Neuroendocrine Neoplasms

Definition

Neuroendocrine neoplasms, ^, formerly called neuroendocrine tumors, are now subclassified as well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. This new division has important implication for both prognosis and treatment. Neuroendocrine neoplasms occur in almost all tissues but have historically been divided into two large groups, pancreatic neuroendocrine neoplasms/tumors compared with neuroendocrine neoplasms in other locations, often called carcinoid tumors in older classifications.

Epidemiology

The annual incidence of neuroendocrine neoplasms in the United States is estimated to be about 12,000, a with prevalence of about 175,000. About 50% occur in the gastrointestinal tract, 20% in the lung, and 12% with an unknown primary. Pancreatic neuroendocrine tumors account for 1 to 10% of all diagnosed pancreatic neoplasms, with a prevalence of 1 per 100,000 and an annual incidence of 1 to 4 per million. However, pancreatic neuroendocrine neoplasms are seen in 0.5 to 1.5% of autopsies, thereby indicating that the vast majority are not clinically evident. About 60 to 80% of all pancreatic neuroendocrine neoplasms are nonfunctioning ( Table 213-1 ). Among functional pancreatic neuroendocrine neoplasms, insulinomas and gastrinomas are the most common, with annual incidences of 0.5 to 3 per million. In general, insulinomas and gastrinomas are 8-fold more frequent than VIPomas,17-fold more frequent than glucagonomas, and greater than 20-fold more frequent than the others.

TABLE 213-1

PANCREATIC NEUROENDOCRINE NEOPLASMs (pNENs)

NAME OF TUMOR	NAME OF SYNDROME	MAIN SIGNS OR SYMPTOMS	LOCATION (%)	MALIGNANCY (%)	HORMONE CAUSING SYNDROME
I. FUNCTIONAL pNEN
Gastrinoma	Zollinger-Ellison syndrome	Abdominal pain, diarrhea, esophageal symptoms	Pancreas—10-30 Duodenum—70-90 Other—0-10	60-90	Gastrin
Insulinoma	Insulinoma	Hypoglycemic symptoms	Pancreas—100	5-15	Insulin ( Chapter 211 )
Glucagonoma	Glucagonoma	Dermatitis, diabetes/glucose intolerance, weight loss	Pancreas—100	60	Glucagon
VIPoma	Verner-Morrison, Pancreatic cholera, WDHA	Severe watery diarrhea, hypokalemia	Pancreas—90 Other—10 (neural, adrenal, periganglionic tissue)	80	Vasoactive intestinal peptide (VIP)
Somatostatinoma	Somatostatinoma	Diabetes mellitus, cholelithiasis, diarrhea	Pancreas—56 Duodenum/jejunum—44	60	Somatostatin
GRFoma	GRFoma	Acromegaly	Pancreas—30 Lung—54 Jejunum—7 Other—13 (adrenal, foregut, retroperitoneum)	30	Growth hormone–releasing factor (GRF)
ACTHoma	ACTHoma	Cushing syndrome	Pancreas—4-16 of all ectopic Cushing syndrome cases	>95	Adrenocorticotropic hormone (ACTH)
pNEN causing carcinoid syndrome	pNEN causing carcinoid syndrome	Diarrhea, flushing	Pancreas—<1 of all carcinoids	60-90	Serotonin, tachykinins
pNEN causing hypercalcemia	pNEN causing hypercalcemia	Signs/symptoms of hypercalcemia	Pancreas (rare cause of hypercalcemia)	>85	PTHrP, other unknown
pNEN secreting erythropoietin	pNEN secreting erythropoietin	Polycythemia	Pancreas	Unknown	Erythropoietin
pNEN secreting renin	pNEN secreting renin	Hypertension	Pancreas	Unknown	Renin
pNEN secreting luteinizing hormone syndrome	pNEN secreting luteinizing hormone	Masculinization, loss of libido	Pancreas	Unknown	Luteinizing hormone
CCKoma	CCKoma	Diarrhea, peptic ulcer, gallstone	Pancreas	Unknown	Cholecystokinin
pNEN secreting enteroglucagon	pNEN secreting enteroglucagon	Small intestinal hypertrophy	Pancreas, renal, duodenal	Unknown	Enteroglucagon
pNEN secreting IGF-2 or GLP-1	pNEN secreting IGF-2 or GLP-1	Hypoglycemic symptoms	Pancreas	Unknown	IGF-2/GLP-1
pNEN secreting secretin	Secretinoma	Diarrhea	Pancreas	Unknown	Secretin
II. NF-pNEN
NONFUNCTIONAL/PPoma	NONFUNCTIONAL/PPoma	Weight loss, abdominal mass, hepatomegaly	Pancreas—100	60-90	None: pancreatic polypeptide, chromogranin released but no known symptoms due to hypersecretion

CCKoma = cholecystokinin-secreting NEN; Duod = duodenum; GLP-1 = glucagon-like peptide 1; IGF-2 = insulin-like growth factor-II; pNEN = pancreatic neuroendocrine neoplasm; PP = pancreatic polypeptide; PPoma = pancreatic polypeptide secreting NEN; PTHrP = parathormone-related peptide; WDHA = watery diarrhea, hypokalemia, and achlorhydria.

Pathobiology

Pathology/Classification

Neuroendocrine neoplasms originate from the diffuse neuroendocrine system, which is present throughout the body. All neuroendocrine neoplasms share cytologic features of an endodermal origin. Ultrastructurally, these neoplasms have electron-dense granules that contain multiple peptides/amines, neuron-specific enolase, synaptophysin, and chromogranins. Histologically, they characteristically show small cells with uniform nuclei and low rates of mitotic figures. Chromogranin immunoreactivity in the tumor is now widely used to identify them as neuroendocrine neoplasms. Malignancy can be determined reliably only by demonstrating the presence of metastatic disease.

Classification systems for staging and grading neuroendocrine neoplasms consider the neoplasm’s differentiation (good vs. poor), tumor size, invasion, and extent. The neuroendocrine neoplasms are also divided into three grades depending on proliferative indices, including mitotic rate and the expression of Ki-67. An important differentiation is between the well-differentiated neuroendocrine neoplasms as compared with the poorly differentiated neuroendocrine carcinomas.

Molecular Pathogenesis

Unlike nonendocrine tumors, neuroendocrine neoplasms rarely have mutations of common oncogenes ( ras, fos, myc, etc.) or common tumor suppressor genes (p53, rb). Pancreatic neuroendocrine neoplasms, gastrointestinal neuroendocrine neoplasms, and lung neuroendocrine neoplasms all have a different molecular pathogenesis. Furthermore, the pathogenesis is different for well-differentiated neuroendocrine tumors as compared with poorly differentiated neuroendocrine carcinomas.

Pancreatic neuroendocrine neoplasms most commonly have allelic losses at chromosomal loci 1p, 1q, 3p, 11p, and 22p. Somatic mutations in pancreatic neuroendocrine neoplasms are commonly found in four main pathways, including genes involved in chromatin remodeling, DNA repair, mammalian target of rapamycin (mTOR) signaling, and telomere maintenance. Sequencing studies of pancreatic neuroendocrine neoplasms show that 44% have inactivating mutations of the multiple endocrine neoplasia type 1 gene (MEN1), 43% have mutations in genes encoding either of two subunits of a transcription/chromatin remodeling complex composed of DAXX (death domain–associated protein) and ATRX (α-thalassemia/intellectual disability syndrome X-linked chromatin remodeler), and 14% have mutations in the mTOR pathway.

Gastrointestinal neuroendocrine neoplasms usually have losses at chromosomal loci 18q, 18p, 9p, and 16q. For small intestinal carcinoids, sequencing studies demonstrate a low mutation rate, with recurrent somatic mutations and deletions in CDKN1B , which is the cyclin-dependent kinase inhibitor gene that encodes p27, in 8% of tumors.

In contrast, neuroendocrine carcinomas have distinctive activations in tumor protein 53 (TP53) and retinoblastoma gene (RB1) . Recent studies suggest that epigenetic dysregulation may play an important role in the pathogenesis of neuroendocrine neoplasms.

Four autosomal dominant inherited disorders are associated with pancreatic neuroendocrine neoplasms: MEN1 (in 80 to 100% of patients); von Hippel-Lindau disease (VHL; in 10 to 17% of patients); tuberous sclerosis (in 0.5% of patients); and von Recklinghausen disease (neurofibromatosis-1; 12% develop duodenal somatostatinomas). Familial syndromes associated with carcinoids are uncommon.

Clinical Manifestations and Diagnosis

Clinical manifestations of neuroendocrine neoplasms depend on whether the tumor is functional and secretes a biologically active peptide or whether it is nonfunctional and causes symptoms via a mass effect from the tumor. Diagnosis relies on biochemical testing to detect the hormonal excess as well as imaging, endoscopic, and pathologic studies to localize the tumors and identify its neuroendocrine nature.

To assess the primary location and extent of a neuroendocrine neoplasm, the initial tumor localization study is generally a cross-sectional imaging examination, such as triphasic computed tomography (CT) or magnetic resonance imaging (MRI) with contrast. More than 90% of well-differentiated neuroendocrine neoplasms overexpress one of the five subtypes of somatostatin receptors (sst1-5), with sst2 the most frequently overexpressed (>80%). Somatostatin receptor imaging using radiolabeled somatostatin analogues with high affinity for sst2 is now the most sensitive imaging modality. The most frequently used modality is ⁶⁸ Ga-DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)–labeled somatostatin analogues with positron emission tomography combined with CT (PET/CT) or MRI (PET/MRI).

Endoscopic studies are particularly important for localizing duodenal, gastric, and rectal neuroendocrine neoplasms. Endoscopic ultrasound is widely used to localize pancreatic neuroendocrine neoplasms and to assess the depth of penetration of gastric and rectal neuroendocrine neoplasms.

Treatment

Treatment should be initiated urgently in patients who have to address a heavy tumor burden with mass-related symptoms, symptoms related to an uncontrolled functional tumor, compromised liver function, poorly differentiated or high-grade tumor, or rapid growth on imaging. Conversely, treatment has little urgency if tumors have small volume, are low grade, and are asymptomatic.

For patients with neuroendocrine neoplasms, two treatment issues must be addressed. First, any excess hormone state must be controlled; and second, treatment must be directed against the tumor itself because of its frequently malignant nature. Surgical resection can solve both problems, but unfortunately many patients present with disease that is advanced and unresectable.

Specific Neuroendocrine Neoplasms

Pancreatic Neuroendocrine Neoplasms

Pancreatic neuroendocrine neoplasms are also called islet-cell tumors, but this latter term is also a misnomer because 7 different neoplasms (see Table 213-1 ) can occur outside the pancreas. Several of the functional neuroendocrine syndromes are very uncommon (<5 cases reported), including neuroendocrine neoplasms that secrete renin, erythropoietin, enteroglucagon, luteinizing hormone, secretin, cholecystokinin, glucagon-like peptide-1 (GLP-1), and insulin-like growth factor-II. In addition, pancreatic neuroendocrine neoplasms can also synthesize neurotensin, calcitonin, and ghrelin, but no related syndromes have been established. Except for insulinomas, pancreatic neuroendocrine neoplasms are frequently malignant (>50%).

Functional Pancreatic Neuroendocrine Neoplasms

Zollinger-Ellison Syndrome (Gastrinomas)

Zollinger-Ellison syndrome is a clinical syndrome caused by a gastrin-secreting neuroendocrine neoplasm that is usually located in the pancreas or duodenum. The syndrome is characterized by clinical symptoms and signs that result from hypersecretion of gastric acid: peptic ulcer disease, diarrhea, and esophageal reflux disease.

Zollinger-Ellison syndrome has an annual incidence of 0.5 to 2 per million. It is diagnosed most frequently between ages 35 and 65 years, but has been reported in both children and the elderly.

Pathobiology

Gastrinomas are found in the duodenum (80 to 100%) more frequently than in the pancreas (0 to 20%). Duodenal gastrinomas are generally small (<1 cm), whereas pancreatic gastrinomas are generally larger. Occasionally Zollinger-Ellison syndrome results from a gastrinoma in the splenic hilum, mesentery, stomach, or only in a lymph node or an ovary. Extra-gastrointestinal gastrinomas producing Zollinger-Ellison syndrome have been reported in the heart and with small cell lung cancer ( Chapter 177 ).

Gastrin stimulates parietal cells to secrete acid and has a growth effect on the gastric mucosa. Chronic hypergastrinemia leads to increased gastric mucosal thickness, prominent gastric folds, and increased numbers of parietal cells and gastric enterochromaffin-like cells. Patients with gastrinomas have increased basal and maximal acid outputs from the stomach. Helicobacter pylori appears not to be important in the pathogenesis of the ulcer disease in Zollinger-Ellison syndrome, in contrast to common peptic ulcers ( Chapter 125 ). Diarrhea is common because the large-volume gastric acid output leads to structural damage to the small intestine (inflammation, blunted villi, edema), interference with fat transport, inactivation of pancreatic lipase, and precipitation of bile acids. These same mechanisms, if prolonged, can lead to steatorrhea. If acid hypersecretion is controlled, the diarrhea will stop.

From 20 to 25% of Zollinger-Ellison syndrome patients have MEN1 (MEN1/Zollinger-Ellison syndrome) ( Chapter 125 ). These patients have hyperplasia or tumors of multiple endocrine glands (parathyroid hyperplasia [>90%], pituitary tumors [60%]). In MEN1/Zollinger-Ellison syndrome patients, 80 to 95% of the gastrinomas are in the duodenum, where they are frequently small (<0.5 cm), almost always multiple, and associated with lymph node metastases in 40 to 60% of cases.

Clinical Manifestations

Abdominal pain resulting from a peptic ulcer is the most common symptom (>80%). Most ulcers occur in the duodenum (>85%), but they occasionally occur in the postbulbar area, jejunum, or stomach, or in multiple locations. Initially, the pain is usually like that of patients with typical peptic ulcer disease ( Chapter 125 ). With time, however, the symptoms become persistent and generally respond poorly to treatments aimed at eliminating H. pylori and to conventional doses of histamine-2 receptor antagonists. By comparison, conventional doses of proton pump inhibitors (e.g., omeprazole, lansoprazole, pantoprazole, esomeprazole, rabeprazole; Table 124-1 ) frequently control the symptoms of most patients with Zollinger-Ellison syndrome.

Heartburn is also common (20%). Diarrhea (60 to 70%) occurs frequently and may be the first symptom (10 to 20%). In MEN1, Zollinger-Ellison syndrome is the most common functional syndrome (55%), although patients typically first develop renal stones ( Chapter 111 ) related to hypercalcemia from the associated hyperparathyroidism ( Chapter 227 ) or have elevated prolactin levels resulting from pituitary tumors that only develop later.

Almost all the initial symptoms of Zollinger-Ellison syndrome result from the effects of acid hypersecretion, but patients can have tumor-related symptoms late in the disease. Approximately one third of patients have metastatic liver disease at presentation, but less than 20% of other patients develop metastatic disease to the liver during a 10-year follow-up period.

Up to 5% of patients with Zollinger-Ellison syndrome develop ectopic Cushing syndrome ( Chapter 208 ) because the gastrinoma secretes adrenocorticotropic hormone (ACTH). These patients usually have a metastatic gastrinoma in the liver, have Zollinger-Ellison syndrome without MEN1, and have a poor prognosis.

Diagnosis

Zollinger-Ellison syndrome should be suspected in any patient whose peptic ulcer disease is accompanied by diarrhea, is recurrent, does not heal with treatment, is not associated with H. pylori infection, is associated with a complication (bleeding, obstruction, esophageal stricture), is multiple, occurs in unusual locations, or is associated with a pancreatic tumor. Zollinger-Ellison syndrome also should be suspected in patients who have chronic secretory diarrhea ( Chapter 126 ), as well as when peptic ulcer disease is associated with large gastric folds, a family/personal history of nephrolithiases/endocrinopathies, or the finding of hypercalcemia, hypergastrinemia, or acid hypersecretion.

When suspected, the initial test is a fasting serum gastrin level, which is elevated in 99 to 100% of patients with Zollinger-Ellison syndrome. Besides Zollinger-Ellison syndrome, other causes of fasting hypergastrinemia include conditions that also are associated with hyperchlorhydria (e.g., retained antrum, antral hyperfunction/hyperplasia, renal failure, H. pylori infections) and conditions that are associated with hypochlorhydria or achlorhydria (e.g., physiologic hypergastrinemia in pernicious anemia, atrophic gastritis, or the use of proton pump inhibitors or histamine-2 antagonists). If the serum gastrin level is elevated, a fasting gastric pH should be determined. If the serum gastrin is greater than 1000 pg/mL (normal <100) and the gastric pH is less than 2.0, the patient almost certainly has the Zollinger-Ellison syndrome. If the gastrin level is increased less than 10-fold above normal and the gastric pH is less than 2.0, basal acid output should be measured and a secretin test (see Table 126-6 ) should be performed. More than 95% of patients with Zollinger-Ellison syndrome have a basal acid output greater than 15 mEq/hour if no previous gastric acid–reducing surgery has been performed, and 94% have a positive secretin test (a >120 pg/mL stimulated increase in serum gastrin). If possible, proton pump inhibitors should be discontinued for up to 1 week to ensure that the cause of the hypergastrinemia is not the drug itself. Since discontinuing a proton pump inhibitor in a patient with undiagnosed Zollinger-Ellison syndrome can lead to complications of peptic ulcer disease, this approach should be undertaken with care and preferably by expert physicians who are well versed in making this diagnosis.

Differential Diagnosis

A positive secretin test in a patient who is not taking proton pump inhibitors or histamine-2 antagonists excludes other causes of hypergastrinemia and hyperchlorhydria that may mimic the Zollinger-Ellison syndrome. In all patients with Zollinger-Ellison syndrome, evaluation must exclude MEN1 syndrome by searching for other endocrinopathies and assessing the family history.

Treatment

Medical Therapy

Patients require medical therapy directed at controlling the gastric acid hypersecretion and, if possible, surgical therapy to remove the gastrinoma. Proton pump inhibitors ( Table 124-1 ), which are the drugs of choice, can control hypersecretion in almost every patient. The recommended starting dose is omeprazole 60 mg once a day. In 30% of patients, higher doses or more frequent doses are needed, particularly in patients with complicated disease (e.g., MEN1, previous gastric surgery, or a history of severe esophageal reflux). With time, the omeprazole dose can be reduced in most patients with uncomplicated disease to 20 to 40 mg/day. Patients must be treated indefinitely unless surgically cured. Long-term therapy is generally safe, and patients have been treated for up to 20 years with omeprazole without loss of efficacy, although reduced vitamin B ₁₂ levels may be a side effect that requires treatment ( Chapter 150 ). Histamine-2 receptor antagonists ( Table 124-1 ) are also effective, but frequent (every 4 to 6 hours), and high doses are needed. Long-acting somatostatin analogs can also control the acid hypersecretion but are uncommonly used because parental administration is needed, whereas proton pump inhibitors are effective with oral dosing.

Surgical Therapy

Surgical exploration for cure is recommended in all patients who do not have unresectable liver metastases, MEN1, or complicating medical conditions that limit life expectancy. Tumors are found by experienced endocrine surgeons in 95% of patients at surgery. At exploration, a duodenotomy to locate small duodenal gastrinomas is essential, as is the use of operative ultrasound to find and stage small pancreatic tumors. Surgical treatment of MEN1/Zollinger-Ellison syndrome patients is controversial, because 80 to 90% have multiple small duodenal tumors; 50 to 60% of patients have metastatic lymph nodes and cannot be cured without extensive resections (usually a Whipple procedure).

Total gastrectomy is now performed only in patients who cannot or will not take oral antisecretory medications. Parathyroidectomy should be performed in MEN1 patients with hyperparathyroidism and Zollinger-Ellison syndrome because the procedure reduces acid secretion and increases the sensitivity to antisecretory drugs.

Metastatic Disease

If the metastatic disease can be resected, surgery should be considered (5 to 15% of cases). Otherwise, however, treatment of advanced disease is as for other advanced pancreatic neuroendocrine neoplasms (see later).

Prognosis

MEN1/Zollinger-Ellison syndrome patients with an imaged tumor that is less than 2 to 2.5 cm have an excellent prognosis without surgery. Approximately 25% of gastrinomas, however, show aggressive growth. Surgical resection decreases the metastatic rate, increases survival, and results in a 5-year cure rate of 30 to 40%. Patients with metastatic gastrinoma in the liver have a poor prognosis, with a 5-year survival rate of 30%. The presence of advanced gastrinoma grade or stage, large primary tumor, a pancreatic tumor, bone metastases, development of ectopic Cushing syndrome, or a high fasting gastrin level is associated with aggressive growth.

Glucagonomas

Glucagonomas are pancreatic neuroendocrine neoplasms that ectopically secrete glucagon, thereby causing a specific syndrome that includes glucose intolerance and unique dermal manifestations.

Glucagonomas have an annual population incidence of about 1 per 10 to 100 million. Patients typically present in their fifth decade. In many series, patients present late with large primary tumors, and more than 50 to 80% are metastatic at presentation.

Pathobiology

The hypersecretion of glucagon causes glucose intolerance. The exact origin of the rash (necrolytic migratory erythema) is unclear. Some data suggest that prolonged glucagon infusions can cause the characteristic skin lesions. Zinc deficiency may play a role because the rash is similar to what can be seen with zinc deficiency (acrodermatitis enteropathica) and because the rash improves in some patients who are given zinc. The hypo-aminoacidemia is thought to be secondary to the effect of glucagon on amino acid metabolism by altering gluconeogenesis. Wasting and weight loss, which are intrinsic components of the glucagonoma syndrome, may be caused by an anorectic substance distinct from glucagon.

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