Small bowel carcinoids
What is a small bowel carcinoid or a small bowel neuroendocrine tumor?
Neuroendocrine or carcinoid tumors of the small intestine, arise from serotonin-producing, intraepithelial cells in the small intestine referred to as enterochromafin cells. The term enterochromafin is used to describe cells that stain with potassium chromate, a characteristic of cells that contain serotonin. Small intestinal neuroendocrine tumors are typically round, well circumscribed neoplasms found in the submucosa of the bowel wall. Cells of small intestinal neuroendocrine tumors take up silver and are also referred to as argentaffin cells. Neuroendocrine tumors of the small intestine are most often well-differentiated tumors that behave in an indolent fashion, although their biologic behavior is variable. These tumors have amine precursor uptake and decarboxylation ( APUD ) activity and may elaborate various humoral factors, which are responsible for symptoms that patients may experience. The diagnosis of the carcinoid tumor is based on histologic examination and immunohistochemical staining for neuroendocrine markers. The use of the term carcinoid has since been discouraged and these tumors are better referred to as neuroendocrine tumors based on the World Health Organization revised histologic classification. The World Health Organization classifies neuroendocrine tumors of the small intestine into: well differentiated endocrine tumors (noninvasive tumors with features consistent with benign behavior or uncertain malignant potential); well differentiated neuroendocrine carcinoma (tumors with invasion of the muscle layer of the small intestine or metastases and poorly differentiated neuroendocrine carcinoma.
Neuroendocrine tumors are the most common small bowel tumor, accounting for 41.8 % of all small bowel malignancies. Neuroendocrine tumors of the small intestine are also the most common gastrointestinal neuroendocrine tumor. The most common location for gastrointestinal neuroendocrine tumors is in the ileum within 60 cm of the ileocecal valve. Based on data accumulated at the National Cancer Institute, the age adjusted incidence rates of small intestinal neuroendocrine tumors are estimated to be 0.88 and 0.63 cases per 100,000 per year for white men and women and 1.65 and 1.15 cases per 100,000 per year for African American men and women. From 1973 -2002, the incidence of small intestinal neuroendocrine tumors has increased by 3.8% per year and the age-adjusted incidence has increased by 460% over 30 years. Patients with small intestinal neuroendocrine tumors most commonly present in the 6th or 7th decade. The mean age at the time of tumor discovery is between 55 and 60 years.
Clinical Presentation. Symptoms related to a neuroendocrine tumor of the small intestine generally do not appear until there are hepatic metastases which impair the ability of the liver to metabolize the humoral factors secreted by the tumor or there is obstruction or ischemia of the small intestine. As a result, most patients with small intestinal neuroendocrine tumors have regional or distant metastases at initial presentation. Abdominal pain, which is usually vague and nonspecific, is the most commom symptom. The pain can be intermittent and colicky in nature especially when associated with small bowel obstruction. Small bowel obstruction may result from a dense, fibrotic, desmoplastic reaction involving the small bowel mesentery resulting in shortening of the mesentery and kinking of the bowel. Small bowel obstruction may also be caused by an intraluminal tumor growth or invasion, or intussusception. Abdominal pain may also occur as a result of mesenteric ischemia, which results from vascular compromise related to bulky lymphadenopathy encasing major mesenteric vessels or from serotonin induced microvascular angiopathy.
Carcinoid syndrome. Five to seven percent of patients with small intestinal neuroendocrine tumors may present with a carcinoid syndrome which occurs as a result of release of humoral factors from the tumor. Flushing is a hallmark of the syndrome, occurring in 75% or more of patients with carcinoid syndrome. Patients with carcinoid syndrome related to a small intestinal neuroendocrine tumor typically develop a diffuse erythematous flushing affecting the face, neck, and upper chest. It may be precipitated by certain foods, alcohol or stress and typically lasts for 2-10 minutes. Watery diarrhea and crampy abdominal pain occur in 75-80% of patients with carcinoid syndrome. Cardiac lesions may develop over time and occur in 40% of patients with carcinoid syndrome. The right side of the heart is most often affected with plaque like thickening of the endocardium and the tricuspid and pulmonic valves resulting in pulmonary stenosis, tricuspid stenosis, and tricuspid insufficiency. Bronchoconstriction, manifested by wheezing, is the least common manifestation, occurring in approximately 20% of patients with carcinoid syndrome. Carcinoid syndrome is a marker for advanced disease. Patients usually have extensive liver metastases. As a result, the metabolism of hormonal mediators released by the tumor is impaired and the metastatic tumor foci in the liver can also release nondetoxified mediators into the blood stream. A diagnosis of carcinoid syndrome is confirmed by an elevated 24 hour urinary 5-hydroxyindoleacetic acid (HIAA) level, a metabolite of serotonin.
Biochemical Markers For Diagnosis. A diagnosis of carcinoid syndrome is confirmed by an elevated 24 hour urinary 5-HIAA level. The normal range for 24 hour urinary 5- HIAA is 2-8 mg/day. Certain drugs, tryptophan-rich foods and malabsorption syndromes, such as celiac and Whipple's disease, may increase 24 hour urinary HIAA levels to up to 30 mg/day. Most patients with carcinoid syndrome will have 24 hour urinary 5-HIAA levels greater than 100 mg/day. Small intestinal neuroendocrine tumors also produce increased concentrations of chromogranins, which are proteins that are stored and released with peptide and amine humoral factors. Elevation of plasma chromogranin A concentration is a sensitive marker for a neuroendocrine tumor but is not specific. A plasma chromogranin A level greater than 32 U/L has a sensitivity and specificity of 75% and 84%, respectively. A plasma chromogranin A level greater than 5000 ug/L is an independent predictor of poor overall survival in patients with carcinoid tumors. Serum chromogranin A levels correlate with tumor burden. Measurement of serum chromogranin A levels may be very useful in monitoring patients for the development of recurrent disease. False positive serum chromogranin A levels may occur with liver, kidney, or heart failure; chronic atrophic gastritis; chronic use of proton pump inhibitors, prostate cancer, hyperthyroidism and inflammatory bowel disease. Measurement of whole blood serotonin concentration may be helpful in patients when 24 hour urinary 5-HIAA levels are equivocal. Whole blood fasting serotonin levels have been reported to vary between 71 and 310 mg/ml in normal individuals. Patients with carcinoid syndrome have been documented to have markedly elevated levels varying from 790-4500 mg/ml.