Insulinomas are the most common type of NET. They occur more commonly in females in the fifth or sixth decade. These tumors secrete insulin or less commonly proinsulin which lead to the clinical syndrome of hypoglycemic symptoms, low blood glucose, and relief with administration of glucose, referred to as Whipple’s triad. These symptoms are often exacerbated with fasting and relieved by food consumption. Patients will have an elevated serum insulin or proinsulin level in the setting of a low or normal glucose level (ratio >0.3). A serum C-peptide level should be obtained (and >1.7 ng/ml in the case of insulinoma) to rule out exogenous insulin administration. Occasionally, patients may be admitted to the hospital for diagnosis. During this time, patients are fasted and serum insulin levels monitored for up to 72 hours. The majority of insulinomas are small (< 2cm), solitary, benign (>90%) and uniformly distributed throughout the pancreas. CT, transabdominal ultrasound, and MRI have a <50% sensitivity. Unlike other NETs, insulinomas are rarely detected with somatostatin (octreotide) radionucleotide scanning. Endoscopic ultrasound has reported sensitivities up to 80%. Arteriography with portal venous sampling has sensitivity in the 80-90% range but is an invasive procedure. The most sensitive imaging technique is intraoperative ultrasound, which localizes over 90% of insulinomas. Therefore, after the biochemical diagnosis of insulinoma is made, we usually obtain a CT scan and, if negative, an endoscopic ultrasound. Even if the lesion does not localize, we would still proceed to the operating room and perform intraoperative palpation and ultrasound for localization. The treatment of choice for insulinoma is complete resection of the tumor. Because the vast majority of insulinomas are benign, enucleation is performed when possible.
Gastrinoma (Zollinger-Ellison Syndrome)
Gastrinomas are the second most common type of pancreatic NE tumor and occur in 0.1-1% of all patients with peptic ulcer disease. They occur more commonly in males and usually in the sixth or seventh decade. About 75% occur sporadically while 25% are associated with the MEN-1 syndrome. The diagnosis of gastrinoma is confirmed by a basal serum gastrin level >1000 pg/ml off proton-pump inhibitors with a gastric pH less than 5. A basal gastrin levels >250 pg/ml is suggestive and can be confirmed with a secretion stimulation test showing a gastrin elevation of >200 pg/ml above baseline. A similar but less sensitive test for gastrinoma is the calcium infusion test showing a gastrin rise of more than 50% after administration of calcium gluconate. A basal acid output of >15 mEq/hour supports the diagnosis of gastrinoma.
The gastrinoma triangle is a well-described anatomic region in which 90% of gastrinomas can typically be found. The points of the gastrinoma triangle are the junction of the pancreatic body and neck, the junction of the second and third portions of the duodenum, and the junction of the cystic and common bile ducts. Sixty percent of gastrinomas are located within the pancreas and 30% are located within the duodenum. In contrast to insulinomas, most gastrinomas are malignant (60%). Gastrinomas are very small and CT, transabdominal ultrasound, and MRI only detect <50% of lesions. Octreotide scanning has a reported sensitivity of 80-90% and when combined with endoscopic ultrasound will detect over 90% of all gastrinomas. Similar to insulinomas, gastrinomas not detected pre-operatively can be usually found at the time of surgery with intraoperative palpation and ultrasound.
As with all NETs, the only chance for complete cure of gastrinoma is surgical resection. The role of operative exploration in patients with sporadic gastrinomas is relatively well defined. Most of these non-MEN 1 gastrinomas are solitary, identifiable at laparotomy, and resectable with simple enucleation. Formal pancreatic resections are typically reserved for patients with local tumor invasion. Duodenotomy should be routinely performed for all patients with ZES. The role for surgical exploration in patients with ZES and MEN 1 is extremely controversial. The controversy centers on the question as to whether surgical resection can increase the chances for prolonged postoperative eugastrinemia and decrease the chances for malignant progression of the disease. One approach advocates aggressive, early surgical exploration for all patients with ZES, MEN 1, and no evidence for hepatic metastases. Others recommend selective exploration for those patients who fail medical management and/or have larger tumors greater than 3 cm.
Pancreatic Polypeptide-Secreting Tumor (Ppoma)
The third most common type of islet cell tumor is a PPoma. The function of pancreatic polypeptide is not completely understood. Patients present with weight loss, jaundice, and abdominal pain. The diagnosis is confirmed by pancreatic polypeptide levels > 300 pg/ml. Because other NETs many secrete pancreatic polypeptide, to be classified as a PPoma, > 50% of the tumor must stain for pancreatic polypeptide by immunohistochemistry. PPomas tend to be large by the time of diagnosis and are usually seen in CT or MRI. Octreotide scanning is also sensitive for the detection of these tumors. Surgical resection is the only chance for cure for those patients without widely metastatic disease. Since many of these tumors are large and located in the pancreatic head, ampulla, or duodenum when diagnosed, a pancreaticoduodenectomy may be needed.
Patients typically present in the fifth decade of life with an even gender distribution. Hepatic metastases have been reported in more than 50% of patients at the time of diagnosis. Glucagonomas are very rare tumors that cause the “4D syndrome”: diabetes, dermatitis, deep vein thrombosis, and depression. Additional findings associated with glucagonoma include cheilitis, anemia, weight loss, hypoaminoacidemia, and other neuropsychiatric symptoms. Patient often present with elevated glucose and a characteristic rash called necrolytic migratory erythema seen in the face, lower abdomen, perineum, and lower extremities. Skin biopsy can occasionally confirm the diagnosis. Because of the risk of deep vein thrombosis (>30%), heparin prophylaxis is needed. The diagnosis of glucagonoma is made by a serum glucagon level of > 500 pg/ml. Because glucagonomas are rare and often go undiagnosed for many years, they tend to be very large at the time of presentation (>5 cm) and metastatic (75%). Thus, CT or MRI often detects the lesion. Octreotide scanning has a sensitivity exceeding 75%. Glucagonomas tend to be solitary and are more commonly occur in the body and tail of the pancreas. A distal pancreatectomy is usually the operation of choice for these tumors without evidence for metastatic disease; however, enucleation, partial resection, and pancreaticoduodenectomy have all been described and are appropriate options based on the location of the tumor.
Vasoactive Intestinal Peptide-Secreting Tumor (Vipoma)
VIPomas are also extremely rare tumors that cause the “WDHA syndrome”: watery (secretory) diarrhea, hypokalemia, and achlorhydria. The WDHA syndrome has also been called pancreatic cholera or Verner-Morrison syndrome. Other symptoms include abdominal pain, flushing, muscle weakness, and weight loss and can often been mistaken for carcinoid syndrome. The diagnosis is made by a serum VIP level > 200 pg/ml. These rare tumors occur with a frequency of 1 per 10,000,000 per year. These tumors arise in the pancreas 90% of the time, but have also been described in the colon, bronchus, adrenals, liver, and sympathetic ganglia. Adults typically present between ages 30 and 50 years. VIPomas are typically solitary and greater than 3 centimeters in diameter with 75% located in the tail of the pancreas. The majority of VIPomas can be localized with CT or MRI. Octreotide scanning is also highly sensitive. Sixty to eighty percent are metastatic at the time of diagnosis. The first course of action once VIPoma has been diagnosed is to aggressively correct the dehydration and metabolic derangements intrinsic to the syndrome. Octreotide can stop the diarrhea and allow for the correction of hypokalemia and other metabolic abnormalities in the majority of these patients. Occasionally, enucleation can be performed but resection often consists of a distal pancreatectomy.
Somatostatinomas are the rarest pancreatic NE tumor. Patients present with symptoms such as abdominal pain, weight loss, steatorrhea, hyperglycemia, and cholelithiasis. An elevated somatostatin level (>10 ng/ml) confirms the diagnosis. The median age at diagnosis is 50, and gender distribution is equal. Most somatostatinomas are solitary. Fifty-six to seventy percent of these tumors are located in the pancreas. Even though somatostatin-secreting delta cells are diffusely located throughout the pancreas, two-thirds of pancreatic somatostatinomas are located in the head of the pancreas. Most of the extrapancreatic tumors are located in the duodenum, ampulla, or remaining small bowel. Somatostatinomas often go undiagnosed for years and therefore very large (> 5cm) at the time of presentation. The majority of somatostatinomas are metastatic are presentation (90%) and can be localized with CT or MRI. Octreotide scanning is also highly sensitive. Most somatostatinomas require a pancreaticoduodenectomy for resection.
Non-Functional Islet Cell Tumors
Non-functional islet cell tumors histologically resemble other NETs but do not secrete biologically active substances that result in a detectable clinical syndrome. Most likely, they either secrete low levels of hormones, biologically inactive hormones, or hormones that are presently unidentified. Most of these tumors, however, secrete chromogranin A which can be detected in the serum and thus confirm the diagnosis. Most patients present with abdominal pain or other vague symptoms prompting diagnostic studies. Almost all of non-functional islet cell tumors are diagnosed by CT or MRI due to the lack of symptomatology. The tumors are very large at the time of presentation (>6cm) and >50% are malignant. Most non-functional islet cell tumors arise in the pancreatic head and require a pancreaticoduodenectomy for resection.
Otto Lubarsch made the first to description of these small multicentric tumors in 1888, but it was Oberndorfer in 1907 that first applied the term “karzinoid”. In 1954, Thorson was the first to describe the clinical “carcinoid syndrome”. Carcinoids are derived from Kulchinsky or enterochromaffin cells, which are part of the diffuse neuroendocrine cells of the gut. The incidence of carcinoid tumors is estimated to be 1-2 cases per 100,000 people, accounting for just 0.5% of all malignancies. The diagnosis of a carcinoid tumor is based on histology with confirmation by immunohistochemical staining with neuroendocrine markers. Serotonin or 5-hydroxytryptamine (5-HT) is the most commonly secreted substance and can cause the symptoms of the classic “carcinoid syndrome”, consisting of flushing, diarrhea, bronchoconstriction, and ultimately valvular heart disease. Unfortunately, histologic examination cannot predict the aggressiveness or metastatic potential of carcinoid tumors. Malignancy is based upon the presence of metastatic disease. The most common sites of metastases are the lymph nodes, liver, and less frequently bone. The prognosis of carcinoid tumors varies greatly depending on the location of the tumor and the extent of spread at the time of diagnosis.
Pulmonary Carcinoid Tumors
Pulmonary carcinoids account for 2% of primary lung tumors and about 25% of all carcinoid tumors. These tumors can be classified as typical or atypical based upon their histologic features. Two-thirds of pulmonary carcinoids are considered typical, are found in a perihilar location, and most commonly present in the fifth decade. The carcinoid syndrome occurs in less than 5% of these patients, with more common symptoms being recurrent pneumonia, cough, hemoptysis, or chest pain. Atypical carcinoids, defined by their increased cellular atypia, typically occur in the periphery of the lungs and arise in older patients. Their course is more aggressive with up to 50% having lymph node metastasis, leading to a 5-year survival of only 40-75%.
Gastric Carcinoid Tumors
Type 1 gastric carcinoids are the most frequent, accounting for 63-75% of cases. These tumors develop in patients with type A chronic atrophic gastritis (CAG-A) and are believed to be due to overproduction of gastrin in these patients. These tumors tend to be non-functional and asymptomatic. Type 1 gastric carcinoid tumors rarely metastasize. Type 2 gastric carcinoids are rare (0-10%) and arise in the setting of Multiple Endocrine Neoplasia 1 and Zollinger-Ellison syndrome. These tumors are often multiple and display a low grade of malignant behavior. Hypergastrinemia plays an important role in stimulating the growth of both Type 1 and 2 gastric carcinoids, although hypergastrinemia alone is not believed to be causative. Type 3 gastric carcinoids are the sporadic variety which accounts for 13-20% of tumors. Gastric carcinoids may cause an atypical carcinoid syndrome: flushing, hypotension, lacrimation, edema, and bronchoconstriction or may secrete adrenocorticotropic hormone (ACTH). They may secrete small amounts of 5-hydroxytryptophan (5-HTP), but since they lack the enzyme aromatic acid decarboxylase, they are unable to convert it to its active form of 5-HT. Therefore, 5-HT levels and urinary 5-HIAA levels are often normal in these patients.
Small Intestinal Carcinoid Tumors
The most common location for carcinoid tumors is the small bowel (29%), with over half being in the distal ileum. Patients typically present with symptoms of abdominal pain or intestinal obstruction. These lesions can create a characteristic fibrotic reaction in the mesentery that may cause kinking of the bowel leading to intermittent obstruction or intestinal ischemia. These tumors tend to be slow growing and have a prolonged disease course. The classic carcinoid syndrome is present in only 5% of patients. The majority of these lesions have spread to the lymph nodes (39%) or have distant metastases (31%) at the time of diagnosis. The 5-year survival is 65% with localized/regional disease, but falls to 36% when distant disease is present.
Appendiceal Carcinoid Tumors
The majority of appendiceal carcinoids are diagnosed incidentally during surgery. Over half of patients with appendiceal carcinoids present with signs and symptoms suggestive of acute appendicitis. The prognosis of appendiceal carcinoids is very good. The 5-year survival is 94% for local disease, 85% for regional metastasis, and 34% when distant metastases are present.
Colonic Carcinoid Tumors
Colonic carcinoid tumors are rare and typically present during the seventh decade of life. These tumors are more frequent in women and are often symptomatic at the time of diagnosis, with abdominal pain being the most common complaint. These tumors tend to be large and are most commonly located in the right colon. At the time of diagnosis, approximately 44 % have spread to the lymph nodes and 38% have spread to distant locations. The overall 5 year survival of these lesions is 25-41%.
Rectal Carcinoid Tumors
About 50% of these tumors are diagnosed incidentally on routine endoscopy. The size of these tumors is closely correlated to their risk of metastasis as well as their survival. The five year survival rates for these patients is 81% if there is only local disease, 47% if regional metastasis are present, and 18% if distant metastases are found.