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Carcinoid Biochemical Monitoring

Once carcinoid syndrome has been diagnosed and the likelihood of its progression has been established, a variety of treatment options are available, including surgical and medical therapies.

Regardless of which therapeutic approach is employed, regular biochemical monitoring is important for purposes of assessing disease progression and evaluating treatment effectiveness. Two frequently monitored markers are Chromogranin A (CgA) and urinary 5-hydroxyindoleacetic acid (5-HIAA). Although other markers can be used as well (Tables 1 and 2), these two markers will be the focus of this section.

Plasma Chromogranin A

CgA is ubiquitous in endocrine tissues, and the measurement of CgA is considered the "gold standard" of biochemical tests for confirming the diagnosis of carcinoid and neuroendocrine tumors and following their course.1 There is a clear correlation between tumor burden and serum CgA concentrations. High levels of CgA in carcinoid patients are indicative of high tumor burden (Figure 1).2

Plasma chromogranin A

The predictive value of CgA levels

The highest levels of serum CgA (up to 1000 times the upper limit of the normal range) have been found in patients with metastatic carcinoid tumors. In patients with midgut carcinoid tumors, an elevated CgA level is an independent predictor of death.2 The survival at 5 years in patients with high CgA is 22%, while it is 63% in patients with low CgA.1 As such, CgA measurements have become the most important parameter for monitoring disease spread and are used to follow results of treatment.

Specimen collection

CgA is a stable molecule and no special precaution is needed to handle or store the serum or plasma. Most assays are sensitive enough to measure CgA in normal patients. Elevations can be seen in conditions other than neuroendocrine tumors, such as renal or hepatic failure, and only slight elevations may be seen in inflammatory conditions of the bowel, such as ulcerative colitis and Crohn's disease.

Urinary 5-HIAA

5-HIAA is the metabolite of serotonin that is broken down by the liver and excreted via the kidneys (Figure 2). It is the primary biochemical marker for midgut carcinoid tumors and, less often, foregut tumors. An elevated 5-HIAA level is associated with a classic carcinoid syndrome of flushing, diarrhea, and carcinoid heart disease. The 24-hour urinary 5-HIAA as a measure of the biochemical activity of these tumors is preferred over plasma serotonin, which is highly variable over a 24-hour period.3

Figure 2. Measurement of urinary 5-HIAA.

Measurement of urinary 5-HIAA

The predictive value of 5-HIAA

Elevated levels of urinary 5-HIAA generally occur at advanced stages of the disease and generally indicate presence of liver metastases.4 Patients with elevated urinary 5-HIAA have been associated with shorter survival than those with normal levels.4 The severity of elevation of urinary 5-HIAA also correlates with the severity of carcinoid syndrome, and the highest levels of the metabolites are observed in patients with heart failure.5

Specimen collection

Urinary 5-HIAA is a useful biochemical marker that is widely available, with a specificity of approximately 88%. Certain serotonin-rich foods (bananas, avocados, plums, eggplant, tomatoes, plantain, pineapples, and walnuts) can increase urinary 5-HIAA levels and should be avoided during specimen collection.3

Table 1. Utilizing Markers to Optimize Biochemical Control6

Markers useful for:

Tumor Diagnosis

Syndrome Diagnosis

Progression Evaluation

Prognosis

CgA

X

 

X

X

5-HIAA

X

X

X

X

Substance P (tachykinin)

X

X

X

X

Histamines, urine

X

X

 

 

CHD

 

 

 

X

Table 2. Selected Biological Markers Information6

Test

5-Hydroxyindoleacetic acid (5-HIAA), 24-hour urine assay

Chromogranin A

Histamine

Substance P

Special notes

Collect 24-hour urine. Refrigerate during collection. Record 24-hour volume and collection dates (start and end) on requisition. Twenty-four hour collections are generally recommended, but random collections may be used.

Serum or plasma should be separated from cells and transferred to plastic transport tube. CgA can be elevated in patients with severe renal failure.

Collect 24-hour urine. Refrigerate during collection.

Separate plasma from cells as soon as possible and freeze immediately after separation.

Container

Plastic urine container. May collect in 25 to 30 mL 6N HCl or 1 g/L boric acid as preservative if urine is needed for other tests.

Red-stopper tube or serum gel separator, lavender-stopper EDTA plasma tube, green-stopper heparinized plasma tube.

Plastic urine container.

7 mL lavender (EDTA) or pink (K2EDTA) stopper plasma tube.

Transport

Send a 20-to 30-mL refrigerated aliquot of well-mixed 24-hour urine.

Store specimens refrigerated at 2°C to 8°C (if assayed within a week) or freeze at –20°C for up to 6 months. Send refrigerated or frozen specimens.

Send a 4.5 mL aliquot of well-mixed 24-hour urine or well-mixed random urine, frozen.

Send two 1-mL frozen samples.

Instruction to patients

Patients should avoid the following foods: bananas, walnuts, plantains, hickory nuts, pineapple, pecans, kiwi fruit, avocado, plums, tomatoes, eggplant. ALL of the above contain 5-hydroxytryptamine (serotonin). Patients should abstain, if possible, from medications, over-the-counter drugs, and herbal remedies for at least 72 hours prior to the test.

Patients should be fasting before sample collection.

NA

NA

Methodology

High performance liquid chromatography

Enzyme immunoassay (EIA)

Enzyme immunoassay (EIA) Radioimmunoassay (RIA)

Enzyme immunoassay (EIA) Radioimmunoassay (RIA)

Reference interval

Reference values differ from lab to lab, so use the same lab for accurate predictability. 0-8 mg/day (LabCorp), 0-15 mg/day (ARUP)

Reference values differ from lab to lab, so use the same lab for accurate predictability.0-5 nmol/L (LabCorp) 0-76 mcg/L men; 0-51 mcg/L women (ARUP)

Reference values differ from lab to lab, so use the same lab for accurate predictability. 0-386 nmol/g CRT

Reference values differ from lab to lab, so use the same lab for accurate predictability.

Lab Contact Information
Additional information can be obtained by contacting:

You can also contact the customer service number for the laboratory your office currently uses. Reference values may differ from lab to lab, so it is important to remain consistent by using the same lab for accurate predictability.

References:

  1. Ardill JES, Erikkson B. The importance of the measurement of circulating markers in patients with neuroendocrine tumours of the pancreas and gut. Endocrine-Related Cancer. 2003;10:459-462.
  2. Oberg K, Kvols L, Caplin M, et al. Consensus report on the use of somastatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Annals of Oncology. 2004;15:966-973.
  3. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Current status of gastrointestinal carcinoids. Gastroenterology. 2005;128:1717-1751.
  4. Jensen RT, Doherty GM. Carcinoid tumors and the carcinoid syndrome. Pathology and Tumor Histology. In: Devita VT Jr., Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa.; Lippincott Williams & Wilkins, 2005: 1559-74.
  5. Zutenborst JM, Taal BG. Metastatic carcinoid tumors: a clinical review. Oncologist. 2005;10:123-131.
  6. Data on File. Novartis Pharmaceuticals, 2007.