Carcinoid tumors were first described in a 1907 paper titled “Karzinoide Tumoren des Dünndarms,” or “Cancer-like Tumors of the Gut,” by the German pathologist Siegfried Oberndorfer.1 He used the word karzinoide to illustrate the benign behavior of a tumor whose cells appeared malignant under the microscope.1 Later in 1914, Gosset and Masson characterized the endocrine-related properties of carcinoid tumors.2 Over the years, a considerable amount of confusion has developed over the definition of carcinoid tumors, largely because, historically, the name carcinoid was used in reference to all neuroendocrine tumors. In general, the term carcinoid refers to endocrine tumors of the gastrointestinal (GI) tract, bronchopulmonary epithelium, and rare other sites but not to pancreatic neuroendocrine tumors (PNETs), also called islet cell tumors. This chapter focuses on GI carcinoid tumors, which arise from enterochromaffin, enterochromaffin-like, or Kulchitsky cells that are part of the diffuse neuroendocrine cell types of the gut. These cells are distinguished by their ability to secrete bioactive peptides and amines, such as serotonin, somatostatin, gastrin, and histamine.

In the United States, the overall age-adjusted incidence of carcinoid tumors has increased over the past 5 decades from about 1.5 to 2.75 per 100,000 people.3 This trend has mirrored the increased incidence observed in all neuroendocrine tumors over the same time period from about 2.5 to 5.0 cases per 100,000.3 Carcinoid tumors make up almost 50% of all neuroendocrine tumors, with the majority of carcinoid tumors (68%) occurring in the GI tract and the remainder in the bronchopulmonary system (25%).3 Rarely, carcinoid tumors have been reported in other locations, including the esophagus, ovaries, testis, thymus, and other endocrine tissues of the body.3 Classically, the appendix was thought to be the most predominant site within the GI tract for these tumors. However, more recent studies reveal that the majority of GI carcinoid tumors occur in the small intestine (42%), rectum (27%), and stomach (9%), with only about 5% of these tumors being found in the appendix. In addition, approximately 1% of patients present with more than one primary site of disease.

The rates of carcinoid tumors have been examined in various subsets of the population. The age-adjusted incidence of carcinoid tumors is higher in African Americans compared with whites and is highest in African-American men.3 Tumors with the highest rates of metastases include cecal, pancreatic, and small intestinal carcinoid tumors (82%, 72%, and 58%, respectively).

The exact etiology of carcinoid tumors remains unknown. However, certain risk factors and conditions are associated with a predisposition for developing carcinoid tumors. Furthermore, genetic studies have revealed chromosomal abnormalities that occur more frequently in patients with these tumors. As mentioned, African-American men have the highest rate of developing GI carcinoid tumors.3 People with well-educated social backgrounds (relative risk [RR] = 2.8), living in major metropolitan areas (RR = 1.39), or who have a family history of a first-degree relative with a carcinoid tumor (RR = 3.6) also have an increased risk for carcinoid development.4 In addition, cigarette smoking and alcohol consumption are connected to an increased chance of having a GI, but not a pulmonary, carcinoid tumor.5 Currently, no dietary risks have been identified. GI conditions, including peptic ulcer disease, pernicious anemia, chronic atrophic gastritis, and Zollinger-Ellison syndrome, are also known to increase the risk for carcinoid tumors of the GI tract, especially gastric carcinoid tumors.

Genetics

Specific genetic disorders and chromosomal abnormalities are associated with a predisposition for developing carcinoid tumors. Multiple endocrine neoplasia type 1 (MEN1) is one disorder that has been identified as a risk factor for neuroendocrine tumor development, including carcinoid tumors. Loss of heterozygosity at 11q13, which codes for the menin gene, has been observed in sporadic duodenal and Zollinger-Ellison syndrome–associated carcinoid tumors.6,7 In addition, case reports of patients with neurofibromatosis type 1 and ampullary carcinoid tumors as well as von Hippel-Lindau syndrome and gallbladder carcinoid tumors have been published, but molecular data are lacking.6 Increased use of gene sequencing techniques, comparative genomic hybridization, and microsatellite analysis has allowed identification of chromosomal abnormalities that occur with increased frequency in GI carcinoid tumors. Chromosomal losses on chromosomes 9, 11, 16, and 18 and gains on chromosomes 4, 5, 17, and 19 all have been shown in GI carcinoid tumors. However, because of the rarity of these tumors, several of the studies examining risk factors and genetic alterations associated with carcinoid tumors are limited by sample size.

The majority of patients with carcinoid tumors are asymptomatic, and their tumors are found incidentally on imaging studies or during a procedure such as endoscopy or surgery. However, for patients with symptoms, the clinical behavior of GI carcinoid tumors varies greatly and depends largely on the origin of the primary tumor and whether or not the tumor is functioning (i.e., secretes bioactive hormones or peptides that cause symptoms). Traditionally, GI carcinoid tumors have been classified based on their embryologic origin—foregut (gastric and duodenal), midgut (small intestine, appendix, and proximal colon), or hindgut (distal colon and rectum). Functioning tumors secrete a myriad of substances, including (but not limited to) serotonin, histamine, somatostatin, chromogranin A, bradykinin, tachykinin, substance P, gherlin, secretin, melatonin, gastrin, motilin, and vasoactive intestinal peptide. These substances cause the symptoms that are associated with the carcinoid syndrome, including flushing, diarrhea, wheezing, heart disease, and pellagra. However, only about 10% of patients develop the carcinoid syndrome because the majority of carcinoid tumors are nonfunctioning.4 Because of the indolent nature of these tumors and frequent nonspecific signs, patients commonly have symptoms for 1 to 2 years before diagnosis. At the time of diagnosis, 10% to 15% of patients with carcinoid tumors have distant metastases, and up to 80% of symptomatic patients are found to have metastatic or advanced disease.3

Patients with foregut carcinoid tumors may present with symptoms of GI or biliary obstruction, abdominal pain, duodenal or peptic ulcers, bleeding, atypical carcinoid syndrome, or a history of Zollinger-Ellison syndrome. However, these cancers are often found incidentally on upper endoscopy. The atypical symptoms of carcinoid syndrome are uncommon and include more intense, protracted, purplish flushing and the development of telangectasias on the extremities and upper body.8 Gastric carcinoid tumors are usually multiple small tumors and have been classified into three main types with different characteristics. Type I represent the majority (80%) of these tumors and is associated with chronic atrophic gastritis and pernicious anemia.6 Type I gastric carcinoid tumors rarely metastasize and are usually nonfunctional and asymptomatic.6 Type II gastric carcinoid tumors are the least common (5%), are seen in patients with MEN1 or Zollinger-Ellison syndrome, and exhibit more aggressive behavior.6 Last, type III tumors are larger often single tumors with the most aggressive behavior.6

Midgut carcinoid tumors are the most common type of carcinoid tumors and, when in the small bowel, frequently cause abdominal pain, GI obstruction, bleeding, or diarrhea. Small bowel carcinoid tumors usually present in the fifth and sixth decades of life. These tumors may be multicentric and may cause mesenteric fibrosis, which may result in mesenteric kinking, mesenteric strangulation with ischemia, or ureteral obstruction. Tumors that originate in the jejunum, distal ileum, and cecum metastasize to the liver almost twice as often as other GI tumors, so they are associated with a higher rate of carcinoid syndrome.3,4 When metastatic liver disease is present, the bioactive hormones secreted by these tumors reach the systemic circulation, resulting in the carcinoid syndrome. Appendiceal carcinoid tumors most commonly present as appendicitis or are found incidentally during surgery for another disease. Carcinoid tumors of the appendix are usually localized, small, and found during the fourth or fifth decades of life.9

Carcinoid tumors of the hindgut tend to be large cancers with frequent metastases when located in the distal colon but small and localized tumors when located in the rectum.10 Symptoms of pain, anorexia, weight loss, and bleeding can been seen with colonic carcinoid tumors. These colonic hindgut carcinoid tumors are also present more commonly in women and during the seventh decade of life.11 Many of these tumors metastasize to regional lymph nodes and to the liver but not as frequently as right-sided colonic carcinoid tumors.3 Rectal carcinoid tumors, on the other hand, rarely metastasize and even more rarely lead to the carcinoid syndrome.11 Patients with rectal carcinoid tumors may present with pain, bleeding, or constipation, but almost 50% of these patients are diagnosed during colonoscopy screening.9

The wide spectrum of biologic and clinical characteristics of GI carcinoid tumors frequently makes diagnosis difficult. A high index of suspicion is needed to ensure timely diagnosis and treatment of these patients. Clinical presentation, laboratory tests, and histologic evaluation all play a role in the diagnosis of GI carcinoid tumors. However, microscopic confirmation of tumor pathology with immunohistochemical staining of neuroendocrine tumor markers provides the most definitive diagnosis. Figure 19-1 provides an algorithm for the diagnostic evaluation of carcinoid tumors of the GI tract.

Biochemical Tests

Several biochemical tests for various tumor markers may be performed to help diagnose carcinoid tumors. Classically, diagnosis of GI carcinoid tumors has been made by measuring 24-hour urinary 5-hyrdroyindolacetic acid (5-HIAA), the breakdown product of serotonin. In patients with symptoms of the carcinoid syndrome, the sensitivity and specificity of this test are both nearly 100%.11 However, in the absence of carcinoid syndrome, the sensitivity is closer to 70%, and in patients with foregut or hindgut tumors, urinary 5-HIAA levels are even less sensitive.8,11 To obtain accurate 5-HIAA measurements, certain dietary and drug restrictions must be followed. Both urinary and serum serotonin levels may also be elevated in patients with GI carcinoid tumors but are used infrequently.

Serum chromogranin A measurement is another commonly used test for the diagnosis of GI carcinoid tumors and has a similarly high sensitivity (80% to 100%), but is less specific than urinary 5-HIAA levels.11 Renal failure, inflammatory bowel disease, atrophic gastritis, and chronic use of proton pump inhibitors can all cause falsely elevated chromogranin A levels.10,11 Unlike urinary 5-HIAA, chromogranin A is very sensitive in patients with foregut and hindgut carcinoid tumors (87% and 100%, respectively).11 Chromogranin A is useful as a marker to follow for tumor recurrence as well because a direct correlation has been found with serum levels and tumor burden. In addition, chromogranin B has high specificity for patients with GI carcinoid tumors.10