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Pancreatic Neuroendocrine Tumor Locations and Classifications

Pancreatic Neuroendocrine Tumor Histological Features

Since neuroendocrine tumors, including pancreatic neuroendocrine tumors, represent a heterogeneous group of tumors, the World Health Organization in 2000 updated the classification system for them based upon their clinical pathological criteria (Brandi, Gagel, Angeli, Bilezikian, Beck-Peccoz, Bordi, Conte-Devolx, Falchetti, Gheri, Libroia, Lips, Lombardi, Mannelli, Pacicni, Ponder, Raue, Skogseid, Tamburrano, Thakker, Thompson, Tomassetti, Tonelli, Wells, and Marx, 2002). Each category includes both functioning and non-functioning tumors.

  • Well-differentiated endocrine tumors, with benign or uncertain behavior.
  • Well-differentiated endocrine carcinomas, with low-grade malignant behavior.
  • Poorly differentiated endocrine carcinomas, with high-grade malignant behavior.
  • Endocrine/exocrine carcinomas with characteristic of both endocrine and exocrine tumors.

Carcinoid tumors and pancreatic neuroendocrine tumors fall within the classification of well-differentiated endocrine tumors. Tumors classified as poorly differentiated endocrine carcinoma or endocrine/exocrine carcinoma with characteristics of both endocrine and exocrine tumors are not covered on the Caring for Carcinoid Foundation’s website. For these types of tumors please contact your physician for more information.

For our purposes, the terms carcinoid tumors and pancreatic neuroendocrine tumors refer to well-differentiated endocrine tumors and the information provided should not be applied to any tumors not characterized as well-differentiated.

Presence of Clinical Syndrome

Pancreatic neuroendocrine tumors are classified as functioning or non-functioning.

  • Functioning: A functioning pancreatic neuroendocrine tumor secretes biochemically active substances such as hormones which cause specific clinical syndromes such as Carcinoid Syndrome, Zollinger-Ellison Syndrome, or symptoms from hormone over secretion such as insulin or glucagons.
  • Non-functioning: A non-functioning pancreatic neuroendocrine tumor secretes specific substances but these substances are either inactive and/or do not cause any clinical syndrome.

Pancreatic Neuroendocrine Tumor Classification

Pancreatic neuroendocrine tumors vary in clinical course, location, and hormone secretion. Pancreatic neuroendocrine tumors can occur outside of the pancreas such as the duodenum and small intestine.

Functioning pancreatic neuroendocrine tumors

  • Insulinoma – characterized by excess secretion of insulin and pro-insulin which causes confusion, sweating, dizziness, weakness and unconsciousness (Ramage, Ahmed, Ardill, Bax, Breen, Caplin, Corrie, Davar, Davies, Lewington, Meyer, Newell-Price, Poston, Reed, Rockall, Steward, Thakker, Toubanakis, Valle, Verbeke, Grossman, and UK and Ireland Neuroendocrine Tumor Society, 2012; Tomasseti, Migliori, Lalli, Campana, Tomassetti, Corinaldesi, 2001). Prolonged hypoglycemia (low blood sugar) can have permanent impact on brain function. Insulinomas tend to be small and rarely metastasize (Metz & Jensen, 2008; Modlin, Oberg, Chung, Jensen, de Herder, Thakker, Caplin, Delle Fave, Kaltsas, Krenning, Moss, Nilsson, Rindi, Salazar, Rusziniewsku, & Sundin, 2008; Kulke, Anthony, Bushnell, de Herder, Goldsmith, Klimstra, Marx, Pasieka, Pommier, Yao, and Jensen, 2010), many report metastases in about 10% of patients (Ramage et al., 2012).  Insulinomas can be associated with MEN1. (Tomasetti, et al., 2001).
  • Gastrinoma – characterized by Zollinger-Ellison Syndrome caused by excess secretion of gastrin (Tomasetti et al., 2001). Zollinger-Ellison syndrome causes diarrhea and peptic-ulcers.  Patients with Zollinger-Ellison syndrome may also develop gastric carcinoid as a result of prolonged gastrin hypersecretion (over production).  Patients frequently have liver and lymph node metastasis at diagnosis (Tomasetti et al., 2001).  Gastrinomas occur mainly in the duodenum and pancreas (Tomasetti et al., 2001). When Gastrinomas occur in the duodenum they are frequently associated with MEN1. (Tomasetti et al., 2001; Ramage et al., 2012).  All patients with Zollinger-Ellison Syndrome should be screened for MEN1 (Mamikunian, Vinik, O’Dorisio, Woltering, & Go, 2009).
  • Glucagonoma – characterized by hypersecretion of glucagon which causes skin rash, diabetes, and weight loss (Tomasetti et al., 2001; Ramage et al., 2012; Metz & Jensen, 2008). Glucagonomas occur mainly in the pancreas, are typically large, and are highly metastatic. Glucagonoma is rarely associated with MEN1 (Tomasetti et al., 2001).
  • VIPoma – characterized by hypersecretion of Vasoactive Intestinal Peptide (VIP) which causes Verner-Morrison Syndrome.  Symptoms of Verner-Morrison Syndrome include severe watery diarrhea, which can be life threatening.
  • Somatostatinoma –Somatostatinomas are primarily or exclusively composed of somatostatin producing cells.  Somatostatinomas are found in the pancreas and duodenum. (Tomasetti et al., 2001; Metz & Jensen, 2008; Mamikunian, 2009). Somatostatinomas may not provoke clinical symptoms or they may be characterized by clinical symptoms of gallbladder stones, diabetes, weight loss, and diarrhea (Metz & Jensen, 2008).

Non-functioning pancreatic neuroendocrine tumors

Non-functioning pancreatic neuroendocrine tumors are not associated with characteristic clinical symptoms from secretion of hormones.  Non-functioning pancreatic neuroendocrine tumors occur in the pancreas.  They do not cause hormonal symptoms but can cause pain, weight loss and jaundice.  Because there is no characteristic clinical syndrome associated with non-functioning pancreatic neuroendocrine tumors they can be difficult to diagnosis and are often diagnosed after presenting with large tumors and liver metastases (Metz & Jensen, 2008; Kulke et al., 2010).

Inherited versus Sporadic

  • Sporadic: Cancer causing mutation arise randomly 
  • Inherited: Cancer causing mutations are inherited such in the case of MEN-I.

Pancreatic neuroendocrine tumors can be sporadic or familial, when the patient has genetically inherited mutations, which predispose development of tumors.

Pancreatic neuroendocrine tumors can be associated with genetic syndromes such as Multiple Endocrine Neoplasia Type 1 (MEN1), Von Hippel-Lindau Disease (VHL), Tuberous Sclerosis Complex and Neurofibromatosis Type 1 (NF1) (Metz & Jensen, 2008). MEN1 is the most significant genetic syndrome - over 80% of patients with MEN1 develop pancreatic neuroendocrine tumors, over 40% of patients develop gastrinomas and smaller percentages develop other types of pancreatic neuroendocrine tumors (Metz & Jensen, 2008; Gibril & Jensen, 2004; Brandi et al., 2002).

MEN1 is an autosomal dominant inherited syndrome characterized by multiple endocrine and non-endocrine tumors (Brandi et al., 2001). The tumors most frequently observed in patients with MEN1 include parathyroid adenomas, pituitary adenomas, and pancreatic endocrine tumors.

VHL is an autosomal dominant inherited syndrome caused by a mutation in the VHL gene.

Pancreatic neuroendocrine tumor patients should always have a clinical examination including family history to exclude genetic syndromes like MEN1 (Ramage et al., 2012). Presence of MEN1 or another clinical syndrome may change the optimal treatment course and so it is important to rule out.  If a patient has a genetic syndrome it may be advised that certain family members are tested as well.  

References

Brandi, M., Gagel, R., Angeli, A., Bilezikian, J., Beck-Peccoz, P., Bordi, C., Conte-Devolx, B., Falchetti, A., Gheri, R., Libroia, A., Lips, C., Lombardi, G., Mannelli, M., Pacicni, F., Ponder, B., Raue, F., Skogseid, B., Tamburrano, G., Thakker, R., Thompson, N., Tomassetti, P., Tonelli, F., Wells, S., and Marx, J. (2002). Guidelines for diagnosis and therapy of MEN type 1 and type 2. The Journal of Clinical Endocrinology and Metabolism, 86(12): 5658-5671. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/11739416 

Gibril, F. and Jensen, R. (2004). Zollinger-Ellison syndrome revisited: diagnosis, biologic markers, associated with inherited disorders, and acid hypersecretion. Current Gastroenterology Reports, 6(6), 454-463. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/15527675.

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

Mamikunian, G., Vinik, A., O’Dorisio, T., Woltering, E., and Go, V. (2009). Neuroendocrine Tumors: A Comprehensive Guide to Diagnosis and Management, 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.

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.

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

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.

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