Neuroendocrine tumors (NETs) of the gastrointestinal (GI) tract can be broadly classified as gastrointestinal NETs (GI-NETs) also referred to as previously and more commonly as carcinoid tumors and pancreatic NETs (PNETs). The NETs can be functional (secreting peptides and amines) or nonfunctional and are classified based on histology, mitotic counts, and Ki67 staining into low, intermediate, and high grade, that is, Grades 1, 2, and 3, respectively. In this chapter, we briefly review the physiology and biochemistry of the hormones resulting in clinical syndromes and then discuss the clinical presentation and diagnosis of the more common syndromes. Whilst we discuss the clinical syndromes such as PNETs and GI-NETs, it is important to emphasize that some of these tumors can emanate from both the pancreas and intestinal cells (e.g., gastrinomas). It appears that up to 25% are associated with inherited disorders including multiple endocrine neoplasia type 1 (MEN1), von Hippel–Lindau disease, neurofibromatosis 1 (NF-1), and tuberous sclerosis complex. It appears that the commonest type of NET is a nonfunctional PNET. In fact, loss of heterozygosity at the MEN1 locus on chromosome 11q13 is seen in 93% of sporadic PNETs .
Biochemistry and physiology of the more common gastrointestinal hormones
Enteroendocrine cells of the GI tract release numerous hormones that orchestrate the complex digestive functions of the stomach, intestines, and pancreas. Even before the consumption of food has begun, the anticipation of food triggers gastric secretions that will prime the GI lining for pending food ingestion, a process commonly referred to as the cephalic phase. Gastric and intestinal phases follow once the food reaches the stomach lumen, during which the GI hormones regulate digestion, absorption, and gut motility. In addition to their roles in digestion, the GI hormones aid in the growth and maintenance of gut mucosa, and in excess, they are implicated in the pathogenesis of NETs of the GI tract, as will be discussed in the following sections of this chapter. There have been over 50 gut hormones that have been discovered, only a fraction of which has been heavily investigated in the medical science community. Among the well-established and understood gut hormones are gastrin, cholecystokinin (CCK), secretin, somatostatin, ghrelin, motilin, and vasoactive intestinal peptide (VIP). While all of these are peptide hormones, they are varied in their chemical make-up and function .
Gastrin is a linear peptide hormone released from G cells in the gastric antrum in response to stomach distension, increased pH, and vagal stimulation. It is the primary hormone for gastric acid secretion, as it stimulates parietal cells to release hydrochloric acid (HCl). The mechanism of action is via one of two ways: a direct pathway and an indirect pathway. Gastrin can exert its effects on parietal cells by directly binding gastrin receptors on parietal cells or by stimulating enterochromaffin-like cells (ECL) to release histamine, which then binds its receptors on parietal cells. Gastrin also stimulates the growth of gastric mucosa and is a known contributor to the pathophysiology of gastrinoma. The precursor peptide, preprogastrin, could be cleaved into three forms: gastrin-34 (big gastrin), gastrin-17 (little gastrin), and gastrin-14 (minigastrin). Gastric acid secretion can be terminated by low levels of pH and somatostatin, both of which signal fasting .
Somatostatin is a peptide hormone released by D cells throughout the GI tract. It naturally occurs in two forms: 14 and 28 amino acids. Additionally, there is a widely used 8-amino acid synthetic analog, which has a much longer half-life. Its release is triggered by low levels of gastric pH, and subsequently it acts to inhibit most GI hormones, including insulin, glucagon, and gastrin. This essentially blocks the release of HCl from parietal cells and their powerful downstream stimulatory pathway. It inhibits growth hormone release from the hypothalamus and most GI hormones such as insulin, glucagon, and gastrin. Inhibition of CCK release and the resultant reduction in gallbladder contractility lead to cholelithiasis in patients with somatostatinomas. Pancreatic insufficiency and associated fat malabsorption may result in diarrhea and steatorrhea. Decreased gastrin secretion can also present as gastric hypochlorhydria. Measurement of somatostatin is inherently difficult. Because somatostatin is labile in vitro, it requires special handling and rapid separation. Somatostatin presents with a 20% diurnal variation: it peaks at midnight and is at its nadir at 8 a.m. .
Secretin prepares for the intestinal phase of digestion by promoting secretions from the pancreas and gallbladder and simultaneously inhibiting gastrin and halting acid secretions from parietal cells. It is secreted by duodenal S cells, and it acts to induce bicarbonate release from pancreatic duct cells, effectively raising the pH in the small intestines. Clinically, secretin is used as a diagnostic test for gastrinomas, as it increases the release of gastrin in patients with gastrinoma .
CCK, in Greek for “gallbladder move,” promotes contraction of gallbladder and relaxation of sphincter of Oddi for the secretion of pancreatic enzymes. In line with its role in aiding in fat digestion in the intestines, CCK also acts to suppress gastric emptying. CCK is released from intestinal I cells by the presence of fatty acids and monoglycerides, as well as amino acids in the intestines .
Pancreatic polypeptide (PP) is a 36-amino acid peptide, which is predominantly produced by F cells in the pancreas. Besides its function of stimulating pancreatic enzyme secretion and contraction of the bladder, little else is known about its actions . The World Health Organization classified PP tumors as well-differentiated NETs with features such as solid, trabecular, gyriform, or glandular pattern, uniform nuclei, and finely granular cytoplasm The head of the pancreas has the greatest density of PP cells, which produce PP. PP secreting tumors are highly vascular and can have the ability to invade the wall of the duodenum or cause thrombosis of the splenic or portal vein . In Table 6.1 summarized the physiology of the GI hormones.
|Hormone||Cells of production (section of intestine)||Major actions|
|Cholecystokinin||CCK (duodenum, jejunum)||Gallbladder contraction, amylase secretion by pancreas, decreases appetite|
|Somatostatin||D (diffuse)||Inhibits glucagon and insulin production, intestinal motility, gastric acid secretion|
|Serotonin||Enterochromaffin-like cells (stomach)||Stimulates gastric acid secretion|
|Gastrin||G (stomach)||Stimulates gastric acid secretion|
|Ghrelin||P/D1 (stomach, duodenum)||Increases food intake, decreases insulin|
|GIP||GIP (duodenum, jejunum)||Increases glucose-mediated insulin release; inhibits gastrin production|
|GLP-1, PYY||L (jejunum, ileum, colon)||(both) Decreases appetite; (GLP-1) increases insulin, slows gastric emptying|
|Glucagon||Α||Increases blood glucose|
|Insulin||B||Decreases blood glucose|
|Pancreatic polypeptide||PP||Stimulates bile flow and exocrine pancreatic secretion|
Pancreatic neuroendocrine tumors
Pancreatic NETs (PNETs) are a group malignancies of pancreatic islet cells. Pathologies of this category are insulinoma, Zollinger–Ellison syndrome (ZES) (gastrinoma), α-cell tumors (glucagonomas), δ-cell tumors (somatostatinomas), VIPoma, and pancreatic carcinoid tumors. Making up merely 2% of all pancreatic tumors, NETs are rare in comparison to those of pancreatic exocrine counterparts. Presentations vary from single to multiple lesions, benign to malignant, nonfunctional to hyperfunctional neoplasms. Malignancy is determined by the presence and progression of metastases, vascular invasion, and local infiltration .
Glucagon, a hormone secreted by pancreatic alpha cells, is primarily responsible for breaking down glycogen to glucose in the liver. Glucagonoma (α-cell tumor) is a very rare malignancy of pancreatic islet cells with an approximate annual incidence of 0.01–0.1 per 100,000 . Most glucagonomas are sporadic, and <10% of cases present in association with MEN1 syndrome. They are usually solitary tumors and located in the body and tail of the pancreas and >50% are metastatic at diagnosis .
Glucagonomas are functional neoplasms and are thus associated with increased serum levels of glucagon resulting in a clinical syndrome including mild diabetes mellitus, a characteristic skin rash necrolytic migratory erythema (NME), and anemia. They present more frequently in women than men, and particularly in perimenopausal and postmenopausal women.
The development of symptoms in glucagonomas is driven by the supraphysiologic levels of circulating serum glucagon. Glucagon increases hepatic catabolic reactions through amino acid oxidation and gluconeogenesis, which leads to the characteristic weight loss. The cause of NME is still not elucidated, but hyponutrition with low zinc and amino acid levels could be important. Diarrhea may be present due to excess glucagon and cosecretion of other digestive hormones such as gastrin, vasoactive intestinal peptide, serotonin, or calcitonin.
Hypersecretion of the hormone glucagon causes a combination of symptoms, easily summarized as the 4Ds: Dermatosis, Diabetes, Deep Vein Thrombosis, and Depression.
Present in up to 90% of patients, the dermatosis associated with glucagonoma syndrome is referred to as NME. It is a red, blistering rash that is itchy and painful. NME can commonly affect the genitals, buttocks, groin, and the extremities, and severity may fluctuate. Mucosal abnormalities include glossitis, stomatitis, and cheilitis. The NME initially starts out as erythematous papules or plaques and may enlarge and develop into bullae in severe forms. In a subset of patients, hair loss and nail dystrophy may also be present. The mechanism of NME is likely due to malnutrition and amino acid deficiency .
Glucose intolerance affects 75%–95% of patients, with elevated fasting glucose levels. Of note, hyperglycemia due to glucagonoma rarely develops into diabetic ketoacidosis, since beta cells are preserved and able to secrete insulin in response to circulating levels of glucagon .
Up to 50% patients can present with deep vein thrombosis including pulmonary embolism. The high incidence of thromboembolism in glucagonoma patients is still poorly understood. Unexplained deep vein thrombosis in patients with NET should alert the possibility of glucagonoma .
The mechanistic explanation for depression in glucagonoma patients is poorly studied, but has traditionally been attributed to other associated symptoms such as hair loss and NME. There are many other neuropsychiatric manifestations reported in glucagonoma patients, including dementia, psychosis, agitation, hyperreflexia, ataxia, paranoid delusions, and proximal muscle weakness, which may suggest underlying physiologic or biochemical mechanisms driving such family of symptoms .
In patients with new onset of diabetes, rash, and weight loss, glucagonoma should be suspected. Diagnosis of glucagonoma can be made with an elevated fasting plasma glucagon level (>500 pg/mL), usually 10–20 times the reference range. Glucagon level above 1000 pg/mL can be pathognomonic. Increased glucagon levels can be due to other conditions including acute trauma, diabetes, burns, cirrhosis, etc., but levels do not exceed 500 pg/mL in these contexts. Mahvash disease, which is due to a homozygous inactivating mutation in the glucagon receptor gene, GCGR, similarly results in hyperglucagonemia, alpha cell hyperplasia, and adenomas, but without clinical features of glucagonoma .
Since all these tumors are rare, the required assays are usually performed in reference laboratories and require careful sample preparation such as addition of a protease inhibitor, using chilled tubes and freezing the sample at below 20°C immediately . Working with the reference laboratory will be most helpful to obtain a valid result. Glucagon assays from different vendors show variable cross reactivity with different isoforms of glucagon.
It is also prudent to check both zinc and amino acid levels as part of the work-up .
As is the case with other NETs, imaging studies are necessary for accurate localization and staging of primary and metastatic glucagonomas. Somatostatin receptor scintigraphy, in combination with either Cat Scan (CT) or magnetic resonance imaging (MRI), is invaluable in the work-up of a patient with glucagonoma.
Treatment of glucagonoma should focus on the management of glucose intolerance and nutritional support for counterbalancing the catabolic effects of glucagon. In advanced, metastatic disease, surgical resection of the liver or hepatic artery embolization with or without chemotherapy may be used not for curative, but palliative intent . Somatostatin analog is the current treatment of choice, especially for metastatic disease, as these tumors have abundant somatostatin receptors. In addition to decreasing the level of secreted hormones, somatostatin analog have been shown to have some cytostatic activity .
Somatostatinomas are tumors of pancreatic D cells that secrete increased amounts of somatostatin. These tumors are extremely rare, with the annual incidence rate estimated at 1 in 40 million. Somatostatinomas are the least likely to be present in patients with MEN1 syndrome. The tumors are typically present in the pancreas, and less frequently in the duodenum and jejunum. Symptoms are more common with pancreatic than intestinal tumors. Tumors are usually solitary and large and liver metastases are present in over 69% of cases . Patients with this neoplasm typically present with diabetes mellitus, cholelithiasis, steatorrhea, and hypochlorhydria due to the inhibitory effects of somatostatin on cellular function. Nonfunctional somatostatinomas are also seen frequently in 0%–10% of patients with neurofibromatosis .
Somatostatinomas are functional neoplasms and secrete high levels of somatostatins. Unlike other functional endocrine tumors of the GI tract, however, somatostatinoma less frequently presents with symptoms in relation to excess somatostatin secretion. As somatostatin is a well-known inhibitor of all the GI hormones that have been studied, excess secretion of it could lead to an increase in GI transit time and decrease in intestinal motility and nutrient absorption. Appropriately, the most common presenting symptoms in patients with somatostatinoma are abdominal pain and weight loss. In a smaller percentage of patients, somatostatinomas present with diabetes mellitus, cholelithiasis, and diarrhea/steatorrhea, the triad termed somatostatinoma syndrome. This syndrome is more commonly reported in patients with pancreatic somatostatinomas than duodenal somatostatinomas .
Somatostatinomas are usually found during exploratory laparotomy or upper GI radiographic studies with CT or MRI for patients with unexplained abdominal pain, nausea, vomiting, melena, hematemesis, persistent diarrhea, weight loss, fatigue, and anemia. Patients presenting with the triad of diabetes mellitus, cholelithiasis, and diarrhea/steatorrhea should be suspected of having somatostatinomas and evaluated for fasting plasma levels of somatostatin. Hormone level greater than 30 pg/mL can establish diagnosis. Other methods of diagnosis include evaluating tissue concentrations of somatostatin by immunohistochemistry or, when applicable, histopathology of surgical specimen that demonstrates positivity for somatostatin on immunohistochemistry . Imaging studies with OctreoScan, CT, and MRI can also be considered for localization and staging of advanced disease, as these malignancies express somatostatin receptors on their cell surface.
While somatostatinomas are highly associated with metastatic disease, the survival rate is considerably high. Thus aggressive management and attempts to surgically remove these tumors, in the case that they are primary, are important for curative intent. As most somatostatinomas are present in the head of the pancreas or duodenum, surgical resection via a pancreaticoduodenectomy is the treatment of choice. Patients with metastatic disease, or inoperable tumors, however, should be treated medically. Therapy with somatostatin analog that inhibits the secretion of somatostatin is the first line of treatment and symptom relief in patients with unresectable tumors . However, its role in antitumor activity has not been demonstrated. In this regard, other lines of treatment can be considered, such as with molecularly targeted therapy (e.g., everolimus, sunitinib, etc.), cytotoxic chemotherapy, or peptide receptor radioligand therapy .
Vasoactive intestinal peptide tumors are usually solitary NETs, which secrete the hormone VIP in an uncontrolled manner. They were first described in 1958 by Verner and Morrison as a pancreatic tumor resulting in watery diarrhea with hypokalemia that was resistant to treatment. Because of the severity of its course and similarity to Vibrio cholerae infection, it was later nicknamed pancreatic cholera. It is also referred to as the WDHA syndrome since there is W atery D iarrhea, H ypokalemia, and A chlorhydria. In 1973, Bloom, Polak, and Pearse identified the VIP hormone as the cause of this syndrome . Moreover, they are extremely rare tumors with an incidence between 0.05% and 2% that present in both adults and children. In 95% of cases the tumor is intrapancreatic and most commonly occurs between the ages of 30–50 years . VIPomas are part of MEN1 in around 5% of cases and >50% have metastasized by the time of diagnosis.
The 28-amino acid VIP is posttranslationally modified from its 170-amino acid precursor prepro VIP. VIP is a neuropeptide present in both central and peripheral nervous systems that very strongly stimulates intestinal secretion of water and electrolytes. It is a member of the secretin-glucagon family. In addition, this neuropeptide has an inhibitory effect on gastrin secretion and is a vasodilator and promotes blood flow in the GI tract mainly. It modulates these actions through its stimulation of intestinal cyclic adenosine monophosphate (cAMP) production. VIPoma is caused by excess secretion of this neuropeptide. Through continuous stimulation of cAMP, VIPoma presents with enormous secretion of water and electrolytes. The common presentation of hypochlorhydria occurs from the direct inhibitory effect of VIP on gastrin-17 . Seventy-five percent of VIPomas initially present in the body and tail of the pancreas, while the other 25% originate in the head of the pancreas.
VIPoma classically presents with greater than 3.0 L of watery stool per day, hypokalemia, and achlorhydria . The hypokalemia and hyperchloremic metabolic acidosis are due to the copious diarrhea and substantial loss of bicarbonate. The hypercalcemia could be due to dehydration on part of the MEN syndrome. In this early stage, this tumor predominantly presents with episodic and intermittent diarrhea. As the tumor progresses and enlarges, this diarrhea becomes continuous with presentation of severe electrolyte abnormalities. Unfortunately, at the time of presentation, 70% of patients will already have metastases of the tumor . Hyperglycemia, hypercalcemia, and flushing are common accompanying presentations as well. Especially in the context of features such as hypercalcemia, VIPoma may be associated with a MEN1 syndrome. Other important features that can present include tetany, from hypomagnesemia, myopathy, and cardiac arrhythmias from hypokalemia. In the pediatric population, VIPoma may present as a failure to thrive. Other mimickers of VIPoma that must be ruled out include ZES, chronic laxative abuse, AIDS, and celiac sprue .
Patients with excessive tea colored diarrhea along with electrolyte abnormalities and other possible features such as flushing should be suspected of having a VIPoma. The diarrhea is secretory; that is, it persists after 48 h of fasting. Also the diarrhea has a low osmotic gap below 50 mOsm/Kg. The diagnosis of VIPoma is made with secretory diarrhea greater than 3 L/day with a VIP level of 250–500 pg/mL (normal range: 0–190 pg/mL). Biochemical detection of VIP levels is achieved through measurement of VIP by immunoassay. The serum sample needs to be added to tubes containing the protease inhibitor, aprotinin, centrifuged and frozen below 20°C . It is critical to repeat this test, as a single plasma VIP level value cannot diagnose or exclude VIPoma. Between bouts of diarrhea, the VIPoma endocrine tumor may not actively be secreting VIP. Moreover, it is most accurate to obtain VIP levels from the patient when he or she is actively having diarrhea .
Localization of the tumor itself is initiated through contrast-enhanced CT scan. This imaging modality has greater than 80% sensitivity for detecting intrapancreatic NETs. It should be noted that endoscopic ultrasound has been shown to have a higher sensitivity for detecting NETs, compared to CT, but is not as commonly used . Intravenous (IV) contrast can also be utilized for detection of smaller tumors that may not be possible by contrast CT. In scenarios of identifying extrapancreatic VIPomas, such as metastases, somatostatin receptor scintigraphy can be used.
Treatment of VIPomas is focused on a combination of medical and surgical management. Because of the profuse diarrhea that patients present with, initial treatment must always focus on aggressive replacement of fluids and electrolytes. Isotonic fluid should be used and electrolyte replacement can prevent dangerous sequelae such as cardiac arrhythmias and neurovascular defects. Somatostatin analogs such as octreotride and lanreotide can be used for symptomatic control by inhibiting secretion of VIP. Octreotide doses of 50–100 μg administered subcutaneously every 8 h or intramuscular long-acting formulation of octreotide and Sandostatin LAR can be used. Glucocorticoids and interferon-alpha have been used in patients refractory to the above treatments .
Surgical resection is the treatment of choice in regard to removal of the VIPoma tumor itself. If complete resection is not possible, surgical debulking may also be done for palliative purposes. Surgical removal has been shown to be very effective in treating symptoms of VIPoma. When the tumor has metastasized, other approaches must be pursued . For instance, when the tumor has metastasized to the liver, resection of the liver is often times merited. Radiofrequency ablation and cryoablation have been effective treatment modalities for metastases less than 3 cm . Unfortunately, systemic chemotherapy has not been proven to be effective in cases of extrahepatic metastases or large, bulky tumors. Currently, newer agents such as sunitinib, a tyrosine kinase inhibitor, and everolimus, an mTOR inhibitor, have been approved in the United States for treatment of advanced and well-differentiated PNETs such as VIPomas. These modalities have proven to be effective with Everolimus treatment resulting in stable disease in 67.8% of patients with VIPoma, for example .
Median survival is 96 months in patients with VIPomas. Prognostic factors depend on tumor stage, grade, and surgical resectability. Postresection follow-up includes history and physical exam, imaging such as multiphasic CT, and measurement of serum VIP in the initial 3–12 months. After 1 year, it is recommended to follow these guidelines every 6–12 months .
Insulinomas are detailed in the chapter on hypoglycemia. Suffice it is to say is that the majority are benign tumors that present with fasting or exercise induced hypoglycemia, which can be confirmed with a 72-h fast under medical supervision. Also both C-peptide and proinsulin levels can be increased and helpful in the differential diagnosis of fasting hypoglycemia
Gastrointestinal neuroendocrine tumors
Gastrinomas are neuroendocrine neoplasms resulting in excessive secretion of gastrin resulting in severe acid-related peptic ulceration and diarrhea. The clinical syndrome accompanying hypergastrinemia is referred to as the ZES . Sporadic gastrinomas are frequently found in the duodenum (50%–90%), followed by the pancreas (10%–40%). Gastrinomas can either be sporadic or as a part of multiple endocrine neoplasia type 1 syndrome .
Gastrin is the key promoter of gastric acid release from parietal cells, an important mechanism for macronutrient breakdown in the stomach. In the context of uncontrolled growth, gastrinomas cause excessive stimulation of parietal cells, resulting in inappropriate acid secretion, hypertrophy/hyperplasia of gastric mucosa, and ulceration. These clinical symptoms are collectively coined the ZES. In ZES, hypergastrinemia provokes the hypersecretion of gastric acid, leading to multiple peptic ulcerations in unusual locations, such as the jejunum. Interestingly, these ulcers are typically unresponsive to treatment with proton pump inhibitors, in contrast to ulcers that occur independently of gastrinomas.
The major symptoms are related to peptic ulcer disease (PUD) or severe gastroesophageal reflux disease with or without diarrhea . PUD is usually in the duodenum but multiple ulceration, refractory to medical therapy, and PUD associated with prominent gastric folds should increase suspicion for ZES. ZES can present as diarrhea in 50% of the patients, and in 30% of patients, it is the presenting symptom. Unfortunately, more than half of gastrin-secreting tumors are already metastatic at the time of diagnosis. Twenty-five percent of gastrinoma patients also copresent with other NETs, which is then identified as MEN1 syndrome .
As with any other functional GI-NETs, gastrinomas are diagnosed based on inappropriate circulating levels of the hormone, gastrin. As the initial presentation of ZES is very similar to PUD, physicians must use clinical judgment in deciding which patients with PUD need to be worked up for ZES, based on family history of endocrinopathy, diarrhea, and hypercalcemia. In general, patients with peptic ulcers that are refractory to proton pump inhibitor treatment should be suspected of having a gastrinoma and be followed up as such .
Initial evaluation is through a fasting serum gastrin level. Gastrin circulates in at least three forms: G34, G17, and G14. Hence, immunoassays report different levels depending on the epitopes targeted by the respective antibodies. Patients need to be fasted prior to the study since circulating levels increase after a meal. Given the instability of the hormone, the separated sample should preferably be frozen to below −70°C immediately .
Fasting serum gastrin level of 1000 pg/mL, a 10-fold excess of the normal range, is pathognomonic of gastrinoma. Higher levels of serum gastrin are correlated with tumors of pancreatic origin, larger tumor size, and metastases. ZES patients also present with less than 10 times the normal range of fasting serum gastrin 60% of the time. In order to confirm the diagnosis in these patients, they should be given the secretin stimulation test, which remains the most sensitive and accurate test of ZES. Secretin which normally is inhibitory of G cells and gastrin secretion paradoxically stimulates gastrinomas to secrete gastrin, which serves as the mechanistic basis of the secretin stimulation test. This study involves IV administration of 2 μg/kg secretin and monitoring serum levels of gastrin at 2, 5, 10, 20, and 30 min. Greater than 200 pg/mL increase in gastrin level strongly suggests ZES .
As there are other possible causes of hypergastrinemia, clinicians must ensure to exclude these following factors before diagnosing ZES: postvagotomy state, atrophic gastritis, retained antrum syndrome, primary G-cell hyperplasia, and achlorhydria primary or secondary to proton pump inhibitor therapy . The diagnosis is enhanced if the hypergastrinemia is associated with a gastric pH <2.0 and the basal acid output is >15 mEq/h .
MEN1 syndrome must be excluded from patients with ZES. If a patient with ZES has a family history of a similar endocrinopathy or hypercalcemia at the time of diagnosis, then serum PTH, prolactin GH, and insulin-like growth factor-1 should also be assayed.
Imaging studies may also be pursued for assessing tumor burden and localizing and staging the metastases of gastrinomas. As somatostatin receptors are ubiquitously expressed on the cell surfaces of NETs, recent radiologic developments have progressed to use fluorescence-tagged somatostatin receptor ligands for NET imaging, called OctreoScan. In modern practice, images taken from OctreoScan are combined with SPECT or CT for their advantages in anatomical resolution .
Gastrinomas can be managed medically or treated surgically. Medical therapy is the treatment of choice for most patients with ZES as a manifestation of MEN1 syndrome. Surgical therapy can be considered for patients with sporadic ZES.
The goal of management in ZES is to manage the symptoms and complications of PUD. This can be achieved via high-dose proton pump inhibitors, which bind and inhibit hydrogen/potassium ATPase on the luminal surface of parietal cells, or in refractory cases, with octreotide, a somatostatin analog. Patients with ZES should be started on a high dose of a proton pump inhibitor (omeprazole 60 mg daily, esomeprazole 120 mg daily, lansoprazole 45 mg daily, rabeprazole 60 mg daily, or pantoprazole 120 mg daily) .
In patients with no signs of metastatic spread or MEN1 syndrome, an attempt can be made at exploratory laparotomy and resection with curative intent .
NETs are malignant growths that stem from neuroendocrine cells . NETs arising from the intestine were formerly known as carcinoid tumors, though this term is still widely used by physicians today . In 1888 Otto Lubarsch was credited with documenting the presence of ileal carcinoid tumors in two patients at autopsy. In 1953 Lembeck identified serotonin in an ileal carcinoid tumor and as the predominant hormone responsible for carcinoid syndrome . Forty-eight percent of NETs arise in the GI tract, while 25% arise in the lungs and 9% arise in the pancreas. NETs are extremely rare and compromise less than 2% of all malignancies in the United States. Moreover, in the United States, there is a prevalence of less than 200,000 cases. Detection of these tumors has recently been on the rise, most likely due to incidental findings on increasing utilization of imaging. The hallmark of NETs is their ability to produce the hormone serotonin, which leads to symptoms such as flushing and diarrhea .
Carcinoid tumors are thought to originate from Kulchitsky cells, enterochromaffin cells, in the crypts of Lieberkuhn of the gut. These cells secrete a variety of substances such as 5-hydroxytryptamine (5-HT), 5-hydroxytryptophan (5-HTT), histamine, kallikrein, and prostaglandins . Carcinoid syndrome, which classically presents with watery diarrhea, bronchospasm, flushing, hypotension, and right-sided heart disease, is caused by the release of these various substances and appears to occur in <10% of patients with carcinoids. The Kulchitsky cells use the majority of tryptophan stores to metabolize into serotonin. In contrast, a healthy individual without serotonin syndrome only has 1% of total tryptophan stores metabolized into serotonin. This serotonin is eventually excreted in the urine as 5-hydroxyindoleacetic acid (5-HIAA). Carcinoid syndrome presents only when the tumor metastasizes to the liver or bypasses the portal circulation. This is because serotonin, as well as other biologically active amines and peptides, is typically inactivated in the liver before reaching systemic circulation .
In most scenarios, carcinoid tumors are asymptomatic until advanced stages. When these tumors metastasize to liver and or bypass the portal circulation, the manifestation of carcinoid syndrome presents with distinct characteristics. Midgut carcinoids account for around 60% of all carcinoid syndromes. Biologically active amines, peptides, and prostaglandins produce a variety of vasodilatory effects such as flushing and diarrhea (secretory), which occur in around 70% of patients at onset . In fact, flushing is the most common clinical feature, with 85% of patients presenting with this symptom. The flushing can be precipitated by stress, certain foods, and medications. This flushing is very distinct, with a salmon pink to dark discoloration of skin in the upper body. Because of serotonin’s effect of increased motility and secretion of the GI tract, patients often presents with diarrhea and malabsorption. The diarrhea is watery and explosive, occurring up to 30 times a day. Patients can also present with steatorrhea. Valvular disease secondary to plaques on the endocardium has been described in up to 60%–70% of patients. The valvular defects are tricuspid regurgitation, tricuspid stenosis, and pulmonary stenosis in order of frequency. Signs of right-sided heart failure are seen. Just as carcinoid syndrome can cause valvular fibrosis, it can also cause mesenteric and small bowel fibrosis. Secretion of serotonin, along with tachykinins and growth factors, is involved in the pathogenesis of this fibrosis through stimulation of fibroblasts. Additionally, with the conversion of most tryptophan stores in the body to serotonin, there is niacin deficiency with the patients presenting with diarrhea, dermatitis, and dementia, a constellation of pellagra. Late stages of carcinoid syndrome can present with a purple rash due to prolonged vasodilation. A feared complication of carcinoid syndrome is carcinoid crisis, a life threatening presentation of flushing, bronchospasm, and rapidly fluctuating blood pressure precipitated by anesthetic or tumor manipulation .
Diagnosis of carcinoid tumor is inherently difficult. This is because of low incidence, small size of the tumor with high metastatic potential, and varied clinical presentation. Moreover, early diagnosis requires highly sensitive and specific biomarkers. Twenty-four hour measurement of 5-HIAA urinary secretion is the initial gold standard screening test, as it has a 90% sensitivity and specificity for diagnosis of intestinal carcinoid. The urine should be collected in acidified containers. Patients cannot eat serotonin rich foods for 3 days before this test to prevent false positive results. Recent studies have also validated plasma HIAA levels to aid in diagnosis. Plasma levels are not affected by eating or time of day but are increased with renal impairment (Estimated glomerular filtration rate <60 mL/min) . Since the majority of serotonin resides in platelets, whole blood serotonin is the best measure but the sample has to be taken in a tube containing a reducing agent such as ascorbate . Concentration of chromogranin A (CgA), a glycoprotein secreted by carcinoid tumors, can also be measured. However, this biomarker is better suited for follow-up rather than diagnosis due to its poor specificity and is a measure of tumor burden. Issues with the measurement of CgA are detailed under nonfunctional NETs .
After laboratory testing is completing, imaging must be pursued to localize and stage the tumor. CT/MRI imaging and functional imaging are the two modalities that are generally utilized. Because of its wide availability, CT with contrast is most commonly used. It is recommended that all patients with a suspected carcinoid tumor should receive CT of chest, abdomen, and pelvis. Disadvantages of CT include a low specificity, difficulty in detecting tumors less than 1 cm, and difficulty differentiating between colorectal adenocarcinomas and colorectal carcinoid tumors. MRI is pursued if there is suspicion of liver metastases. Functional imaging, such as the octreotide scan, can be used to detect metastasis beyond the abdominal region. Octreotide scan is used with positron emission tomography scanning to detect octreotride uptake in the abdominal region. This modality has a sensitivity in asymptomatic patients of 80%–90%. However, its utility in surveillance of carcinoid syndrome is questionable. Newer modalities such as the Gallium-68 positron emitter have also emerged as highly sensitive tests for detecting carcinoid tumors .
Similar to other endocrine tumors of the GI tract, treatment resolves around both medical and surgical management. Medical management is preferred for patients with carcinoid syndrome and carcinoid tumors that are unresectable. On the other hand, surgical intervention is most important for cure of carcinoid tumor. Octreotride and lanreotide, somatostatin analogs, are used to inhibit release of biogenic amines that cause classical symptoms of serotonin syndrome such as flushing and diarrhea. This is effective as 80% of NETs have somatostatin receptors. These somatostatin analogs have been shown to provide relief in 50%–70% of patients. Short-acting octreotide subcutaneous injection is preferred for patients with severe symptoms. A common side effect of these analogs is pancreatic malabsorption, with pancreatic enzyme supplementation often provided for patients.
Surgical resection with negative margins is the main treatment for nonmetastatic carcinoid tumors confined to the intestine. Because tumors in the small intestine have a high chance of metastasis, the involved area of the small bowel along with small bowel mesentery must be resected. On the other hand, colorectal carcinoid tumors tend to be greater than 2 cm and more invasive. These tumors must be treated with partial colectomy and lymphadenectomy. Cytoreductive surgical resection is preferred for metastatic tumors along with concomitant medical therapy. Patients with hepatic metastases are candidates for percutaneous hepatic transarterial embolization.
Complications from carcinoid syndrome such as valvular failure are treated with tricuspid valve replacement. For this reason, it is critical to perform echocardiograms in patients with significantly elevated levels of 5-HIAA and/or symptoms of carcinoid syndrome. The complication of carcinoid crisis is treated with a 500–1000 mg IV bolus of octreotide followed by continuous infusion at 50–200 μg/h. Treatment options for refractory symptoms include interferon-alpha, Telotristat, an oral tryptophan hydroxylase inhibitor, and systemic chemotherapy such as everolimus .
Nonfunctioning neuroendocrine tumor (pancreatic neuroendocrine tumors)
The WHO classification of neoplasms of the neuroendocrine pancreas includes the category of nonfunctioning NETs. These tumors are generally pancreatic neoplasms that have no functional clinical syndrome, and symptoms are largely due to the tumor mass itself . Nonfunctioning PNETs are now considered to represent >60% of all PNETs. Although these tumors are not associated with a clear clinical syndrome, they secrete numerous peptides, the most relevant of which are PP, CgA, and neuron-specific enolase (NSE), amongst others. These nonfunctional tumors are also frequently seen in systemic diseases such as MEN1, von Hippel–Lindau disease, and tuberous sclerosis .
These tumors present with the nonspecific features of a tumor mass and this includes abdominal pain, jaundice, weight loss, bleeding, and an abdominal mass . Furthermore, because of late presentation the tumors are large (around 5 cm), invasive, and around 50% have liver metastases. Imaging is very useful and the modalities discussed above for functioning tumors including CT, MRI, Endoscopic Ultrasound, and somatostatin receptor scintigraphy are extremely useful. The diagnosis requires a biopsy and measurement of CgA, PP, and NSE. In well-differentiated functional and nonfunctional tumors, immunohistochemistry confirms staining for CgA, synaptophysin, NSE, PP and cluster of differentiation 56 (CD56-neural cell adhesion molecule) .
CgA, PP, NSE, and pancreastatin have been found to be the best biomarkers for diagnosis of nonfunctioning tumors. PP serum levels are measured by immunoassay using Ethylenediamine tetraacetic acid plasma. PP levels are increased in nonfunctioning and functioning tumors. Since levels increase with exercise and eating, fasting levels are desired to diagnose and monitor therapy. Also levels are not altered by proton pump inhibitor therapy . CgA is widely distributed in neuroendocrine cells and could serve as a useful biomarker for both nonfunctioning and functioning tumors, as well as it correlate with tumor burden. It is not specific for malignancy. However, the assay has several limitations in addition to the well-known effects of heterophile antibody interference and the hook effect . It has a large biological variation, significant differences between plasma and serum samples, increases with food intake, large assay-to-assay variation possibly due to antibodies directed to different epitopes, and increases with impaired renal function . Levels are also increased with gastric achlorhydria (e.g., pernicious anemia and proton pump inhibitor therapy). Despite these issues it generally serves as a reliable biomarker for the diagnosis, monitoring and prognosis of neuroendocrine tumors both functional and nonfunctional. NSE can also serve as a tumor marker for gastroenteropancreatic NETs. It appears to be a more valid marker of prognosis and is increased with poorly differentiated, rapid growing tumors . Caveats include its biological variability and the major interference from hemolysis due to the abundance of NSE in erythrocytes .
Pancreastatin has shown utility in monitoring effects of treatment and progression of these tumors . Staging is performed through CT of the abdomen, pelvis, and thorax. MRI is performed to identify liver metastases, while upper digestive endoscopy with ultrasound allows for detection of small lesions. The combination of 111-labeled octreotide scintigraphy with CT/MRI imaging has improved detection of both primary and metastatic lesions. Functional staging through the use of plasma CgA further guides staging and treatment of these tumors .
Because most patients at the time of diagnosis have metastatic disease, curative surgical resection can only be done in about 10% of cases. In cases of isolated metastases to the liver, liver resection can lead to both symptomatic relief and increased survival. Hepatic artery embolization poses as another option in patients with predominantly hepatic involvement. For candidates where curative surgery is not possible, debulking can be considered to reduce hormonal production by the tumor, symptoms, and tumor mass. Similar to other GI endocrine tumors, somatostatin analog of octreotide and lanreotide can be utilized as medical therapy when surgery is not possible or ineffective. Systemic chemotherapy involving agents such as streptozocin, doxorubicin, and cyclophosphamide can be used in progressive metastatic disease. Streptozocin and doxorubicin is the current combination of choice. Even with chemotherapy, PP secreting tumors exhibit a high rate of recurrence. As a result, tyrosine kinase inhibitors such as sunitinib have been explored to improve survival . In Table 6.2 is summarized the neuroendocrine tumor syndromes.