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 non-life-threatening conditions such as irritable bowel syndrome1.
This section will cover both detection and testing methods for carcinoid syndrome, including:
- Initial Diagnosis
- Diagnostic 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, severe diarrhea, and other symptoms of carcinoid syndrome trigger recognition of this condition1
- In some cases, intestinal symptoms caused by primary tumors (eg, abdominal pain or intestinal bleeding) are the presenting complaint2
- In other cases, tumors are found incidentally during unrelated surgical procedures, such as an appendectomy2
Initial Diagnosis
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-HIAA2
- 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%3,4
- 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 somatostatin5
- A number of imaging modalities contribute to tumor localization3:
- Imaging studies such as computed tomography (CT) scan, magnetic resonance imaging (MRI), ultrasound, and GI endoscopy
*OctreoScan is a trademark of Covidien AG or one of its affiliates.
Biochemical Testing
The most common biochemical test used to help diagnose carcinoid disease is 5-hydroxyindoleacetic acid (5-HIAA).
Urinary 5-HIAA
Urinary 5-HIAA—the primary biochemical marker for midgut carcinoid tumors and, less often, foregut tumors—is the metabolite of serotonin that is broken down by the liver and excreted via the kidneys2.
An elevated 5-HIAA level is often associated with a classic carcinoid syndrome of flushing and severe diarrhea. 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. Elevated levels of urinary 5-HIAA generally occur at advanced stages of disease and indicate the presence of liver metastases5. Urinary 5-HIAA is a useful biochemical marker that is widely available; however, false positive results are still possible.
†Tylenol is a registered trademark of McNeil Consumer Products Company.
How the 5-HIAA Test Works3,6:
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.
5-HIAA testing then proceeds as follows7
1. Dietary and medicinal intake controlled
2. Assessment of 5-HIAA by high-performance liquid chromatography with electrochemical detection
3. Total serotonin production analysis
What to Expect:
5-HIAA testing has a sensitivity of 73% and a specificity of 100% for carcinoid tumors2.
When to Test:
5-HIAA tests should be performed every 3 to 6 months5.
| Advantages5,8,9 | Disadvantage5,9 |
|---|---|
| Specific to carcinoid tumors | Medicinal and dietary restrictions required |
| Levels are not elevated with other types of tumors | |
| Useful in estimating extent of disease and survival |
Pathology
The Ki-67 protein (also known as antigen identified by monoclonal antibody Ki-67 or MKI67) is a cellular marker for proliferation. This proliferation index can be used to determine the rate of tumor cell growth fraction. A high Ki-67 index, coupled with a high mitotic count, may call for more aggressive treatment alternatives like chemotherapy and interferon-∝ in most cases10.
Diagnostic Imaging
Diagnostic imaging plays a key role in diagnosing and monitoring NETs. There are multiple imaging techniques available to diagnose, stage, and monitor the progression of NETs16:
- OctreoScan®11
- Spect/CT Hybrid Imaging in SRS With Triple Phase CT Scanning12
- MIBG13
- CT/MRI14
- Endoscopic Ultrasound8
- Capsule Endoscopy or Camera Pill8
Less commonly used imaging techniques:
An OctreoScan® of a patient with liver metastasis from a carcinoid tumor is shown below. The primary tumor located in the distal ileum also is present in the figure.
Ultrasonography of liver metastases from a patient with carcinoid tumor. Ultrasound-guided biopsy can be taken during this procedure. CT picture of liver metastases in a patient with an endocrine pancreatic tumor.
Somatostatin Receptor Scintigraphy (SRS) Testing Using OctreoScan®
Clinical experience has established SRS as one of the imaging techniques of choice for carcinoid tumors3,14,16. 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 metastases4,17,18. Because the somatostatin analogue octreotide binds with high specificity to sst-2 and sst-5 receptors4, radiolabeled octreotide probes for initial whole body imaging have been useful2,16. SRS will not detect the ~10% of tumors that fail to express somatostatin receptors19. 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 therapy14,20. An additional advantage is that SRS testing allows for estimation on somatostatin receptor density21.
In addition to imaging somatostatin-rich tumors, the normal pituitary gland, thyroid gland, liver, spleen, urinary bladder, and bowels may also be visualized22.
How SRS Testing Works16:
- Intravenous administration
- Planar images taken 4 hours postinjection
- Planar and single photon emission computed tomography images obtained 24 hours postinjection
- Additional images may be needed 48 hours postinjection
| Advantages2,23 | Disadvantage19,23 | |||
|---|---|---|---|---|
| Highly accurate in indicating neuroendocrine tumors with receptors present | Will not detect tumors that fail to express somatostatin receptors (10% of tumors) or are small | |||
| Images all body systems | ||||
INDICATIONS AND USAGE
Sandostatin® LAR Depot (octreotide acetate for injectable suspension) is indicated for patients in whom initial treatment with immediate release Sandostatin® (octreotide acetate) Injection has been shown to be effective and tolerated for:
- Long-term maintenance therapy in acromegalic patients who have had inadequate response to surgery and/or radiotherapy or for whom surgery and/or radiotherapy is not an option (the goal of treatment in acromegaly is to reduce GH and IGF-1 levels to normal).
- Long-term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors.
- Long-term treatment of the profuse watery diarrhea associated with VIP-secreting tumors.
In patients with carcinoid syndrome and VIPomas, the effect of Sandostatin Injection and Sandostatin LAR Depot on tumor size, rate of growth and development of metastases has not been determined.
IMPORTANT SAFETY INFORMATION
Warnings and Precautions:
- Gallbladder abnormalities may occur: Patients should be monitored periodically.
- Glucose Metabolism: Hypoglycemia or hyperglycemia may occur. Blood glucose levels should be monitored when Sandostatin LAR Depot treatment is initiated or when the dose is altered. Antidiabetic treatment should be adjusted accordingly.
- Thyroid Function: Hypothyroidism may occur. Baseline and periodic assessment of thyroid function (TSH, total and/or free T4) is recommended.
- Cardiac Function: Bradycardia, arrhythmia, conduction abnormalities, and other EKG changes may occur. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease. Use with caution in at-risk patients.
- Nutrition: Octreotide may alter absorption of dietary fats. Monitoring of vitamin B12 levels is recommended during therapy with Sandostatin LAR Depot. Patients on total parenteral nutrition (TPN) and octreotide should have periodic monitoring of zinc levels.
Drug Interactions: The following drugs require monitoring and possible dose adjustment when used with Sandostatin LAR Depot: cyclosporine, insulin, oral hypoglycemic agents, beta-blockers, bromocriptine. Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Drugs mainly metabolized by CYP3A4 and which have a low therapeutic index should be used with caution.
Adverse Reactions: The most common adverse reactions occurring in patients receiving Sandostatin LAR Depot are:
- Acromegaly: biliary abnormalities (52%), diarrhea (36-48%), cholelithiasis (13-38%), abdominal pain or discomfort (11-29%), flatulence (26%), influenza-like symptoms (20%), constipation (19%), headache (15%), anemia (15%), hyperglycemia (15%), injection site pain (2-14%), hypertension (13%), dizziness (12%), fatigue (11%), nausea (10%), vomiting (7%), hypothyroidism (2%), hypoglycemia (2%), and goiter (2%).
- Carcinoid Tumors and VIPomas: biliary abnormalities (62%), injection site pain (20-50%), nausea (24-41%), abdominal pain (10-35%), fatigue (8-32%), headache (16-30%), hyperglycemia (27%), back pain (8-27%), constipation or vomiting (15-21%), dizziness (18-20%), sinus bradycardia (19%), pruritus (18%), URTI (10-18%), myalgia (4-18%), flatulence (9-16%), arthropathy (8-15%), rash (15%), generalized pain (4-15%), sinusitis (5-12%), conduction abnormalities (9%), hypoglycemia (4%), and arrhythmia (3%).
