As previously mentioned, carcinoid tumors are classified according to the different embryonic divisions of the GI tract (fore-, mid-, and hindguts). The individual cells are further divided as “typical” and “atypical,” with typical cells classified as insular, trabecular, glandular, undifferentiated, and mixed [2, 5]. Malignant versus benign is based on cellular histology as well as tumor size at surgery and site of primary occurrence. “Typical” pulmonary carcinoids are indolent and perihilar in location, with less than 15% metastasizing. In contrast, “atypical” carcinoids of the lung have a 30% to 50% incidence of metastases and are often more aggressive. They may secrete ACTH and result in Cushing syndrome. Of the gastric carcinoids, up to 75% are type 1 and associated with chronic atrophic gastritis, 10% to 15% type 2 and associated with Zollinger-Ellison syndrome, and the remainder sporadic or type 3. Most tumors are less than 1 cm in diameter, and types 1 and 2 have a more benign course. Those tumors greater than 2 cm (and type 3 tumors) are more likely to have metastatic disease at the time of diagnosis. Small bowel carcinoid is most commonly found in the ileum and often has multiple local sites of involvement. Unlike gastric tumors, size greater or less than 2 cm is a less reliable predictor of metastasis [6]. It has been observed that ileal tumors greater than 2 cm in size at surgery will metastasize locally or regionally 100% of the time. Within the appendix, most tumors occur at the tip and, most, are not associated with symptoms. Of appendiceal tumors, 95% are less than 1 cm; however, the 2-cm size delineation appears to correlate with both metastatic disease and the carcinoid syndrome [6]. Colonic tumors are often right sided with most occurring around the cecum. These tumors tend to be larger at diagnosis (5 cm) and more commonly associated with distant metastases, although less than 5% exhibit features of carcinoid syndrome. Rectal carcinoids occur predominantly (99%) within the zone defined as 4 to 13 cm above the dentate line, though the reason for this is not known. The majority (2/3) are less than 1 cm, but the association with metastatic disease and carcinoid syndrome is again defined by an absolute size of 2 cm.

Among all carcinoid tumors, more than 80% express somatostatin receptors. Of the five somatostatin receptor subtypes currently known to exist, types 2, 3, and 5 have been demonstrated on carcinoid tumors with type 2 predominating. As previously noted, carcinoid syndrome can be attributed to altered metabolism of tryptophan and subsequent conversion to serotonin or other breakdown products. Diarrhea, flushing, nocturnal perspiration, and cardiac manifestations (especially right-sided valve disease) have all been linked with this mechanism, while histamine from some gastric tumors may be associated with atypical flushing and pruritus as well as an increased occurrence of duodenal ulcers seen in this population. The syndrome usually is directly related to the ability of the tumor to secrete serotonin into the circulation system and bypass the breakdown that occurs in the liver [7]. As well, it can exceed the liver metabolism threshold resulting in high circulating serotonin concentrations. Evidence of this can be seen in the high association with hepatic metastases and the low incidence in patients with limited or local disease. One caveat to this syndrome is ovarian carcinoids; while rare, these are more often associated with this syndrome due to their direct vascular access. It is thought that the episodic secretion of serotonin and vasoactive peptides is due to the nonautonomous nature of the neuroendocrine tumors and the presence of somatostatin subtype 2 receptors on them.