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How is a carcinoid tumor diagnosed?
Carcinoid tumors, like many neuroendocrine tumors, can be very difficult to diagnose. It is common for individuals with carcinoid cancer to remain asymptomatic until the tumors have metastasized or grow large enough to affect normal bodily functions. After an individual develops symptoms, diagnosis can be problematic since the symptoms of carcinoid cancer can mimic other diseases.
If your physician suspects you have a carcinoid tumor, there are specific biochemical tests which measure tumor markers and imaging tests that can help confirm a diagnosis and potentially determine the tumor type, location, load and prognosis. A tissue biopsy of a suspected tumor is, in most cases, the only definitive test.
If you have already been diagnosed with carcinoid cancer, biochemical and imaging tests are very important tools for disease staging and clinical management.
Neuroendocrine tumors, such as carcinoid, produce a variety of substances which include hormones, proteins, and biogenic amines. Some tumors are termed functional since they are able to secrete an active form of these substances, which can cause a specific clinical syndrome such as Carcinoid Syndrome, Zollinger-Ellison Syndrome, and Cushing’s Syndrome. However most carcinoid tumors are non-functioning and are not associated with a characteristic clinical syndrome either because the substances secreted are biologically inactive or because they do not cause any specific symptoms.
The substances secreted by a carcinoid tumor can be measured by biochemical tumor markers. Biochemical tumor markers can be divided into two categories: those which are specific to a particular carcinoid tumor location and those which are general. The most common tumor markers are:
Chromogranin A (CgA): Chromogranin A is a secretory protein that is common to most neuroendocrine tumor cells, including carcinoid, and is a general tumor marker for neuroendocrine tumors. Since it is secreted into the blood stream it can be measured by a simple blood test. Blood plasma levels of CgA have been shown to relate to prognosis. (Janson, Holmberg, Stridsberg, Eriksson, Theodorsson, Wilander, & Oberg, 1997; Kulke, 2007a). In patients treated with somatostatin analogs CgA should be used with caution as somatostatin analogs can affect CgA levels (Oberg, Kvols, Caplin, Delle Fave, de Herder, Rindi, Rusniewski, Woltering, & Wiedenmann 2004). It has been recommended that CgA readings be taken at consistent time periods from somatostatin analog treatment (Vinik, Woltering, Warner, Caplin, O’Dorisio, Wiseman, Coppola, Go, 2010).
5-hydroxyindoleacetic acid (5-HIAA): 5-HIAA is a metabolite (a product from the breakdown) of serotonin. Serotonin is one of the most commonly secreted hormones by carcinoid tumors of the midgut and sometimes those of the foregut (Vinik, Silva, Woltering, Go, Warner, & Caplin, 2009). Consequently, 5-HIAA is usually elevated in midgut carcinoids but not in any others (Kulke, 2007a). A 24-hour urine collection is used to measure 5-HIAA levels. While 5-HIAA levels are commonly used to monitor patients with metastatic carcinoid tumors, studies have documented metastatic carcinoid tumors without elevated 5-HIAA levels (Feldman & O’Dorisio, 1986). 5-HIAA can also be elevated in patients with celiac, Whipple’s disease, and afterwards in those eating tryptophan-rich foods (Kulke, 2007a).
Certain foods such as bananas, walnuts, avocados and caffeine can also have an effect on 5-HIAA levels. Be sure to speak with your physician for a complete list before testing. More specifics can be found in the Inter Science Institute’s (ISI) handbook, Neuroendocrine Tumors: A Comprehensive Guide to Diagnosis and Management. Click here (http://www.interscienceinstitute.com/docs/Neuroendocrine-Tumors-4th-Edition.pdf to access the handbook.
All neuroendocrine tumors, including carcinoid tumors, secrete hormones. However, what they secrete depends upon the type of tumor and the tumor location. Secretions of neuroendocrine tumors can sometimes change over time and so your physician may recommend evaluating a panel of markers over time. Generally speaking, all markers should be evaluated at a fasting state and at a consistent interval from long acting somatostatin analog treatment (Vinik et al., 2010). The following sections are divided by tumor location and the secreted substances associated with them.
Vasoactive intestinal peptide (VIP)
Insulin, proinsulin, C peptide
pancreatic polypeptide (PP), CgA, neurotensin
Small Intestine (Ileum)
Colon and Rectum
PP, enteroglucagon, acid phosphatase (ACP), Human chorionic gonadotrophin (hCG-b)
All neuroendocrine tumors
various (see above)
(Sundin, Garske, & Orlefors, 2007; Akerstrom, Hellman, & Osmak, 2005; Jensen et al, 2008)
Along with biochemical testing, there are several imaging techniques which are useful to help determine a carcinoid tumor’s location, size, and extent of metastases. The imagining technique used and the combination thereof depend upon the primary tumor type, location, presence or absence of hormonal symptoms (functioning vs. non-functioning), and extent of the disease (Sundin et al., 2007). Imaging is especially important when liver metastases are suspected because liver function tests can be an unreliable predictor of liver metastases (Kulke, 2007a, Kulke, 2007b).
Computed Tomography (CT) and Magnetic Resonance Imaging (MRI):
Computed Tomography (CT) is an imaging technique that uses a highly specialized X-Ray machine and computers to create multiple cross sectional images of the body. CT can generate images of different body tissues as well as help detect tumors.
Magnetic Resonance Imaging (MRI) uses radio waves, a powerful magnetic field and a computer to generate detailed (2 or 3 dimensional) images of the body. These images are very useful in contrasting different types of tissue as well as detecting abnormal growths such as tumors within the body. MRI can create better images than CT, but is less commonly used.
CT/MRI are useful imaging techniques when used to visualize foregut carcinoids (those of the lungs, thymus, stomach and pancreas), to define the extent of metastasis (particularly liver and lymph-node metastasis), and to image secondary effects of midgut and hindgut carcinoids (such as scaring of the intestinal wall caused by tumor growth) (Dromain, de Baere, Caillet, Laplanche, Boige, Ducreux, Duvillard, Elias, Schlumberger, Sigal, & Baudin, 2005). CT/MRI can be used to detect midgut carcinoids although the detection of midgut carcinoids is often difficult due to the environment of the intestine and tumor size (Rockall & Rodney, 2007; Kulke, 2007a).
Somatostatin Receptor Scintigraphy (SRS) is a type of radionuclide scan that uses the radionuclide (radioactive substance) Octreotide (111-In-DTPA-octreotide) and a highly specialized machine to detect carcinoid tumors. When octreotide is injected into a patient’s vein, it can travel through the bloodstream and bind to carcinoid tumors.
Octreotide is a synthetic (man-made), radio-labeled analogue of the naturally occurring hormone somatostatin. Over 90% of all carcinoid tumor cells have receptors for somatostatin (Kvols, Brown, O’Connor, Hung, Hayostek, Reubi, & Lamberts, 1993; Reubi & Waser, 2003). Octreotide, like somatostatin, is able to bind to two of the five receptors (receptors two and five) on carcinoid tumors (Oberg, Reubi, Kwekkeboom, & Krenning, 2010).
SRS is used to find the tumors which bind octreotide. If the octreotide binds to the tumors, doctors can visualize them through the use of an imaging machine. Scans can be done at different intervals following an octreotide injection: 4 hours, 24 hours and 48 hours (Mamikunian, Vinik, O’Dorisio, Woltering, & Go, 2009). However a scan at 24 hours after octreotide injection is preferred (Sundin, et al., 2007). An octreotide scan is able to detect carcinoid tumors that bind octreotide and are larger than 1 - 1 1/2cm (Dromain et al., 2007).
Patients who are being treated with a somatostatin analogue such as Sandostatin or Lanreotide are strongly encouraged to temporarily discontinue treatment before undergoing SRS because somatostatin analogues used for treatment and for the scan compete for the same receptors (Sundin, et al., 2007). Patients should speak with their physicians to determine when and for how long they should discontinue treatment to maximize SRS.
SRS is not only useful in imaging carcinoid tumors but is also commonly used to predict response to somatostatin analogue therapy as well as peptide receptor radionuclide therapy (PRRT) (Reidy, Tang, & Saltz, 2009; Modlin, Oberg, Chung, Jensen, de Herder, Thakker, Caplin, Delle Fave, Kaltsas, Krenning, Moss, Nilsson, Rindi, Salazar, Rusziniewsku, & Sundin, 2008).
Positron Emission Tomography (PET):
Positron Emission Tomography (PET) is another form of radionuclide scan that uses a radioactive material and a special scanning device to detect cancerous tumors. Most commonly, the radionuclide 18F-labelled deoxy-glucose (FDG) is used to detect many forms of cancer. However FDG is not effective in detecting most carcinoid tumors with the exception of tumors with high proliferative activity and low differentiation (Adams, Baum, Rink, Schumm-Drager, Usadel, & Hor, 1998). I Instead, 68Ga-DOTA-TOC is the radionuclide that is most commonly used with PET to detect carcinoid (Sundin, et al., 2007).
PET with 68Ga-DOTA-TOC works in a similar fashion to octreotide in that like octreotide, 68Ga-DOTA-TOC is able to bind to specific receptors on carcinoid tumors. Once bound, the tumors can be visualized with a PET scan. However, 68Ga can be accumulated much faster by carcinoid tumors and so the scan for the tumors can be done approximately one hour after the 68Ga has been administered (Sundin, et al., 2007). There is evidence that like SRS, 68Ga can be used to predict response to PRRT (Haug, Auernhammer, Wangler, Schmidt, Uebleis, Goke, Cumming, Bartenstein, Tiling, & Hacker, 2010). 68Ga-DOTA-TOC has been effective in detecting carcinoid tumors that are greater in size than 0.5 cm.
Other radionuclides that are used with PET are: 11C-labelled L-dihydroxyphenylalanine, 18F L-dihydroxyphenylalanine, and 5-Hydroxly-L-tryptophan.
Endoscopy is a medical procedure that uses an endoscope to view the lining of multiple organs and tracts of the body. An endoscope is a flexible or rigid tube that has imaging capabilities and can enable small surgical procedures. Endoscopy can be used to visualize carcinoid tumors in the lungs and gastrointestinal tract (stomach, small and large intestine and rectum).
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