Gastrointestinal Neuroendocrine Tumors and Carcinoid Syndrome

Endocrinologically active neuroendocrine tumors (NETs) of the diffuse peripheral endocrine or paracrine system produce various amines and polypeptides with corresponding symptoms and signs, including carcinoid syndrome. Carcinoid syndrome is usually due to endocrinologically active NETs that develop from neuroendocrine cells (mostly in the ileum—see Small Bowel Tumors) and produce serotonin. It can, however, occur as a result of neuroendocrine tumors elsewhere in the gastrointestinal tract (particularly the appendix and rectum), pancreas, bronchi, or, rarely, the gonads. Rarely, certain highly malignant tumors (eg, oat cell carcinoma of the lung, pancreatic islet cell carcinoma, medullary thyroid carcinoma) are responsible.

An intestinal serotonin-producing NET does not usually cause carcinoid syndrome unless hepatic metastases have occurred because metabolic products released by the tumor are rapidly destroyed by blood and liver enzymes in the portal circulation (eg, serotonin by hepatic monoamine oxidase). Hepatic metastases, however, release metabolic products via the hepatic veins directly into the systemic circulation. Metabolic products released by primary pulmonary and ovarian carcinoids bypass the portal route and may similarly induce symptoms. Rare intestinal NETs with only intra-abdominal spread can drain directly into the systemic circulation or the lymphatics and cause symptoms.

Serotonin, the primary hormone produced by some NETs, acts on smooth muscle to cause diarrhea, colic, and malabsorption. Histamine and bradykinin, which are produced in smaller amounts, cause flushing through their vasodilator effects.

The role of prostaglandins and various polypeptide hormones, which may be produced by paracrine cells, awaits further investigation; elevated human chorionic gonadotropin and pancreatic polypeptide levels are occasionally produced by NETs.

Some patients develop right-sided endocardial fibrosis, leading to pulmonic stenosis and tricuspid regurgitation. Lesions of the left side of the heart, which have been reported with bronchial NETs, are rare because serotonin is destroyed during passage through the lungs.

The most common (and often earliest) sign of carcinoid syndrome is

• Uncomfortable flushing, typically of the head and neck

Flushing is often precipitated by emotional stress or the ingestion of food, hot beverages, or alcohol.

Striking skin color changes may occur, ranging from pallor or erythema to a violaceous hue.

Abdominal cramps with recurrent diarrhea occur and are often the patient’s major complaint. Malabsorption syndrome may occur.

Carcinoid Syndrome (Facial Flushing)

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Patients with valvular lesions may have a heart murmur. A few patients have wheezing due to bronchospasm, and some have decreased libido and erectile dysfunction. Pellagra, due to the diversion of tryptophan to serotonin production, develops rarely.

• Tests for urinary 5-hydroxyindoleacetic acid (5-HIAA) and serum chromogranin A (CgA)

Serotonin-producing NETs are suspected based on their symptoms and signs. Diagnosis is confirmed by demonstrating increased urinary excretion of the serotonin metabolite 5-HIAA. To avoid false-positive results, clinicians do the test after the patient has abstained from serotonin< 10 mg/day (< 52 micromol/day); in patients with carcinoid syndrome, excretion is usually > 50 mg/day (> 260 micromol/day).

Serum chromogranin A (CgA), a well-established marker for NETs, is helpful in the diagnosis of NETs. Combining measurements of serum CgA with 24-hour urine 5-HIAA results in increased overall test sensitivity in patients with carcinoid syndrome.

• Somatostatin analogs (SSAs) and other medications for symptoms

• Surgical resection of the tumor

1), which are the guideline-recommended medications of choice for controlling diarrhea and flushing. For refractory diarrhea that is not controlled with SSAs, all guidelines recommend telotristat etiprate, an oral tryptophan hydroxylase inhibitor (2).

Resection of primary gastrointestinal and bronchial NETs in patients with carcinoid syndrome is often curative.

For patients with hepatic metastases, surgical debulking of the tumor, while not curative, may relieve symptoms and, in certain instances, prolong survival (34).

Radiation therapy is unsuccessful, in part because of the poor tolerance of normal hepatic tissue to radiation.

Prognosis of neuroendocrine tumors depends on primary site, grade, and stage. Despite metastatic disease and the carcinoid syndrome that can accompany it, NETs are slow growing, and survival of 10 to 15 years is not unusual.