Syndromic vs Non-Syndromic Neuroendocrine Tumors

Medullary carcinomas of the thyroid can produce large amounts of the hormone calcitonin. Calcitonin is a hormone that functions to regulate the levels of calcium in the blood. Patients with medullary thyroid carcinomas sometimes experience diarrhea, itching (pruritis), and flushing. All of these are believed to be caused by elevated levels of calcitonin in the blood.

Carcinoid tumors are well or moderately differentiated neuroendocrine tumors that arise in the gastrointestinal tract (gut) or lung. Carcinoid tumors of the gastrointestinal tract, especially those that have spread (metastasized) to the liver, can produce a distinctive clinical syndrome called the “carcinoid syndrome.” The carcinoid syndrome is characterized by flushing, diarrhea and wheezing, and is believed to be the result of the production and release of serotonin by the tumor.

Gastrinomas are neuroendocrine tumors of the pancreas or duodenum that release large quantities of the hormone gastrin into the blood stream leading to stomach and duodenal ulcers. This syndrome was first described by Drs. Zollinger and Ellison in 1955, and so this syndrome sometimes carries their name (“Zollinger-Ellison syndrome). Gastrinomas are rare, and only one in 1,000 patients with primary duodenal ulcer disease has a gastrinoma. Seventy-five percent of gastrinomas occur in people without a family history of cancer, whereas 25% are associated with the multiple endocrine neoplasia, type 1 (MEN-1) syndrome [link to familial page here]. In the past, the majority of gastrinomas had already metastasized (spread to other organs) at the time of diagnosis. More recently, with increased awareness and earlier screening, the diagnosis of gastrinoma is being made earlier, leading to the discovery of a higher percentage of localized and therefore curable neoplasms.

The overall survival results in patients with gastrinoma have improved markedly since the initial description of the syndrome, with the best results obtained with surgical resection of tumors that are localized.

Glucagonomas are islet cell tumors neuro endocrine tumors of the pancreas that cause symptoms by releasing large quantities of the hormone glucagon into the blood stream. The most common findings in the glucagonoma syndrome include severe dermatitis (skin rash), mild sugar diabetes, stomatitis (mouth sores), anemia (low red blood cell count), and weight loss. The dermatitis is manifested by a characteristic skin rash called "necrolytic migratory erythema." This rash exhibits cyclic migrations with erythematous (red) patches that spread with central healing points of resolution.

The diagnosis of glucagonoma may be suggested by the clinical presentation and biopsy of the skin lesions, but is secured by the documentation of elevated levels of glucagon in the blood. By the time they are diagnosed most glucagonoma have spread to involve other organs (they have metastasized). Even if the glucagonoma has spread, safe surgical debulking of these metastatic lesions should be considered.

Insulinoma is the most common syndromic neuroendocrine tumor of the pancreas. The insulinoma syndrome is associated with the clinical findings of "Whipple's triad." These include: 1) symptoms of hypoglycemia (low blood sugar levels) during fasting, 2) documentation of hypoglycemia with blood glucose (sugar) levels less than 50 mg/dl, and 3) relief of symptoms when the patient is given glucose. Symptoms of hypoglycemia include confusion, seizures, obtundation (difficulty being roused), personality change and coma, as well as palpitations (racing heart), tremulousness, diaphoresis (sweating) and tachycardia (fast heart rate). In most cases, patients consume sugar-rich meals and snacks to relieve or prevent these symptoms.

After the diagnosis of insulinoma is confirmed by blood tests, the next step is usually to identify the location of the insulinoma and to stage the patient. For insulinoma the standard imaging studies include abdominal computerized tomography (CT scanning), endoscopic ultrasound (EUS) and in some cases interventional radiology to sample blood from locations around the pancreas (visceral angiography). The treatment of insulinoma is surgical removal when clinically possible.

In approximately 10% of all cases insulinoma will be found to have spread (metastasized) to lymph nodes or to the liver, justifying a diagnosis of metastatic insulinoma. Under these circumstances, cautious and safe resection of the primary tumor and accessible metastases can be considered. Such tumor debulking can be helpful in reducing problematic hypoglycemic symptoms which can be extremely debilitating. Many patients with an insulinioma are cured if the tumor can be removed surgically.

Pheochromocytomas are distinctive neuroendocrine tumors of the adrenal glands. Pheochromocytomas can produce large amounts of catecholamine hormones, particularly noirepinephrine. When released into the blood stream, norepinephrine can cause an elevation in the heart rate (pulse), high blood pressure (hypertension), palpitations (the sensation of a racing heart), sweating (diaphoresis), headaches and anxiety. Because pheochromocytomas can raise the blood pressure to dangerously high levels, patients with these tumors have to be managed very carefully.

Somatostainomas are pancreatic neuroendocrine tumors that cause symptoms by releasing large quantities of the hormone somatostatin into the blood stream. The somatostatinoma syndrome is the least common of the five functional pancreatic neuroendocrine tumor syndromes (listed above), with an estimated annual incidence of less than one in forty million people. The clinical features of the somatostatinoma syndrome are nonspecific and include steatorrhea (oily stools), sugar diabetes, hypochlorhydria (low blood chloride levels), and cholelithiasis (stones in the gallbladder). A fasting blood somatostatin level can be used to confirm the diagnosis of a somatostatinoma.

VIPomas are pancreatic neuroendocrine tumors that cause symptoms by releasing large amounts of the hormone vasoactive intestinal polypeptide (VIP) into the blood stream. Synonyms for this syndrome include the WDHA syndrome (watery diarrhea, hypokalemia (low potassium levels in the blood), and either achlorhydria or hypochlorhydria (low chloride)) and the pancreatic cholera syndrome. Patients characteristically present with intermittent severe diarrhea, typically of a watery nature, averaging 5 liters/day (that is an awful lot of diarrhea!).

Hypokalemia (low blood potassium) results from the fecal loss of large amounts of potassium, and low blood potassium levels may be associated with muscular weakness, lethargy, and nausea. VIPomas are extremely rare, and the diagnosis of VIPoma is typically made after excluding other more common causes of diarrhea. When clinically appropriate, surgical excision of the tumor is appropriate in all patients with a VIPoma.