Carcinoid Syndrome & VIPomas

Epidemiology and Pathophysiology

• Epidemiology of GEP Tumors
  • Prognosis of Patients with Carcinoid Syndrome
• Pathophysiology of carcinoid tumors
  • Serotonin Metabolism in Carcinoid Syndrome
  • Development of Carcinoid Syndrome
  • Clinical Symptoms of Carcinoid Syndrome
• VIPomas

Epidemiology of GEP Tumors

Gastroenteropancreatic (GEP) tumors are rare, with an estimated U.S. prevalence of not more than of 5.6 cases per 100,000 of the population, affecting approximately 15,440 people in the United States as of July, 2000. Types of GEP tumors according to incidence include (1):

Prognosis of Patients with Carcinoid Syndrome

After the onset of clinical symptoms, median survival times of 3.5 to 8.5 years have been reported; 5-year survival has ranged from 30% to 67% (2).

• The prognosis for poor patient outcome generally correlates inversely with increasing levels of urinary 5-HIAA excretion (2).
• Other biochemical indicators of a bad prognosis are high levels in the plasma of neuropeptide K and chromogranin A (3).
• Patients with fewer liver metastases have longer life expectancies (3).
• Patients with extensive liver metastases should be treated more aggressively since they have a worse prognosis (3).
• Factors associated with an increased risk of poor prognosis are the following (3):
  • Advanced stage of the disease
  • Tumors located in the large bowel
  • Occurrence of another malignancy

Pathophysiology of Carcinoid Tumors

Carcinoid tumors originate from the diffuse neuroendocrine system, specifically the enterochromaffin (EC) cells. EC cells are widely distributed throughout the body, but are most prevalent in the submucosa of the intestine and main bronchi (2). Carcinoid tumors have the following characteristics (2):

• Are classified as APUDomas (amine precursor uptake and decarboxylation). Pituitary adenomas, pancreatic islet cell tumors, and oat cell carcinomas are also APUDomas.
• Produce a variety of biogenic amines and peptide hormones that vary with location, as do their effect on the body.
• Can be assessed for malignant status based on the presence of lymph node invasion and distant metastases rather than histologically.
• Carcinoid tumors are classified by site of origin (i.e., foregut, midgut, hindgut), because histochemistry, secretory products, and manifestations vary with location.
• Primary occurrence in the appendix (38%), ileum (23%), rectum (13%), and bronchus (11.5%) (2).
• Occurrence with an incidence of less than 1% in the pancreas, gallbladder, liver, ovaries, larynx, and testes, but these tumors have a high incidence of metastases (2, 4).

Carcinoid Syndrome

Malignant carcinoid syndrome, the predominant clinical feature of carcinoid tumors, results from excessive secretion of hormone products into the systemic circulation. These hormones (peptides and amines) cause the extreme symptoms of the disease, and a reduction in their circulating blood concentrations through targeted treatment is a therapeutic goal (1, 2).

Gastrointestinal Peptides and Amines Secreted by Carcinoid Tumors

• ACTH
• Gastrin
• Pancreatic polypeptide
• Insulin
• Tachykinins
• Vasoactive intestinal polypeptide (VIP)
• Serotonin
• 5-hydroxyindoleacetic acid (5-HIAA)

Serotonin Metabolism in Carcinoid Syndrome

Many of the symptoms of carcinoid syndrome are produced by serotonin or its metabolites. Serotonin metabolism in carcinoid disease is illustrated below (3).

Serotonin Metabolism in Carcinoid Disease

Development of Carcinoid Syndrome

Carcinoid syndrome does not usually develop until a tumor has metastasized — usually to the liver — and the hormonal products released by the tumor reach the circulation in substantial concentrations (5, 6).

• Although it is the most common systemic clinical manifestation of carcinoid tumors, carcinoid syndrome occurs in fewer than 10% of patients with carcinoid tumors and has an incidence of about 3.2 to 5 cases per 1,000,000 population (7).
• The likelihood of occurrence and the associated severity of carcinoid syndrome depend on several factors: tumor size, whether its location is in an area draining into the systemic circulation, and the degree of metastasis (6).
• Carcinoid syndrome exhibits slow growth with early ill-defined symptoms and is frequently misdiagnosed as "irritable bowel syndrome" or "spastic colon" (1).
• Carcinoid syndrome has an insidious progression, with recognition of the disease frequently occurring in late disease stages (1).
• The incidence of metastases in carcinoid tumors is less than 2% in tumors smaller than 1 cm and almost 100% in tumors greater than 2 cm (1).
• Surgical removal of the tumors is the primary therapeutic option; chemotherapy is less effective (2).
• Octreotide is the primary medical therapy for the management of certain symptoms associated with carcinoid syndrome.

Progression of Carcinoid Disease.

• Patient age at diagnosis ranges widely — from 10 to 93 years; however, carcinoid tumors are most frequently reported between 50 and 70 years with a mean of approximately 55 years (2).
• Overall, the prognosis for patients with carcinoid tumors is relatively good compared with other malignancies (1).

Clinical Symptoms of Carcinoid Syndrome

A variety of different symptoms are associated with carcinoid syndrome:

Clinical Presentation of Carcinoid Syndrome

• Flushing, the most frequent symptom, may occur spontaneously or be precipitated by stress, alcohol, certain foods, exercise, or pharmacologic agents. Flushing episodes may be brief (2 to 5 minutes) or last for several hours, particularly in later stages of the disease (6).
• Diarrhea usually accompanies flushing but occurs alone in approximately 15% of cases; abdominal pain or cramping may or may not be associated with diarrhea (6).
• Other symptoms include a unique type of endocardial fibrosis and wheezing or asthma-like symptoms (6).
• Myopathy, arthritis, arthralgias, and changes in mental state are reported, although only rarely (6).

Carcinoid Heart Disease

Carcinoid heart disease develops in about 50% to 60% of patients with carcinoid syndrome (3).

• This condition involves development of superficial plaques that adhere to the surface of the endocardium.
• Fibrous deposits may affect valve function, and can lead to heart failure.
• The right side of the heart is most commonly affected.
• This condition is severe in about 25% of patients with heart involvement (3).

VIPomas

VIPomas are rare endocrine tumors that occur with an annual incidence of 1 per 10 million (5). VIPomas are

• Often large, solitary tumors that occur primarily (80% to 90%) in the pancreas (2)
• Characterized by severe symptoms

• Associated with secretory diarrhea, a major marker of VIPoma syndrome, which is severe and of a high volume, i.e., usually more than 3 L/day (2, 5)
• Diagnosed based on the demonstration of elevated VIP in plasma and presence of large volume secretory diarrhea (2)
• Associated with VIPoma syndrome, often referred to as pancreatic cholera, Verner-Morrison syndrome, or watery diarrhea, hypokalemia, and achlorhydria (WDHA) (2, 5)