Evaluation and Treatment of Small Bowel Carcinoids

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 “enterochromaffin” 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 stain 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. These factors are responsible for symptoms that patients may experience. The diagnosis 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 (WHO) revised histologic classification. The WHO classifies neuroendocrine tumors of the small intestine into: well-differentiated neuroendocrine 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, and 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 increased by 3.8% per year and the age-adjusted incidence increased by 460% over 30 years. Patients with small intestinal neuroendocrine tumors most commonly present in the 6th or 7th decade.

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 if 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 common 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 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 heart 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 non-detoxified 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.

Radiographic tests in the evaluation of small bowel carcinoid tumors

Computed tomography (CT) is the most commonly used imaging modality for evaluation of patients with carcinoid tumors (Figure 1). However, it is often not helpful in detecting the primary small bowel tumor, which is usually small. It is useful for identifying bulky lymph node metastases (Figure 2) and liver metastases. Liver metastasis from carcinoid tumors are often hypervascular and become hypodense relative to the normal liver parenchyma after administration of intravenous contrast.  Contrast-enhanced triple-phase CT scanning should be performed with pre-and post-contrast studies.

Somatostatin receptor scintigraphy (SRS) can aid in the identification of metastatic disease. More than 90% of carcinoid tumors have high concentrations of somatostatin receptors and, as a result, can be imaged using an indium-111 labeled analog of octreotide. The accuracy of SRS can be further improved with the addition of single photon emission computer tomography to help distinguish areas of abnormal uptake from areas of physiologic uptake in the abdomen. Magnetic resonance imaging (MRI) is the best modality for diagnosis of liver metastases. Barium upper gastrointestinal small bowel series may demonstrate a filling defect related to the carcinoid tumor; however, this is a nonspecific finding with a low sensitivity and is rarely helpful.

Treatment of small bowel carcinoid tumors

Patients with a small intestinal neuroendocrine tumor should undergo an exploratory laparotomy. The primary tumor can be identified intraoperatively and the entire small intestine is examined for synchronous neuroendocrine tumors, which are present in 30% of patients. Twenty-nine percent of patients will have synchronous or metachronous non-carcinoid tumors, most commonly adenocarcinoma of the colon. The small bowel mesentery is examined for lymphadenopathy and the liver is examined for metastatic disease. Intraoperative ultrasound exam of the liver is also of value in determining the extent of metastatic involvement of the liver. Approximately one-third of patients with small intestinal neuroendocrine tumors will have metastases to the liver. The metastatic potential of small bowel neuroendocrine tumors best correlates with the size of the primary tumor.

Surgical treatment of the primary tumor consists of a segmental resection of the involved small intestine along with its mesentery (Figure 3). It is important to pay close attention to the adequacy of the resection margins of the small intestine and the lymphatic drainage of the tumor, and preserve the blood supply to the bowel margins. Intraoperative lymphatic mapping using lymphazurin blue dye has been used to map the subserosal lymphatic channels for the purpose of ensuring adequate resection margins and preserving the ileocecal valve when conditions permit.

In patients with known liver metastases, resection of the involved segment of small bowel and its associated mesentery is recommended for palliation of abdominal pain and prevention of vascular compromise and small bowel obstruction. Most patients who have small bowel neuroendocrine tumors will eventually be treated with octreotide, which is known to be associated with a high incidence of gallstones. As a result, cholecystectomy should be considered in patients undergoing exploratory laparotomy for treatment of a small bowel neuroendocrine tumor.

Surgical resection of liver metastases can improve survival in selected patients. A wedge resection or lobectomy is indicated for patients with metastases confined to one lobe of the liver. In patients with diffuse hepatic metastases, tumor debulking may help ameliorate symptoms of carcinoid syndrome. Hepatic artery chemoembolization and radiofrequency ablation are therapeutic options when liver metastases are not amenable to complete surgical resection.

A long acting somatostatin analog, administered two to three times per month, is useful for helping control hormonal symptoms. It may also have an antitumor effect, slowing tumor growth and stabilizing disease. The perioperative use of somatostatin analog has also been shown to prevent the development of carcinoid crisis, an uncommon life threatening manifestation of carcinoid syndrome. Carcinoid crisis can be precipitated by tumor manipulation, medications that promote histamine release or that stimulate the autonomic nervous system, hypotension, hypercapnia, and hypothermia. Intraoperatively, it is manifested by tachycardia, arrhythmias, blood pressure lability, and cardiovascular collapse. Carcinoid crisis is best treated by tumor removal and intravenous octreotide therapy.

Prognosis for small bowel carcinoid tumors

There has been little change in the prognosis of small intestinal neuroendocrine tumors over the past 30 years. The overall five year survival for small intestinal neuroendocrine tumors varies from 52-77%. Larger tumors, lymph node metastases, liver metastases, carcinoid syndrome, plasma chromogranin A levels > 5000 mg/ml and certain histologic features are associated with a worse prognosis. Histologic features that are predictive of reduced survival include an increased depth of invasion, vascular or lymphatic invasion, cellular atypia, necrosis, increased mitotic index, and an increase Ki-67 proliferative index. The five year survival rate is approximately 75% in patients with localized disease, 59-72% in patients with regional lymph node metastases and 20-43% in patients with distant metastases. Although patients with liver metastases and carcinoid syndrome have a worse prognosis than those who have liver metastasis alone, the median survival is still 5-8 years.