ABSTRACT: Neuroendocrine tumors of the pancreas (islet cell tumors) and of the luminal gastrointestinal tract (carcinoids) are a heterogeneous group of epithelial neoplasms that share certain common characteristics. First, they are similar histologically and are difficult to distinguish under light microscopy. Second, they can be associated with hypersecretory syndromes. Third, they are generally slow-growing and have a better prognosis than adenocarcinomas at the same site; however, they do become incurable when they progress to unresectable metastatic disease. Surgery is the only curative treatment and is recommended for most patients for whom cross-sectional imaging suggests that complete resection is possible. This article reviews the surgical management of gastrointestinal neuroendocrine tumors, including the preoperative control of hormonal symptoms, extent of resection required, postoperative outcomes, and differing management strategies as determined by whether the tumor has arisen sporadically or as part of a familial disorder, such as multiple endocrine neoplasia type 1 (MEN1).
Neuroendocrine tumors (NETs) are a diverse group of epithelial tumors that can originate from almost any organ derived from the primitive endoderm, including pancreatic islet cells (pancreatic NETs), diffuse neuroendocrine cells distributed throughout the gut (gastrointestinal carcinoids), the respiratory epithelium (bronchial carcinoids), the thymus (thymic carcinoids), and parafollicular cells distributed within the thyroid gland (medullary thyroid carcinoma). Despite their different sites of origin, however, these tumors can be considered as a common entity since they are very difficult to distinguish under the microscope and can share certain common biological features, such as an association with hormonal hypersecretory syndromes. The purpose of this article is to review the important aspects of the diagnosis, preoperative treatment, and operative treatment of neuroendocrine tumors of the pancreas and the luminal gastrointestinal tract. Specific management strategies, which are dependent on whether the tumor has arisen sporadically or as part of a familial disorder, such as multiple endocrine neoplasia type 1 (MEN1), are also discussed.
Pancreatic Neuroendocrine Tumors
Pancreatic NETs (PNETs) account for 2% of all pancreatic neoplasms.[1] Their annual incidence in the United States is estimated to be approximately three cases per million persons but appears to be increasing.[2] The majority of these tumors can be associated with the hypersecretion of detectable hormones, such as insulin, gastrin, glucagon(Drug information on glucagon), vasoactive intestinal polypeptide (VIP), or somatostatin(Drug information on somatostatin), leading to specific clinical syndromes. PNETs generally arise sporadically. However, 80% to 100% of patients with MEN1 will develop a PNET, most commonly a gastrinoma, with insulinoma the next most common type.[3]
Insulinoma
Insulinoma is the most common functional sporadic PNET. Clinical symptoms result from episodes of hypoglycemia; patients can present with neuroglycopenia (headaches, blurred vision, confusion) or sympathoadrenal stimulation (tachycardia, diaphoresis).[4] Symptoms can be insidious and are often prevented or ameliorated by increased caloric intake, sometimes leading to weight gain. Although Dr. Alan Whipple's diagnostic triad of symptomatic hypoglycemia, low blood glucose level, and relief of symptoms with glucose administration is still valid,[5] most patients today are diagnosed using a monitored fast and serial serum measurements of glucose and insulin every 4 to 6 hours. The fast is terminated after 72 hours—or sooner if the patient develops neuroglycopenic symptoms.[4] Measurement of serum proinsulin and C-peptide levels is useful in ruling out surreptitious insulin administration (the condition is ruled out if these values are elevated).
The first step in the management of insulinomas consists of dietary changes and medical control of the symptoms. Adding cornstarch to the diet can slow the absorption of food, while diazoxide(Drug information on diazoxide) (Proglycem), an antihypertensive, can suppress insulin secretion in approximately 60% of patients.[6] For patients unable to tolerate the nausea, hirsutism, and sodium retention associated with diazoxide, other options include calcium channel blockers, beta-adrenergic antagonists, and octreotide(Drug information on octreotide) (Sandostatin).
Pancreatic Insulinoma
The only potentially curative therapy for insulinomas is surgical removal. The cure rate and disease-specific survival can be as high as 100% after resection of sporadic insulinomas, as these tumors are generally (> 90%) benign.[7,8] Insulinomas are typically small (< 2 cm) and can be difficult to localize preoperatively. In addition, they lack a high density of type 2 somatostatin receptors, making somatostatin receptor scintigraphy (SRS, or octreotide scan) rarely helpful (in only 10% of cases). For most patients, pancreatic protocol computed tomography (CT) (Figure 1A) and endoscopic ultrasound (EUS) are the best preoperative tools for localization; they have a combined sensitivity of as high as 90%.[9] If the tumor cannot be localized preoperatively, measurement of the insulin gradient in the hepatic veins after selective intra-arterial calcium stimulation can localize the tumor in up to 87% of cases.[7,10] Furthermore, surgical exploration with intra-operative ultrasound and bimanual palpation has a 95% sensitivity in localizing these tumors, and in the authors' experience, the addition of preoperative calcium angiography to intra-operative ultrasound has been found to localize 100% of occult insulinomas.[7] Since the majority of insulinomas (80% to 90%) are typically small (< 2 cm), solitary, and benign, these tumors can be removed through enucleation rather than pancreatic resection (Figure 1B). Enucleation has the benefit of sparing normal pancreatic parenchyma as long as the integrity of the pancreatic duct is preserved. If enucleation is not possible, then pancreaticoduodenectomy for head tumors and central or distal pancreatectomy for body or tail tumors may be necessary. Laparoscopic enucleation is also becoming increasingly common. When tumors cannot be identified intra-operatively, a pancreatic biopsy is warranted, as the patient may have adult nesidioblastosis.[4] However, this diagnosis is controversial and the authors think that it is seldom, if ever, valid.
The management of insulinomas in patients with MEN1 is complicated by the presence of multiple tumors in 89% of cases.[11] A single large (2- to 3-cm) dominant tumor can usually be identified in this setting, and removal will lead to control of the hypoglycemic episodes and long-term cure in 86% of patients.[11] However, some surgeons have advocated subtotal distal pancreatectomy with enucleation of head tumors as an alternative approach; this approach has a lower risk of recurrence but a higher rate of iatrogenic diabetes mellitus.[12,13]
Gastrinoma
Distribution of Gastrinomas
Patients with Zollinger-Ellison syndrome (ZES) present with severe peptic ulcer disease and secretory diarrhea caused by gastric acid hypersecretion secondary to gastrin-secreting tumors. Gastrinomas arise sporadically in 70% to 80% of patients and are the second most common functional PNET. However, 20% to 30% of affected patients have MEN1, and gastrinomas are the most common PNET in these patients.
ZES is a rare cause of peptic ulcer disease (0.1% to 1% of cases) but should be suspected in patients with recurrent or multiple peptic ulcers or ulcers located in the distal duodenum or jejunum. The diagnosis is made based on elevated fasting serum gastrin levels (> 100 pg/mL) and basal acid output > 15 mEq/hr when patients abstain from antisecretory medications, such as histamine (H2) antagonists and proton pump inhibitors. An additional useful test is the secretin stimulation test; approximately 90% of patients with ZES will have a paradoxical increase (> 200 pg/mL over baseline) in serum gastrin in response to intravenously administered secretin.
The first step in the management of ZES consists of controlling acid hypersecretion. Modern proton-pump inhibitor drugs can control acid secretion in almost all patients. Dose titration should be driven by measurement of basal acid output since the relief of symptoms is an unreliable indicator of effective acid control. The typical dose of omeprazole(Drug information on omeprazole) to control acid hypersecretion in ZES is 40 mg twice daily.
Localization of Duodenal Gastrinomas
The best modality for visualizing gastrinomas is SRS in conjunction with CT and magnetic resonance imaging (MRI). Using the radiolabeled somatostatin analog 111In-pentetreotide, SRS has a sensitivity of 80% and a specificity of 100% in this setting. Approximately 80% of gastrinomas are found within the gastrinoma triangle, an anatomic area that includes the first, second, and third portions of the duodenum and the head of the pancreas (Figure 2).[14,15] Full-body imaging with SRS also allows for detection of metastatic disease and detection of primary tumors in unusual locations, such as the ovaries and heart. The one limitation of SRS is that it misses 50% of small duodenal gastrinomas.[16] Overall, approximately 20% of patients with ZES have tumors that cannot be detected by SRS, CT, or MRI. One option for these patients is EUS, which has a sensitivity of 75% to 89% for gastrinomas located in the pancreas. Sensitivity for duodenal gastrinomas is lower, at 28% to 63%.[16] Another option is angiography with secretin stimulation and hepatic vein gastrin sampling. This option is useful in that it is not dependent on tumor size and is sensitive for duodenal gastrinomas.[17] However, it is invasive, only provides regional localization, and often localizes to where most gastrinomas are found, the gastrinoma triangle (see Figure 2).
The most common site for a gastrinoma is not the pancreas but the duodenum (Figure 3A). Gastrinomas located in the head of the pancreas can generally be enucleated, while those in the body and tail are removed through a distal pancreatectomy. In addition, a duodenotomy should be performed routinely, since most missed gastrinomas are small (< 5 mm) tumors in the submucosa of the duodenal wall. When performing a duodenotomy, we try to open the duodenum longitudinally and close it transversely (Figure 3C). Duodenotomy ensures that most gastrinomas (98%) will be found, compared with only 76% of gastrinomas being found when a duodenotomy is not performed.[18] The duodenotomy affords the opportunity to carefully palpate the duodenal wall and feel the gastrinoma as a firm nodule between two fingers. Endoscopic transillumination (Figure 3B) was the initial method for finding duodenal gastrinomas, but it misses tumors on the medial (pancreatic) wall and is not as sensitive as duodenotomy. Routine duodenotomy also significantly improves the immediate postoperative (biochemical and radiographic) cure rate (65% vs 44%) and long-term cure rate (52% vs 26%).[18] Inspection and removal of regional peripancreatic and paraduodenal lymph nodes should also be performed routinely, since approximately a third to half of patients will have lymph node metastasis.[16] Moreover, evidence suggests that gastrinomas may originate primarily in a lymph node in up to approximately 10% of sporadic cases, presumably due to entrapment of neuroendocrine cells in abdominal lymph nodes during development.[19,20]
Impact of Surgery on Disease-Specific (A) and Liver Metastasis–Free Survival (B) in Patients With Gastrinoma
For patients with sporadic gastrinomas, surgery can offer biochemical and oncologic cure. The majority of gastrinomas are malignant, and while most tumors are slow-growing, there appears to be a more aggressive type that is found in approximately a quarter of patients.[21] These more aggressive gastrinomas are commonly associated with pancreatic tail primary tumors outside the gastrinoma triangle. Patients who undergo surgical resection have improved 20-year survival compared with those not undergoing surgery (98% vs 74%, Figure 4A), mainly as the result of a decrease in the rate of development of liver metastasis (Figure 4B).[22]
The role of surgery in patients with gastrinoma and MEN1 is more controversial. Because primary hyperparathyroidism resulting from multiple gland disease is usually present, subtotal (3 1/2 gland) parathyroidectomy is advocated first as it lessens the end-organ effects of hypergastrinemia and markedly improves the management of ZES (hypercalcemia acts as a secretagogue for gastrin).[23] However, unlike with sporadic gastrinomas, the long-term (biochemical and radiographic) cure rate in patients with MEN1 who undergo surgery is low, mainly because of gastrinoma multifocality (Figure 5).[16,23] Only 3% of patients who undergo surgery develop liver metastases, however, compared with 23% of patients who are managed medically.[24] Preventing the development of hepatic metastases is important, since these represent a major cause of death in these patients. Ten-year survival probability after gastrinoma resection can drop from 95% with no liver metastases present, to 60% in the presence of fewer than five liver metastases, and to 15% in patients with more advanced liver disease.[25] Since gastrinomas > 2.5 cm in size are associated with a higher incidence of liver metastases, our current approach is to resect dominant tumors > 2.5 cm in size in patients with MEN1 to reduce this risk.[26] Pancreaticoduodenectomy has been proposed as an option for improving the cure rate in patients with MEN1, but its role in this setting still remains controversial. A series of three patients with MEN1 gastrinoma undergoing the Whipple procedure reported a 100% cure rate with a median follow-up of 6 years.[27]
Duodenectomy Specimens of a Sporadic, Solitary Gastrinoma (A) and Multiple Familial Gastrinomas in the Setting of MEN1(B)
The arguments against routine pancreaticoduodenectomy, however, are (1) that patients with MEN1 already have excellent overall survival outcomes (86% at 15 years) with less aggressive surgery (enucleation),[23] (2) that these patients may develop and die from other neuroendocrine neoplasias, and (3) that the Whipple operation may further complicate future liver-directed therapy (resection or embolization) for metachronous hepatic metastases because of the increased risk of liver abscess and ascending infection.[16] Because patients who have MEN1 have a high incidence of disease recurrence following surgery, these are important considerations that must be taken into account when planning surgical intervention.
Glucagonoma
Glucagonomas are classically associated with necrolytic migratory erythema and the “4Ds” (diabetes mellitus, dermatitis, deep vein thrombosis, and depression).[28] The characteristic rash (Figure 6) is related to hypoaminoacidemia, and can be reversed by parenteral nutrition.[29] At the time of diagnosis, most glucagonomas are large (mean, 6 cm) and located in the body and/or tail of the pancreas. Most (60% to 70%) are malignant, with liver metastases present at diagnosis.[4,30] Elevated fasting plasma levels of glucagon (typically > 500 to 1000 pg/mL) and decreased plasma levels of amino acids are diagnostic. Initial management often consists of total parenteral nutrition supplemented with zinc, trace metals, and insulin to counteract the long-standing malnutrition and hypoaminoacidemia. Octreotide also plays an important role in reducing the levels of glucagon. Resection of these tumors is often feasible with distal pancreatectomy. Safe debulking of metastatic lesions should be considered.
VIPoma
Typical Skin Rash (Necrolytic Migratory Erythema) in a Patient With a Pancreatic Glucagonoma
Vasoactive intestinal peptide–secreting tumors (VIPomas) are associated with “WDHA” syndrome: watery diarrhea, hypokalemia, and achlorhydria. The tumors are typically solitary pancreatic lesions > 3 cm in size, with 70% to 80% metastatic at presentation.[30] Although typically intrapancreatic, about 10% can be found in the colon, bronchus, adrenals, liver, or sympathetic ganglia. Initial management consists of correcting the dehydration and metabolic abnormalities with IV fluid and electrolyte supplementation, but this can be challenging. Octreotide is often useful in this setting and for long-term control in patients unable to undergo resection.
Somatostatinoma
Somatostatinomas are the rarest of the PNETs and are often discovered only incidentally. No specific syndrome exists, but suggestive symptoms include diabetes mellitus, cholelithiasis, weight loss, steatorrhea, and anemia.[30] Patients may also present with duodenal obstruction from duodenal tumors. Approximately 50% of tumors arise in the pancreas (with two-thirds located in the head of the pancreas); the remainder are found in the small intestine.[30] Most are malignant and large (> 5 cm) at presentation. Diagnosis is made with elevated somatostatin levels. Surgical resection, if feasible, is the first-line treatment.
Nonfunctional PNETs
Recent series report that 35% to 50% of PNETs are nonfunctional, that is, they do not secrete detectable levels of functional hormones. Patients with nonfunctional tumors often present at a later stage, with large (> 5 cm) tumors and liver metastases, although as a result of the widespread use of cross-sectional imaging, a growing number of these tumors are being identified incidentally at an earlier stage. These tumors can be differentiated from pancreatic adenocarcinoma on CT, since they are more likely to be enhancing or associated with cystic degeneration or calcifications; however, they are less likely to encase vascular structures or obstruct the pancreatic duct. Nonfunctional tumors secrete a variety of peptides, such as pancreatic polypeptide (PP) and chromogranin A, which can serve as tumor markers. A positive SRS scan can confirm the diagnosis and reveal occult metastatic disease. PNETs are classified by the World Health Organization as low-grade if the mitotic count is < 2/10 high-power fields (HPF) and the Ki-67 proliferation index is < 3%, as intermediate-grade if the mitotic count is 2/10 to 20/10 HPF or Ki-67 is 3% to 20%, and as high-grade if the mitotic count is > 20/10 HPF or the Ki-67 is > 20%.[1] For low- and intermediate-grade tumors, upfront surgical resection is undertaken, with 10-year disease-specific survival rates of 80% and 30%, respectively.[31] Small superficial tumors can be enucleated, but larger tumors may require pancreatic resection with pancreaticoduodenectomy, or central or distal pancreatectomy.[30] High-grade PNETs (poorly differentiated neuroendocrine carcinomas, large-cell or small-cell) are very aggressive malignancies that should be treated upfront with platinum-etoposide combination chemotherapy, potentially followed by a form of local therapy (surgery or radiotherapy) if localized tumor persists.[32,33]
A 47-year-old male with complaints of chronic abdominal pain and episodes of flushing presents for evaluation. What is your diagnosis?
