Content created by Nicolas Jabbour, M.D., NZTI medical director
and Sharad Sharma, M.D., research fellow.

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The pancreas is a spongy, tube-shaped organ about 6 inches long. It is located in the back of the abdomen, behind the stomach. The head of the pancreas is on the right side of the abdomen. It is connected to the duodenum, the upper end of the small intestine. The narrow end of the pancreas, called the tail, extends to the left side of the body.

The pancreas makes pancreatic fluids and hormones. The glandular functions of the pancreas can be divided into;

• Exocrine: The exocrine glands secrete enzymes into ducts that eventually empty into the duodenum. These enzymes then help in the digestion of food as it moves through the intestines.
• Endocrine: The endocrine glands secrete hormones, including insulin, into the bloodstream. Insulin is carried by the blood throughout the rest of the body to assist in the process of using sugar as an energy source. Insulin also controls the levels of sugar in the blood.

The pancreas can be divided into the following 4 anatomical sections: 

• Head - The rightmost portion that lies adjacent to the duodenum 
• Uncinate process - An extension of the head of the pancreas 
• Body - The middle portion of the pancreas 
• Tail - The leftmost portion of the pancreas that lies adjacent to the spleen

In a healthy body, the cells continuously die and are replaced through the process of cell division; however this type of cell division is controlled and has no adverse consequence on the body. In case the cell multiplication becomes unregulated then it can lead to the formation of the growth or tumors. Tumors can be benign or malignant.

• Benign tumors are not cancer. They do not spread to other parts of the body and are seldom a threat to life. Often, benign tumors can be removed by surgery, and they do not recur and grow very slowly.
• Malignant tumors are cancer. They can invade and destroy nearby healthy tissues and organs. Cancer cells also can break away from the tumor and spread to other parts of the body. The spread of cancer is called metastasis. In addition, they grow at a rapid rate as compared to benign tumors and can spread to the lymph nodes.

Commonly pancreatic cancer arises from the exocrine glands and is called adenocarcinoma of the pancreas. The endocrine glands of the pancreas can give rise to a completely different type of tumors, which is rare entity, called as islet cell cancer, or pancreatic neuroendocrine tumors.

Pancreatic adenocarcinoma is among the most aggressive of all cancers. By the time that pancreatic cancer is diagnosed, most people already have disease that has spread to distant sites in the body (spread to the liver or to the lung). Pancreatic cancer is also relatively resistant to medical treatment, and the only potentially curative treatment is surgery.

Intraductal papillary mucinous neoplasia (IPMN) is a type of pancreatic cancer that is beginning to be recognized more frequently. This pancreatic cancer has a better prognosis than other types of pancreatic cancer. Intraductal papillary mucinous neoplasia is usually diagnosed endoscopically.

Spread

Cancer that starts in the pancreas is called pancreatic cancer. As it increases in size, it can spread into the lymphatic vessels and nodes. The lymphatic system includes a network of thin tubes that branch, like blood vessels, into tissues all over the body. Cancer cells are carried through these vessels by lymph, a colorless, watery fluid that carries white blood cells, which fight infection. Along the network of lymphatic vessels are groups of small, bean-shaped organs called lymph nodes. It is necessary to remove the lymph nodes along the path of the spread of the cancer and those lymph nodes, which are enlarged and show signs of cancer.
 
Cancer cells can also be carried through into the bloodstream to the liver, lungs, bone, or other organs. Pancreatic cancer that spreads to other organs is called metastatic pancreatic cancer.

Risk Factors

• Smoking (2-3 times increases the risk compared to non-smoking individuals)
• Advanced age (above 60 years) 
•  Male sex – The male-to-female ratio of pancreatic cancer is 1.3:1. 
•  Chronic pancreatitis- Inflammation of the pancreas, usually from excessive alcohol intake or gallstones 
•  Diabetes mellitus 
•  Race- African American Blacks are prone to risk for having pancreas cancer 
•  Family history of pancreatic cancer- The risk of developing pancreatic cancers three times higher if patients first line relationships (mother, father, sister or brother) had the disease. Moreover, a family history of colon and ovarian cancer also increases the risk of pancreatic cancer.

Most of pancreatic cancers however are seen in the absence of above mentioned risk factors.

Symptoms

In general, pancreatic cancer does not cause any complaints for patients in early stage of disease. In this phase, disease is almost always “silent”.
If symptoms are present, they commonly include;

• Jaundice
• Abdominal pain (radiating to back) 
• Weight loss 
• Loss of appetite 
• Nausea and vomiting 
• Bloating 
• Diarrhea 
• Ascites (fluid in the abdomen) 
• Lymph node swelling on the left side of the neck

Unawared symptoms such as nausea, loss of appetite, vomiting and diarrhea are not unique for pancreatic cancer. Therefore, diagnosis can easily be overlooked in early stage of the disease. People, who think they may be at aforementioned risk for pancreatic cancer with such kind of complaints, should discuss this concern with their primary physician.

Weight loss (means loosing pounds greater than 10% of the body weight in the last 6 months) is also significant for any kind of cancer. Jaundice may be the most important symptom for pancreatic cancer (due to externally compressing mass on the extrahepatic bile duct). Abdominal pain, which is radiating to the back, is also important symptom but ‘unfortunately’ above named symptoms refer late stages (means delayed diagnosis) for pancreas cancer. Hence, majority of patients apply to the hospital in the late stages due to obscure complaints.

Diagnosis

The first step for to establish diagnosis for pancreas cancer is getting natural history of illness (should be asked to the patient “when”, “how”, and “along with complaints”), which means the course of events, personal and family medical history. Social life and possibility of exposure any kind of chemicals should also be demanded.

The second step includes obtaining general appearance and systemic physical examination (hair to toe) of the patient. Physical examination is again obscure because of the pancreas localization. Jaundice, painful view, cachectic appearance are strong evidence for pancreatic cancer, but again ‘unfortunately’ refer late stage of the disease. Therefore, laboratory and radiological investigation are more reliable than physical examination alone, in early stages of pancreatic cancer.

Laboratory tests:

• Complete blood count (CBC) is not significant for pancreas cancer. Mild to moderate anemia can be noticed due to general consumption of erythrocytes that is generally seen in the cancer patients.
• Liver function tests 
  • Elevated serum bilirubin levels (can be occurred when the cancer of the pancreas invades or blocks to the bile duct). The elevation of direct bilirubin level is predominant. 
  •  Transaminases (ALT, AST) levels are being noticed 3-5 times elevated than normal 
  •  Alkaline phosphatase (ALP) is more specific for extrahepatic biliary obstruction unless there is no bone diseases and/or metastasis. 
• Tumor markers: CA 19-9, CEA. These are substances present in the blood in the presence of the cancers and usually their levels correlates with the size and the extend of the disease in the body. Again, these markers are not specific for pancreas cancer. It means pancreas cancer can be seen without any elevation of these markers. It is also correct visa versa. However, if CA 19-9 level is found as elevated, mass of the pancreas or bile duct pathologies should be eliminated.

Radiological evaluation:

• Ultrasonography (US) of the abdomen: In this procedure, an instrument that sends out high-frequency sound waves, which cannot be heard, is passed over the abdomen. The sound waves echo off the pancreas. The echoes form a picture on a screen that looks like a computer screen. Ultrasound feature in pancreatic cancer may include ascites (free fluid in the abdomen), nodular liver enlargement (due to metastasis in the liver), generalized enlargement of the liver (due to obstruction of the extrahepatic bile duct) dilated intrahepatic and extrahepatic bile duct (secondary to compression of the bile duct by the tumor) and sometimes even the pancreatic mass can also be seen by the ultrasound. This modality depends on user. Technician or radiologist should have more experienced particularly for pancreas cancer. On the other hand, since the pancreas localized retroperitoneal area, intestinal air zone does not allow clear vision to technician especially in obese patients.
  • Dupplex US that is giving more information about the vasculature of the mass can obtain additional information such as invasion of the tumor into major vessels (portal vein, inferior vena cava etc).
    
    

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  • Endoscopic ultrasonography is a relatively new procedure that can be used to diagnose pancreatic cancer. For the procedure, an endoscope and on the tip of the endoscope combined with ultrasound probe, which scans adjacent structures (esp. pancreas) of stomach and duodenum. Because the ultrasound probe is closer to the pancreas than with conventional transabdominal ultrasound, it is possible to identify small cancers within the pancreas; in addition, it is very accurate in determining the extent of the growth (i.e. lymphatic metastasis). The cancers also can be biopsied through the endoscope.
• ERCP (Endoscopic Retrograde Cholangio Pancreatography) is a special x-ray of the common bile duct. For this invasive test, a long, flexible tube (endoscope) is passed down the patient's throat through the stomach and into the small intestine. A dye is injected into the common bile duct, and x-rays are taken. The advantages of this procedure are; i. the doctor can also look through the endoscope, ii. Take tissue samples, which can provide preoperative diagnosis of cancer for periampullary region, iii. It also used for putting a stent in the bile duct in case there is very severe jaundice or infection of the bile (cholangitis). 
• Contrast enhanced CT scan of abdomen. CT scan, which is improved X-Ray machine, takes multiple images of the body in cross sections and the all the images are viewed through the computer. It is used in the context of the pancreatic cancers to delineate the size and the local extend of the tumor. Various CT findings that may be seen in the context of the pancreatic cancer include ascites, hepatomegaly, dilated bile duct and intrahepatic ducts, size of the tumor and local extent like involvement of the adjacent major vessels
• Magnetic resonance imaging (MRI) is a novel, non-invasive modality which gives detailed information for pancreatic cancer. It is also important to surgeon that can easily show relationship of mass with adjacent structure esp. splancnic vessels, preoperatively.
• Additionally, magnetic resonance cholangiopancreatography (MRCP) is an alternative to ERCP for investigating biliary obstruction. The use of MRCP may prevent the use of unnecessary invasive procedures. In recent meta-analyze, it has been shown that MRCP is comparable to ERCP for diagnosing biliary obstruction. Unlike ERCP, MRCP does not offer any therapeutic intervention.
• An angiogram, a special x-ray for blood vessels after injecting the dye. This investigation is rarely required because a good quality triphasic CT scan and/or MRI with fine cuts offer and excellent evaluation of the tumors and its relation to the surrounding vessels. 
• Laparoscopy, this procedure help the doctor determine the stage, or extent, of the disease. Knowing the stage helps the doctor plan the treatment. It is a common practice to subject the patient to laparoscopy before proceeding to major resection as sometimes the presence of small deposits of cancer in the abdominal cavity can be detected and thus helping avoid unnecessary laparotomy. However, with continuous improvement in the quality of CT scan and MRI, this procedure is usually unnecessary.

Staging:

All diagnostic tests are serving the understanding of the current stage of pancreas cancers. Physicians are generally following the algorithm, which is the best for individual patients.

Current Staging of Pancreas Cancer:

TNM definition

Primary tumor (T)

TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ
T1: Tumor limited to the pancreas, 2 cm or less in greatest dimension
T2: Tumor limited to the pancreas, more than 2 cm in greatest dimension
T3: Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery
T4: Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor)

Regional lymph nodes (N)

NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis

Distant metastasis (M)

MX: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis

Management
Treatment for pancreatic cancer depends on a number of factors. Among these are the type, size, and extent of the tumor as well as the patient's age and general health. A treatment plan is tailored to fit each patient's needs. Various options include;

Surgical Options:
Cancer of the pancreas is curable only when it is found in its earliest stages, before it has spread. Otherwise, it is very difficult to cure. However, it can be treated, symptoms can be relieved, and the quality of the patient's life can be improved. Surgical option include;

1. Radical surgery: In this type of surgery, every attempt is made to achieve R0 resection (no microscopic cancer tissue left in the filed of the surgery and elsewhere in the body).
   
   • Whipple’s Procedure – This procedure is well known a radical surgery of the pancreas. It is major surgery of the abdomen and can last from 3-8 hours depending on the complexity. The procedure involves the resection of the head of the pancreas along with the gall bladder, bile duct, duodenum, portion of the stomach and all the lymph nodes lying along with the bile duct.
     
     If the tumor invades part of the portal/superior mesenteric vein, the involved vein may be removed in selected patients along with the tumor. Continuity of portal vein is reestablished either primarily (up to 2 cm of portal vein may be removed without needing a graft), using a graft (Jugular vein of reconstructed saphenous vein) or venous patch (saphenous vein).
     
     The following patient has a neuroendocrine tumor of the pancreas with complete involvement of the portal vein/splenic vein junction. He underwent Whipple procedure with excision of 2 cm of the portal vein. The portal vein was reconstructed primarily.
     
     The following patient have a neuroendocrine tumor partially involving the portal vein. Whipple procedure was done. Portal vein was partially removed and reconstructed using saphenous vein patch.
     
   • Total pancreatectomy: The procedure is more extensive and radical than Whipple’s operation and includes the removal of whole of the pancreas, in the context of pancreatic cancers it is done when almost whole of the pancreas is involved by cancer.
     
   • Distal pancreatectomy with splenectomy: Performed in patient with tumor where the growth is confined to the tail of the pancreas. Splenic preservation depends on the interaction of the mass with splenic vessels and the nature of the mass i.e. benign or malignant. In malignant cases, splenectomy has to be performed along with the pancreatic mass removal.
     
2. Limited Resections: This resection type is performing for benign lesions of periampullary area. It is usually called ampullectomy since it involve the resection of the ampulla of Vater with reconstruction on the pancreatic and biliary duct.
   
   • Distal pancreatectomy with spleen preservation: Technically demanding procedure, used for benign tumors of the tail of the pancreas has the advantage of preserving the spleen.
     
     This patient have a complex cystic lesion in the tail of the pancreas suggestive of benign disease. She underwent splenic preserving distal pancreatectomy. 
     
3. Total pancreatectomy with resection of the vessels and reconstruction 
   
4. Palliative surgery; these procedures are attempted with the intention of providing relief from the disabling symptoms or providing a better quality of life to the patient. In these cases the disease is usually too advanced for undertaking a major resection.
   • Gastrojejunostomy; provides relief from obstruction of the gastric outlet
   • Double bypass; provides relief from obstruction of the gastric outlet and the obstruction of the bile duct.
   • Celiac ganglion block; used in cases where the advanced disease causes crippling pain the abdomen which does not respond to usual painkillers. 
   • Biliary stenting: This involves placing a hollow tube, called a stent, into the bile duct to keep it open despite the external pressure from a growing pancreatic tumor. This prevents jaundice by allowing the bile to flow freely and unimpeded from the liver, past the pancreas, and into the intestine. This procedure is usually performed with an endoscope by a gastroenterologist, but it can also be performed percutaneously (through the skin) under CT guidance by an interventional radiologist.

RADIATION THERAPY (RADIOTHERAPY)

It uses high-powered rays to damage cancer cells and stop them from growing. Radiation is usually given 5 days a week for 5 to 6 weeks. This schedule helps to protect normal tissue by spreading out the total dose of radiation. The patient doesn't need to stay in the hospital for radiation therapy. Radiation is also being studied as a way to kill cancer cells that remain in the area after surgery. In addition, radiation therapy can help relieve pain or digestive problems when the common bile duct or duodenum is blocked. Side effects include;

• Fatigue
• Skin reactions (redness, dryness, desquamation-flakes on the skin) 
• Nausea and vomiting

CHEMOTHERAPY:

In this modality chemotherapeutic agents are using for killing cancer cells. Either one drug or a combination of drugs may be used to increase the response rate. Chemotherapy may be given by mouth or by injection. Chemotherapy is usually given in cycles; a treatment period followed by a recovery period, then another treatment period, and so on. The side effects of chemotherapy depend on the type of drugs that are given. Chemotherapy affects rapidly growing cells, such as blood-forming cells, those that line the digestive tract, and those in the skin and hair. Complication of the chemotherapy includes;

• Lowered resistance to infection,
• Less energy, 
• Loss of appetite, 
• Nausea and vomiting 
• Mouth sores 
• Loss of hair.

PANCREATIC ENDOCRINE TUMORS 

Introduction

Pancreatic endocrine tumors are rare tumors of neuroendocrine origin, which usually arise in proximity on with the pancreas. Roughly, 80%of these secrete important hormones, which results in specific symptoms and approx 20% are nonfunctional and they do not produce symptoms until they grow big in size. These tumors appear identical in microscopy but they can be differentiated in the basis of specific immunohistochemical stains.
The majority of pancreatic endocrine tumors can be recognized on the basis of the resulting clinical syndrome because of excessive peptide secretion, and associated biochemical abnormalities. These tumors are named after the predominant hormone that they secrete

Types

• Insulinomas are the most common type of hormone-secreting tumor, accounting for 60 percent of all pancreatic endocrine tumors. Roughly 90 % of these tumors are benign, 90% are single, 5-10% are part of MEN syndrome (multiple endocrine gland tumors-pancreas, pituitary, parathyroid tumors)
• Gastrinomas are the second most common type, occurring in about 20 percent of cases. (tumor of the gastrin producing cells) 
• Glucagonomas (tumor of the glucagon producing cells) 
• Somatostatinomas and tumors secreting vasoactive intestinal peptide (VIP) are much rarer. 
• Carcinoids they are different in the sense that they can arise anywhere in the gastrointestinal tract as compared to the above mentioned tumors which are specific to the pancreas

Symptoms

Insulinoma: The characteristic clinical manifestation of an insulinoma is fasting hypoglycemia, with symptoms of sympathetic stimulation such as sweating, tremors, fainting, visual changes, palpitation. These manifestations are episodic and can be terminated by the ingestion of sugar. The hypoglycemia is primarily due to reduced hepatic glucose output rather than increased glucose utilization.

Carcinoid tumor: The majority of patients with carcinoid tumors are asymptomatic, and the tumor is diagnosed incidentally at endoscopy, surgery, or autopsy .The initial symptoms of carcinoid may be nonspecific. When present, symptoms correlate with the location and extent of the tumor.

• Foregut tumors: the symptoms associated with foregut carcinoid tumors vary with the site. Gastric carcinoids may present with peptic ulcer disease, abdominal pain or bleeding, and occasionally with atypical carcinoid syndrome. In comparison, duodenal carcinoids may produce duodenal or biliary obstruction or duodenal ulcer.
• Bronchial carcinoid can have a variant carcinoid syndrome with flushes of the skin that are severe and prolonged, lasting hours to days. These flushes may be associated with disorientation, anxiety, and tremor.
• Midgut tumors: The most common initial symptom of small intestinal carcinoids is abdominal pain; the pain is usually vague and nonspecific. Intermittent obstruction is seen in 25 percent of all small intestinal carcinoids, obstruction may be caused by intraluminal tumor
•  Hindgut tumors: The hindgut carcinoids (transverse, descending colon, and rectum) are usually nonsecretory. When symptoms do occur, they are the same as those of cancer, changes in bowel habit, obstruction, or bleeding. 
• Carcinoid syndrome: Carcinoid syndrome is the term applied to a constellation of symptoms mediated by various humoral factors elaborated by some carcinoid tumors especially when they have spread to the liver. It is characterized by episodic flushing, wheezing, diarrhea, and the eventual development of carcinoid heart disease. Carcinoid heart disease is characterized by the development of plaque-like endocardial thickening involving the right side of the heart. Tricuspid regurgitation is a nearly universal finding, and, when severe, may lead to right sided heart failure.

VIPoma: The tumors produce vasoactive intestinal peptide (VIP) and the manifestation are called VIPoma syndrome or pancreatic cholera syndrome or Verner-Morrison syndrome, or watery diarrhea, hypokalemia, and hypochlorhydria or achlorhydria (WDHA) syndrome. It is characterized by severe diarrhea and the stool volume exceeds 700 mL/day in all patients (even during fasting) and 3 L/day in approximately 70 percent. The stools are tea-colored, odorless, with features of a secretory diarrhea such as persistence with fasting, high sodium concentration. Associated symptoms include flushing episodes and symptoms such as lethargy, nausea, vomiting, muscle weakness, and muscle cramps.

Glucogonoma- The clinical syndrome classically associated with glucogonoma includes necrolytic migratory erythema (Red colored lesions of the skin involving the face, perineum, and extremities which over a period of 7 to 14 days enlarge and coalesce. Central clearing then occurs, the affected areas are often pruritic and painful) cheilitis, diabetes mellitus, anemia, weight loss, venous thrombosis, and neuropsychiatric symptoms.

Diagnosis

Insulinoma

• Inappropriately high serum insulin concentrations during an episode of hypoglycemia
• Relief of symptoms after consumption of glucose

Carcinoid

• 5-hydroxyindoleacetic acid (HIAA) in 24-hour urine collections has been commonly used for monitoring of patients with metastatic and midgut carcinoid tumors. The normal rate of 5-HIAA excretion ranges from 2 to 8 mg/day (10 to 42 µmol/day). While urinary 5-HIAA excretion in patients with the carcinoid syndrome ranges from 99 to 2070 mg/day.
• Plasma chromogranin A is a more sensitive marker than urinary 5-HIAA in patients with carcinoid tumors. 
• Blood serotonin concentration: Determination of the whole blood serotonin concentration is often helpful when urinary 5-HIAA testing yields equivocal results. The mean fasting blood serotonin concentration in normal subjects ranges from 71 to 310 ng /mL (0.4 to1.8 µmol/L). While patients with the carcinoid syndrome had markedly elevated values, from 790 to 4500 ng /mL

Gastrinoma

• Fasting serum gastrin concentration: Fasting serum gastrin should be measured in any patient suspected of having the Zollinger-Ellison syndrome. The upper limit of normal for serum gastrin is 110 pg/mL. In the presence of gastric acid (a gastric pH below 5.0), a serum gastrin value greater than 1000 pg/mL (475 pmol /L) is virtually diagnostic of the disorder. 
• Secretin stimulation test: The secretin stimulation test is performed by administering 0.4 µg of secretin per kg body weight intravenously over one minute; a baseline serum gastrin is measured twice before the secretin is administered and classically 2, 5, 10, 15, and 20 minutes later. Several criteria have been proposed to define a positive test; one of the most commonly used is a rise in serum gastrin by 200 pg/mL (95 pmol /L) or more 
• Gastric acid secretion studies-no longer performed 
• Serum chromogranin A is a general marker for neuroendocrine tumors that does not differentiate between the various subtypes of tumors. Nevertheless, it is elevated in most patients with gastrinoma, and the level of elevation correlates with tumor volume.

VIPoma

• High volume secretory diarrhea
• Serum VIP concentration in excess of 75 pg/ mL. A single elevated VIP level should be confirmed by additional testing.

Glucagonoma 

• It is associated with markedly elevated serum concentrations of glucagon (>500 pg/mL), multiple molecular weight forms of glucagon, and the classical clinical syndrome.

Localization

Once a diagnosis of a hormone-secreting tumor is established, the primary tumor must be localized and the possible presence of metastases must be determined. If metastatic disease is not present, identification of the primary tumor is critical so that curative surgical resection can be attempted. If metastatic disease is present, its extent must be determined so that optimal therapy can be instituted .These tumors are often small and hard to detect by radiological techniques.

• Endoscopic ultrasonography (EUS) provides high-resolution imaging of the pancreas and can distinguish structures as small as 2 to 3 mm in diameter. EUS is more accurate than computed tomography or ultrasonography for detection and localization of these tumors. An important limitation of this test is the dependence on the operator experience and an inability to consistently visualize the pancreatic tail.
• Somatostatin-receptor scintigraphy: Many pancreatic endocrine tumors have high concentrations of somatostatin receptors and can therefore be imaged with a radiolabeled form of the somatostatin analogue octreotide (111-indium pentetreotide). This technique has proven particularly effective for visualizing gastrinomas, glucagonomas, nonfunctioning pancreatic tumors, and carcinoid tumors. It has the advantage of instantaneous whole body scanning, which also allows detection of distant metastases. Accuracy can be improved further with the addition of single photon emission computed tomography (SPECT) to somatostatin receptor scintigraphy since SPECT permits more accurate differentiation between areas of abnormal and normal uptake in the abdomen. 
• MRI appears to have greater sensitivity for detection of liver metastases compared with planar or SPECT somatostatin receptor scintigraphy.

Computed tomography is also noninvasive and readily available. Without contrast the pancreatic tumor appear isodense and the liver metastasis appears hypodense, after the administration of the contrast the pancreatic tumor becomes hyperdense and the liver tumor becomes isodense. CT scans can usually detect tumors which are more than 2 cm and as nonfunctioning tumors, VIPoma and glucagonoma are usually large (>3 cm) at the time of diagnosis CT scan are the investigation of choice.

• Angiography and arterial stimulation venous sampling being invasive in nature it remains an important tool for the detection of both primary and metastatic tumors that elude identification by other imaging methods. Arterial stimulation venous sampling involves selective injections into arteries supplying the pancreas of a stimulating secretagogue (secretin for gastrinomas and calcium gluconate for insulinoma) with subsequent sampling of the hepatic venous effluent
• Intraoperative localization techniques: Intraoperative ultrasonography allows high resolution examination of the pancreas. When combined with palpation of the organ during surgery it the remains the best test to detect these tumors.

Best tests for localization

• Gastrinoma: SPECT imaging with pentetreotide, if no tumor is found, but clinical suspicion remains high, EUS should be performed to locate the primary tumor. If these studies fail to document metastatic disease, MRI or helical CT should be used. Finally, if these relatively noninvasive tests fail to identify the tumor, the patient should undergo angiography or be taken to the operating room, where intraoperative palpation and ultrasonography can be performed
• Carcinoid: Pentetreotide imaging can identify the vast majority of carcinoid tumors that have metastasized to the liver. If negative, helical CT should be done to examine the abdomen and the chest. 
• Insulinoma: Because pentetreotide imaging fails to identify most insulinomas, it should not be used as a primary imaging test. Hence, when an insulinoma is suspected, MRI or CT should be performed. If no primary tumor or metastatic lesions are found, EUS should be used to locate the primary tumor. 
• Glucagonoma, somatostatinoma, VIPoma, and nonfunctioning pancreatic endocrine tumors: Pentetreotide imaging may be utilized for the detection of these tumors. These tumors usually are large (>3 cm) and can thus be readily detected by CT.

Management

Insulinoma

1. Surgical removal is the treatment of choice. The options include
   • Enucleation 
   • Distal Pancreatectomy 
   • Whipple procedure 
   • Total Pancreatectomy (reserved for patents with MEN syndrome or those with extensive malignant tumors) 
   • Liver resection and liver transplantation in very selected patients
2. Medical therapy should be considered in the patients who are not candidates for or refuses surgery, or who have metastatic disease. 
   • Diazoxide: It diminishes insulin secretion and is used for controlling hypoglycemia 
   • Octreotide: An analog of somatostatin (growth hormone-inhibitory hormone) inhibits GH secretion, but in large doses, also inhibits the secretion of TSH, insulin, and glucagons

Carcinoid tumors 

• Surgical removal of the tumor is the treatment of choice.
• Octreotide is used for the control of symptoms, in patients where disease is unresectable. One problem with octreotide is the requirement for frequent dosing, a limitation that is abrogated by availability of long-acting preparations. A depot form of octreotide, which can be administered monthly, is equally effective and significantly easier to administer. The addition of IFN-α to octreotide or lantreotide has also been effective in controlling symptoms in patients who are resistant or refractory to octreotide alone. 
• RFA and cryoablation: these approaches to the treatment of hepatic metastases include radiofrequency ablation (RFA) and cryoablation, either alone or in combination with surgical debulking.

These approaches can be performed percutaneously or laparoscopically, and both appear to be less morbid than either resection or hepatic artery embolization. 

• Liver transplantation -the number of patients with liver-isolated metastatic disease in whom orthotopic liver transplantation (OLT) has been attempted is small, and the role of OLT is unclear and limited to very selected group of patients.

VIPoma and Glucagonoma:

• Somatostatin analogs are highly effective in controlling the symptoms associated with efficacy somewhat less predictable than symptomatic patients with insulinoma or gastrinoma.
• Surgery is used for resectable hepatic lesions.
• Chemotherapy has minor activity, response rates with streptozocin and doxorubicin as high as 69 percent are reported
• RFA and cryoablation- these approaches to the treatment of hepatic metastases include radiofrequency ablation (RFA) and cryoablation, either alone or in conjunction with surgical debulking.
• These approaches can be performed percutaneously or laparoscopically, and both appear to be less morbid than either resection or hepatic artery embolization. 
• Liver transplantation -the number of patients with liver-isolated metastatic disease in whom orthotopic liver transplantation (OLT) has been attempted is small, and the role of OLT is unclear

Gastrinoma

• Patients with gastrinoma often achieve excellent symptomatic relief simply with proton pump inhibitors.
• Surgery — Patients with a sporadic gastrinoma who do not have evidence of metastatic spread of disease should be offered exploratory laparotomy with curative intent. Resection of hepatic metastases can effectively palliate symptoms of hormonal hypersecretion. The majority of cases will not be cured by surgery; however, given the slow-growing nature of the tumor, extended survival is often possible 
• RFA and cryoablation- these approaches to the treatment of hepatic metastases include radiofrequency ablation (RFA) and cryoablation, either alone or in conjunction with surgical debulking. These approaches can be performed percutaneously or laparoscopically, and both appear to be less morbid than either resection or hepatic artery embolization. 
• Liver transplantation -the number of patients with liver-isolated metastatic disease in whom orthotopic liver transplantation (OLT) has been attempted is small, and the role of OLT is unclear 
• Hepatic artery embolization-Hepatic artery occlusion or embolization is an alternative for patients who are not candidates for hepatic resection. A commonly used technique is the infusion of gelfoam powder into the hepatic artery through an angiography catheter, with or without antineoplastic agents

The efficacy of this approach for liver-isolated metastatic disease is based upon the principle that metastases derive most of their blood supply from the hepatic artery, whereas hepatocytes derive nutrients from the portal venous circulation.