Malignant Carcinoid Syndrome Workup

Updated: Mar 02, 2017
  • Author: Luigi Santacroce, MD; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Workup

Laboratory Studies

Hormones in blood and urine are measured to monitor the growth, activity, and eventual recurrence of the primary tumor. The biochemical diagnosis of carcinoid tumors is based on the measurement of the serotonin metabolite 5-HIAA in a 24-hour urine collection (normal value [NV] = 0-8.9 mg/d; plasma serotonin NV is 0.04–0.2 mg/mL).

Consumption of foods that contain serotonin can complicate the biochemical diagnosis of malignant carcinoid syndrome; in fact, the following foods contain an amount of serotonin that can produce abnormally elevated excretion of urinary 5-HIAA after ingestion:

  • Spinach
  • Eggplant
  • Cheese (eg, parmesan, Roquefort)
  • Wine (chianti, burgundy)
  • Caffeine
  • Tomatoes
  • Kiwi fruit
  • Bananas
  • Walnuts
  • Pineapples
  • Red plums
  • Avocados

The following drugs may have the same effects:

  • Isoniazid
  • Phenothiazine
  • Phenacetin
  • Monoamine oxidase inhibitors
  • Acetaminophen
  • Fluorouracil
  • Iodine solutions

If dietary (or pharmaceutical) 5-hydroxyindoles are excluded, a urinary excretion of 5-HIAA of 25 mg/d is diagnostic of carcinoid. If the range value is 9-25 mg/d, the differential diagnosis includes carcinoid syndrome, nontropical sprue, or acute intestinal obstruction.

The measurement of other bioactive amines (eg, serotonin, catecholamines, histamine, histamine metabolites [25] ) in the platelets, plasma, and urine of patients with carcinoid tumors is of interest but has less diagnostic value than an assay of the major metabolite of serotonin in the urine.

Some authors have used high-performance liquid chromatography and gas chromatography mass spectrometry to characterize carcinoids. According to these authors, the platelet serotonin level seems to have a higher sensitivity for detection of carcinoid tumors and is more consistently elevated than urinary 5-HIAA, especially with tumors characterized by a low rate of serotonin production. However, in patients with a high rate of serotonin secretion, the platelet serotonin level reaches a maximum, whereas urinary 5-HIAA does not, indicating that the platelet compartment is saturable. Differing from urinary 5-HIAA, platelet serotonin is not influenced by the consumption of a serotonin-rich diet; therefore, the measurement of platelet serotonin should be preferred for making the primary diagnosis.

Platelet serotonin levels are also monitored during different treatments to evaluate the effect of therapy. According to one study, chromogranin A measurement with a cutoff range of 84 to 87 U/L yields a specificity of 95% and a sensitivity of 55% for the diagnosis of endocrine tumors. These authors recommended the high cutoff range in order to exclude patients in whom the chromogranin A level was elevated as a result of other non-neoplastic diseases. [26]

Recommended follow-up studies vary according to the location of the carcinoid tumor, as follows:

  • Hindgut carcinoids - Chromogranin A, alpha human chorionic gonadotropin (α-HCG), beta human chorioinic gonadotropin (β-HCG), and polypeptides are essential assays
  • Lung carcinoids - Gastrin, adrenocorticotropic hormone (ACTH), growth hormone (GH), α-HCG, and β-HCG are helpful
  • Midgut carcinoids - Levels of urinary 5-HIAA, chromogranin A, and tachykinins are useful

Apart from measuring daily urinary 5-HIAA secretion, determining the presence of other bioactive amines enables more sensitive detection and also may indicate specific measures in particular patients.

Platelet aggregation testing may show increased aggregation with certain agonists. This test helps to diagnose platelet dysfunction and to distinguish between inherited and acquired bleeding problems (eg, DIC occurring in some patients with malignant carcinoid syndrome). Platelet aggregation normally occurs within 3-5 minutes.

Total protein levels in blood are often low because of malabsorption. Tryptophan levels may be low for the same reason, but also because of conversion to serotonin by the tumor.

N-terminal pro-brain natriuretic peptide (NT-pro-BNP) may serve as a biomarker for the detection of carcinoid heart disease. One study found that at a cut-off level of 260 pg/ml, NT-pro-BNP has a sensitivity of 92% and a specificity of 91% for detection of carcinoid heart disease. [27]

Routine allergy test results are not usually positive in cases that simulate an anaphylactic attack.

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Imaging Studies

Modalities that have been evaluated for the diagnosis of carcinoids include the following:

  • Barium examinations
  • Iodine-131 metaiodobenzylguanidine (MIBG) scanning [28]
  • Octreotide scanning
  • Computed tomography (CT)
  • Angiography
  • Venous blood sampling with radioimmunoassay of tumor products
  • Echocardiography [29]
  • Magnetic resonance imaging (MRI) [30]

For imaging studies, current National Comprehensive Cancer Network (NCCN) guidlines recommend multiphasic CT or MRI for the evaluation of carcinoid tumors, as follows [31] :

  • Gastrointestinal tumors: Abdominal/pelvic multiphasic CT or MRI
  • Bronchopulmonary tumors: Chest CT and abdominal multiphasic CT or MRI
  • Thymus tumors: Chest/mediastinal multiphasic CT and abdominal multiphasic CT or MRI

The NCCN recommends additional studies (eg, somatostatin scintigraphy) as appropriate.

Scintigraphy

Scintigraphy with indium-111 diethylenetriamine pentaacetic acid (DTPA) octreotide (In-111 DTPA Octr), or OctreoScan, localizes the primary carcinoid and eventual recurrences, as well as other neuroendocrine tumors, with high sensitivity and specificity. The 3-day half-life of this radionuclide allows for a scan after 24, 48, and 72 hours.

This diagnostic tool also has obviated many of the problems of differential diagnosis with other neuroendocrine tumors that are frequent, using iodine-131 MIBG or iodine-123 tyrosine 3 octreotide scanning.

False-negative results are possible in 2% of cases (the mean percentage of carcinoids without receptors).

A positive test result usually predicts a good patient response to treatment with octreotide.

When administering a radioactive somatostatin analogue (In-111 DTPA-D-Phe1 octreotide), some authors have attempted to provide internal radiation therapy, hoping to kill the tumor cells, but adverse effects limit the clinical application of this therapy.

Radiography

Barium examination is rarely diagnostic but may show a benign-appearing submucosal lesion or a large bulky ulcerating mass with bowel deformity.

A smooth polyp observed in the terminal ileum should always be considered a probable carcinoid tumor.

The importance of angiography for carcinoid diagnosis has been decreased by the availability of more recent imaging methods.

Computed tomography

CT scanning may be used to find the primary tumor or to check for any disease spread. Primary carcinoids of the bowel are usually not observed on CT scanning; otherwise, this study allows the assessment of the extent of tumor spread to the mesentery and bowel wall and metastases to the lymph nodes and liver.

CT scanning typically shows a homogeneous, ill-defined mesenteric mass with calcifications. A stellate or curvilinear fibrosis radiating from the mass, representing thickened neurovascular bundles and distorting surrounding bowel loops, is usually observed.

Positron emission tomography (PET) scanning

Considerations regarding PET scanning are as follows:

  • Experience with PET scanning to detect carcinoids is very limited
  • Either tryptophan or its metabolite 5-hydroxytryptophan (5-HTP) has been used as a tracer substance
  • PET scanning seems to be capable of identifying carcinoid metastases to various sites, and it may be valuable in the follow-up care of treated patients
  • According to initial reports, only C11-5-HTP is taken up by serotonin-producing tumors

Ultrasonography

Ultrasonographic examination of the abdomen is usually not the first diagnostic method; instead, it is used to further confirm the diagnosis and establish the site and extent of the disease.

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Other Tests

Several provocation tests have been developed for carcinoid syndrome. Intravenous infusion of pentagastrin appears to provoke flushing and other symptoms more reliably than the traditional test, which uses alcohol (10 mL PO), calcium (10 mg/kg of calcium gluconate in 4 h), or catecholamines (norepinephrine 1-20 mcg). These tests must be performed with caution because they can trigger crises.

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Procedures

A percutaneous or laparotomy biopsy may be performed, when possible, after the primary tumor and its eventual metastases are detected. Fine-needle biopsy of hepatic lesions can precipitate carcinoid crisis in a patient with carcinoid liver metastasis, however, so personnel performing these procedures should be prepared for this possibility. [32]

Diagnostic and operative endoscopy of the lower and upper GI tract may be helpful for diagnosis. [33]

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Histologic Findings

In 1963, Williams and Sandler began to classify the carcinoid tumors anatomically and clinically according to embryologic origin from the foregut, midgut, or hindgut. Grossly, these tumors appear as submucosal or intramural masses (see images below), and they are usually single but may be multiple. After fixation, the tumor mass appears yellow or brownish, small, and firm. The intestinal mucosa over the tumor is often intact. Submucosal infiltration, often extending beyond the muscularis propria, is the rule.

A section (on the right) of an intestinal carcinoi A section (on the right) of an intestinal carcinoid mass arising from the mucosa (150 X). Image courtesy of Professor Pantaleo Bufo, University of Foggia, Italy.
A section of a carcinoid mass (350 X). Image court A section of a carcinoid mass (350 X). Image courtesy of Professor Pantaleo Bufo, University of Foggia, Italy.

Histologically, the tumor consists of uniform small cells arranged as islands separated by a fibrous stroma. Cells show a scant pink cytoplasm that is finely granulated and stippled with small round nuclei and small nucleoli. Several patterns can be observed in carcinoid tumors (ie, trabecular and tubular arrangements may be present and include intraluminal mucin). All carcinoids react positively with antichromogranin A antibodies and usually Masson staining, which indicates serotonin production and is positive in midgut primary tumors. Two main histologic features are described by observing with 10X high-power fields, as follows:

  • Typical, showing fewer than 2 mitoses per 2 mm 2 of viable tumor and lacking necrosis
  • Atypical, showing 2-10 mitoses per 2 mm 2 with or without foci of necrosis
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Staging

No internationally accepted staging system exists for carcinoid tumors.

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