How can I be sure that the patient has pancreatic neuroendocrine tumor(s)?

See Table I, “Pancreatic neuroendocrine tumors (PNETs).”

Pancreatic neuroendocrine tumors (PNETs) can either cause a functional symptom due to ectopic secretion of a biologically active hormone (functional PNET) or not be associated with a functional syndrome (nonfunctional PNET; NF-PNET). The functional PNETs can be diagnosed by demonstrating effects of overproduction (e.g., hypoglycemia in insulinoma) combined with elevated serum hormone levels (elevated proinsulin, insulin in insulinomas). Nonfunctional PNETs can only be diagnosed by histological conformation of a PNET.

The specific clinical symptoms for each functional PNET syndrome vary with the type of hormone being ectopically secreted and are listed in Table I, in part 2.

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NF-PETs do not cause specific symptoms. Patients usually present with abdominal pain; nonspecific upper gastrointestinal symptoms, asymptomatic with an enlarged liver with metastases or found incidentally as an abdominal mass; and histology or cytology shows a PNET.

A tabular or chart listing of features and signs and symptoms

The functional syndromes present with the various symptoms listed in Table I. The symptoms are not pathognomonic but should strongly suggest the possible diagnosis.

The functional syndromes can mimic any disorders that cause the general symptoms, as listed in Table I. For example, insulinoma causes hypoglycemia, which characteristically results in CNS symptoms (e.g., diplopia, confusion, dizziness), and each of these can be caused by many other disorders. In the case of insulinomas, they characteristically occur during fasting, exercise, or when a meal is delayed. Zollinger-Ellison syndrome characteristically causes severe peptic ulcer disease, with or without diarrhea or severe GERD symptoms.

Less common clinical presentations can occur with each functional syndrome presenting with more mild expression of symptoms or without the full constellation of symptoms characteristically seen.

Each of the functional syndromes can mimic any disease that also causes any of the symptom complexes associated with the functional syndrome, as shown in Table I. For example, insulinoma can be mimicked by diseases causing alimentary hypoglycemia, or Zollinger-Ellison syndrome by idiopathic peptic ulcer disease.

How can I confirm the diagnosis?

Each functional PNET syndrome should be suspected because of the clinical signs and symptoms it presents. Then a fasting hormone level is usually drawn, as well as a measure of hormone function. In some cases, various provocative tests are needed. For example, in the case of insulinoma, fasting insulin and proinsulin levels are drawn along with a blood glucose level. If results are equivocal, a 72-hour fast in the hospital, where testing for regular insulin, proinsulin, c-peptide levels, and blood glucose is performed. Each syndrome has its own specific determinations.

Diagnostic algorithm

The general algorithm for diagnosis is (1) suspect diagnosis; (2) measure specific fasting hormone level; (3) assess some measure of hormone function (e.g., blood glucose in insulinoma, gastric acid secretion in ZES, diarrhea level in VIPoma, etc.).

After establishing the diagnosis, each patient needs to have the functional syndrome controlled by the appropriate treatment prior to surgery if localized disease is present. For example, with insulinomas, frequent small meals and diazoxide are used with ZES gastric antisecretory drugs such as PPIs.

Imaging studies such as CT with IV contrast, MRI endoscopic ultrasound, and octreoscan are used to image the tumors.

What other diseases, conditions, or complications should I look for in patients with pancreatic neuroendocrine tumors?

What diseases may mimic functional pancreatic neuroendocrine tumors?

See Table I for a listing of diseases that cause symptoms that may mimic the symptoms of each functional PNET.

Complications include the effects of not treating the hormone excess state of each syndrome or the development of advanced tumoral disease because of the malignant nature of most of these PNETs.

What is the right therapy for the patient with pancreatic neuroendocrine tumor(s)?

See above discussion under diagnostic algorithm. The appropriate therapy for each functional PNET syndrome is the treatment of the individual hormone excess states and surgical resection of the PNET, if possible; or, if advanced tumoral disease is present, then treatment should be directed at the malignant PNET.

Such treatment for advanced disease includes the use of somatostatin analogues in slow growing tumors, and the use of everolimus and sunitinib; in liver-predominant disease, liver-directed therapies such as radiolabeled microspheres, embolization, and chemoembolization are used. Peptide radioreceptor therapy with radio-labeled somatostatin anlogues is a new form of treatment; however, it is still investigational.

What is the most effective initial therapy?

To carry out appropriate treatment of the PNET, tumor localization studies are essential. Such studies would allow the primary tumor to be localized and the extent of the tumor burden to be determined. The localization of the primary tumor can assist the surgeon performing the operation to determine possible cure, and the assessment of the tumor extent allows the selection of the proper treatment for the PNET. Specifically, if diffuse metastatic disease of the liver is present, then another treatment directed at the tumor is required because surgical resection is not possible. Similarly, if distant metastases to the bone or other sites is present, surgical resection is not possible.

The localization methods commonly used include cross-sectional imaging (ultrasound, MR, CT scanning), with the most effective method being a triphasic CT scan with contrast. If the primary tumor is not seen and an intrapancreatic PNET is suspected (e.g., an insulinoma), endoscopic ultrasound is frequently used. In addition, octreoscan is usually performed because it is the most sensitive modality for imaging distant lesions and will detect most primary tumors that are larger than 1 cm, except in patients with insulinomas.

Therapy of metastatic disease if surgical resection is not possible

To treat metastatic disease if surgical resection is not possible, a number of different modalities can be used. Long-acting somat ostatin analogues such as octreotide-LAR or lanreotide autogel, which can be given once per month; tyrosine kinase inhibitors (sunitinib); mTor inhibitors (everolimus); and various chemotherapeutic combinations (streptozotocin with doxorubicin, capecitabine, and temozolomide) are each frequently used for their antitumor effects in patients with nonresectable well-differentiated (Grade 1 or 2) PNETS that are symptomatic or increasing in size. If the primary tumor can be removed and the tumor is localized to the liver, various liver-directed treatments are frequently used (chemoembolization, embolization, radiolabeled microspheres).

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

What therapy is best if initial therapy fails, including definitions of failure?

See above discussion (i.e., the appropriate therapy for each is the treatment of the individual hormone excess state and surgical resection of the PNET, if possible. Or, if advanced disease is present, then treatment should be directed at the malignant PNET).

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

What side effects should I expect from therapy?

See above discussion.

Listing of these, including any guidelines for monitoring side effects.


How should I monitor the patient with PNETs?

If surgical resection is done, then the patient needs to be followed for possible cure by assessing hormone levels and symptoms.

If the patient is not cured, the hormone excess state must be treated and the patient followed regularly to assess possible tumor growth with imaging studies.

What's the evidence?

Metz, DC, Jensen, RT. “Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors”. Gastroenterology . vol. 13. 2008. pp. 1469-92.

Scherübl, H, Jensen, RT, Cadiot, G, Stölzel, U, Klöppel, G. “Management of early gastrointestinal neuroendocrine neoplasms”. World J Gastrointest Endosc. vol. 3. 2011. pp. 133-9.

Kulke, MH, Anthony, LB, Bushnell, DL. “North American Neuroendocrine Tumor Society (NANETS). NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas”. Pancreas. vol. 39. 2010. pp. 735-52.

Jensen, RT, Berna, MJ, Bingham, DB, Norton, JA. “Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies”. Cancer. vol. 113. 2008. pp. 1807-43.

Fendrich, V, Bartsch, DK. “Surgical treatment of gastrointestinal neuroendocrine tumors”. Langenbecks Arch Surg. vol. 396. 2011. pp. 299-311.

Oberg, K. “Pancreatic endocrine tumors”. Semin Oncol. vol. 37. 2010. pp. 594-618.

Faivre, S, Sablin, MP, Dreyer, C, Raymond, E. “Novel anticancer agents in clinical trials for well-differentiated neuroendocrine tumors”. Endocrinol Metab Clin North Am. vol. 39. 2010. pp. 811-26.

Ekeblad, S. “Islet cell tumours”. Adv Exp Med Biol. vol. 654. 2010. pp. 771-89.

Vanderveen, K, Grant, C. “Insulinoma”. Cancer Treat Res. vol. 153. 2010. pp. 235-52.

Desai, KK, Khan, MS, Toumpanakis, C, Caplin, ME. “Management of gastroentero-pancreatic neuroendocrine tumors (GEP-NETs)”. Minerva Gastroenterol Dietol. vol. 55. 2009. pp. 425-43.