Abstract

Neuroendocrine tumors (NETs) are rare, slow-growing neoplasms characterized by their ability to store and secrete different peptides and neuroamines.1 Some of these substances cause specific clinical syndromes,2 whereas other may have elevated plasma or urine levels that are not associated with specific syndromes or symptom complexes Unfortunately, there is no "ideal neuroendocrine tumor marker,"3 but according to the presentation, the sensitivity and specificity of each marker vary, and it is generally possible to choose those of greatest value for each clinical syndrome. The biochemical markers are those hormones or amines secreted by the neuroendocrine cells from which these tumors are derived. Some of these are not specific to any tumor, but are produced and secreted by most NETs, whereas other biochemical markers are more specific to the type of tumor and where their quantification can lead to the suspicion or confirmation of the presence of such a tumor. The annual incidence of NETs has risen to 40 to 50 cases per million, perhaps because of better diagnosis and the availability of highly specific and sensitive ways to measure these tumors' products, improved immunohistochemistry, and enhanced techniques for tumor detection. Thus, the perceived increase in incidence may not be a real change in the incidence of the disease. There are a number of impediments to the diagnosis of these tumors. They are rare, comprising less than 2% of gastrointestinal (GI) malignancies, and are therefore not high on the list of causes of specific symptom complexes. Symptoms themselves are often nonspecific and do not lend themselves readily to identifying the specific underlying tumor. In addition, the manifestations are protean and mimic a variety of disorders. Tumors may be found incidentally on laparoscopy for abdominal pain or during the surgical removal of an appendix or even during a computerized tomographic scan of the abdomen for unexplained symptoms. Lung carcinoids may present with hemoptysis or asthma-like symptoms, and midgut carcinoids may be confused with irritable bowel syndrome (IBS). The natural history of this disease is invariably attended by a long history of vague abdominal symptoms, a series of visits to a primary care practitioner, and referral to a gastroenterologist, often with a misdiagnosis of IBS. These symptoms persist with a median latency to correct diagnosis of 9.2 years by which time the tumor has metastasized, causing symptoms such as flushing and diarrhea and progressing on its slow but relentless course until the patient dies. Clearly, a greater index of suspicion and a carcinoid tumor profile screen are warranted for all patients presenting with "traditional IBS symptoms." Midgut carcinoids are associated with mesenteric fibrosis, which can compress mesenteric vessels and cause bowel ischemia and malabsorption, which may be found in the absence of an abdominal mass. The diagnosis of metastases to the liver is generally more obvious but often still takes place only after a delay of many years. Even then, an incorrect diagnosis is not uncommon. Unless biopsy material is examined for the secretory peptides chromogranin, synaptophysin, or neuron-specific enolase (NSE), tumors may be labeled erroneously as adenocarcinoma, with a negative impact on physician's attitudes regarding management and underestimation of prospects for survival.4 The common symptomatic manifestations of patients with carcinoid tumors are illustrated in Tables 1 and 2.TABLE 1: Clinical Presentations, Syndromes, Tumor Types, Sites, and Hormones4TABLE 2: Clinical Presentation, Syndrome, Tumor Type of Ectopic Pancreatic Tumors, and the Hormones ProducedFlushing It is vitally important to obtain a good history of the nature of the flushing to ascertain whether this can be ascribed to a NET. Is the flushing wet or dry? If dry, it is almost always due to a NET. If it is wet, it may still be due to a NET, but the diaphoresis is due to coexistent anxiety. Intermittent flushing suggests menopause or a NET, for example, systemic mastocytosis or pheochromocytoma. Constant flushing is found with alcoholism, polycythemia, and mitral valve disease, either stenosis or prolapse. If there is a facial rash, it may be rosacea, and if more diffuse, consider mastocytosis with the attendant dermatographia or dermatomyositis. If there are associated symptoms or signs such as diarrhea, this suggests a NET, either carcinoid or medullary carcinoma of the thyroid (MCT). Headache occurs with mastocytosis or pheochromocytoma, and syncope suggests autonomic neuropathy, pheochromocytoma, or epilepsy. Flushing in NETs is quite different depending on the location of the tumor. Foregut The flushing in foregut carcinoid tumors is dry, long lasting, and intense and has a purplish or violet hue in contrast to the common red/pink hue seen in other NE-related flushing. It is related to telangiectasia and skin hypertrophy mostly in the face and upper neck but can also involve the limbs, and it can lead to a leonine appearance after repeated episodes. Midgut In midgut tumors, it is faint pink to red and involves the face and upper trunk as far as the nipple line. The flush is initially provoked by exercise, alcohol, and food-containing tyramines (eg, blue cheese, chocolate, red sausage, and red wine). With time, the flush may occur spontaneously and without provocation. It usually is ephemeral, lasting only a few minutes, and may occur many times per day; however, over many years, patients may develop a persistent flush with a purpuric malar and nasal complexion. The differential diagnosis of flushing includes the postmenopausal state, simultaneous ingestion of chlorpropamide and alcohol, panic attacks, MCT, autoimmune epilepsy, autonomic neuropathy, and mastocytosis.5 To differentiate all those causes from a carcinoid tumor, besides knowing the differences in the characteristics of the flushing, it is also necessary to know what is producing the flushing (Table 3).TABLE 3: Differential Diagnosis of Flushing and Recommended TestsFlushing in carcinoid syndrome has been ascribed to prostaglandins, kinins, and serotonin (5-HT). With the advent of sophisticated radioimmunoassay methods and region-specific antisera, a number of neurohumors now are thought to be secreted by carcinoid tumors, including 5-HT, dopamine, histamine, and 5-hydroxyindoleacetic acid (5-HIAA), kallikrein, substance P, neurotensin, motilin, somatostatin, vasoactive intestinal polypeptide (VIP), prostaglandins, neuropeptide K, and gastrin-releasing peptide. Several provocative tests have been developed to identify the cause of flushing in carcinoid syndrome. These tests are based on the need to distinguish the flushing from that found in a host of other conditions particularly in panic syndrome in which the associate anxiety and phobias usually establish the cause, but frequently, the physician and patient need reassurance that there is no underlying malignancy. Feldman and O'Dorisio6 have previously reported the incidence of elevated levels of plasma neuropeptide concentrations in patients with flushing. Despite the elevated basal concentrations of substance P and neurotensin, these authors were able to document further increases in these neuropeptides during ethanol-induced facial flushing. Ahlman and colleagues7 reported the results of pentagastrin (PG) provocation in 16 patients with midgut carcinoid tumors and hepatic metastases. All patients tested had elevated urinary 5-HIAA levels, and 12 had profuse diarrhea requiring medication. Pentagastrin uniformly induced facial flushing and GI symptoms in patients with liver metastases, but it had no effect in healthy control patients. All patients with PG-induced GI symptoms demonstrated elevated 5-HT levels in peripheral blood. Administration of a 5-HT-receptor antagonist had no effect on 5-HT release but completely aborted the GI symptoms. The authors emphasized the improved reliability of PG compared with calcium infusion, another provocative test popularized by Kaplan and colleagues,8 and pointed out that PG provocation occasionally can be falsely negative in patients with subclinical disease. Vinik et al9 reported that PG uniformly induced flushing in patients with gastric carcinoid tumors that was associated with a rise in circulating levels of SP in 80%. Thus, Substance P is a neurohumor that may be involved in the flushing of carcinoid syndrome. Substance P has also been found in tumor extracts and plasma from patients with carcinoid tumors and, in 1 reported case, was useful for tumor localization. Neurokinin A (NKA), its amino-terminally extended form, neuropeptide K, and SP are a group of peptides (ie, tachykinins) with common biologic properties. Norheim and colleagues measured peptide responses to PG or ingestion of food or alcohol in 16 patients with metastatic carcinoid tumors and demonstrated 2-fold or greater increases in NKA and neuropeptide K in 75% of patients, as well as variable increases in SP in approximately 20% of patients. Conlon and colleagues10 used region-specific antisera to SP and NKA to measure circulating tachykinins during a meal-induced flush in 10 patients with metastatic carcinoid tumors. Five patients had undetectable levels of NKA and SP after stimulation, thus suggesting that elevated tachykinin concentrations are not a constant feature of such patients. The authors also studied the effect of a somatostatin-analog administration on meal-induced tachykinin responses in 3 patients with carcinoid tumors. Flushing was aborted in 2 patients, but tachykinin levels were only partially suppressed, indicating that these peptides cannot be solely responsible for the carcinoid flush. When the diagnosis of the underlying cause of flushing has been established, pathogenesis-oriented treatment can be very helpful.5 Janet et al also performed a study, in which they used patients with metastasizing ileocecal 5-HT-producing carcinoid tumors and looked for the relationship of flushing to tachykinin production. They concluded that metastasizing ileocecal 5-HT-producing carcinoids produce many biologically active substances with partially overlapping biological functions. The biological processes underlying the specific symptoms of the carcinoid syndrome are probably multifactorial. They confirmed results from earlier studies showing that tachykinins and 5-HIAA levels are elevated in patients with daily episodes of flushing. The hormone effects were not mutually independent. It is possible that the development of flushing is the result of multihormonal stimulation. Other biologically active substances, such as kallikrein, and prostaglandins, may also contribute.11 Diarrhea, Abdominal Pain, Dyspepsia The key question to ask is whether the diarrhea persists with fasting. Diarrhea of NETs is always secretory, whereas diarrhea from other GI causes is usually malabsorptive. Perhaps the most vexing question is to differentiate the diarrhea and abdominal pain and dyspepsia from IBS. Irritable bowel syndrome affects a large proportion of the American population (6%-12%), and in Pakistan, Mexico, and Brazil, it may be as high as 40%. Abdominal pain and discomfort are the most prominent symptoms prompting consultation with a physician. Irritable bowel syndrome occurs more frequently in young white females, beginning before the age of 35 years in 50% of cases, and the symptoms typically do not disturb sleep, quite unlike that of NETs. Bleeding, fever, weight loss, and persistent severe pain are not features of IBS. Most sufferers (7.4%) report alternating constipation and diarrhea distinguishing them from NETs, and the diarrhea does not persist with fasting. Secretory diarrhea is characteristic of NETs, causing large-volume stools, and persists with fasting, and there is no osmotic gap between serum and stool. There are several causes of secretory diarrhea that need to be taken into consideration in the differential diagnosis: watery diarrhea, hypokalemia, hyperchlorhydria, and acidosis syndrome, the Zollinger-Ellison syndrome (ZES), carcinoid tumors, MCT, secreting villous adenoma of the rectum, surreptitious laxative abuse, and idiopathic. Diarrhea that disappears with the use of a proton pump inhibitor (PPI) is very suggestive of a gastrinoma because acid overproduction precipitates bile salts; inactivates lipase, amylase, and trypsin; and damages the intestinal mucosa. Another confounding issue is the change in the character of the diarrhea from a secretory diarrhea to a malabsorptive one with the use of somatostatin analogs. The stools become foul smelling; there is an inability to flush the toilet; and the stools float on the surface of the water and contain undigested food particles because somatostatin analogs cause inhibition of pancreatic enzyme secretion and the intestinal absorption of fluid and nutrients. Neuroendocrine tumors can produce diarrhea by different mechanisms, depending on their secretory products. Gastrin can increase the acid secretion by the stomach, which in turn inactivates lipase, amylase, and trypsin and damages the mucosa of the small bowel, leading to decreased absorption and impaired digestion in the small bowel, exceeding the absorptive capacity of the colon, what gives an increased fecal volume and malabsorptive syndromes and sometimes steatorrhea. On the other hand, carcinoid or other NETs can produce other substances such as VIP, pancreatic polypeptide (PP), SP, calcitonin gene-related peptide, and/or thyrocalcitonin, all of which will act on the small bowel increasing the secretion of fluids and ions, which in turn will also exceed the colonic absorptive capacity, producing an increased fecal volume as well as a great losses of potassium and bicarbonate. A disturbing cause of diarrhea that may be very difficult to detect is laxative abuse, and, in all circumstances, a KOH stool preparation to detect laxatives is mandatory. Measurement of intestinal secretion by passing a multilumen tube and quantifying electrolytes and water transport, in addition to the measurement of stool electrolytes, which should account for the total osmolarity, will help to exclude laxative abuse but is rarely performed. It is important to mention that Janet et al found, in their study of tachykinins and NETs, that there is an association between the elevation of tachykinins and the severity of the diarrhea. They concluded that all biochemical markers concentrations were elevated in patients with daily episodes of diarrhea, although the association between increased plasma tachykinins and the severity of diarrhea was independent of both chromogranin A (CgA) and 5-HIAA concentrations.11 Bronchoconstriction Wheezing due to bronchospasm occurs in up to one third of patients with carcinoid syndrome. Lung function tests show a prolonged forced expiratory volume in the first second. Differential diagnoses are asthma and chronic obstructive pulmonary disease. In the carcinoid syndrome, the cause of bronchoconstriction is usually substance P, histamine, or 5-HT that should be measured in patients who present with this symptom.4 Dyspepsia or Peptic Ulcer The ZES is characterized by peptic ulcers and diarrhea that responds to therapy with PPIs, in the setting of hypergastrinemia and low gastric pH. Gastrinomas are localized 90% of the time in the "gastrinoma triangle." As discussed in the previous section, the measurements that should be drawn for these tumors are fasting serum gastrin (FSG) and gastric acid output and, to differentiate gastrinoma from other cause of hypergastrinemia, a secretin- or calcium-stimulated gastrin. Hypoglycemia The Whipple triad (symptoms of hypoglycemia, low blood glucose levels VIPomas > somatostatinomas > others.29,30,32,33 Pancreatic NETs can occur both sporadically and in patients with various inherited disorder.25,30 Pancreatic NETs occur in 80% to 100% of patients with MEN I; in 10% to 17% of patients with von Hippel-Lindau syndrome (VHL); up to 10% of patients with von Recklinghausen disease (neurofibromatosis type 1 [NF-1]), and occasionally in patients with tuberous sclerosis.34 Each of these is an autosomal dominant disorder.34 Of these disorders, MEN I is the most frequent, in patients with PNETs.34,35 Multiple endocrine neoplasia type I is caused by mutations in chromosome 11q13 region resulting in alterations in the MEN I gene, which encodes for a 610-amino acid nuclear protein, menin, which has important effects on transcriptional regulation, genomic stability, cell division, and cell cycle control.34 Patients with MEN I develop hyperplasia or tumors of multiple endocrine and nonendocrine tissues including parathyroid adenomas (95%-100%) resulting in hyperparathyroidism, pituitary adenomas in 54% to 65%, adrenal adenomas (27%-36%), various carcinoid tumors (gastric, lung, thymic) (0%-10%), thyroid adenomas (up to 10%), various skin tumors (80%-95%), central nervous system tumors (up to 8%), and smooth muscle tumors (up to 10%).34 In MEN I patients, 80% to 100% develop pancreatic NF-PNETs, but in most patients, they are small and microscopic, causing symptoms in only 0% to 13%.34 Gastrinomas (>80% duodenal) develop in 54% of MEN I patients; insulinomas develop in 18%, and glucagonomas, VIPomas, GRFomas, somatostatinomas in less than 5%.34 In VHL, 98% of