Definition

Neuroendocrine tumors (NETs) derive from neuroendocrine cells (also called enterochromaffin cells or enterochromaffin-like cells) of the endoderm of the fore-, mid-, and hindgut. These cells are diffusely distributed in the epithelium of the gastroenteropancreatic system, the bronchial system, and the thymus and produce peptide hormones or neurotransmitters, such as serotonin, tachykinin, kallikrein, histamine, insulin, gastrin, vasoactive intestinal polypeptide, glucagon, somatostatin, growth hormone–releasing hormone, corticotropin-releasing hormone, adrenocorticotropic hormone, and pancreatic polypeptide. The entity of these amine- and peptide-producing cells is very polymorphic.

In 1966, Anthony G. E. Pearse described the neuroendocrine cells as descending from an amine precursor uptake and decarboxylation system because of their functional resemblance to neurons. He wrongly suspected a neuroectodermal origin from the neural crest. The term carcinoid was shaped by the German anatomist Oberndorfer in 1907 as “cancerlike” in order to distinguish these tumors from cancer because of their relatively benign behavior and slower growth patterns compared with carcinomas. This term was abandoned in favor of terms such as neuroendocrine tumor or neuroendocrine neoplasm . The term carcinoid syndrome is reserved for symptomatic serotonin-producing tumors. These symptoms are present in only approximately 10% of NETs and occur when secretory products gain access to the systemic circulation either by bypassing hepatic metabolism as a result of liver metastases or by direct access in locally advanced tumors (i.e., retroperitoneal infiltration). This occurrence is more frequent in small intestinal NETs because of their more aggressive behavior compared with NETs of the appendix, colon, or rectum. NETs were formerly classified with respect to their origin into NETs of the fore-, mid-, and hindgut. However, lately this classification has been replaced by the more appropriate allocation to the organ where they are found.

Incidence, Epidemiology, and Research

NETs are rare, with an incidence of 5.0 to 5.5 per 100,000 per year. They account for approximately 0.5% of all malignant neoplasms. The anatomic distribution reflects the localization of neuroendocrine cells. Most NETs originate in the gastroenteropancreatic system, with one quarter originating in the bronchopulmonary system and a minority in other sites. The incidence of gastrointestinal NETs has increased during the past 40 years and now ranges from 1.3 to 1.4/100,000/year. The site of predilection has changed from a historical preponderance of appendiceal NETs to a preponderance of pancreatic and small intestinal NETs. The incidence of rectal NETs in particular has increased. Depending on the source of information, appendiceal NETs account for only 4% of NETs; however, data on anatomic distribution vary widely. According to most publications, the predominant intestinal origins are the ileum, followed by the appendix, jejunum, rectum, and colon. NETs of the stomach, esophagus, biliary tract, thymus, and ovaries are very rare.

The clinical characteristics of NETs of the small and large intestine are outlined in Table 77-1 .

An incidence of 0.32 to 1.12/100,000/year is reported for small intestinal NETs. However, the incidence in postmortem studies is higher. NETs constitute between one third and half of small intestinal malignancies. The site of predilection is the ileum (the terminal ileum in particular). Twenty percent to 50% of small intestinal NETs display malignant behavior, and approximately 30% have metastasized at the time of diagnosis. Age at diagnosis is usually in the sixth and seventh decade. Prevalence is probably similar for both genders; however, a slight male preponderance is possible.

NETs of the appendix show an incidence of 0.15 to 0.60/100,000/year. Depending on the source of information, they are nearly as frequent as small intestinal NETs, although newer data suggest a lower frequency. With a percentage of approximately 80%, NETs constitute the most common appendiceal neoplasm. An incidental diagnosis at appendicectomy is frequent, with 3 to 9 NETs per 1000 appendicectomies. Approximately 70% are localized at the tip of the appendix, followed by the middle third and then the appendiceal base. Patients are considerably younger than other patients with intestinal NETs, with a mean age of 40 to 50 years at diagnosis.

NETs of the colon have an incidence of 0.1 to 0.2/100,000/year and represent about 4% to 8% of all NETs. They are frequently malignant and can occur in association with adenocarcinomas.

Rectal NETs are usually small tumors that are diagnosed in younger patients (the mean age at diagnosis is 56 years) at screening sigmoidoscopy. Persons with a black or Asian ethnic background seem to be more frequently affected by rectal NETs. Rectal NETs are often localized on the anterior or lateral wall of the upper and middle rectum.

Multicentricity is frequent with small but not with large intestinal NETs. Second primary tumors, particularly colorectal adenocarcinomas, occur frequently with all intestinal NETs and increase with the patient’s age.

Mechanisms of carcinogenesis of NETs are not well known. Chromatin remodeling, DNA damage, apoptosis inhibition, and RAS signaling are suggested oncogenic mechanisms. Ki67 and mutated p53 correlate with adverse prognosis and metastasis. Clinical trials target the PI3K/AKT/mTORC1 pathway (with the mTOR inhibitor everolimus).

Familial clustering is rare in intestinal NETs. Sporadic mutations were discovered in the FGFR2, MEN1, HOOK3, EZH2, MLF1, CARD11, VHL, SRC , and SMAD genes. Germline mutations, as in the case of multiple endocrine neoplasia type 1 (MEN1) syndrome with a loss of heterozygosity of the tumor suppressor gene MEN1 as a result of inactivating mutation of p16 and chromosomal instability or in the case of von Hippel–Lindau disease with mutations of the von Hippel–Lindau tumor suppressor gene, are associated with pancreatic but not intestinal NETs. Genetic counseling or germline or somatic DNA testing are not indicated in intestinal NETs.

Clinical Presentation

Intestinal NETs are frequently asymptomatic, particularly if they are in the colon or rectum, because of their rare hormonal activity and the larger diameter of the bowel. Symptoms occur in persons with advanced disease and are often nonspecific (e.g., abdominal pain, anorexia, bowel dysmotility, fatigue, and intestinal bleeding). Visceral fibrosis may be responsible for more pronounced symptoms because of bowel obstruction or ischemia.

Hormone-specific symptoms are less frequent, and given the hepatic metabolism of hormones secreted into the portal circulation, they usually occur only in persons with metastatic disease or bulky tumors only. NETs of the terminal ileum are the most frequent cause of hormone production, followed by NETs originating from the appendix and jejunum. Hormonally active NETs of the colon and rectum are very rare. Serotonin is the predominant hormone in intestinal NETs; however, many intestinal NETs are inactive. Symptoms caused by serotonin, tachykinin, and kallikrein are referred to as the carcinoid syndrome and include abdominal cramps, secretory diarrhea, flushing, and bronchial wheezing. Furthermore, these hormones may cause carcinoid heart disease, also called Hedinger syndrome, which is present in 25% to 50% of patients with carcinoid syndrome. It can lead to right heart failure or cardiac arrhythmias as a result of an endocardiac fibrosis and bears a poor prognosis. Rare but potentially life-threatening is the carcinoid crisis, which may occur with stimuli such as surgery, anesthesia, or chemotherapy. Other conditions attributed to hormone-producing NETs include the Whipple triad (hypoglycemia, neurohypoglycemia that immediately improves with administration of glucose, and glucose <4 mmol/L) caused by insulin (pancreatic NETs), acromegaly caused by growth hormone–releasing hormone (bronchial and pancreatic NETs), Cushing syndrome caused by corticotropin-releasing hormone or adrenocorticotropic hormone (bronchial and pancreatic NETs), Zollinger-Ellison syndrome (multiple ulcers, diarrhea, and reflux disease) caused by gastrin (pancreatic, duodenal, and gastric NETs), diabetes and necrolytic migratory erythema caused by glucagon (pancreatic and rectal NETs), Werner Morrison syndrome (watery diarrhea, hypokalemia, and achlorhydria—i.e., WDHA syndrome) caused by vasoactive intestinal polypeptide (pancreatic NETs), and diabetes, steatorrhea, and cholelithiasis caused by somatostatin (pancreatic and duodenal NETs).

Clinical Presentation

Intestinal NETs are frequently asymptomatic, particularly if they are in the colon or rectum, because of their rare hormonal activity and the larger diameter of the bowel. Symptoms occur in persons with advanced disease and are often nonspecific (e.g., abdominal pain, anorexia, bowel dysmotility, fatigue, and intestinal bleeding). Visceral fibrosis may be responsible for more pronounced symptoms because of bowel obstruction or ischemia.

Hormone-specific symptoms are less frequent, and given the hepatic metabolism of hormones secreted into the portal circulation, they usually occur only in persons with metastatic disease or bulky tumors only. NETs of the terminal ileum are the most frequent cause of hormone production, followed by NETs originating from the appendix and jejunum. Hormonally active NETs of the colon and rectum are very rare. Serotonin is the predominant hormone in intestinal NETs; however, many intestinal NETs are inactive. Symptoms caused by serotonin, tachykinin, and kallikrein are referred to as the carcinoid syndrome and include abdominal cramps, secretory diarrhea, flushing, and bronchial wheezing. Furthermore, these hormones may cause carcinoid heart disease, also called Hedinger syndrome, which is present in 25% to 50% of patients with carcinoid syndrome. It can lead to right heart failure or cardiac arrhythmias as a result of an endocardiac fibrosis and bears a poor prognosis. Rare but potentially life-threatening is the carcinoid crisis, which may occur with stimuli such as surgery, anesthesia, or chemotherapy. Other conditions attributed to hormone-producing NETs include the Whipple triad (hypoglycemia, neurohypoglycemia that immediately improves with administration of glucose, and glucose <4 mmol/L) caused by insulin (pancreatic NETs), acromegaly caused by growth hormone–releasing hormone (bronchial and pancreatic NETs), Cushing syndrome caused by corticotropin-releasing hormone or adrenocorticotropic hormone (bronchial and pancreatic NETs), Zollinger-Ellison syndrome (multiple ulcers, diarrhea, and reflux disease) caused by gastrin (pancreatic, duodenal, and gastric NETs), diabetes and necrolytic migratory erythema caused by glucagon (pancreatic and rectal NETs), Werner Morrison syndrome (watery diarrhea, hypokalemia, and achlorhydria—i.e., WDHA syndrome) caused by vasoactive intestinal polypeptide (pancreatic NETs), and diabetes, steatorrhea, and cholelithiasis caused by somatostatin (pancreatic and duodenal NETs).