These are found mainly in the GI tract, although a minority are located in the lungs and a few arise in other locations. The appendix is the most frequent site of origin; these are almost always benign. Carcinoid are next most frequent in the terminal ileum and colon; these are frequently malignant. Carcinoid are considered part of the amine precursor uptake and decarboxylation (APUD) system, composed of cells derived from embryonic neuroectoderm that migrate from the primitive neural crest. These cells are located in embryonic GI tract derivatives, which include the GI tract, GI tract accessory glands (pancreas, biliary system), and organs with a very early embryonic GI source (lungs, thymus, genitourinary tract). They potentially can synthesize and secrete most body hormones (amines or peptides) except for steroids. Carcinoid cells contain fluorogenic amine substances and in certain areas characteristically contain secretory granules or material that stains with silver (argentaffin or argyrophilic). GI carcinoid cells are considered to be derived from Kulchitsky’s cells of GI epithelium.

Intestinal carcinoid may be multiple and frequently are associated with noncarcinoid malignancies (about 30% of cases, literature range, 7%–38%).

Carcinoid Syndrome. Carcinoids typically produce the vasoconstrictor substance serotonin, which induces several of the symptoms that are part of the carcinoid syndrome (Table 33-9). Carcinoid arising in foregut derivatives (bronchus, stomach, pancreas, duodenum, biliary tract) may produce the carcinoid syndrome and may be associated with the multiple endocrine neoplasia type I (MEN I) syndrome (with parathyroid, pituitary, and pancreatic islet cell tumors). Bronchial carcinoid may also secrete adrenocorticotropic hormone (ACTH) and may even produce the ectopic ACTH syndrome. These carcinoid usually do not stain with silver methods. Carcinoid of midgut origin (jejunum, ileum, appendix, and right side of the colon) typically are silver positive, and the jejunum and ileum are the most frequent source of the carcinoid syndrome. Carcinoid of hindgut origin (left side of the colon, rectum, and anus) usually do not have stainable argentaffin granules and usually do not produce the carcinoid syndrome.

Effect of origin site on carcinoid tumors

Table 33-9 Carcinoid syndrome

When carcinoid cells produce serotonin, in most cases the venous drainage of the tumor is routed through the liver, which metabolizes or alters the hormone and prevents the carcinoid syndrome. If liver metastases develop in sufficient quantity or location, serotonin from carcinoid tumor in the liver bypasses hepatic portal vein drainage into the liver and exerts its effect unaltered. The same thing occurs with bronchial and ovarian carcinoid, because their venous drainage does not enter the hepatic portal vein system. Most carcinoid that produce the carcinoid syndrome originate in the intestine, and the syndrome usually does not appear until there is extensive metastasis by the carcinoid to the liver. However, the syndrome may occur without liver metastasis, especially when the primary site is the ovary. Conversely, in one third to two thirds of patients, liver metastases develop without the carcinoid syndrome.

Urine 5-hydroxyindoleacetic acid assay. Diagnosis of carcinoid syndrome can usually be made by testing for abnormal urine levels of 5-hydroxyindoleacetic acid (5-HIAA), the chief metabolic breakdown product of serotonin. Interestingly, there is very little specific information in the literature regarding the incidence of 5-HIAA elevation in either the carcinoid syndrome or in carcinoid patients without the carcinoid syndrome. In three studies of carcinoid patients (some with and some without the carcinoid syndrome), incidence of elevated urine 5-HIAA levels in those patients assayed was about 65% (range, 60%–87%). References that mention incidence of elevated 5-HIAA levels usually state that most patients with the malignant carcinoid syndrome have elevated 5-HIAA levels. However, some patients do not have continually elevated values; and in some cases repeated specimens may be necessary. Some patients with carcinoid may have elevated urine 5-HIAA levels without manifestations of the carcinoid syndrome; how often this happens is not known. Certain foods may elevate urine 5-HIAA levels. A few conditions, such as nontropical sprue and Whipple’s disease may produce mildly elevated urinary 5-HIAA in some patients. One study found that a few carcinoid patients with normal or only slightly elevated urine 5-HIAA had elevated urine serotonin (5-hydroxytryptamine). However, serotonin assay is difficult and expensive.