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Caring for Carcinoid Foundation

Diagnosis

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.

Biochemical Testing

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.

 

Primary Site

Secreted Peptide/Marker

Symptoms

 Thymus

 ACTH

 Cushing’s Syndrome

 Bronchus

 ACTH

 Cushing’s Syndrome

 5-HIAA

 Carcinoid Syndrome

 Stomach

 Gastrin

 Zollinger-Ellison Syndrome

 Pancreas & Duodenum

-

 Obstructive symptoms

 5-HIAA

 Carcinoid Syndrome

 Gastrin

 Zollinger-Ellison Syndrome

 Vasoactive intestinal peptide (VIP)

 Verner-Morrison Syndrome

 Insulin, proinsulin, C peptide

 Insulinoma

 glucagon

 Glucagonoma Syndrome

 pancreatic polypeptide (PP), CgA, neurotensin

 no symptoms

 Small Intestine (Ileum)

 5-HIAA

 Carcinoid Syndrome

 Appendix

 5-HIAA

 Carcinoid Syndrome

 Colon and Rectum

 PP, enteroglucagon, acid phosphatase (ACP), Human chorionic gonadotrophin (hCG-b)

 no symptoms

 All neuroendocrine tumors

 various (see above)

 CgA

(Sundin, Garske, & Orlefors, 2007; Akerstrom, Hellman, & Osmak, 2005; Jensen et al, 2008)

Imaging

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) or Octreotide Scan: 

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

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).

References

Adams, S., Baum, R., Rink, T., Schumm-Drager, P., Usadel, K., and Hor, G. (1998). Limited value of fluorine-18 fluorodeoxkyglucose positron emission tomography for the imaging of neuroendocrine tumours. European Journal of Nuclear Medicine, 25(1), 79-83. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/9396878.

Akerstrom, G., Hellman, P., Hessman, O., and Osmak, L. (2005). Management of midgut carcinoids. Journal of Surgical Oncology, 1(89), 161-169. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/15719373.

Dromain, C., de Baere, T., Caillet, H. Laplanche, A., Boige, V., Ducreux, M., Duvillard, P., Elias, D., Schlumberger, M. Sigal, R., Baudin, E. (2005). Detection of liver metastases from endocrine tumors: a prospective comparison of somatostatin receptor scintigraphy, computed tomography, and magnetic resonance imaging. Journal of Clinical Oncology, 23(1), 70-78. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/15625361.

Feldman, J., O’Dorisio, T. (1986). Role of neuropeptides and serotonin in the diagnosis of carcinoid tumors. American Journal of Medicine, 81(6B), 41-48. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/2432780.

Haug, A., Auernhammer, C., Wangler, B. Schmidt, G., Uebleis, C., Goke, B., Cumming, P., Bartenstein, P., Tiling, R., and Hacker, M. (2010). 68GA-DOTATTATE PET/CT for the early prediction of response to somatostatin receptor-mediated radionuclide therapy in patients with well-differetiated neuroendocrine tumors. Journal of Nuclear Medicine, 51(9), 1349-1356. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/20720050.

Janson E., Holmberg, L., Stridsberg, M., Eriksson, B., Theodorsson, E., Wilander, E. and Oberg, K. (1997). Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center. Annals of Oncology, 8(7), 685-690. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/9296223.

Jensen, R. T., Berna, M. J., Bingham, D. B., and Norton, J. A. (2008) Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies, Cancer 113, 1807-1843.

Kulke, M. H. (2007). Clinical Presentation and Management of Carcinoid Tumors. Hematology/Oncology Clinics of North America, 21, 433-455. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/17548033.

Kulke, M. H., (2007). Gastrointestinal neuroendocrine tumors: a role for targeted therapies? Endocrine Related Cancer, 14(2), 207-219. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/17639038.

Kvols, L., Brown, M., O’Connor, M., Hung, J., Hayostek, R., Reubi, J., Lamberts, S. (1993). Evaluation of a Radiolabeled Somatostain Analog (I-123 Octreotide) in the Detection and Localization of Carcinoid and Islet Cell Tumors. Radiology, 187(1), 129-133. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/8383865.

Mamikunian, G., Vinik, A., O’Dorisio, T., Woltering, E., Go, V. (2009). Neuroendocrine Tumors: A Comprehensive Guide to Diagnosis and Management. InterScience Institute, Fourth Edition.   Retrieved from: http://www.interscienceinstitute.com/docs/Neuroendocrine-Tumors-4th-Edition.pdf

Modlin, I., Oberg, K., Chung, D., Jensen, R., de Herder, W., Thakker, R., Caplin, M., Delle Fave, G., Kaltsas, G., Krenning, E., Moss, S., Nilsson, O., Rindi, G., Salazar, R., Rusziniewski, P., Sundin, A. (2008). Gastroenteropancreatic neuroendocrine tumors. Lancet Oncology, 9(3), 203. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/18177818.

Oberg, K., Kvols, L., Caplin, M., Delle Fave, G., de Herder, W., Rindi, G., Rusniewski, P., Woltering, E., Wiedenmann, B. (2004). Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Annals of Oncology, 15(6), 966-973. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/15151956

Oberg, K., Reubi, J., Kwekkeboom, D., Krenning, E. (2010). Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy. Gastroenterology, 139(3), 742-753. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/20637207.

Rockall, A. G., Rodney, H. R. (2007). Imaging of neuroendocrine tumors (CT/MR/US). Best Practice & Research, Clinical Endocrinology & Metabolism, 21(1), 43-68. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/17382265.

Reubi, J. C., Waser, B. (2003). Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting. European Journal of Nuclear Molecular Imaging, 30(5), 781-793. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/12707737.

Sundin, A., Garske, U., Orlefors, H. (2007). Nuclear imaging of neuroendocrine tumours. Best Practice & Research, Clinical Endocrinology & Metabolism, 21(1), 69-85. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/17382266.

Vinik, A. I., Silva, M. P., Woltering, E. A., Go, V., Warner, R., Caplin, M. (2009). Biochemical Testing for Neuroendocrine Tumors. Pancreas, 38(8), 876-899. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/19855234.

Vinik, A. I., Woltering E. A., Warner, R. P., Caplin, M., O'Dorisio, T. M., Wiseman, G. A., Coppola, D., Go, V. L. W. (2010). NANETS Consensus Guidelines for the Diagnosis of Neuroendocrine Tumor. Pancreas 39(6), 713-734.  Retrieved from: http://nanets.net/pdfs/pancreas/03.pdf

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