Last updated:
January 04, 2017
Years published: 1990, 2000, 2011, 2014, 2017
NORD gratefully acknowledges Simon Schimmack, MD, University Hospital of General, Visceral and Transplantation Surgery of Heidelberg, Germany, and Gastrointestinal Pathobiology Research Group, Department of Gastroenterological Surgery, Yale University School of Medicine, for assistance in the preparation of this report.
The pancreas is a gland located between the stomach, spleen, duodenum and colon transversum. It contains specialized exocrine cells that secrete enzymes that travel to the intestines and aid in digestion as well as endocrine cells, so called islet cells. Pancreatic neuroendocrine neoplasms (pNENs) are an increasingly common group of malignancies that arise within the endocrine tissue of the pancreas. Endocrine tissue is specialized tissue that contains hormone-secreting cells (e.g. α-cells, ß-cells). These cells secrete several different hormones into the blood (endocrine) or to local cells (paracrine, autocrine). These hormones have a variety of functions within the body (e.g. glucose-metabolism). Neoplasms that arise from endocrine tissue may also secrete hormones, resulting in excessive levels of these hormones in the body and potentially a wide variety of symptoms. There are several different subtypes of functioning pNENs distinguished by the specific type of hormone that they secrete. Insulinomas and gastrinomas are the most common types of hormone secreting pNENs.
Although there is no difference in diagnosis and therapy, pNENs can be differentiated as functioning or nonfunctioning. Functioning pNENs secrete hormones into the bloodstream, which cause special symptoms; nonfunctioning neoplasms may produce hormones, but no systemic symptoms. Nonfunctioning neuroendocrine neoplasms can still cause symptoms relating to tumor size and location such as obstruction or internal bleeding. They have some different differentiation (G1-3), but all of them have the potential for malignant transformation. Most pNENs occur sporadically, but in some cases, pNENs may occur as part of a larger genetic syndrome such as multiple endocrine neoplasia type 1 (MEN1) or von Hippel Lindau (VHL) syndrome.
Pancreatic cancer as a general term usually refers to pancreatic adenocarcinoma, an aggressive malignant cancer with a poor prognosis. Approximately 95 percent of pancreatic malignancies are adenocarcinomas, for which the prognoses are in general worse than the prognosis of G1- and G2 pNENs. G3 neuroendocrine carcinomas have a similar poor prognosis as pancreatic adenocarinomas.
The symptoms, severity and rate of progression of pNENs can vary greatly from one person to another, even among individuals with the same type of malignancy.
ASYMPTOMATIC NEOPLASMS
The so called nonfunctioning pNENs may not cause any symptoms and will sometimes be diagnosed incidentally. Since nonfunctioning pNENs do not secrete hormones that cause symptoms, they often continue to grow undetected. When nonfunctioning pNENs are eventually detected, they are often quite large. More than half are metastasized upon diagnosis, usually because they remained undetected for so long.
As nonfunctioning pNENs grow they may eventually cause symptoms, most often related to their size and specific location. The most common symptom associated with nonfunctioning pNENs is abdominal pain and, in some cases, an abdominal mass may be present. Affected individuals may also have a variety of additional nonspecific symptoms including nausea, diarrhea, indigestion and unintended weight loss. Additional symptoms are caused by the size and bulk of a tumor, which can cause obstruction or compression of nearby structures. Some individuals may have yellowing of the skin (icterus) and whites of the eyes (jaundice). Nonfunctioning pNENs can potentially bleed into the gastrointestinal tract.
SYMPTOMATC NEOPLASMS
The symptoms of so called functioning pNENs can vary widely from one person to another, depending upon the specific subtype present and the specific hormone that is overproduced. Some pNENs may secrete more than one hormone, but usually one hormone is produced more than the others. Most individuals usually only have symptoms relating to the hormone that is chiefly produced.
Insulinomas
These neoplasms are mostly small and 90 percent of them behave benign. They are the most common form of pancreatic neuroendocrine neoplasms. Insulinomas produce insulin, a hormone that helps to regulate blood sugar levels by promoting the movement of glucose (a simple sugar) into cells for energy production or into the liver and fat cells for storage. The most common symptom of insulinomas is low blood sugar (hypoglycemia) and slow gain of weight, which can be present for years before a diagnosis is made. Untreated hypoglycemia can cause headaches, visual disturbances, personality changes, seizures and, in severe cases, coma and death.
Insulinomas can cause additional symptoms including irritability, confusion, weakness, tremors, loss of muscular coordination (ataxia), palpitations, a rapid heartbeat (tachycardia) and excessive sweating (diaphoresis).
Therapy of choice is an enucleation of the insulinoma, which is a small pancreas protective operation.
Gastrinomas
These tumors produce the hormone gastrin, which stimulates the stomach to release too much acid. Gastrinomas can cause abdominal pain, diarrhea, excess fat in the feces (steatorrhea), backflow of the contents of the stomach into the esophagus (gastroesophageal reflux) and erosions on the lining of the stomach (peptic ulcers). These lesions may bleed. Peptic ulcers can also cause an intense, burning sensation in the stomach that may last from a few minutes to several hours. In individuals with gastrinomas, peptic ulcers may keep coming back even after treatment. More than 50 percent of gastrinomas are malignant and can potentially spread (metastasize).
The symptoms caused by gastrinomas have been classified as a specific syndrome known as Zollinger-Ellison syndrome. (For more information on this disorder, choose “Zollinger Ellison” as your search term in the Rare Disease Database.)
Glucagonomas
These tumors produce the hormone glucagon, which increases the amount of glucose in the blood. Glucose is a simple sugar. Too much sugar in the blood is known as hyperglycemia. Glucagonomas can cause a distinct skin rash (dermatitis) usually on the face, stomach or legs. Mild diabetes may also develop. Some affected individuals may develop blood clots, especially in the lungs potentially causing shortness of breath, cough or pain in the chest. Blood clots in extremities may cause deep vein thrombosis, a condition in which blood clots form in the legs causing the legs to become painful and swollen.
In addition, anemia, unintended weight loss, and inflammation or sores on the mucous membrane lining the inside of the mouth (stomatitis) have also been associated with glucagonomas. Glucagonomas tend to grow quite large and approximately 70 percent are malignant with the potential to spread (metastasize).
VIPomas
These tumors produce the hormone vasoactive intestinal polypeptide, which increases secretions from the intestines and relaxes certain muscles within the gastrointestinal tract. VIPomas can cause large amounts of chronic, watery diarrhea that can eventually result in dehydration, unintended weight loss, and loss of potassium in body (hypokalemia). Additional symptoms may occur including abdominal pain and cramping, lethargy, nausea, and flushing or redness of the face.
Many VIPomas are malignant by the time they are first diagnosed and often have already spread (metastasized). VIPomas and their associated symptoms may also be known as Verner-Morrison syndrome or pancreatic cholera.
Somatostatinomas
These tumors produce the hormone somatostatin, which inhibits the secretion of other hormones. Somatostatinomas can cause excessive glucose (hyperglycemia) levels in the blood. Additional symptoms that can develop include diabetes mellitus, gallstones (cholelithiasis), diarrhea, unintended weight loss and excess levels of fat in the feces (steatorrhea). Additional symptoms include abdominal pain, nausea, and vomiting. Most somatostatinomas are large and have spread (metastasized) upon diagnosis.
ACTHomas
These tumors produce the hormone adrenocorticotropin, which stimulates the adrenal glands to overproduce cortisol. Cortisol is a hormone that is release in response to stressful situations. Cortisol increases blood pressure and blood sugar and inhibits the immune system. ACTHomas can result in Cushing’s syndrome, a disorder characterized by excessive amounts of weight gain (central obesity). Affected individuals may have a round, moon-shaped face, thin, fragile skin that bruises easily, high blood pressure (hypertension), generalized muscle weakness, behavioral changes, facial flushing, and weakened bones that fracture easily (osteoporosis). (For more information, choose “Cushing’s” as your search term in the Rare Disease Database.)
GRFomas
These tumors produce the hormone growth hormone release factor, which stimulates the production of growth hormone. GRFomas can result in acromegaly, a disorder characterized by abnormal enlargement of bones of the arms, legs and head. (For more information, choose “acromegaly” as your search term in the Rare Disease Database.)
Additional pNENs
Some extremely rare pNENs include PPHrPomas, which secrete parathyroid hormone-related protein and may cause hyperparathyroidism; calcitoninomas, which secrete calcitonin and can cause watery diarrhea and facial flushing; and neurotensinomas, which can cause low blood pressure (hypotension), flushing, diarrhea, unintended weight loss, and diabetes. PPoma secrete pancreatic polypeptide, but usually do not cause any discernable symptoms.
The exact cause of pancreatic neuroendocrine neoplasms is unknown. Most pNENs occur randomly for no apparent reason (sporadically). Some individuals may have a genetic predisposition to developing pNENs. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but the disorder may not be expressed unless it is triggered or activated under certain circumstances, such as due to certain environmental factors. The genetic or environmental factors associated with pNENs are unknown. More research is necessary to determine what specific factors may play a role in the development of pNENs.
Some individuals develop a pNEN as part of a larger genetic syndrome such as multiple endocrine neoplasia type I (MEN1), von Hippel-Lindau syndrome (VHL) or neurofibromatosis type I (NF-1). These disorders have additional symptoms and physical characteristics. (For more information on these disorders, choose the specific name as your search term in the Rare Disease Database.)
PNENs seem to affect women slightly more often than men. Individuals of any ethnic or racial group may develop a pNEN. Affected individuals usually develop sporadic pNENs between the ages of 30-60. When pNENs occur as part of a genetic syndrome, they tend to occur during childhood or young adulthood. PNENs affect approximately ~1 in 100,000 individuals in the general population per year. They account for approximately 2-4 percent of all pancreatic neoplasms.
A diagnosis of a pancreatic neuroendocrine neoplasms is made based upon identification of characteristic symptoms (if present), a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including advanced imaging techniques (octrotide-scintigraphy, CT, MRI, PET-CT, PET-MRI), blood tests (Chromogranin A, NETest), biochemical tests, and also biopsies.
Treatment
The therapeutic management of individuals with pNENs may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), specialists in diagnosis and treatment of gastrointestinal disorder (gastroenterologists), specialists in the diagnosis and treatment of hormone-related disorders (endocrinologists), surgeons, oncology nurses, and other healthcare specialists.
Specific therapeutic procedures and interventions may vary depending upon numerous factors, such as primary tumor location and extent of the primary tumor (stage); whether the tumor is malignant and whether it has spread to lymph nodes or distant sites; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.
Surgery is the treatment of choice. Other techniques used to pNENs include hormonal and drug therapy, chemotherapy and supportive therapy. In most cases, these therapies are used in conjunction with one another.
SURGERY
The only curative therapy for pNENs is surgery. A variety of different surgical techniques may be used based upon the size, location and spread of the tumor. Such techniques include removal of only the tumor (enucleation), removal of as much as the tumor as possible (debulking), and removal of the tumor and nearby tissue and structures (e.g., a portion of the pancreas). If the cancer has spread, surgical removal of affected areas (e.g., affected lymph nodes or liver metastases) may be necessary. In special cases, liver transplantation may be considered for treatment of metastasized pNENs.
Two other surgical techniques that may be used to treat individuals with pNENs include radiofrequency ablation or cryosurgery. Radiofrequency ablation uses high energy radio waves to destroy cancer cells. During this procedure, a small, thin tube is run through the skin and into the tumor. The tip of the tube contains tiny electrodes that release the high energy radio waves that destroy the tumor cells.
Cryosurgery (also known as cryoablation) is a procedure that uses extreme cold to destroy cancer cells. A metal instrument is passed through the skin and inserted into the tumor where a substance like liquid nitrogen or liquid carbon dioxide is uses to freeze and destroy the tumor cells.
HORMONE THERAPY
Some individuals with pNENs may be treated with somatostatin analogue, a drug (such as octreotide) that mimics the effects of somatostatin. Somatostatin is a hormone the blocks the activity of other hormones in the body. Ocetreotide can block the effects of hormones that are released by pNENs. Ocetreotide has improved symptoms in most individuals with pNENs.
CHEMOTHERAPY
For some affected individuals, particularly those who have locally advanced, metastatic, or recurrent disease, therapy with certain anticancer drugs (chemotherapy) may also be recommended, possibly in combination with surgical procedures; physicians may recommend combination therapy with multiple chemotherapeutic drugs that have different modes of action in destroying tumor cells and/or preventing them from multiplying.
In May of 2011, a specific chemotherapeutic drug known as Afinitor® (everolimus) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of progressive neuroendocrine neoplasms of pancreatic origin in individuals with unresectable (cannot be treated surgically), locally advanced or metastatic disease. Afinitor delays tumor growth and reduces the risk of disease progression. For more information, contact: Novartis Oncology US.
Website: https://www.afinitor.com/pnet
In May of 2011, the FDA also approved Sutent® (sunitinib malate) for the treatment of pNENs. In studies, Sutent slowed tumor growth in individuals whose cancer had spread or couldn’t be surgically removed. For more information, contact: Pfizer Oncology.
Website: https://www.sutent.com
LIVER THERAPY
When pNENs become malignant and spread, a frequent site of metastases is the liver. Embolization or chemoembolization are two procedures that may be used to treat pNENs that have metastasized to the liver. Embolization is a non-surgical procedure that hampers blood flow in small blood vessels, thereby decreasing the blood supply to the tumor sites within the liver and can control disease for some time. Chemoembolization used chemotherapy drugs, which are directly injected into small blood vessels that supply tumors with blood. Since tumors need a steady blood supply to grow and spread, these procedures can help to stop tumor growth and reduce symptoms. In individuals with pNENs that have spread to the liver these procedures block the flow of blood through the hepatic artery, which is the main artery that supplies blood to the liver.
In some cases, surgical removal of a portion of the liver may be necessary. In very rare cases, individuals with pNENs may ultimately require a liver transplant.
SUPPORTIVE CARE
Supportive care is therapy that reduces symptoms of a disease or minimizes side effects of other therapies but does not cure or change the course of a disease.
For example, gastrinomas (which cause an increase in stomach acid production) can be treated by drugs that block the production of stomach acid (proton pump inhibitors) such as omeprazole.
Individuals with VIPomas who have associated severe diarrhea may be treated by intravenously replacing fluids and electrolytes.
Some individuals with glucagonomas may have significant loss of essential nutrients, requiring blood transfusions and/or total parenteral nutrition.
Individuals with somatostatinomas may require supplemental nutrition and should have their sugar levels monitored.
Additional therapeutic options have been used to treat individuals with pNENs including immunotherapy and radioimmunotherapy. Immunotherapy is the enhancement or suppression of the body’s natural immune system to fight disease such as cancer. Interferon alpha is a type of immunotherapy that has been used to treat individuals with pNENs. Radioimmunotherapy uses radiation along with cancer-specific antibodies to attack cancer cells. More research is necessary to determine the long-term safety and effectiveness of these potential therapies for individuals with pNENs.
Information on current clinical trials is posted on the Internet at https://www.clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Jensen RT. Endocrine Tumors of the Gastrotintestinal Tract and Pancreas. In: Harrison’s Endocrinology. Jameson JL, editors. 2006 McGraw-Hill Companies, Columbus, OH. Pp:367-386.
Lairmore TC.Islet Cell Tumors of the Pancreas.NORD Guide to Rare Disorders.Lippincott Williams & Wilkins. Philadelphia, PA. 2003:408-409.
JOURNAL ARTICLES
Liu JB, Baker MS. Surgical Management of Pancreatic Neuroendocrine Tumors. Surg Clin North Am. 2016 Dec;96(6):1447-1468.
Kunz PL, Reidy-Lagunes D, Anthony LB, Bertino EM, Brendtro K, Chan JA, Chen H, Jensen RT, Kim MK, Klimstra DS, Kulke MH, Liu EH, Metz DC, Phan AT, Sippel RS, Strosberg JR, Yao JC; North American Neuroendocrine Tumor Society.
Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas. 2013;42(4):557-77.
Falconi M, Bartsch DK, Eriksson B, Klöppel G, Lopes JM, O’Connor JM, Salazar R, Taal BG, Vullierme MP, O’Toole D; Barcelona Consensus Conference participants.
ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors. Neuroendocrinology. 2012;95(2):120-34.
Lawrence B, Anderson M, Schimmack S, Findlay M, Kidd M, Modlin IM. Neoplastic lesions of endocrine cells in the gastrointestinal tract: ten evolving principles as a basis for clinical understanding. Gastrointestinal Cancer: Targets and Therapy. 2012:2 1-17.
Schimmack S, et al., The diversity and commonalities of gastroenteropancreatic neuroendocrine tumors. Langenbecks Arch Surg. 2011;396:273-98.
Modlin, I., et al., The archaic distinction between functioning and non-functioning neuroendocrine neoplasms is no longer clinically relevant. Langenbecks Arch Surg. 2011;396(8):1145-56.
Shaib W, Mitchell K, Saif MW. Amelioration of symptoms and reduction of VIP levels after hepatic artery chemoembolization in a patient with sandostatin resistant VIPoma. Yale J Biol Med. 2010;83:27-33.
Chadha MK, Lombardo J, Mashtare T, et al. High-dose octreotide acetate for management of gastroenteropancreatic neuroendocrine tumors. Anticancer Res. 2009;29:4127-4130.
Ong SL, Garcea G, Pollard CA, et al. A fuller understanding of pancreatic neuroendocrine tumours combined with aggressive management improves outcome. Pancreatology. 2009;9:583-600.
Nissen NN, Kim AS, Yu R, et al. Pancreatic neuroendocrine tumors: presentation, management, and outcomes. Am Surg. 2009;75:1025-1029.
Modlin IM, Oberg K, Chung DC, et al., Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2008;9:61-72.
Toumpanakis CG, Caplin ME. Molecular genetics of gastroenteropancreatic neuroendocrine tumors. Am J Gastroenterol. 2008;103:729-732.
Nakura EK, Bergsland EK. Islet cell carcinoma: neuroendocrine tumors of the pancreas and periampulllary region. HematolOncolClin N Am. 2007;21:457-473.
Warner RRP. Enteroendocrine tumors other than carcinoid: a review of clinically significant advances. Gastroenterology. 2005;128:1668-1684.
INTERNET
Ong ES. Neoplasms of the Endocrine Pancreas. Medscape. Last Update April 14, 2015. Available at: https://emedicine.medscape.com/article/276943-overview Accessed December 5, 2016.
Amand MKN. Pancreas Islet Cell Tumor Imaging. Medscape, Last Update October 15, 2015. https://emedicine.medscape.com/article/369655-overview Accessed December 5, 2016.
Cleveland Clinic.Islet Cell Carcinoma (Endocrine Pancreas). Last Update 8/7/2009. https://my.clevelandclinic.org/disorders/pancreatic_cancer/hic_islet_cell_carcinoma_endocrine_pancreas.aspx Accessed December 5, 2016.
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