Carcinoid tumor and bowel obstruction
A 65-year-old woman with a history of type 2 diabetes, coronary artery disease with congestive heart failure and nephropathy presented with severe, intermittent, crampy abdominal pain and chronic constipation alternating with diarrhea. She complained of a long history of subjective flushing, but denied wheezing and palpitations. She was felt to have a possible bowel obstruction, and an abdominal CT scan was performed that showed a mass near the terminal ileum.
The patientâ€™s subjective flushing symptoms with an ileal mass suggested a carcinoid tumor. A 24-hour urine 5-hydroxyindoleacetic acid (5-HIAA) test was mildly elevated at 18.4 mg per day (normal range 2 mg to 8 mg per day). Somatostatin receptor scintigraphy (SRS) with indium-111 octreotide was performed. Standard anterior and posterior imaging was unrevealing due to normal isotope trapping in the overlying normal bowel, liver and kidneys (Figure 1). However, single-photon emission CT revealed an area of increased, persistent radiotracer activity within the right side of the abdomen (Figure 2) that localized to the area of the terminal ileum. There were no other areas of isotope accumulation suggesting metastases. These findings are consistent with a midgut carcinoid tumor of the small intestine.
Characteristics of carcinoid tumors
Carcinoid tumors are amine precursor uptake and decarboxylation-omas that arise from the enterochromaffin cells of the gastrointestinal tract. They are neuroendocrine tumors that secrete several hormones and amines. In midgut tumors, 5-hydroxytryptophan is converted by an enzyme dopa decarboxylase into serotonin (5-hydroxytryptamine). Monoamine oxidase in the blood rapidly converts serotonin to 5-HIAA, which can be measured by laboratory testing. Other potentially bioactive molecules, including histamine, prostaglandins, kallikrein and other polypeptides, can also be secreted.
Carcinoid tumors are well-circumscribed, round and submucosal masses that can be classified according to embryologic origin into foregut (bronchial, stomach, duodenum, biliary tract and pancreas), midgut (small intestine, appendix and proximal colon) and hindgut (distal colon, rectum and genitourinary tract).
The estimated prevalence is about five per 100,000, but the true prevalence is probably higher as many indolent tumors are found incidentally, such as this case.
Gastrointestinal carcinoid tumors are the most common (64%), followed by lung and bronchial tumors (28%). Of the gastrointestinal tumors, the ileum is the most common site (45%), followed by the rectum (20%), appendix (16%), colon (11%) and stomach (7%). WHO divides carcinoid tumors into four grades: well differentiated; moderately differentiated; poorly differentiated; and undifferentiated. Typical tumors with characteristic growth patterns are classified as well-differentiated neuroendocrine tumors and are slow-growing. Metastatic tumors are divided into well-differentiated and poorly differentiated tumors.
Photos courtesy of: Stephanie L. Lee, MD, PhD
Figure 2. Single-photon emission CT images of the indium-111 octreotide scan. Two adjacent tomographic images are shown. The yellow area in the left side of the panel indicates the uptake of tracer into the midgut carcinoid tumor located in the terminal ileum. The right side of the panel shows isotope uptake into the carcinoid tumor at the intersection of the crosshairs in the three orthogonal planes: coronal, sagittal and axial.
Clinical presentation of tumors
Most gastrointestinal carcinoids are sporadic and have a loss of heterozygosity of chromosome 18. Midgut â€” not foregut or hindgut â€” carcinoid tumors contain the enzyme dopa decarboxylase, which converts 5-hydroxytryptophan into serotonin. Carcinoid tumors of the foregut and hindgut are usually biologically inactive. Clinical features vary with the location of the tumor, the products secreted and the presence of liver metastases. For example, gastric carcinoids can be associated with chronic atrophic gastritis (type 1), with Zollinger-Ellison syndrome or with multiple endocrine neoplasia 1 (type 2); they may also be sporadic (type 3).
Hindgut tumors rarely secrete serotonin and usually present with bleeding or obstruction. Midgut or small intestinal tumors can secrete serotonin, but the most common clinical presentation is a prolonged, nonspecific abdominal discomfort. Serotonin is a mediator of fibrosis with intense desmoplastic and fibrotic reactions in the mesentery seen in the area of these tumors, which may result in abdominal pain or obstruction.
These tumors are frequently multiple, malignant and diagnosed late with partial, small intestinal obstruction with intermittent cramps. When the tumor is limited to a gastrointestinal location, biochemically, they are silent. The venous drainage of the gut goes through the liver before returning to the systemic circulation. The liver inactivates gastrointestinal carcinoid secretory products, so the presence of the systemic carcinoid syndrome depends on having both a secretory tumor and either liver metastases or an extraintestinal location that allows bypass of the portal circulation.
Effects of carcinoid syndrome
The typical carcinoid syndrome occurs in 10% of patients and is most often associated with midgut tumors. It is characterized by episodic flushing of the face, neck and upper chest, as well as the presence of watery diarrhea. As the disease progresses, the episodes of flushing may last more than 30 minutes. The prolonged vasodilation results in venous telangiectasia of the nose, upper lip and malar regions. Bronchospasm, wheezing, tachycardia and hypotension are less common. Up to 50% of patients with carcinoid syndrome develop carcinoid heart disease. The fibrous plaque-like lesions most commonly develop on the tricuspid valve and cause tricuspid regurgitation. Baseline and repeated echocardiograms are useful in monitoring for the development of disease. Advanced disease can cause pulmonary fibrosis and pleural thickening. Release of peptides such as adrenocorticotropin-releasing hormone or growth hormone-releasing factor may rarely cause Cushingâ€™s syndrome, acromegaly or other clinical syndromes.
Carcinoid crisis is a potentially fatal complication that can develop in patients during anesthesia induction after manipulation of a tumor mass or after chemotherapy or hepatic artery embolization. Symptoms include flushing, bronchoconstriction, hypotension or hypertension, and mental status changes that last for several hours or days. Prophylaxis with octreotide is required before such procedures.
Biochemical diagnosis of carcinoid syndrome is made with measurement of the 24-hour urinary 5-HIAA, which has a sensitivity of 75% and a specificity of 100%. Malabsorption syndromes, such as celiac disease, small bowel obstruction, ingestion of tryptophan-rich foods and several medications (See chart) can alter the levels of 5-HIAA and should be avoided if possible before urine collection. Even with this interference, generally, a secretory tumor is associated with very high levels of 5-HIAA, between 99 mg and 2,070 mg per day. Chromogranin A, proteins stored in neuroendocrine cells and whole blood serotonin, are sensitive but nonspecific markers. In patients with flushing due to carcinoid syndrome, the epinephrine provocation test will result in transient flushing, hypotension and tachycardia. Other secretory products can be measured if clinically indicated, such as gastrin and histamine.
Tumor assessment, management
SRS with indium-111-labeled somatostatin analogue octreotide can be used to localize primary and metastatic tumors with a sensitivity of 73% to 90%. CT or MRI scans can be used to assess the size and location of the primary or metastatic tumors, calcifications and mesenteric fibrosis with a sensitivity of more than 80%. False positives on SRS can occur with granulomas, thyroid diseases and activated lymphocytes. Bronchial carcinoids are diagnosed by chest X-ray and CT scans. Endoscopy may detect tumors that were not identified on imaging studies.
Localized disease can often be cured with surgical resection. Surgery is an option for bronchial or ovarian tumors, for small bowel neoplasms to prevent the desmoplastic reaction and in select cases for hepatic metastasis resection.
Medical treatment is generally effective for symptomatic treatment in patients with extraintestinal or metastatic disease. Treatment can be symptom-specific. For example, ondansetron is a serotonin antagonist and can be used for refractory diarrhea, and histamine-secreting gastric carcinoids may respond to a histamine blocker. If symptoms are more severe, somatostatin analogues can be used.
Octreotide and lanreotide are well tolerated, available in sustained-release form and can be titrated to symptom control. These medications do not reduce the carcinoid size or slow the growth of the tumor. Interferon-alpha may be used alone or in combination with octreotide, but its use is limited by side effects. Chemotherapy and radiation have been used in patients unresponsive to medical therapies without much success. Selective ligation, embolization or chemoembolization of the branches of the hepatic artery is an alternative treatment to metastatic hepatic lesions.
Prognosis is based on tumor size, location, histology and the presence of carcinoid syndrome or metastatic disease. Median survival for patients with metastases is 5 to 8 years, although those with severe carcinoid heart disease have a 30% 5-year survival.
The patient presented underwent resection of the terminal ileum mass, which was confirmed by pathology as a carcinoid tumor without liver lesions or a documented carcinoid syndrome. Postoperatively, her 5-HIAA was lower within the reference range at 11.2 mg per day. Her intermittent mild flushing, constipation and diarrhea were unchanged postoperatively, suggesting that the carcinoid tumor was not the cause of her gastrointestinal symptoms or subjective flushing.
Varsha Vimalananda, MD, is a fellow in endocrinology; and Stephanie L. Lee, MD, PhD, is professor of medicine and associate chief, both in the section of endocrinology, diabetes and nutrition at Boston Medical Center.
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