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Pancreatic Neuroendocrine Tumor Diagnosis

Pancreatic neuroendocrine tumors, like many neuroendocrine tumors, can be very difficult to diagnose.  It is common for individuals with pancreatic neuroendocrine tumors 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 neuroendocrine tumors can mimic other diseases.

If your physician suspects you have a pancreatic neuroendocrine tumor, there are specific biochemical tests which measure tumor markers and imagining tests that can help confirm a diagnosis or pancreatic neuroendocrine tumor 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 to diagnosis a pancreatic neuroendocrine tumor.  

If you have already been diagnosed with a pancreatic neuroendocrine tumor, biochemical and imaging tests are very important tools for disease staging and clinical management.

Pancreatic Neuroendocrine Tumor Biochemical Testing

Pancreatic neuroendocrine tumors produce a variety of substances which include hormones, proteins, and biogenic amines.  Some tumors are termed functioning since they are able to secrete an active form of these substances, which can cause a characteristic clinical syndrome such as Carcinoid Syndrome, Zollinger-Ellison Syndrome, and Cushing’s Syndrome.  Biochemical tests are necessary to diagnosis a functional pancreatic neuroendocrine tumor (Vinik, Woltering, Warner, Caplin, O’Dorisio, Wiseman, Coppola, Go, 2010).  However most pancreatic neuroendocrine tumors are non-functioning  and are not associated with a characteristic syndrome either because the substances secreted are biologically inactive or because they do not cause any specific symptoms (Metz & Jensen, 2008).

The substances secreted by a pancreatic neuroendocrine tumor can be measured by biochemical tumor markers. Biochemical tumor markers can be divided into two categories: those which are specific to a particular type of pancreatic neuroendocrine tumor and those which are general.  The most common tumor marker for pancreatic neuroendocrine tumors is:

Chromogranin A (CgA):

Chromogranin A is a secretory protein that is common to most neuroendocrine tumor cells, and is a general tumor marker for neuroendocrine tumors.  CgA is a useful marker for diagnosing, staging and monitoring pancreatic neuroendocrine tumors (Metz & Jensen, 2008; Tomasetti, Migliori, Lalli, Campana, Tomassetti, & Corinaldesi, 2001). 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 ( Kulke, 2007a). Somatostatin analogs can reduce CgA levels and so CgA should be used with caution among patients using somatostatin analogs (Vinik, Woltering, Warner, Caplin, O’Dorisio, Wiseman, Coppola, Go, 2010).

Drugs such as PPI's can also affect CgA levels, please discuss medications that may affect CgA levels with your physician .  For patients with confirmed or suspected Zollinger-Ellison Syndrome there can be risks to discontinuing PPI’s and patients should speak with a physician regarding appropriate use of PPI’s prior to CgA testing (Vinik et al., 2010).

Other general markers for pancreatic neuroendocrine tumors include neuron specific enolase, pancreatic polypeptide, and pancreastatin (Metz & Jensen, 2008).  Specific tumor markers for functioning pancreatic neuroendocrine tumors include: gastrin, insulin, pancreatic polypeptide, glucagon, somatostatin, and vasoactive intestinal peptide.  (Tomasetti, Migliori, Lalli, Campana, Tomassetti, & Corinaldesi, 2001)

All neuroendocrine tumors, including pancreatic neuroendocrine tumors, secrete hormones.  However, what they secrete depends upon the type of tumor and the tumor location.  The following table depicts pancreatic neuroendocrine tumors by type, secreted substances, and symptoms associated with secreted substances.

Tumor Type

Tumor Marker

Characteristic Symptoms

All pancreatic neuroendocrine tumors

CgA

None

Non-functioning

CgA, Pancreatic Polypeptide

Abdominal pain, weight loss, jaundice

Gastrinoma

CgA, Gastrin

Zollinger-Ellison Syndrome

Insulinoma

CgA, Insulin, Pro-insulin, C-peptide

Hypoglycemia

Glucagonoma

Cga, Glucagon

Rash, diabetes, weight loss

VIPoma

Cga, Vasoactive Intestinal Peptide

Verner Morrison syndrome

Somatostatinoma

CgA, Somatostain

 

Gall-bladder stones, diabetes, diarrhea, steatorrhea, anemia

Pancreatic neuroendocrine tumor causing Carcinoid Syndrome

CgA

Carcinoid Syndrome

Pancreatic neuroendocrine tumor causing Cushing’s Syndrome

CgA, ACTH

Cushing’s Syndrome

 (Tomasetti et al., 2001; Metz & Jensen, 2008; Ramage et al., 2012; Vinik, Strodel, Eckhauser, Moattari, & Lloyd, 1987; Kulke,  Anthony, Bushnell, de Herder, Goldsmith, Klimstra, Marx, Pasieka, Pommier, Yao,  Jensen, 2010)

Depending upon the tumor markers your physician is testing for there are certain foods and medications to avoid prior to testing.  Speak with your physician to discuss foods and medications to discontinue prior to testing. 

Pancreatic Neuroendocrine Tumor Imaging

Along with biochemical testing, there are several imaging techniques which are useful to help determine a 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, Garske, Orlefors, 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.(Rockall & Reznek, 2007)

CT/MRI can be useful to detect both functioning and non-functioning tumors in the pancreas and to define the extent of metastasis (particularly liver and lymph node metastasis).   Effectiveness of CT/MRI for pancreatic neuroendocrine tumors is dependent upon tumor size and location with difficulties visualizing tumors smaller than 3 centimeters, and tumors in the tail of the pancreas and duodenum. (Rockall & Reznek, 2007). As gastrinomas, insulinomas, and duodenenal somatostinomas are frequently small they may be missed with CT/MRI. (Metz & Jensen, 2008)

Both CT and MRI are useful to define liver metastasis in pancreatic neuroendocrine tumors and some studies have show n that these modalities have better results in imaging liver metastases than Somatostatin Receptor Scintography. (Dromain, de Baere, Caillet, Laplanche, Boige, Ducreux, Duvillard, Elias, Schlumberger, Sigal, & Baudin, 2005).

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 Neuroendocrine tumors.  When octreotide is injected into a patient’s vein, it can travel through the bloodstream and bind to pancreatic neuroendocrine tumors. 

Octreotide is a synthetic (man-made), radiolabled analogue of the naturally occurring hormone somatostatin.  Over 90% (Kulke 2007a) of all neuroendocrine tumor cells have receptors for somatostatin (Reubi, Kvols, Waser, Nagorney, Heitz, Charboneau, Reading, & Moertel, 1990).  Different types of pancreatic neuroendocrine tumors express different levels of somatostatin receptors.  Insulinomas less frequently express somatostatin receptors than other types of pancreatic neuroendocrine tumors (Oberg, 2010).  Octreotide, like somatostatin, is able to bind to two of the five receptors (receptors two and five) on pancreatic neuroendocrine tumors (Oberg, 2009).  

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.  However a scan at 24 hours after octreotide injection is preferred (Sundin, Garske, & Orlefors, 2007; Mamikunian, Vinik, O’Dorisio, Woltering, & Go, 2009). SRS can be used to detect neuroendocrine tumors that bind octreotide and are greater than 1- 1.5 cm (Dromain, de Baere, Caillet, Laplanche, Boige, Ducreux, Duvillard, Elias, Schlumberger, Sigal, & Baudin, 2005).  SRS can be used to find primary pancreatic neuroendocrine tumors as well as metastases to the liver, lungs and bones (Metz & Jensen, 2008).

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 receptor (Sundin, Garske, & Orlefors, 2007). Patients should speak with their physicians to determine when and for how long they should discontinue treatment to maximize SRS.

SRS has varying effectiveness in detecting different types of pancreatic neuroendocrine tumors.  SRS is useful in detecting gastrinomas, non-functioning tumors, somatostatinomas, and VIPomas.  SRS is not as effective in detecting insulinomas because insulinomas express lower levels of somatostatin receptors and are frequently small.

SRS is not only useful in imaging tumors but because it is a functional imaging technique SRS is also commonly used to predict response to somatostatin analogue therapy as well as peptide receptor radionuclide therapy (PRRT) (Kulke, Anthony, Bushnell, de Herder, Goldsmith, Klimstra, Stephen, Pasieka, Pommier, Yao, & Jensen, 2010).

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 tumors with the exception of tumors with high proliferative activity and low differentiation (Adams, Baum, Rink, Schumm-Drager, Usadel, &  Hor, 1998). Instead, 68Ga-DOTA-TOC is the radionuclide that is most commonly used with PET to detect pancreatic neuroendocrine tumors (Sundin, Garske, & Orlefors, 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 pancreatic neuroendocrine tumors tumors.  Once bound, the tumors can be visualized with a PET scan.  However, 68Ga can be accumulated much faster by pancreatic neuroendocrine tumors and so the scan for the tumors can be done approximately one hour after the 68Ga has been administered (Sundin, Garske, & Orlefors, 2007) .68Ga-DOTA-TOC has been effective in detecting pancreatic neuroendocrine tumors that are greater in size than 0.5 cm (Sundin, Garske, & Orlefors, 2007) 68 GA DOTA-TOC is not currently FDA approved for use in the United States.

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.   Endoscopic ultrasound can be used to locate small tumors in the pancreas and duodenum including those such as small gastrinomas and insulinomas that are often missed by CT, MRI, and SRS (Metz & Jensen, 2008).

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.

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.

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.

Kulke, M. H., Anthony, L., Bushnell, D., de Herder, W., Goldsmith, S., Klimstra, D., Marx, S., Pasieka, J., Pommier, R., Yao, J., Jensen, R. (2010). NANETS Treament Guidelines: Well-Differentiated Tumors of the Stomach and Pancreas. Pancreas, 39(6), 735-752. Retrieved from: http://nanets.net/pdfs/pancreas/04.pdf.

Kvols, L. K., Brown, M. I., O’Connor, M. K., Hung, J.C., Hayostek, R. J., Reubi, J. C., Lamberts, S. W. J. (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.

Metz, D. and Jensen, R. (2008). Gastrointestinal neuroendocrine tumors, pancreatic endocrine tumors. Gastroenterology, 135(5), 1469-1492. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/18703061.

Oberg, K. (2009). Is it time to widen the use of somatostatin analogs in neuroendocrine tumors? Journal of Clinical Oncology, 27(28), 4635-4636. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/19704053.

Oberg, K. E., Reubi, J. C., Kwekkeboom, D. J., Krenning, E. P. (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.

Ramage, J., Ahmed, A., Ardill, J., Bax, N., Breen, D.J, Caplin, M.E., Corrie, P., Davar, J., Davies, A.H., Lewington, V., Meyer, T., Newell-Price, J., Poston, G., Reed, N., Rockall, A., Steward, W., Thakker, R.V., Toubanakis, C., Valle, J., Verbeke, C., and Grossman, A.B., and UK and Ireland Neuroendocrine Tumor Society (2012) . Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut, 61(1):6-32. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/22052063. 

Rockall, A.G., Reznek, R.H. (2007). Imaging of neuroendocrine tumours (CT/MR/US). Best Pract Res Clin Endocrinol Metab. 21(1):43-68. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/17382265

Reidy, D. L., Tang, L. H., Saltz, L. B.  (2009). Treatment of advanced disease in patients with well-differentiated neuroendocrine tumors.  Nature Clinical Practice, Oncology, 6(3), 143-152. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/19190591

Reubi, J., Kvolz, L., Waser, B., Nagorney, D., Heitz, P., Chaboneau, J., Reading, C., Moertel, C. (1990). Detection of somatostatin receptors in surgical percutaneous needle biopsy samples of carcinoids and islet cell carcinomas. Cancer Research, 50(18), 5969-5977. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/2168286.

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.

Tomasseti, P., Migliori, M., Lalli, S., Campana, D., Tomassetti, V., Corinaldesi, R. (2001). Epidemiology, clinical features and diagnosis of gastroenteropancreatic endocrine tumours. Annals of Oncology, 12(2), S95-S99. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/11762360.

Vinik, A., Strodel, W., Eckhauser, F., Moattari, A., Lloyd, R. (1987). Somatostatinomas, PPomas, neurotensinomas. Seminars in Oncology, 14(3), 263-281. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/2820062.

Vinik, A., Woltering, E., Warner, R., Caplin, M., O’Dorisio, T., Wiseman, G., Coppola, D., Go, V. (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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