Carcinoid tumors, also known as gastroenteropancreatic neuroendocrine tumors, are neoplasms of neuroendocrine origin. Traditionally considered slow-growing, they are now known to vary in their aggressiveness. Many patients with carcinoid tumors have no symptoms or present with symptoms that have broad differential diagnoses. Unless the primary care physician suspects that the patient has a carcinoid tumor, the appropriate testing is seldom ordered. In addition, these patients are at higher risk of developing other cancers of the genitourinary, gastrointestinal, and respiratory tracts; this makes close follow-up, especially by the primary care provider, extremely important.
This article reviews the epidemiology, pathogenesis, clinical features, management, and prognosis of carcinoid tumors. A better knowledge of these tumors among physicians will facilitate recognition, early diagnosis, and improved outcomes for these patients.
INCIDENCE IS INCREASING
The overall incidence of carcinoid tumors has increased over the last 30 years, due at least in part to improvements in ways to diagnose them.1,2 The incidence over the last decade has been between 2.47 and 4.48 per 100,000 population, depending on race and sex, with the highest rates in black men.1,3
The small intestine is the most frequent location, followed by the lungs/bronchi, rectum, appendix, and stomach3; 67.5% of carcinoid tumors occur somewhere in the gastrointestinal system.
The cause of carcinoid tumors is unknown, but genetic factors may play a role, since these tumors often occur as part of genetic disorders such as multiple endocrine neoplasia type 1, von Hippel-Lindau disease, and neurofibromatosis type 1.1–3
SEROTONERGIC EFFECTS DEPEND ON LOCATION
Carcinoid tumors are classified on the basis of their embryologic origin:
- Foregut (lungs, bronchi, stomach)
- Midgut (small intestine, appendix, proximal large bowel)
- Hindgut (distal large bowel, rectum). Tumors from each of these origins differ clinically, biochemically, and histologically.
Carcinoid tumors secrete several bioactive compounds, including serotonin and bradykinin, and the secretory pattern varies depending on the location of the tumor. Most foregut carcinoid tumors secrete low levels of serotonin, being deficient in the enzyme needed to convert 5-hydroxytryptophan to serotonin. Midgut tumors secrete high levels of serotonin, whereas most hindgut tumors do not secrete 5-hydroxytryptophan or serotonin. These differences in secretory patterns are responsible for the different clinical manifestations and biochemical characteristics of these tumors.
The systemic effects of the bioactive compounds secreted by carcinoid tumors are responsible for carcinoid syndrome, which has features that can include bronchospasm (possibly mediated by serotonin or bradykinin), diarrhea (likely mediated by serotonin), cutaneous flushing (which has multiple possible mediators), and right-sided valvular heart lesions (possibly mediated by serotonin).2,4 However, the secretory products of midgut carcinoids are normally inactivated by enzymes in the liver before they enter the systemic circulation. Thus, patients with midgut carcinoid tumors develop the carcinoid syndrome only if they have hepatic metastases.4
In contrast, patients with foregut (bronchial and extraintestinal) carcinoids can present with carcinoid syndrome without hepatic metastases, since their secretory products normally bypass the liver and enter the systemic circulation directly.
Hindgut tumors seldom produce this syndrome, since they do not secrete these products.
Another effect of carcinoid tumors is desmoplasia, or fibrosis.
The pathogenesis of this phenomenon is poorly understood. Serotonin was thought to mediate this effect, but serotonin antagonists are ineffective in treating it, casting doubt on this hypothesis.2,4 More recently, growth factors such as transforming growth factor beta, platelet-derived growth factor, and basic fibroblast growth factor have been implicated.4