1. BACKGROUND
Neuroendocrine tumors of the pancreas are uncommon neo- plasms. They may occur as a sporadic lesion or as part of a genetic disease such as the multiple endocrine neoplasia type 1 (MEN-1) syndrome. Sporadic tumors usually arise as a single lesion, whereas those associated with familial disorders gener- ally are multifocal. Tumors may be classified as functioning or nonfunctioning depending on whether or not there is excess hormone production correlated with a clinical syndrome.
Clinical suspicion is based on development of the constella- tion of clinical symptoms characteristic of excess hormone production. In the case of a nonfunctioning tumor, its presence often becomes apparent because of symptoms from local tumor growth or metastatic disease. Once biochemical studies confirm the diagnosis and cross-sectional imaging exclude metastatic disease, endoscopic ultrasound (EUS) can localize the tumor and guide surgical management, providing poten- tially curative resection.
2. INTRODUCTION
Pancreatic neuroendocrine tumors (NETs) are uncommon neoplasms with a prevalence of less than 10 per million popula- tion (1). They may occur as a sporadic tumor or as part of a genetic disease such as the MEN-1 or Von Hippel Lindau (VHL) syndrome. MEN-1 is a genetic disorder that leads to tumor devel- opment in the parathyroid, pancreatic islet cells, and pituitary gland (2). VHL is a genetic disorder that predisposes patients to bilateral and multicentric retinal angiomas, hemangioblastomas in the central nervous system, renal cell carcinomas, pheochromo-
From: Endoscopic Oncology: Gastrointestinal Endoscopy and Cancer Management. Edited by: D. O. Faigel and M. L. Kochman © Humana Press, Totowa, NJ
Pancreatic Neuroendocrine Tumors
E
RIK-J
ANW
AMSTEKER,
MD ANDJ
AMESM. S
CHEIMAN,
MDCONTENTS
BACKGROUND
INTRODUCTION
CLINICALPRESENTATION
DIAGNOSIS
TUMORLOCALIZATION
SURGICALAPPROACH TOSPORADICNEUROENDOCRINETUMORS
SURGICALAPPROACH TOFAMILIALNEUROENDOCRINETUMORS
MEDICALMANAGEMENT OFNETS CONCLUSIONS
REFERENCES
317
cytomas, islet cell tumors of the pancreas, endolymphatic sac tumors, and cysts of the kidney, pancreas, and epididymis (3).
Sporadic NETs usually occur as a single lesion, whereas those associated with familial disorders generally are multi- focal. They may be classified as functioning or nonfunctioning tumors depending on whether or not there is excess hormone production and an associated clinical syndrome. In general, the clinical suspicion of a NET is based on development of clinical symptoms characteristic of excess hormone produc- tion. In the case of a nonfunctioning tumor, its presence becomes apparent because of symptoms from local tumor growth or metastatic disease.
For patients with MEN-1, the lethality of the disease can be substantially attributed to disease burden from the pancreatic tumors. The cause of death in this patient population has been attributed directly to a complication of the neuroendocrine tumors in nearly 50% of patients, leading to an earlier age at death than those who did not die of MEN-1-related disease (47 vs 55 yr of age) (4). Despite these grim statistics, the prog- nosis in patients with NETs is far better than in patients with pancreatic adenocarcinoma, and many patients can expect a cure with surgical resection (5).
In the setting of a family history of MEN-1 or a personal history of VHL, screening programs may be employed, which may detect tumors prior to the onset of clinical symptoms (6).
This chapter will provide a general overview of NETs and con- centrate on the role of endoscopy and EUS in the diagnosis, localization, and management of patients with these tumors.
3. CLINICAL PRESENTATION
Small tumors that present owing to symptoms of hormone excess might be diagnosed at an early and potentially surgically
27
curable stage. If unrecognized early or as a consequence of aggressive tumor biology, patients may present later with symptoms resulting from metastatic disease. Depending on the dominant hormone (the hormone produced in excess), clinical presentations vary. The clinical syndromes that occur with functioning NETs are listed in Table 1.
The most common symptomatic NETs are insulinoma and gastrinoma (7). Insulinomas cause symptoms as a result of excess insulin production with resultant hypoglycemia.
Prolonged fasting will precipitate central nervous system dys- function leading to seizures, difficulty awakening, visual distur- bance, confusion, lethargy, weakness, and transient motor deficits (8). The vast majority of insulinomas are sporadic tumors (90%), with approx 10% presenting as part of MEN-1.
Sporadic insulinomas present most commonly as solitary tumors, whereas in the familial form, they might be multiple (9). Most insulinomas (85–90%) are benign. Of the insulinomas that are malignant, metastases will be present in 15–30% at the time of diagnosis (10).
Gastrinomas produce symptoms as a result of excess gastrin production. Hypersecretion of this hormone drives excess gas- tric acid production leading to peptic ulcer disease, abdominal pain, and diarrhea. Although the approach to hypergastrinemia cannot be exhaustively reviewed in this chapter, it is essential to establish the diagnosis of gastrinoma with appropriate biochem- ical testing prior to studies for tumor localization such as EUS.
Other hormone excess syndromes are summarized in Table 1.
Nonfunctioning NETs do not produce a characteristic clinical syndrome although modest nonspecific elevation in gastrointestinal hormones may be seen in these patients (11).
In patients with a family history of MEN-1 or VHL, biochem- ical testing and screening with imaging studies may be performed on a routine basis. In carefully selected patients, intensive screen- ing with EUS can detect pancreatic endocrine tumors (PETs) prior to clinical symptom production, which will be reviewed in detail later in this chapter.
4. DIAGNOSIS
4.1. SPORADIC PANCREATIC ENDOCRINE TUMORS 4.1.1. Insulinoma
Insulinomas are diagnosed by demonstrating elevation of plasma insulin and C-peptide levels in the setting of recurrent
fasting hypoglycemia. The C-peptide assay is necessary to exclude factitious insulin administration (12). Provocation test- ing is sometimes necessary when insulinoma is suspected.
Diagnostic testing can include an overnight fast as well as a 48–72 h supervised fast. Hypoglycemia needs to be present in order to interpret C-peptide and insulin levels and studies indi- cate that 100% of patients with insulinoma will be detected after a supervised 72-h fast (13). Biochemical testing to con- firm the clinical diagnosis should precede any attempt to image the tumor with either cross-sectional imaging or EUS.
Once the diagnosis is confirmed, pre-operative localization is essential because it directs surgical management. Because these tumors are small, (90% are <2 cm, 40% are <1 cm), and the majority located in the head of the pancreas (which might be more difficult to palpate at the time of surgery), pre-operative localization is critically important (14).
4.1.2. Gastrinoma and the Zollinger-Ellison Syndrome (ZES)
Gastrinomas produce the ZES, named by the surgeons who described the clinical disorder resulting from excessive gastric acid production. The tumor should be suspected after recognition of the constellation of clinical symptoms that include “ulcer-like”
abdominal pain (dyspepsia) with associated diarrhea. The endo- scopic findings of peptic ulcer disease and concomitant esophagi- tis are a clue to the diagnosis. Profound acid hypersecretion leads to ulcerations throughout the upper gut, and the peptic ulcers may be in atypical locations such as the second, third, and fourth portions of the duodenum and jejunum (15).
Most gastrinomas present as solitary tumors (75%).
Approximately 25% of patients with gastrinomas present as part of a familial syndrome, most commonly the MEN-1. This situation should be excluded by obtaining a serum calcium level reflecting the absence of associated parathyroid disease.
The diagnosis of gastrinoma is based on an elevated serum gastrin level (generally levels >1000 pg/mL are felt diagnos- tic) with persistent peptic ulcer disease and a basal acid output (BAO) of greater than 15 mEq/h. When ZES is suspected, but the above criteria are not met, provocation testing with the secretin stimulation test is necessary to exclude other causes of hypergastrinemia. In normal individuals, secretin does not have a stimulatory effect on gastrin. In patients with ZES, secretin has a paradoxical effect resulting in a dramatic Table 1
Endocrine Tumor Syndromes
Tumor type Clinical syndrome Clinical Diagnosis
Insulinoma Insulinoma syndrome/ Headaches, visual disturbances, Glucose levels near or below
neuroglycopenic syndrome irrational behavior, confusion, 40 mg/dL, insulin levels > 6 micU/mL,
drowsiness elevated C-peptide levels
Gastrinoma Zollinger-Ellison syndrome Abdominal pain, peptic ulcer Elevated gastrin, positive secretin disease, diarrhea, reflux stimulation testing, gastric acid analysis esophagitis
Glucagonoma Glucagonoma syndrome Necrolytic migratory erythema, Elevated glucagon diabetes, weight loss
VIPoma Verner-Morrison, pancreatic cholera Secretory diarrhea >1 L/d, Elevated VIP hypokalemia
Somatostatinoma Somatostatinoma-inhibitory syndrome Diabetes, steatorrhea, cholelithiasis Elevated somatostatin
increase in gastrin level and acid secretion (16). In situations in which secretin is unavailable for clinical diagnostic testing, a calcium infusion study can be performed with an anticipated increase in gastrin of more than 400 pg/mL, however, this test lacks in both sensitivity and specificity compared with the secretin provocation test (17).
BAO more than 15 mEq/h is present in more than 90% of patients with ZES, but is also present in a small percentage of patients with common duodenal ulcer disease. The addition of a maximal acid output test, with the use of the secretegogue penta- gastrin, would be expected not to result in a significant increase in gastric acid output in ZES because BAO is already felt to be near maximal in patients with ZES. Therefore, a BAO/MAO ratio of greater than 0.6 is highly suggestive of ZES. Although gastric acid analysis is not completely diagnostic, its importance is in allowing exclusion of patients that have elevated gastrin levels owing to hypo- or achlorhydria. This is a critical issue to differ- entiate given the frequent problem of hypergastrinemia in patients taking potent acid inhibitory medications, such as proton pump inhibitors (PPIs). Such patients, particularly those with concomitant atrophic gastritis, may have similar symptoms and marked hypergastrinemia. However, they have low acid output when formally tested and should not have the diagnostic changes in gastrin levels with secretin administration. Like insulinoma, it is essential to establish the diagnosis before imaging studies to localize tumor, for fear that a false-positive exam leading to inappropriate surgical exploration.
4.1.3. Glucagonoma
Glucagonomas are very rare tumors. They may present with weight loss, necrolytic migratory erythema (a painful, pruritic cutaneous eruption), cheilosis, diabetes mellitus, normochromic and normocytic anemia, venous thrombosis, and neuropsy- chiatric symptoms, as well as diarrhea. The most common presentation is diabetes, necrolytic migratory erythema, and imaging demonstrating an islet cell tumor. The diagnosis is most frequently made by obtaining a fasting glucagon level, which should be markedly elevated, followed by identification of a pancreatic islet cell tumor by imaging.
4.1.4. VIPoma
VIPomas are very rare tumors that are generally malignant and present with a large volume watery secretory diarrhea.
Presenting symptoms may include hypokalemia and dehydra- tion. The general approach to secretory diarrhea is documenta- tion of persistence of diarrhea during fasting followed by stool characterization. If the stool quantity exceeds 1 L/d, this suggests that a VIPoma, rather than another neuroendocrine tumor, is most likely the source of the diarrhea (18). Direct measurement of a fasting VIP level confirms the diagnosis. VIPomas in children might occur in extrapancreatic locations, although generally primary VIPomas in adults are intrapancreatic (19).
4.1.5. Somatostatinomas
Somatostatinomas are the rarest of the neuroendocrine tumors, presenting with signs of inhibition of other endocrine hormone production. The syndrome consists of diabetes melli- tus, gallbladder disease (cholelithiasis), weight loss, anemia, diarrhea, and steatorrhea, all felt to be owing to the inhibitory effects of somatostatin. The most common primary site is the
pancreas followed closely by the duodenum. Somato- statinomas can occur in MEN-1 and in patients with neurofi- bromatosis (20). The diagnosis may be supported by the demonstration of an elevated fasting somatostatin level.
4.2. FAMILIAL FORMS OF PANCREATIC ENDOCRINE TUMORS
4.2.1. MEN-1
This syndrome is characterized by an autosomal-dominant inheritance pattern with variable penetrance. Before the genetic advances of the 1980s and 1990s, MEN-1 was diag- nosed clinically in patients with polyglandular diseases, most commonly hyperparathyroidism with associated pancreatic islet cell tumors and less commonly anterior parathyroid tumors (two or more primary organ sites). Other diagnostic criteria include the presence of one or more primary organ site involvement plus a first-degree relative with MEN-1. The pan- creatic tumors are often multifocal and may secrete several different hormones. With relatively recent genetic advances and the cloning of the gene for MEN-1 (menin) (21), genetic testing may allow for identification of those at risk for the disease.
4.2.2. Von Hippel Lindau
This syndrome is characterized by an autosomal-dominant pattern of inheritance with a high penetrance. There is no single pathognomonic finding. In patients with a family his- tory of VHL, minimal clinical criteria include the presence of a single retinal or cerebral hemangioblastoma, renal cell carci- noma, or pheochromocytoma. In isolated cases, the diagnosis can be established in a person who has two or more retinal or central nervous system hemangioblastomas or a single heman- gioblastomas and a characteristic visceral tumor. A high index of clinical suspicion with strong interdisciplinary collabora- tion among specialists is essential to make the diagnosis (22).
As with MEN-1, the gene for VHL has been identified and may allow for early identification of disease carriers.
5. TUMOR LOCALIZATION
Imaging studies are important to establish the location of the primary tumor to guide surgical extirpation, and to evaluate for metastatic disease, which precludes surgery. Localization of NETs remains challenging. Multiple modalities including tran- scutaneous ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), arteriography, intra-arterial stimula- tion with venous sampling, somatostatin receptor scintigraphy (SRS), EUS, and intra-operative ultrasound have been used for localization with variable success (23). Special attention will be given to EUS and SRS, relatively new approaches, which have had great impact in tumor localization strategies.
Transcutaneous ultrasound, CT, MRI, and diagnostic angiography fail to localize the primary tumor in 40–60% of cases, frequently missing lesions less than 2 cm in size (24).
More invasive angiographic techniques, such intra-arterial cal- cium injection for stimulation of insulin release by the tumor at the time of angiography have been employed in some centers.
Doppman and colleagues (25) reported a sensitivity of 88%
for insulinoma localization using this technique, a result that surpassed ultrasound, CT, MRI, arteriography, and portal venous
sampling with sensitivities of 9, 17, 43, 36, and 67%, respec- tively. However, in most centers these invasive techniques have been relegated to a supportive role given the accuracy of EUS for pre-operative localization.
5.1. SOMATOSTATIN RECEPTOR SCINTINGRAPHY SRS is performed using a radiolabeled analog of the somatostatin analog octreotide, indium 111-penetreotide.
Somatostatin receptor positive tumors might be localized fol- lowing administration of the tracer. Images are captured with a γ-camera so that planar anterior and posterior images of the thorax, abdomen, and pelvis can be acquired at 4 and 24 h.
SRS is of limited value for insulinoma, owing to a low rate of somatostatin receptor expression on the tumors. The test is of greatest value for the diagnosis of occult metastatic disease not seen on cross sectional imaging studies such as CT or MRI.
In a correlation study between EUS and SRS followed subse- quently by surgery, sensitivity was calculated using pathology as the gold standard. Using EUS alone, the sensitivity for identifica- tion of insulinoma and gastrinoma, respectively, were 79 and 73%, respectively. Using SRS alone, the sensitivity for identifi- cation of insulinoma and gastrinoma were 60 and 75%, respec- tively. When the two modalities were combined, the sensitivity for detection of insulinoma and gastrinoma were 89 and 93%, respectively (26). EUS is limited to visualization of the pancreas and its immediate surroundings. SRS has excellent sensitivity but it is often not possible to differentiate uptake in pancreatic tissue vs an adjacent lymph node. It also may poorly localize a PET to a specific anatomical region of the pancreas (27). It there- fore has been advocated that both techniques are useful for local- ization of these tumors and is often necessary (6).
5.2. ENDOSCOPIC ULTRASOUND
When EUS is performed, an echoendoscope is advanced to the descending duodenum beyond the major ampulla and slowly withdrawn from the duodenum to the stomach. Regional anatomy is verified by its relationship to the surrounding vessels and organs. The tumor’s size, echotexture, location within the pancreas, involvement of the peripancreatic vessels, and the pres- ence of regional lymph nodes are documented. Examinations may require approx 30–60 min, even in experienced hands.
Generally, radial scanning instruments are most commonly used, by it is also possible to localize tumors with the linear array instruments used for fine-needle aspiration (FNA).
In experienced hands, EUS is ideal for localization of small tumors because of the ability to produce high-resolution images of the pancreas and surrounding structures. EUS correctly localizes NETs with a sensitivity as high as 93% (Table 2) (28).
The “classical” EUS appearance of a NET is a hypoechoic to isoechoic homogeneous well-demarcated mass within the gland (Fig. 1). Cystic tumors uncommonly occur. The precise locali- zation of the NET can be established by examining relationships with the large vessels and duct. At the University of Michigan, when insulinoma is biochemically confirmed, EUS may be the only localization technique used prior to taking a patient to the operating room based on its high sensitivity and positive predic- tive value of 28. FNA is generally not performed in the setting of a hormone excess syndrome, but can be used to confirm the diag- nosis for nonfunctional sporadic tumors (Fig. 2).
It is important to consider the limitations of EUS given its pre-eminent role in tumor localization. First and foremost, it is operator-dependent, and experience likely is a key determinant to tumor localization. Pitfalls of the techniques may occur owing to differing echotextures of the tumor or the gland itself.
Isoechoic tumors may be very difficult to visualize from sur- rounding pancreatic parenchyma and can be missed by an inex- perienced operator (Table 3). The finding of a subtle hyperechoic rim surrounding the lesion may help to localize the tumor. In the setting of diffuse pancreatic parenchymal abnormalities seen with chronic pancreatitis, small tumors might be impossible to see.
When insulinoma is suspected, a “negative EUS” does not reliably exclude an intrapancreatic insulinoma, whereas when a gastrinoma is suspected, a “negative EUS” in experienced hands appears to reliably exclude an intrapancreatic gastri- noma. A detailed exam with a forward-viewing endoscope might also identify subepithelial duodenal tumors occasion- ally, and should be performed in all patients prior to EUS. We suspect that this might be owing to the very high percentage of hypoechoic gastrinomas as compared with insulinomas that may have a higher percentage of isoechoic lesions (Table 3).
Table 2
Localization of Pancreatic Neuroendocrine Tumors Using EUS:
The University of Michigan Experience
Gastrinoma Insulinoma
N= 36 N= 36
Sensitivity 100% 88%
Specificity 94% 100%
PPV 95% 100%
NPV 100% 43%
Accuracy 97% 89%
PPV, positive predictive value; NPV, negative predictive value.
Modified from ref.28.
Fig. 1. Classical appearance of a pancreatic endocrine tumor imaged by the Pentax radial array echoendoscope.
When EUS is negative, the intra-arterial calcium stimulation is the logical next step for insulinoma localization (25).
The use of EUS for diagnosis and localization of PETs is becoming routine. Compared with other highly accurate moda- lities, EUS is a low-risk procedure that is highly sensitive and accurate. In a case–control study, we demonstrated EUS to be highly cost-effective when used early in the pre-operative loca- lization strategy, leading to reductions in pre-operative testing and intra-operative time (29).
5.3. SELECTIVE ANGIOGRAPHY WITH SECRETIN INFUSION
Another technique, selective angiography with secretin infu- sion (SASI), had also been used for tumor localization in patients
with suspected gastrinomas. This technique suffers from poor sensitivity (41%), however, higher specificity (98%) has been reported (30). Unfortunately another study examining the utility of SASI suggested a much lower specificity, of approx 12%, for this technique. In eight patients with suspected gastrinoma, SASI incorrectly suggested the presence of tumor in seven patients and was correctly negative in one patient (28). As a result of these conflicting studies, the role of SASI remains unclear.
5.4. TUMOR LOCALIZATION IN PATIENTS WITH MEN-1 There is no consensus on the approach to early diagnosis and management of NETs for patients with MEN-1. In MEN-1 kindreds, biochemical screening is often performed.
Detection of tumors by biochemical screening and subsequent imaging may lead to diagnosis two decades before the disease becomes clinically overt. Recently, our group has pioneered the use of EUS (Fig. 3) to discover NETs in this population at an even earlier stage than imaging with cross-sectional imaging such as CT (31).
The timing of surgical treatment remains controversial for these patients. The lethality of MEN-1 is felt to be resulting from complications of excess hormone production and the metastatic potential for these tumors. Little controversy exists about surgical resection when patients present with a VIP or insulin secreting NET or when it is greater than 3 cm in size.
The timing of surgery in MEN-1 patients with ZES remains controversial because of the use of PPIs, which can control nearly all the acid production and protect patients from the complications related to peptic ulcer disease (32).
At the University of Michigan, MEN-1 patients with pan- creaticoduodenal disease are treated with aggressive surgical resection. This approach is based on the results of a series of 40 patients with MEN-1 and ZES where aggressive surgical resection was performed with only 1 patient developing a metachronous solitary liver metastasis with patients followed as long as 19 yr (33). Additionally, in a cohort (11 out of 48 patients) that was explored surgically, no correlation was found between tumor size and the presence of metastases (34). This finding suggests that tumor size alone cannot be used as a Fig. 2. Image of well-circumscribed pancreatic neuroendocrine tumor
undergoing endosonographically guided fine-needle aspiration performed using a Pentax curved linear array echoendoscope.
Table 3
Ultrasonographic Features of the Pancreatic Endocrine Tumors Detected by Endoscopic Ultrasound
Feature Number of tumors (%)
Insulinomas 25
Echogenic pattern
Hypoechoic 17 (68)
Isoechoic 7 (28)
Hyperechoic 1 (4)
Ultrasonographic texture
Homogenous 21 (84)
Inhomogeneous 4 (16)
Gastrinoma 47
Echogenic pattern
Hypoechoic 45 (96)
Isoechoic 2 (4)
Hyperechoic 0
Ultrasonographic texture
Homogenous 45 (96)
Inhomogeneous 2 (4)
Modified from ref. 28.
Fig. 3. Two small (3 mm) pancreatic endocrine tumors identified by screening in an asymptomatic patient with multiple endocrine neo- plasia type-1 syndrome using the Olympus Radial Echoendoscope.
pre-operative criterion for surgical exploration, and might support a more aggressive approach.
5.5. TUMOR LOCALIZATION IN VHL
Pancreatic lesions associated with VHL may be found in up to 75% of patients. Most pancreatic lesions are cysts and by nature are benign. At times, complete replacement of the pan- creas with cystic change can lead to exocrine insufficiency. Solid lesions of the pancreas are less common and may be because of cystic neoplasms (serous cystadenomas) or neuroendocrine tumors. Because studies have demonstrated that neuroendocrine tumors in VHL can demonstrate malignant potential, it has been suggested that surveillance CT imaging be performed in patients with VHL (35). Because patients with VHL are at risk of multi- ple tumors, screening recommendations are provided by the National Institutes of Health. Ultrasound, CT, and MRI are cur- rently used to screen for renal cell carcinoma as well as other abdominal organ complications of the disease. General recom- mendations are to screen starting at the age of 11 and repeat yearly or every other year (except CT, which screening starts at 20 yr and repeated yearly or every other year) (36). The role of EUS in VHL has not been defined. We speculate that the role of EUS might allow for the morphological differentiation of solid pancreatic masses. The differentiation of benign cystic neoplasms from neuroendocrine tumors could alter the surgical approach.
6. SURGICAL APPROACH TO SPORADIC NEUROENDOCRINE TUMORS
6.1. INSULINOMA
Surgical excision is the treatment of choice, and cure rates in the literature range from 77 to 100% (Fig. 4). The surgical procedure varies based on the anatomical position of the tumor as well as its size. The general approach is tumor enucleation whenever possible (37). Some surgeons employ intraoperative ultrasound if EUS or other imaging failed to identify the tumor location pre-operatively. When the tumor is located in the head, enucleation, or rarely a Whipple procedure, is performed (38).
Blind distal pancreatectomy historically was performed when localization was not confirmed either pre- or intra-operatively.
A review of 17 patients referred to the National Institutes of Health for failure to respond after blind distal pancreatec-
tomy, 5 patients had factitious hypoglycemia and the remain- ing 12 patients had the tumor eventually localized to the head, a finding that has resulted in this recommendation being reversed (39).
6.2. GASTRINOMA/ZES
Tumor excision is the goal for treatment. If pre-operative localization with EUS demonstrates that the pancreas appears normal, we assume there is a duodenal primary, and duodeno- tomy with transillumination with or without the use of intra- operative ultrasound is employed at the time surgical excision (Fig. 5). Duodenotomy added to surgical exploration for gas- trinoma has been shown to improve outcomes both in the immediate postoperative cure rate as well as in the long-term cure rate (40). This is likely owing to the increased recognition of duodenal gastrinomas. The surgical approach to gastrino- mas is directed with localization, and enucleation is favored over resection (41). If this is not possible, or multiple tumors are present in a particular location, then resection is performed Fig. 4. Approach to patients with insulinoma.
Fig. 5. (A) Algorithm for the approach to patients with biochemically confirmed gastrinoma/Zollinger-Ellison syndrome. (B) Algorithm for the approach to patients with multiple endocrine neoplasia type-1 and biochemically confirmed insulinoma.
either with a distal pancreatectomy for tumors in the body and tail or Whipple procedure for tumors in the head.
7. SURGICAL APPROACH TO FAMILIAL NEUROENDOCRINE TUMORS
7.1. MEN-1 INSULINOMA
Insulinomas in MEN-1 patients may be multicentric and therefore local tumor resection often is associated with disease recurrence (Fig. 6). Therefore, a different surgical approach in this patient population is advocated. The aim is distal sub- total pancreatectomy and enucleation of any tumor identified in the head of pancreas in patients with MEN-I and hyper- insulinemia (42).
7.2. MEN-1 GASTRINOMA/ZES
ZES in patients with MEN-1 will typically undergo a dis- tal pancreatectomy to the level of the superior mesenteric vein, preserving the spleen when appropriate and feasible.
Duodenotomy is only performed as part of this operation if MEN-1 ZES is suspected or in a patient with an elevated serum gastrin and a positive secretin test. Lymph node dissec- tion is performed in the lymphatic distribution of a tumor that is located in the pancreas or small bowel because these are common locations of metastatic disease (43).
8. MEDICAL MANAGEMENT OF NETS 8.1. INSULINOMA
Chemotherapy is generally reserved for malignant islet cell tumors. Combination streptozocin with 5-fluorouracil or dox- orubicin has response rates significantly better than with strep- tozocin alone (63 vs 36%) (44). The long-acting somatostatin analog octreotide might reduce hormone secretion as well as tumor proliferation in many patients (45). Specific medical treatments depend on the tumor type. Insulinomas may respond to the use of diazoxide, a drug that has been found to inhibit release of insulin and also has a peripheral hyper- glycemic effect. In gastrinomas, medical therapeutics includes the use of intravenous H2 blockers and, more commonly, oral PPIs. Higher doses of PPIs may be required to completely
control excess acid production and prevent acid secretion induced side effects. Nearly 100% of patients can achieve com- plete control of acid production with this class of medications and in the few that cannot comply with medical management, or who have refractory disease, may undergo palliative total gastrectomy (46). Octreotide can also be used in patients who do not have a complete response to anti-secretory agents (47).
9. CONCLUSIONS
Endoscopic methods are primarily used in the pre-operative localization of NETs and have been shown to alter the surgical approach in patients with both sporadic and familial sources of NETs. The use of EUS is highly accurate and cost-effective.
For patients with MEN-1 not only can EUS localize NETs in the head, which might alter the surgical approach, but EUS can identify PETs earlier than any other screening technique to date and can be used to monitor tumor size in surveillance programs (6).
The state of the art in the management of NETs is a multi- disciplinary approach where EUS has an integral role, which, when used in combination with other limited localization tech- niques, facilitates the surgical management of patients with NETs.
REFERENCES
1. Jensen RT. Endocrine neoplasms of the pancreas. In: Yamada T, Alpers DH. Owyang, et al., eds. Textbook of Gastroenterology, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2003; 2108.
2. Glascock JM, Carty SE. Multiple endocrine neoplasia type 1: fresh perspective on clinical features and penetrance. Surgical Oncol 2002; 11:143–150.
3. Hes FJ, Feldberg MAM. Von Hippel-Lindau disease: strategies in early detection (renal-, adrenal-, pancreatic masses). Eur Radiol 1999; 9:598–610.
4. Doherty GM, Olson JA, Frisella MM, Lairmore TC, Wells SA, Nortton JA. Lethality of multiple endocrine neoplasia type 1. World J Surg 1998; 22:581–587.
5. Maton PN, Gradner JD, Jensen RT. Diagnosis and management of Zollinger-Ellison syndrome. Endocrinol Metab Clin North Am 1989; 18:519.
6. Wamsteker EJ. Gauger PG. Thompson NW. Scheiman JM. EUS detection of pancreatic endocrine tumors in asymptomatic patients with type 1 multiple endocrine neoplasia. Gastrointestinal Endosc 2003; 58:531–535.
7. Fraker DL, Jensen RT. Pancreatic endocrine tumors. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles and practice of oncology. Philadelphia: Lippincott-Raven, 1997:1678–1704.
8. Norton JA. Pancreatic Islet Cell Tumors Excluding Gastrinomas.
St Louis, Missouri: Mosby, 1998.
9. O’ Riordain DS, O’Brien T, van Heerden JA, Service FJ, and Grant CS. Surgical management of insulinoma associated with multiple endocrine neoplasia type I. World J Surg 1994; 18:488–494.
10. Grant CS. Surgical management of malignant islet cell tumours.
World J Surg 1993; 17:498–503.
11. Kent RB, Van Heerden JA, Weiland LH. Nonfunctioning islet cell tumors. Ann Surg 1981; 193:185.
12. Grumberger G, Weiner JL, Silvermar R, Taylor S and Gordon P.
Factitious hypoglycemia due to surreptitious administration of insulin. Ann Int Med 1988; 108:252–257.
13. van Heerden JA. Insulinoma: diagnosis and management. Surgical Rounds 1980:40–51.
14. Bliss RD, Carter PB, Lennard TWJ. Insulinoma: a review of current management. Surgical Oncol 1997; 6:49–59.
15. Stage JG, Stadil F. The clinical diagnosis of the Zollinger Ellison syndrome. Scand J Gastroenterol 1979; 14(suppl 33):79.
Fig. 6. Algorithm for the approach to patients with multiple endocrine neoplasia type-1 and biochemically confirmed gastrinoma/Zollinger- Ellison Syndrome.
32. Gauger PG, Thompson NW. Early surgical intervention and strategy in patients with multiple endocrine neoplasia type 1. Best Practice Res Clin Endocrinol Metabol 2001; 15(2):213–223.
33. Thompson NW. Current concepts in the surgical management of multiple endocrine neoplasia type 1 pancreatic-duodenal disease.
Results in the treatment of 40 patients with Zollinger-Ellison syn- drome, hypoglycemia or both. J Int Med 1998; 243:495–500.
34. Lowney JK, Frisella MM, Lairmore TC, Doherty GM. Pancreatic islet cell tumor metastasis in multiple endocrine neoplasia type 1:
Correlation with primary tumor size. Surgery 1999, 125:1043–1049.
35. Lubutti SK, Choyke PL, Bartlett DL, Vargas H, McClellan W, Lubensky I, Glenn G, Linehan WM, Alexander HR. Pancreatic neuroendocrine tumors associated with von Hippel Lindau disease: Diagnostic and management recommendations. Surgery 1998; 124:1153–1150.
36. Choyke PL, Glenn GM, Walther MM, Patronas NJ, Linehan WM, Zbar B. von Hippel-Lindau disease: genetic, clinical and imaging features. Radiology 1995; 194:629–642.
37. Finlayson E, Clark OH. Surgical treatment of insulinomas. Surg Clin North Am 2004; 84:775–785.
38. Geoghegan JG, Jackson JE, Lewis MPN, Owen ERTC, Bloom SR, Lynn JA, Williamson RCN. Localization and surgical management or insulinoma. Br J Surg 1994; 81:1025–1028.
39. Hirshberg B, Libutti SK, Alexander HR, et al. Blind distal pancrea- tectomy for occult insulinoma, an inadvisable procedure. J Am Coll Surg 2002; 194:761–764.
40. Norton JA, Alexander HR, Fraker DL, Venzon DJ, Gibril F, Jensen RT. Does the use of routine duodenotomy affect rate of cure, devel- opment of liver metastases, or survival in patients with Zollinger- Ellison Syndrome? Ann Surg 2004; 239:617–623.
41. Norton JA, Fraker DL, Alexander HR, et al. Surgery to cure the Zollinger-Ellison Syndrome. N Engl J Med 1999; 341:635–644.
42. Lo CY, King-Yin L, Fan ST. Surgical strategy for insulinomas in multiple endocrine neoplasia type 1. Am J Surg 1998; 175:305–307.
43. Thompson NW. Management of pancreatic endocrine tumors in patients with multiple endocrine neoplasia type 1. Surg Oncol Clin North Am 1998; 7:881–891.
44. Moertel CG, Handley JA and Johnson LA. Streptozocin alone com- pared with streptozocin plus 5-fluorouracil in the treatment of advanced islet cell carcinoma. N Engl J Med 1980; 303:1189–1194.
45. Brentjens R, Saltz L. Islet cell tumors of the pancreas. Surgical clin North Am 2001; 81:527–542.
46. Jensen, RT, Fraker, DL. Zollinger-Ellison Syndrome: Advances in Treatment of Gastric Hypersecretion and the Gastrinoma. JAMA 1994;271:1429–1435.
47. Annibale B, Delle Fave G, Azzoni C, et al.. Three months of octreotide treatment decreases gastric acid secretion and argyrophil cell density in patients with Zollinger-Ellison syndrome and antral G- cell hyperfunction. Alimentary Pharmacol Therapeut 1994; 8:95–104.
16. Isenberg JI, Walsh JH, Passaro E Jr, Moore EW, Grossman MI.
Unusual effect of secretin on serum gastrin, serum calcium and gas- tric acid secretion in a patient with suspected Zollinger Ellison syn- drome. Gastroenterology 1972; 62:626.
17. Frucht H, Howard JM, Slaff JI, et al. Secretin and calcium provocative tests in the Zollinger-Ellison syndrome. Ann Intern Med 1989; 111:713.
18. Krejs GJ. VIPoma syndrome. Am J Med 1987; 82:37–48.
19. Verner JV, Morrison AB. Endocrine pancreatic islet disease with diarrhea. Arch Intern Med. 1974; 133:492–500.
20. Soga J, Yakuwa Y. Somatostatinoma/inhibitory syndrome: a statisti- cal evaluation of 173 reported cases as compared to other pancreatic endocrinomas. J Exp Clin Cancer Res 1999; 18:13–22.
21. Chandrasekharappa SC, Guru SC, Manickamp P, et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 1997; 276: 404–407.
22. Couch VMS, Lindor NM, Karnes PS, Michels VV. Von Hippel- Lindau Disease. 2000; 75: 265–272.
23. Chatziioannou A, Kehagias D, Mourikis D, Antoniou A, Limouris G, Kaponis A, Kavatzas N, Tseleni S, Vlachos L. Imaging and localization of pancreatic Insulinomas. J Clin Imag 2001; 25:
275–283.
24. Zimmer T, Ziegler K, Bader M, et al. Localisation of neuroen- docrine tumours of the upper gastrointestinal tract. Gut 1994;
35:471–475.
25. Doppman JL, Chang R, Fraker, et al. Localization of Insulinomas to regions of the pancreas by intra-arterial stimulation with calcium.
Ann Intern Med 1995; 123:269–73.
26. Proye C, Malvaux P, Pattou F, Filoche B, Godchaux JM, Maunorury V, Palazzo L, Huglo D, Lefebvre J, Paris JC. Noninvasive imaging of insulinomas and gastrinomas with endoscopic ultrasonography and somatostatin receptor scintigraphy. Surgery 1998; 124:1134–1144.
27. Nocaudie-Calzada M, Huglo D, Deveaux M, Carnaille B, Proye C, Marchandise X, Iodine-123-tyr-3-octreotide uptake in pancreatic endocrine tumors and in carcinoids in relation to hormonal inhibi- tion by Octreotide. J Nucl Med 1994; 35:57–62.
28. Anderson MA, Carpenter S, Thompson NW, Nostrant TT, Elta GH, Scheiman JM. Endoscopic ultrasound is highly accurate and directs management in patients with neuroendocrine tumors of the pan- creas. Am J Gastroenterol 2000; 95:2271–2277.
29. Bansal R. Tierney W. Carpenter S. Thompson N. Scheiman JM. Cost effectiveness of EUS for preoperative localization of pancreatic endocrine tumors. Gastrointest Endosc 1999; 49:19–25.
30. Gibril F, Doppman JL, Chang R, et al. Metastatic gastrinomas.
Localization with selective arterial injection of secretin. Radiology 1996; 198:77–84.
31. Oberg K, Skogseid B. The ultimate biochemical diagnosis of endocrine pancreatic tumours in MEN-1. J Intern Med 1998; 243:
471–476.
