Carcinoid tumors are rare endocrine tumors that may occur anywhere in the structures derived from the embryonic gut: foregut (bronchus, thymus, stomach, proximal duodenum, pancreas), midgut (distal duodenum to mid-transverse colon), or hindgut (descending colon and rectum). The annual incidence is 0.5-1.5/100,000. The name is derived from the fact that the tumors resembled a cancer under the microscope but with more homogeneity in the morphology of the cells than was usually seen in cancers; furthermore, the slow growth of the tumors led early investigators to underestimate the malignant potential of the tumor.
Carcinoid tumors are derived from enterochromaffin cells or Kulchitsky cells, neuroendocrine cells with the capacity to produce a variety of active products including serotonin and neuropeptide K. In one recent, large series, about 85% of cases were derived from midgut structures, 13% from the foregut, and only 2% from the hindgut. About half of all carcinoid tumors arise in the appendix. Such tumors are usually small, solitary, and benign. Gastric carcinoid tumors may be derived from enterochromaffin cells or from enterochromaffin-like (ECL) cells. The incidence of tumors derived from ECL cells is increased in the setting of Helicobacter pylori infection, atrophic gastritis, and achlorhydria. Gastrin is a growth factor for ECL cells and tumorigenesis is stimulated in the setting of chronic inflammation and hypergastrinemia. Foregut carcinoids can be a component of multiple endocrine neoplasia type I, and thymic carcinoids may occur in the setting of hyperparathyroidism or Cushing’s syndrome.
Symptoms are usually related to the tumor growth and include abdominal pain, bleeding, or intestinal obstruction. The tumors may become the leading point for intussusception. Mesenteric and peritoneal spread stimulates a vigorous local fibrosis that can cause intestinal obstruction or vascular compromise. Small bowel and bronchial carcinoids may behave more aggressively and metastasize locally to lymph nodes and liver or widely to bone or to otherwise uncommon sites such as breast, heart, and eye. In general, metastatic disease only arises after the primary tumor has grown to greater than 2 cm in diameter.
Carcinoid syndrome is defined as the triad of cutaneous flushing, diarrhea, and valvular heart disease. Less common manifestations include telangiectasias, wheezing, and paroxysmal hypotension. About 5% of patients with carcinoid tumors develop one or more symptoms of the carcinoid syndrome. Most patients with the syndrome have liver metastases from a carcinoid tumor. Flushing is the most common single manifestation being noted in 85% of patients with carcinoid syndrome. The syndrome is related to products of the tumor cell. Enterochromaffin cells are related to thyroid C cells, adrenal medulla cells, and melanocytes. All are derived from neural crest. Serotonin is the most common secretory product. Serotonin is made by the conversion of tryptophan. Indeed, in some patients, the conversion of tryptophan to serotonin is sufficiently active to lead to a tryptophan deficiency that can produce protein malnutrition or mild pellagra (from inadequate production of niacin).
Serotonin induces intestinal secretion, inhibits absorption, and promotes intestinal motility. Thus, serotonin can account for the diarrhea. Flushing is more likely to be caused by one or more of the other tumor products such as histamine, catecholamines, or hormones such as neuropeptide K, substance P, neurokinin A, and others.
In the absence of carcinoid syndrome, most carcinoid tumors are either found incidentally (0.3-0.7% of appendectomy specimens contain a carcinoid tumor) or due to local symptoms caused by tumor expansion. When flushing or other manifestations of the carcinoid syndrome are present, the most reliable diagnostic test is urinary levels of 5-hydroxyindoleacetic acid (5- HIAA). Twenty-four hour urine samples with more than 15 mg of 5-HIAA are usually indicative of carcinoid syndrome. However, certain foods and drugs can falsely elevate (bananas, pineapple, kiwi fruit, walnuts, plums, pecans, acetaminophen) or falsely lower (aspirin) 5-HIAA levels. If the index of suspicion is high but the urinary 5-HIAA excretion is not elevated, high plasma serotonin levels may assist in making the diagnosis.
Because carcinoid tumor cells express type 2 somatostatin receptors, octreotide scintigraphy identifies the sites of primary and metastatic tumor in about two-thirds of patients. This imaging test is more sensitive than imaging with metaiodobenzyl guanidine (MIBG), the test that was formerly standard.
Most carcinoid tumors are cured by their primary surgical procedure. However, for those with metastatic carcinoid tumors and/or carcinoid syndrome, a variety of treatment approaches may be required to alleviate symptoms and prolong survival. Resection alone is rarely curative.
Although mild diarrhea may be controlled with lomotil, and flushing may be ameliorated somewhat by combination H1 and H2 receptor antagonists, the treatment that is most effective at controlling carcinoid symptoms is octreotide 150-1500 mcg/d in two or three subcutaneous injections. Octreotide is effective in about 75% of patients. Established cardiac valvular fibrosis is not reversed by any known treatment. Interferon-alpha controls symptoms in about two-thirds of patients and induces regression in the tumor in 20-30%. Combination chemotherapy and aggressive attacks on the hepatic metastases (ethanol infusion, cryoablation, chemoembolization) may produce some symptom relief.
Prognostic Factors and Survival
In a large series of referred patients seen by Oberg’s group in Uppsala, survival was influenced by the number of liver metastases (< 5 or ³ 5) and the levels of urinary 5-HIAA and plasma chromogranin A and neuropeptide K. By multivariate analysis, age greater than 53 years and plasma levels of chromogranin A greater than 5 mg/L were independent predictors of poor survival. For midgut carcinoids median survival was 92 months from diagnosis. For foregut tumors, median survival was 80 months, and for hindgut tumors, 64 months. Those with midgut malignant carcinoids lived longer from the start of treatment, 67 months, compared to 26 months for malignant foregut and 22 months for malignant hindgut tumors.
1. Kaplan LM. In: Harrison’s Principles of Internal Medicine, 14th edition, Fauci AS, et al. eds. New York:McGraw-Hill;1998;584-592.
2. Janson ET, et al. Ann Oncol 1997;8:685-690.