ESSENTIALS OF DIAGNOSIS
Majority are asymptomatic and discovered incidentally at endoscopy or surgery.
Carcinoid syndrome occurs in less than 10%; hepatic metastases are generally present.
Risk of metastasis is related to tumor size and location.
Neuroendocrine tumors are the most common type of tumor arising in the small bowel. Gastrointestinal NETs (also called carcinoids) most commonly occur in the small intestine (45%) but are also found in the rectum (20%), appendix (17%), and colon (11%), with the remainder occurring in the stomach (less than 10%; see Gastric Neuroendocrine Tumors above). Carcinoid tumors are well-differentiated neuroendocrine tumors that may secrete a variety of hormones, including serotonin, somatostatin, gastrin, and substance P. Carcinoid tumors usually display immunoreactivity to chromogranin A.
Small intestinal carcinoids most commonly arise in the distal ileum within 60 cm of the ileocecal valve. Up to 30% are multicentric. The risk of metastatic spread increases when the tumor is 1 cm or larger and when it is larger than 2 cm with invasion beyond muscularis propria. Many small carcinoids are detected incidentally at endoscopy or autopsy. It is not always possible to distinguish benign from malignant disease by histologic examination. Appendiceal carcinoids are identified in 0.3% of appendectomies, usually as an incidental finding. Almost 80% of these tumors are smaller than 1 cm, and 90% are smaller than 2 cm. However, in patients with appendiceal carcinoid tumors larger than 2 cm, approximately 90% develop nodal and distant metastases; right hemicolectomy is recommended in these cases. Lymphatic invasion, lymph node or mesoappendiceal involvement, positive margins, and high tumor grade are also indications to consider right hemicolectomy instead of (or in addition to) appendectomy.
Rectal carcinoids are usually detected incidentally as submucosal nodules during proctoscopic examination and often locally excised by biopsy or snare polypectomy before the histologic diagnosis is known. Endorectal ultrasound is usually recommended to assess the size, presence, and depth of invasion, and presence of lymph node metastases. Rectal carcinoids smaller than 1 cm virtually never metastasize and are treated effectively with local endoscopic or transanal excision. Larger tumors are associated with the development of metastasis in 10%. Hence, a more extensive cancer resection operation is warranted in fit patients with rectal carcinoid tumors larger than 1–2 cm or with high-risk features (such as invasion of muscularis propria or evidence of nodal involvement), or both.
Most lesions smaller than 1–2 cm are asymptomatic and difficult to detect by endoscopy or imaging studies. Through local extension or metastasis to mesenteric lymph nodes, carcinoids engender a fibroblastic reaction with contraction and kinking of the bowel or encasement of mesenteric vessels. Small intestinal carcinoids may present with intermittent abdominal pain, bowel obstruction, bleeding, or bowel infarction. Appendiceal and rectal carcinoids usually are small and asymptomatic, but large lesions can cause bleeding, obstruction, or altered bowel habits. Carcinoid syndrome occurs in less than 10% of patients. More than 90% of patients with carcinoid syndrome have hepatic metastases, usually from carcinoids of small bowel origin. About 10% of patients with carcinoid syndrome have primary bronchial or ovarian tumors without hepatic metastases. Carcinoid syndrome is caused by tumor secretion of hormonal mediators. The manifestations include facial flushing, edema of the head and neck (especially with bronchial carcinoid), abdominal cramps and diarrhea, bronchospasm, cardiac lesions (pulmonary or tricuspid stenosis or regurgitation in 10–30%), and telangiectases.
Serum chromogranin A (CgA) is elevated in the majority of NETs, although its sensitivity for small, localized carcinoid tumors is unknown. CgA is elevated in almost 90% of patients with advanced small bowel carcinoid. Urinary 5-hydroxyindoleacetic acid (5-HIAA) and platelet serotonin levels are also elevated in patients with metastatic carcinoid; however, these tests are less sensitive than CgA. There is increased urinary 5-HIAA in carcinoid syndrome; symptomatic patients usually excrete more than 25 mg of 5-HIAA per day in the urine. Because certain foods and medications can interfere with 5-HIAA levels, these should be withheld for 48 hours prior to a 24-hour urine collection. Patients should be advised to not eat avocados, bananas, cantaloupe, eggplant, pineapples, plums, tomatoes, plantains, kiwi, dates, grapefruit, honeydew, hickory nuts, pecans, or walnuts, not to drink alcohol or coffee and not to smoke. Medications that interfere with 5-HIAA levels include acetaminophen, ephedrine, diazepam, nicotine, glyceryl guaiacolate and phenobarbital.
Abdominal CT may demonstrate a mesenteric mass with tethering of the bowel, lymphadenopathy, and hepatic metastasis. Abdominal CT or enterography may reveal kinking of the bowel, but because the lesion is extraluminal, the diagnosis may be overlooked for several years. Somatostatin receptor scintigraphy (OctreoScan) and gallium Ga-68 DOTATATE PET scan are routinely used in staging and can help identify diseases that may benefit from treatment with somatostatin analogs. Most patients with carcinoid syndrome have liver metastasis on abdominal imaging.
Small intestinal carcinoids generally are indolent tumors with slow spread. Patients with disease confined to the small intestine should be treated with surgical excision. There is no proven role for adjuvant therapy after complete resection. Five-year survival rates for patients with stage I and II disease are 96% and 87%, respectively. In patients with resectable disease who have lymph node involvement (stage III), the 5-year survival is 74%; however, by 25 years, less than 25% remain disease free. Across stages, prognosis is strongly associated with histologic differentiation and grade. Patients with grade 1 disease may not require treatment for many years even with metastatic disease. However, patients with a grade 3 neuroendocrine tumor may have a clinical course more similar to a high-grade neuroendocrine carcinoma.
In patients with advanced disease, therapy historically has been deferred until the patient is symptomatic. Conventional cytotoxic chemotherapy agents do not achieve significant responses in carcinoid tumors and have not been associated with improved outcomes. For patients who are symptomatic either from tumor bulk or carcinoid syndrome, the cornerstone of therapy is typically a long-acting somatostatin analog, which inhibits hormone secretion from the carcinoid tumor. In 90% of patients, this results in dramatic relief of symptoms of carcinoid syndrome, including diarrhea or flushing, for a median period of 1 year. Thereafter, many patients stop responding to octreotide. Options at disease progression include octreotide dose escalation, or addition of everolimus, the mammalian target of rapamycin (mTOR) inhibitor. For patients with somatostatin receptor–positive disease based on imaging, another option after progression on standard dose somatostatin analog therapy is treatment with peptide receptor radionuclide therapy. Peptide receptor radionuclide therapy consists of a somatostatin analog conjugated to a radioactive isotope such as yttrium-90 or lutetium-177. In the United States, peptide receptor radionuclide therapy is specifically approved for gastroenteropancreatic NETs. Additionally, in selected patients with hepatic-dominant disease, resection of hepatic metastases may provide dramatic improvement in carcinoid syndrome symptoms. Tumor debulking with liver-directed therapy (chemoembolization or radioembolization) may also provide symptomatic improvement in some of these patients.
Health care maintenance for patients with carcinoid syndrome should include echocardiographic surveillance and cardiology evaluation, especially prior to major elective surgery due to the risk of carcinoid heart disease. Carcinoid heart disease is typically characterized by right-sided endocardial fibrosis that can cause fixation of the tricuspid and pulmonary valve leaflets. Additionally, due to increased metabolism of tryptophan into serotonin, patients with carcinoid syndrome are at an increased risk for pellagra and they should receive niacin supplementation.
Patients with advanced, poorly differentiated intestinal NETs are treated in a similar fashion to those with small cell cancers. They have a poor prognosis.