–releasing hormone.
Serotonin contributes to the intestinal hypermotility and diarrhoea associated with the carcinoid syndrome. A secondary effect of serotonin overproduction occurs when a large fraction of dietary tryptophan is shunted into the hydroxylation pathway, leaving less tryptophan available for the formation of nicotinic acid and protein. When urinary excretion of 5-HIAA exceeds 100 mg/day, low levels of plasma tryptophan and evidence of nicotinic acid deficiency (pellagra) can be seen. The interaction of serotonin with platelets and the cardiac endothelium is considered the cause of carcinoid heart disease. This hypothesis is supported by the finding of valvular heart disease in patients who took appetite suppressants, such as fenfluramine, that release serotonin. The risk of valvular heart disease in patients with the carcinoid syndrome is correlated with the amount of 5-HIAA excreted in the urine.
Most evidence points to the tachykinins as mediators of the carcinoid flush. Tachykinins are known vasodilators. Tachykinin levels are increased during pentagastrin-induced flushing; when pentagastrin-induced flushing is inhibited by somatostatin, the rise in tachykinin levels is also blocked. Serotonin does not appear to be the mediator of flushing. Flushing attacks can be attributed to histamine in certain gastric carcinoids. Flushing can be triggered by catecholamines, and this probably accounts for the association of flushing with exercise and emotional stimuli. Injection of isoproterenol or pentagastrin can also trigger flushing, an action that may explain the provocation of flushes by eating in some patients. The carcinoid syndrome occurs when mediators produced by the tumour and normally metabolized by the liver escape into the systemic circulation. Thus, most patients with the carcinoid syndrome have hepatic metastasis.
Cutaneous flushing, which occurs in 80% of patients with the carcinoid syndrome, is the most common clinical feature. The typical flush is dark red to violaceous and involves the head, neck, and upper trunk (blush area). The flush usually lasts for 30 seconds to 3 minutes. Neuroendocrine tumours of the foregut produce a slightly different flush, characteristically bright salmon pink to red. Prolonged flushing attacks may be associated with lacrimation and periorbital edema. The flush may be accompanied by tachycardia. The blood pressure usually falls or does not change. A rise in blood pressure during flushing is rare, and the carcinoid syndrome is not a cause of sustained hypertension. Flushing may be provoked by excitement, exertion, eating, and ethanol ingestion. In patients with the bronchial carcinoid variant, flushing may last for hours. In addition to paroxysms of cutaneous vasodilatation, some patients develop telangiectasias, which are most marked in the malar area. These patients may have the characteristic features of rosacea.
Intestinal hypermotility with borborygmi and cramping occurs in 50 to 70% of patients with the carcinoid syndrome. Explosive secretory diarrhoea may occur, although chronic diarrhoea with a secretory component is more common. When diarrhoea is severe, malabsorption may occur. Gastrointestinal transit times through the small and large bowel are two- to six-fold faster than in physiologically normal patients.
Tryptophan is normally used to form nicotinic acid. In patients with the carcinoid syndrome, up to 60% of dietary tryptophan may be used to form 5-HTP and 5-HT. Nicotinic acid levels are occasionally depleted, resulting in symptoms of pellagra (dermatitis, diarrhoea, and dementia).
Symptomatic valvular heart disease is present in 15 to 20% of patients with the carcinoid syndrome. Up to 50% of patients have echocardiographic evidence of heart disease. Plaque-like thickening of the endocardium of the valvular cusps and cardiac chambers occurs primarily on the right side of the heart but may rarely involve the left side (<10%). Lesions of the tricuspid valve (usually regurgitation) are present in 65% of patients with carcinoid heart disease, and pulmonic valvular disease (again, usually regurgitation) is seen in 20%.
Generalized fatigue and debilitation are underappreciated features of the carcinoid syndrome. Bronchoconstriction, usually most pronounced during flushing attacks, is a less common feature of the syndrome, but when it occurs it may be severe. Attacks of severe and sustained flushing with life-threatening hemodynamic compromise and bronchoconstriction are referred to as carcinoid crisis. Precipitating factors include anaesthesia, surgery, tumour necrosis, and catecholamine infusion. Cognitive impairment has also been associated with the carcinoid syndrome.
When all its clinical features are present, the carcinoid syndrome is easily recognized. The diagnosis also must be considered when any one of its clinical manifestations is present. The diagnostic hallmark consists of overproduction of 5-hydroxyindoles accompanied by increased excretion of urinary 5-HIAA in a patient with a biopsy-proven carcinoid tumour. Normally, excretion of 5-HIAA does not exceed 10 mg/day. Ingestion of foods containing serotonin may complicate the biochemical diagnosis of the carcinoid syndrome; bananas, walnuts, and certain other foods contain enough serotonin to produce abnormally elevated urinary excretion of 5-HIAA after their ingestion. Selected drugs (e.g., guaifenesin, acetaminophen) may also falsely elevate urinary 5-HIAA measurements. When dietary 5-hydroxyindoles are excluded, urinary excretion of 25 mg/day of 5-HIAA is diagnostic of the carcinoid syndrome. Elevation in the range of 9 to 25 mg/day may be seen with the carcinoid syndrome, nontropical sprue, vomiting, or acute intestinal obstruction. Measurement of serotonin in blood or platelets is of interest but has less diagnostic value than assay of the major metabolite of serotonin in the urine. Plasma chromogranin A concentrations are often elevated in carcinoid patients, including those who do not have the carcinoid syndrome, and may serve as a marker of tumour mass. The diagnostic value of plasma chromogranin A is relatively low, however, because this substance is increased in patients with renal failure, atrophic gastritis, and patients taking proton pump inhibitors. Assessment of the extent and localization of both primary and metastatic tumour is aided by computed tomography of the abdomen and chest and by imaging with radionuclide-labelled somatostatin receptor ligands.
The typical carcinoid syndrome usually results from tumours of midgut origin, which almost invariably secrete serotonin. In contrast, tumours arising from the embryonic foregut have a lower serotonin content and may secrete 5-HTP. Patients with gastric carcinoids may exhibit unique flushing, beginning as bright, patchy erythema with sharply delineated serpentine borders that coalesce as the blush heightens. Food ingestion is especially likely to produce flushes. With carcinoid tumours arising from the bronchus, attacks of flushing tend to be prolonged and severe and may be associated with periorbital edema, excessive lacrimation and salivation, hypotension, tachycardia, anxiety, and tremulousness. This group is therapeutically unique in that severe flushes can sometimes be prevented by corticosteroids.
Attacks of flushing in a patient with normal urinary excretion of 5-HIAA raise other diagnostic possibilities. Systemic mastocyte activation disorders, including systemic mastocytosis and idiopathic anaphylaxis, produce flushing and diarrhoea and should be considered when 5-HIAA excretion is not elevated. Flushing also occurs in genetically predisposed individuals following ethanol ingestion, in the postmenopausal state, and in conjunction with other neuroendocrine tumours such as VIPomas and medullary carcinomas of the thyroid.
Treatment of the carcinoid syndrome is directed toward pharmacologic therapy for humorally mediated symptoms and at measures designed to reduce the tumour mass.
More than 80% of neuroendocrine tumours have somatostatin receptors on the cell surface. Somatostatin can bind to these receptors and prevent flushing and other endocrine symptoms. The development of analogues of somatostatin with longer biologic half-lives than the native hormone has made subcutaneous and intramuscular administration feasible and has been a major advance in the treatment of these patients.
Roughly 70% of patients with carcinoid syndrome have a 50% or greater reduction in the frequency of diarrhoea and/or flushing with the use of octreotide, one of the somatostatin analogs. Therapy is usually associated with a decrease in urinary 5-HIAA excretion and in plasma tachykinin levels. With the improvement of endocrine symptoms and fatigue, a considerable improvement in quality of life may be achieved. Symptom control with octreotide can be durable, with 50 to 60% of patients continuing to have improvement in symptoms of diarrhoea and flushing following 12 months of therapy. Long-acting somatostatin analogues (octreotide LAR and lanreotide) have been developed, permitting once-monthly dosing. Two to 4 weeks may be required to achieve steady-state levels of octreotide following administration of octreotide LAR, during which time supplementation with subcutaneous octreotide may be needed. Octreotide is generally well tolerated. However, it may suppress pancreatic exocrine function, causing steatorrhea, abnormal glucose control, and inhibition of the release of cholecystokinin. Hyperglycaemia, symptomatic cholelithiasis, steatorrhea, and hypoglycaemia are seen in 9, 15, 3, and 2% of patients, respectively. Octreotide should be used to prevent carcinoid crises that accompany the massive release of mediators that may occur during operative procedures. In patients with histamine-secreting gastric neuroendocrine tumours, blockade of both histamine (H) 1 and H 2 receptors ameliorates flushing. In patients receiving octreotide, regression in tumour mass is uncommon. However, octreotide slows the growth rate of low-grade neuroendocrine tumours. With octreotide therapy, disease stability is seen in 65% of patients at 6-month follow-up, compared to only 35% of patients not receiving octreotide.
Early diagnosis of the carcinoid syndrome leads to complete surgical cure in the few neuroendocrine tumours that release their humoral mediators directly into the systemic circulation (e.g., bronchial carcinoids). In contrast, tumours that release humoral substances into the portal circulation usually produce the syndrome only after hepatic metastases occur. Given the slow growth rate of low-grade neuroendocrine tumours, effective reduction in tumour mass can ameliorate morbidity and improve quality of life even after metastases have occurred. In selected patients, this goal can be achieved by surgical debulking of tumour, including partial hepatectomy for unilobar metastases, excision of large superficial hepatic metastases, and removal of the primary tumour and regional lymph nodes. In selected series, over 90% of patients report symptom relief from pain and/or carcinoid syndrome following cytoreductive surgery (50 to 70%, complete relief). Median time to recurrence of symptoms is 3 years, and overall survival is greater than 5 years. Elective cholecystectomy during the surgical intervention prevents cholelithiasis that may result from octreotide treatment. Because the blood supply of hepatic metastases is largely arterial, percutaneous embolization of the hepatic arterial supply to the most involved hepatic lobe can shrink inoperable hepatic metastases; however, the procedure carries a risk of serious complications, with mortality of up to 6%. In selected series, 90% of patients report improvement in symptoms for an average of 2 years’ duration. Median survival in embolized patients has been 24 to 30 months. Valve replacement surgery is indicated in severe disease, in which it can usually improve life expectancy.
In contrast to high-grade, poorly differentiated neuroendocrine cancers, chemotherapy with single or combination cytotoxic agents rarely produces tumour regression in low-grade neuroendocrine tumours. However, recent studies suggest that several drugs, including the antiangiogenic agents bevacizumab and sunitinib and the mTOR inhibitor everolimus, may slow the growth rate of low-grade neuroendocrine tumours. In a randomized double-blind placebo-controlled study, 10 mg/day of everolimus increased progression-free survival from 11 months in control patients to 16 months (hazard ratio, 0.77). No overall survival advantage was noted, however, and stomatitis, rash, fatigue, and diarrhoea are noted treatment side effects. For patients who exhibit tumour progression or whose clinical syndrome has failed to improve following cytoreduction and octreotide, everolimus may be considered for palliative therapy.
The metastatic potential of localized carcinoid tumours correlates with tumour size, location, and histologic grade. Even when metastatic, typical neuroendocrine tumours generally have a slow rate of growth, and many patients survive for years after metastatic disease is recognized. Prior to development of therapies for the carcinoid syndrome, morbidity resulted from the endocrine manifestations of the tumour. However, with current therapy, symptoms of the carcinoid syndrome can usually be controlled. Death from typical neuroendocrine tumours is usually caused by complications associated with tumour growth, such as bowel obstruction or hepatic failure. A concerted strategy consisting of removal of the primary tumour, reduction in tumour bulk, and administration of octreotide can lead to considerable amelioration of symptoms, improvement in the quality of life, reduction in the release of the humoral substances that engender cardiac lesions, and prolongation of survival. The median survival of patients with metastatic neuroendocrine tumours and the carcinoid syndrome now exceeds 5 years in carefully managed patients, with patients having small bowel primaries living longer than those with lung or colon primaries.