The functional tumors synthesize and release hormones that yield distinct clinical presentations related to the role of the hormone. The five neoplasms below are functional tumors.

Functional ICTs

Insulinomas

These are the most common of ICTs and are often benign. Insulinomas cause excessive secretion of insulin. The resultant hypoglycemia ultimately results in headaches, visual changes, confusion [13]. as well as irritability, weakness, tremors, ataxia, and seizures. Severe cases cause coma and even death.

Gastrinomas

Many of these tumors are typically either malignant or have malignant potential. They secrete elevated amounts of gastrin which cause gastric and duodenal ulcers. Collectively known as Zollinger-Ellison syndrome, the common symptoms are abdominal pain, diarrhea, steatorrhea, and gastric acid reflux. There are frequently found in the head of the pancreas although they can occur in the duodenum.

Glucagonomas

The majority of glucagonomas are malignant. They secrete excessive glucagon causing hyperglycemia and diabetes. Additionally, it leads to unintended weight loss, stomatitis, dermatitis, and anemia. Another severe complication of glucagonomas is thrombosis.

VIPomas

At the time of diagnosis, these tumors are likely to be malignant. They produce vasoactive intestinal polypeptide, which plays a role in the secretion of other hormones and causes gastrointestinal muscle relaxation. The symptoms of VIPomas include copious amounts of watery diarrhea, hypokalemia, and dehydration.

Somatostatinomas

These are large, malignant tumors that secrete somatostatin, which is a hormone that inhibits the release of others. Its sequelae include diabetes and cholelithiasis.

Non-functional ICTs

The tumors of this type are usually asymptomatic. They account for the minority of all ICTs. Almost 90% are malignant but usually diagnosed incidentally or in the later stages when their large sizes cause mechanical complication [14].

In addition to the evaluation of the clinical picture, the clinical assessment consists of a full personal and family history, physical examination, and appropriate testing. Laboratory studies include the measurement of the hormones, polypeptides, prostaglandins, tumor markers, and radioimmunoassays.

Laboratory tests

In the evaluation of insulinomas, investigation includes the fasting serum glucose, serum insulin level, and C-peptide suppression test.

Studies for the assessment of gastrinomas include the measurement of gastric acid secretion including the hormone's basal and maximum acid output. Furthermore, the secretion stimulation test is also useful.

Finally, a fasting serum glucagon level is used to diagnose glucagonomas.

Imaging

The primary imaging technique for localization and staging of ICTs is the CT scan with oral and intravenous contrast [15] [16]. This tool reveals the involvement of peri-pancreatic lymph node, the presence of liver metastases, as well as the blood supply. Very importantly, the CT scan guides the surgical and treatment planning.

Further testing involves angiography, which offers a closer investigation of the pancreatic arterial blood supply. This modality is used as the next step when the CT scan does not detect the tumor [17].

Another advantageous technique is the endoscopic ultrasonography, which displays the tumor and allows for a biopsy [18] [19]. One study reported that ultrasonography demonstrated more sensitivity than the combination of CT and angiography [19].

Magnetic resonance imaging (MRI) with gadolinium-enhancement is helpful as it offers key details.

Somatostatin receptor scintigraphy is beneficial. The associated radionuclide scan detects the somatostatin receptors on the primary ICTs [20]. as well as the metastatic lesions.

In a few cases where the above imaging tools cannot visualize the small tumors, selective transhepatic portal venous hormone sampling can be performed [21] [22].

The therapeutic approach depends on the tumor's size, location, and it metastatic status. It also reflects the overall clinical presentation and presence of co-morbidities [23]. The management of the patient involves multidisciplinary coordination between oncology, surgery, primary care, gastroenterology, endocrinology, and other relevant specialties.

Surgery

Surgical intervention is the treatment of choice. In cases with syndromic ICTs without metastasis, complete surgical resection is warranted. When the tumor is located in the pancreatic tail or body, surgical procedures include distal pancreatectomy. If the lesion is located in the pancreatic head, the Whipple procedure is the preferred procedure. Small single masses can be enucleated. If there is liver metastasis, surgical resection [24]. and debulking may be beneficial.

Ablation through radiofrequency and cryosurgery are alternative procedures for metastatic cases.

Chemotherapy

In patients with extensive metastasis, chemotherapy drugs have produced variable results [25] [26]. Examples of anti-neoplastic agents include cisplatin, 5-fluorouracil, and streptozotocin. Newer drugs are undergoing evaluation in current drug trials.

Chemoembolization

The management of liver metastasis may warrant embolization of the hepatic artery in order to obstruct blood supply to the liver tumor [27].

Hormone therapy

Octreotide, a somatostatin analogue, can be used in cases where the lesion is not resectable or when there is a residual tumor.

Other

Addressing the clinical manifestations of these tumors is paramount to prevent serious complications. For example, supportive therapy for peptic ulcers includes proton-pump inhibitor drugs and histamine blocking medications. Additionally, antidiarrheal drugs and intravenous (IV) fluids with electrolytes are other important considerations. Finally, there are medications regarding the management of blood glucose abnormalities.

Lifestyle modifications such as dietary restrictions, smoking cessation, and abstinence from alcohol are all recommended for patients with these tumors.

If the tumor is detected prior to metastasis, the outcome is typically better. The disease is likely curable if complete surgical removal is possible. For example, if the tumor is resectable, the 5-year survival rate is 55% whereas the rate is 15% when the lesion is not resectable [3]. In cases with advanced disease, aggressive treatment may prolong survival.

A significant predictor of the tumor's behavior is the tumor size which is found to be proportional to the probability of metastasis, invasion, and aggressiveness [11] [12]. Furthermore, the prognosis depends on factors such as the type of islet cell, tumor location, metastatic status, the patient's clinical profile, and if cancer has relapsed. Another pertinent prognostic factor is whether the patient has multiple endocrine neoplasia type 1 (MEN1), von Hippel-Lindau disease (VHL), or neurofibromatosis type I (NF-1).

Note that the percentage of malignant cases is lowest in insulinomas (10%) but is significantly higher in gastrinomas (60%) and glucagonomas (80%). The other types of functional ICTs are also mostly malignant as are the non-functional ones as well.

The etiology is not fully understood. The majority of islet cell tumors develop sporadically. Furthermore, it is believed that some patients have a genetic predisposition in conjunction with an environmental trigger.

ICTs comprise 3% to 5% of all pancreatic malignancies [2] [3]. The incidence of these neoplasms is about 1 per population of 100,000. Furthermore, in the United States, there are approximately 1,000 new cases annually [2].

With regards to patient demographics, ICTs have a slight predilection for women. Additionally, sporadic cases occur between the age of 30 and 60 years while the genetic forms develop in childhood or early adulthood.

Endocrine cells account for less than 5% of the pancreatic mass. These cells are distributed in clusters known as the islet of Langerhans. The three chief types of islet cells are the beta, alpha, and delta cells which secrete insulin, glucagon, and somatostatin, respectively. Furthermore, other hormones are also produced from the minor cells.

Islet cells have access to the bloodstream due to their extensive blood supply as they receive up to 15% of the pancreatic perfusion. Moreover, these cells have neural innervation from the parasympathetic and sympathetic nervous system which modulate the hormonal mechanisms of insulin and glucagon secretion.

Pathophysiology of ICTs

The pancreatic islet cells are a component of the neuroendocrine system of the pancreas and the gut. Since these cells contain high levels of amine and are capable of amine precursor uptake with decarboxylation, they are termed as APUD cells [4] [5]. These cells are pluripotent neuroendocrine cells found in the gastrointestinal tract, pulmonary mucosa, and the nervous system [6]. The APUD cells differentiate into distinct endocrine tissues [5] [7].

Since there are numerous pancreatic cell types, there are at least five different cancers. When functional, each type yields a particular metabolic and clinical picture reflecting the characteristic effects of the specific polypeptide released from the tumor cells. This is in contrast to the non-functional tumors that produces non-specific symptomatology secondary to the tumor bulk or metastases [8]. While 85% these tumors are considered functional, the remaining non-functional cases resemble the clinical picture of the exocrine adenocarcinomas [9] [10].

Histologic evaluation

ICTs display well-differential cells that are arranged in a pattern of nets, trabeculae, or ribbon. It is difficult to predict the behavior of pancreatic neoplasms based on histology. With regards to malignancy, the most remarkable histologic finding is the invasion of neighboring organs and large vasculature, and spread to lymph nodes or elsewhere. However, benign and malignant tumors may resemble each other histologically hence adding to the difficulty in differentiating between the two.

There are no preventive measures for ICTs.

Islet cell tumors (ICTs), also known as pancreatic neuroendocrine tumors, refer to the rare neuroendocrine tumors that stem from the cells of the pancreas. These well-differentiated neoplasms either develop as isolated lesions or arise from genetic syndromes [1]. There are numerous types of islet cells and each produces key hormones that play an integral role in the regulation of metabolic functions.

The main tumors are insulinomas, glucagonomas, and gastrinomas. The clinical presentation reflects the distinctive metabolic effects of these hormones. The former are all functional tumors. In contrast, there are non-functioning tumors which do not cause symptoms until late stages. The etiology of ICTs is not fully elucidated. Some are sporadic and others are likely to develop as a result of genetic and environmental interplay.

ICTs can be detected through a clinical assessment comprised of a physical exam, laboratory tests, and various imaging modalities. Laboratory tests such as measurement of hormone levels, tumor markers, and biochemical studies are key for diagnosis of the disease. Imaging techniques such as computed tomography (CT), endoscopic ultrasonography, and scintigraphy are among the diagnostic modalities that are likely to identify the presence of a lesion.

The therapeutic approach in patients with ICTs is dependent on the location and size of the mass, presence of distant metastasis, presence of co-morbidities, overall clinical picture, and other factors as well. Surgical resection is the preferred therapy, which is the only curative treatment. Furthermore, chemotherapy, hormone therapy, chemoembolization and supportive care may be used in conjunction with surgery as an adjunctive treatment or it may be used as a combination treatment strategy.

An early diagnosis and the absence of metastatic lesions is associated with a good prognosis. The presence of distant metastasis influences the outcome.

What are islet cell tumors?

These are rare tumors that develop in the pancreas. There are numerous types of pancreatic cells called the islet cells. Each type produces a certain hormone that regulates important metabolic functions. For example, the A cells make insulin, the B cells makes glucagon, and the D cells make gastrin. There are other types as well. Some of the tumors are benign while other are malignant. If they are malignant, they spread to other organs such as the liver as well as the lymph nodes.

What are the causes?

The causes are unknown. Some occur sporadically while others develop from a combination of genetic and environmental triggers. Also, these tumors may occur alone or part of genetic syndromes.

What are signs and symptoms?

Each type of tumor produces its own symptoms. In the case of insulinomas, they increase insulin levels in the body, which in turn causes low blood sugar. The following are common symptoms:

• Weakness
• Fatigue
• Headache
• Hunger
• Shaking
• Sweating
• Irritability and nervousness
• Rapid heart beat and sensations
• Fainting
• Seizure
• Coma or even death

Patients with gastrinomas produce gastrin, which is the hormone that releases acid in the stomach. Therefore, it causes stomach and duodenal ulcers. The symptoms are:

• Abdominal pain and discomfort
• Diarrhea
• Bloody vomit

Glucagonomas produce glucagon, which is the hormone that normally increases the blood sugar level. These patients experience:

• Blisters in the mouth, groin, or buttocks
• Diabetes
• Weight loss

How are these tumors diagnosed?

After assessing the patient's symptoms, the physician will obtain the personal and family history of the patient, perform a full physical examination, and order the appropriate blood tests and imaging studies.

Laboratory test include:

• Levels of specific hormones such as insulin, glucagon, or gastrin
• Tumor markers
• Radioimmunoassays

Imaging techniques include:

• Endoscopic ultrasonography with biopsy
• CT scan
• MRI
• Angiography

How are they treated?

There are numerous ways to treat these tumors. Surgical resection of the tumor may cure the disease. The therapeutic approach depends on factors such as the location of the tumor and whether it has spread. The doctor will also assess if the patient is a good surgical candidate on the basis of age and presence of other diseases.

• Surgery: the specific procedure depends on the location of the tumor and whether it has spread
• Chemotherapy: drugs are used to either kill the cancer cells or stop their growth. There are current drug trials testing out new chemotherapy medications
• Embolization: this causes blood to stop flowing to the liver
• Hormone therapy: this can block the effects of the hormone and stop the cancer's growth

Since there are complications caused by these tumors, supportive therapy is important in these patients. For example, patients with ulcers need antacid medications. Also, those with diabetes require insulin or other sugar lowering drugs.

All patients are advised to adhere to healthy diets and to quit smoking.

What is the prognosis?

The earlier the diagnosis, the better the prognosis. Surgical removal of the tumor before it spreads helps the patient achieve long-term survival.

The prognosis also depends on the type of tumor. For example, only 10% of insulinomas are malignant however 60% of gastrinomas and 80% of glucagonomas are malignant.

1. Hoff A, Cote G, Gagel R. Management of neuroendocrine cancers of the gastrointestinal tract: islet cell carcinoma of the pancreas and other neuroendocrine carcinomas. In: Abbruzzese J, Evans D, Willett C, Fenoglio-Preiser C, eds. Gastrointestinal oncology. New York, NY: Oxford University Press, 2004; 780–800.
2. Ries LAG, Young JL, Keel GE, et al. SEER Survival Monograph: Cancer Survival Among Adults: U. S. SEER Program, 1988-2001, Patient and Tumor Characteristics. Bethesda, MD: National Cancer Institute, 2007; NIH Pub. No. 07-6215.
3. Exocrine and endocrine pancreas. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 241-9.
4. Dadan J, Wojskowicz P, Wojskowicz A. Neuroendocrine tumors of the pancreas. Wiadomosci lekarskie. 2008; 61(1-3):43-7.
5. Warner RR. Enteroendocrine tumors other than carcinoid: a review of clinically significant advances. Gastroenterology. 2005;128(6):1668-84.
6. Lavin N. Manual of endocrinology and metabolism. 4th ed. Lippincott Williams & Wilkins; Philadelphia, PA: 2009. pp. 740–741.
7. Schroeder TC, Deftereos G, Lupetin A, et al. A case of primary intrahepatic gastrinoma. Radiology Case Reports. 2012;7(2):577.
8. Davies K, Conlon KC. Neuroendocrine tumors of the pancreas. Current Gastroenterology Reports. 2009; 11 (2): 119-27.
9. Hochwald SN, Zee S, Conlon KC, et al. Prognostic factors in pancreatic endocrine neoplasms: an analysis of 136 cases with a proposal for low-grade and intermediate-grade groups. Journal of Clinical Oncology. 2002; 20(11):2633-42.
10. O'Grady HL, Conlon KC. Pancreatic neuroendocrine tumours. European Journal of Surgical Oncology. 2008; 34(3):324-32.
11. FurukawaH, Mukai K, Kosuge T, et al. Nonfunctioning islet cell tumors of the pancreas: clinical, imaging and pathological aspects in 16 patients. Japanese Journal of Clinical Oncology. 1998; 28(4):255–261.
12. Buetow PC, Parrino TV, Buck JL, et al. Islet cell tumors of the pancreas: pathologic-imaging correlation among size, necrosis and cysts, calcification, malignant behavior, and functional status. American Journal of Roentgenology. 1995; 165:1175–1179.
13. Law JK, Singh VK, Khashab MA, et al. Endoscopic ultrasound (EUS)-guided fiducial placement allows localization of small neuroendocrine tumors during parenchymal-sparing pancreatic surgery. Surgical Endoscopy. 2013; 27(10):3921-3926.
14. Rampurwala MM, Kumar A, Kannan S, et al. Non-functioning pancreatic neuroendocrine tumors--a case report and review of literature. Journal of Gastrointestinal Cancer. 2011; 42(4):257-262.
15. Jensen RT, Berna MJ, Bingham DB, et al. Inherited pancreatic endocrine tumor syndromes: Advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer. 2008; 113(7 Suppl): 1807–1843.
16. Grant C. Insulinoma. Best Practice & Research Clinical Gastroenterology. 2005; 19(5):783–798.
17. Fedorak IJ, Ko TC, Gordon D, et al. Localization of islet cell tumors of the pancreas: A review of current techniques. Surgery. 1993; 113(3):242-249.
18. Frucht H, Doppman JL, Norton JA, et al. Gastrinomas: Comparison of MR imaging with CT, angiography, and US. Radiology. 1989; 171(3):713-717.
19. Wank SA, Doppman JL, Miller DL, et al. Prospective study of the ability of computed axial tomography to localize gastrinomas in patients with Zollinger-Ellison syndrome. Gastroenterology. 1987; 92(4):905-912.
20. Maton PN, Miller DL, Doppman JL, et al. Role of selective angiography in the management of patients with Zollinger-Ellison syndrome. Gastroenterology. 1987; 92(4):913-918.
21. Glover JR, Shorvon PJ and Lees WR. Endoscopic ultrasound for localisation of islet cell tumours. Gut. 1992; 33(1):108-110.
22. Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. New England Journal of Medicine. 1992;326(26):1721-1726.
23. Cummins M, Pavlakis N. The use of targeted therapies in pancreatic neuroendocrine tumours: patient assessment, treatment administration, and management of adverse events. Therapeutic Advances in Medical Oncology. 2013; 5(5):286-300.
24. Vinik AI, Delbridge L, Moattari R,et al. Transhepatic portal vein catheterization for localization of insulinomas: A ten year experience. Surgery. 1991; 109(1):1-11.
25. Evans DB, Skibber JM, Lee JE, et al. Nonfunctioning islet cell carcinoma of the pancreas. Surgery. 1993; 114(6):1175–1182.
26. Sarmiento JM, Que FG. Hepatic surgery for metastases from neuroendocrine tumors. Surgical Oncology Clinics of North America. 2003;12(1):231–24.
27. Fraker DL and Norton JA. Localization and resection of insulinomas and gastrinomas. Journal of American Medical Association. 1988; 259(24):3601-3605.