Carcinoid Syndrome & VIPomas

Diagnosing Carcinoid Syndrome

The diagnosis of carcinoid syndrome is complicated by the fact that many of the symptoms — at least in the early stages — are nonspecific, mimicking those of conditions such irritable bowel syndrome.

• Detection
• Initial Staging
• Chromogranin A (CgA) Testing
• 5-hydroxyindoleacetic Acid (5-HIAA) Testing
• Somatostatin Receptor Scintigraphy (SRS) Testing

Detection of Carcinoid Tumors or Carcinoid Syndrome

Detection of carcinoid tumors or carcinoid syndrome may occur in a variety of ways.

• In the majority of cases, the flushing, diarrhea, and other symptoms of carcinoid syndrome trigger recognition of this condition.
• In about 20% of patients with carcinoid disease, the presenting symptom may be due to heart disease (1).
• In some cases, intestinal symptoms caused by primary tumors (e.g., abdominal pain or intestinal bleeding) are the presenting complaint.

Initial Staging

Initial staging of the disease involves the following:

• Patients with carcinoid syndrome have significantly elevated serum levels of serotonin or its metabolites, of which the most important is 5-HIAA (2).
• Thus, measurement of urinary 5-HIAA is the most commonly used diagnostic test for carcinoid syndrome with a sensitivity of 73% and a specificity of 100% (2)
• Other molecules that may be increased in carcinoid syndrome are substance P (sensitivity: 32%, specificity: 85%) 3 and chromogranin A (99% of patients with verified carcinoid tumors),15 thus chromogranin A, (sensitivity 80%), in particular, may be a useful biochemical marker for carcinoid tumors (2).
• A number of modalities contribute to tumor localization (2):
  • GI endoscopy
  • Abdominal and thoracic radiography
  • Imaging studies such as ultrasound, computed tomography (CT) scan, magnetic resonance imaging (MRI), and angiography
  • Radionuclide scanning
• Since right handed heart disease is a frequent complication, echocardiography is useful for detecting the presence of cardiac abnormalities.
• The diagnosis and management of patients with neuroendocrine cancer has been enhanced through the application of somatostatin receptor scintigraphy (SRS), using OctreoScan®* (indium In 111), a radiolabeled analogue of somatostatin.
  • Eighty-eight percent of carcinoid tumors have high-affinity receptors for somatostatin (3).
  • SRS is recommended as the initial imaging procedure to use to stage carcinoid tumor due to its sensitivity and ability to detect metastases throughout the body (2).

Chromogranin A (CgA) Testing

CgA is an easily tested carcinoid tumor serum marker (4, 5, 6, 7, 8) that has received much attention over the past 10 years. It is part of a water-soluble acidic glycoprotein family stored in the secretory granules of carcinoid tumor cells. CgA may be a precursor of biologically active peptides, and is released into the systemic circulation together with known bioactive factors (4, 6). Some confusion over the sensitivity and marker status of CgA involves use of assays that actually measure pancreastatin, a cleavage product of CgA. Since many carcinoid tumors are unable to splice off pancreastatin, these assays fail to assure an accurate measurement of CgA (9).

Many investigators support the use of CgA testing as the best general marker for monitoring carcinoid tumors (7, 10). Elevated levels of CgA in 80% to 100% of patients with verified carcinoid tumors have been reported (9). In particular, a revealing study of 301 consecutive carcinoid patients compared tumor marker elevations and found that CgA increases were independent of the tumor site, correlated with tumor burden, and, in a multivariate analysis, an independent predictor of poor prognosis (11). However, increases in CgA levels are not limited to carcinoid tumors because elevated concentrations occur in patients with other specific neuroendocrine tumors, such as nonfunctioning tumors of the endocrine pancreas and medullary thyroid cancers (6). Therefore, more extensive testing is recommended, primarily through assessments of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA).

How the CgA Test Works

A typical CgA test measures serum CgA using enzyme immunoassay technology. Measurements may vary with meal consumption and should be drawn fasting. The method uses a CgA-specific antibody, bound to the surface of a plastic microwell.

• An enzyme-conjugated antibody, also specific to CgA, is incubated with the serum specimen that allows the 2 antibodies to bind the CgA protein as a "sandwich."
• After unbound materials are washed away, a substrate is added.
• The conjugated enzyme uses this substrate to produce color.

The intensity of color is proportional to the specimen's CgA concentration The reference interval is dependent on a number of factors, but generally the interval for men falls within 0 to 76 mcg/L, and that of women falls within 0 to 51 mcg/L (12). Reference values differ from lab to lab, so use the same lab for accurate predictability.

What to Expect

Elevated CgA levels are detected in approximately 8 of 10 patients with carcinoid tumors (9). Although this test does not differentiate carcinoid tumors from other neuroendocrine tumors (NETs) or gastroenteropancreatic (GEP) tumors, it is an accurate but not very sensitive test for NETs and GEPs, with a specificity of 86% (4, 7), and a sensitivity of 68% (4, 7).

When to Test

CgA tests should be performed every 3 to 6 months (13).

5-Hydroxyindoleacetic Acid (5-HIAA) Testing

When diagnosing and monitoring for carcinoid tumors, 5-HIAA, a metabolite of serotonin, is the most common biochemical test. The predominantly used 5-HIAA test requires collection of a 24-hour urine sample tempered by pretesting dietary and medical restrictions. Consumption of serotonin-rich foods, such as bananas, plantains, pineapples, kiwis, avocados, or a variety of nuts (walnuts, hickories, and pecans) results in false positives. In addition, many common medicines, such as those containing guaifenesin, acetaminophen, salicylates, and L-dopa, alter 5-HIAA levels.

With a sensitivity of 73% and a specificity of 100% for carcinoid tumors, 5-HIAA measurement of levels greater than 30 mg/day is the primary biochemical determinant for carcinoid syndrome. Sensitivity, in this case, refers to the positive detection of carcinoid tumors, while specificity refers to the accuracy when a detection is made. However, the 5-HIAA marker primarily becomes elevated only upon increases in serotonin levels from liver metastases when the potential for cure is unrealistic (2). A positive correlation between tumor mass and urinary 5-HIAA levels allows for use of 5-HIAA to estimate extent of disease, as a urinary 5-HIAA level greater than 150 mg/day predicts a very poor prognosis (2, 14). The normal range for 5-HIAA is approximately 3 to 15 mg/24 hours.

How the 5-HIAA Test Works

Serotonin synthesized by carcinoid tumors is secreted into the circulation, taken up by platelets, and stored in granules. Most of the serotonin remaining in plasma is converted to 5-HIAA, which is excreted into the urine. The testing then proceeds as follows:

• Dietary and medicinal intake controlled
• 24-hour urine test
• Assessment of 5-HIAA by high-performance liquid chromatography with electrochemical detection
• Total serotonin production is analyzed

What to Expect

5-HIAA testing has a sensitivity of 73% and a specificity of 100% for carcinoid tumors (2).

When to Test

5-HIAA tests should be performed every 3 to 6 months (13).

Somatostatin Receptor Scintigraphy (SRS) Testing

Clinical experience has established SRS as one of the imaging techniques of choice for carcinoid tumors (15). High-affinity somatostatin receptors, including somatostatin receptor subtype 2 (sst-2) are found on 88% to 100% of carcinoid tumors. These receptors are found on both the primary tumor and the metastases (2). Because the somatostatin analogue octreotide binds with high specificity to sst — (2, 16) radiolabeled octreotide probes for initial whole body imaging have been useful (2, 17, 18). SRS will not detect the ~10% of tumors that fail to express somatostatin receptors (15). Additionally, the detection limit is about 0.5 cm. The advantage of SRS over conventional computed tomography or magnetic resonance imaging - which are localized to the suspected disease sites — is the ability to image all body regions with high sensitivity and selectivity, allowing evaluation of tumors for potential octreotide palliation therapy (9, 17). An additional advantage is that SRS testing allows for estimation on somatostatin receptor density (18).

In addition to imaging somatostatin-rich tumors, the normal pituitary gland, thyroid gland, liver, spleen, urinary bladder, and bowels may also be visualized (19).

SRS Whole-Body Scan (OctreoScan®*)

How SRS Testing Works

• Intravenous administration
• Planar images taken 4 hours postinjection (40-minute duration)
• Planar and single photon emission computed tomography images obtained 24 hours postinjection (2-hour duration)
• Additional images may be needed 48 hours postinjection