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Neuroendocrine tumors of the pancreas and duodenum
NEUROENDOCRINE TUMORS OF THE PANCREAS AND DUODENUM
INTRODUCTION
Endocrine neoplasms of the pancreas are classified primarily according to the clinical syndrome that patients manifest (Table 1). In each instance, the principal clinical manifestations of the tumor are due to the uncontrolled excessive release of peptide hormones into the circulation. These hormones occur naturally and are important in mediating various physiologic processes. However, in patients with pancreatic endocrine tumors, the release and secretion of these hormones are not under normal physiologic regulation. Because of extremely high levels of hormones, characteristic signs and symptoms develop (Table 11. Different types of pancreatic endocrine tumors share several features in common, including pathologic characteristics, natural history, management considerations, radiographic localization studies, occurrence in familial syndromes, and propensity to metastasize. Effective therapy of patients with pancreatic endocrine tumors requires treatment of the signs and symptoms of excessive hormone production and the malignant nature of the tumor itself. In this monograph, the common features of islet cell tumors are discussed first, and the distinctive features of individual tumors are described subsequently. Special attention is given to neuroendocrine tumors as part of multiple endocrine neoplasia type 1 (MEN-11 and metastatic islet cell tumors. PREVALENCE
Endocrine tumors of the pancreas are rare, with an incidence of less than 10 per million population per year.” 2 Insulinomas are the most common islet cell tumor, with a prevalence of approximately 1 per million population per year, and gastrinomas are the second most common islet cell tumor, with an incidence of 0.1 to 0.4 per million population per year.3 Some authors suggest that gastrinomas may be as common as insulinomas, with a relative frequency of each of one to three per million population per year.4 Gastrinomas are the most Curr Pmbl Surg, February 1994
89
Neumtensinoma
mH-like-oma
GRFoma ACTHoma
Somatostatinoma
Insulinoma VIPoma Glucagonoma
Rare
1 in 5 million
Neumtensin
Pancreatic polypeptide, neuron-specific enolase
RalX?
WH-like
factor
RalX RaN?
4 in 5 million Rare Rare
2 in 5 million
GRF ACTH
Somatostatin
Insulin VIP Glucagon
Ulcer pain Diarrhea EsophagItis Hypoglycemia Watery diarrhea Rash Weight loss Malnutrition Diabetes Cholelithiasis Steatorrhea Acmmegaly cushing’s syndrome Hypercalcemia Bone pain Hypotension Tachycardia Malabsorption Cyanosis Pain Gastrointestinal bleeding Mass
Gastrinoma
Incidence
100
100
100
100 100
100
80-100 100 98-100
52-87
-
100
-
>99
100
30 100
7 -
50
50
>99 85 >99
15 -
62
38
60
>80
100
30 100
70
5 40 70
50
High
-
-
Occasional
5 Occasional Occasional
18-24
Percentage Percentage with with metastases MEN-l
tumors
Percentage of Tumors identified Percentage in Percentage in at surgery duodenum pancreas
Location
or symptoms, hormone, prevalence, and pathologic features of pancreatic or duodenal neuruendocdne
Signs or symptoms Hormone
Signs
Name of tumor
TABLE 1.
common functional islet cell tumor in patients with MEN-l, and insulinomas are the second most common functional islet cell tumor in these patients. The remaining pancreatic endocrine tumors occur in less than 0.2 per million population per year. Only 100 patients with glucagonoma have been reported worldwide; 21 cases of intestinal somatostatinoma, 27 cases of pancreatic somatostatinomas, and even fewer vasoactive intestinal peptide-secreting tumors WIPomas) and growth hormone-releasing factor-secreting tumors (GRFomas) have been described.5-s The best data on the relative frequency of various islet cell tumors is from Ireland, where an average incidence of 3.6 cases per million population per year has been documented.’ Insulinomas were the most common islet cell tumor, twice as common as gastrinomas, eight times as common as VIPomas, seventeen times as common as glucagonomas, and as common as nonfunctional islet cell tumors (Table 1). Somatostatinomas were rare, with no cases reported.’ In this series, all pancreatic endocrine tumors combined were approximately equal to the incidence of carcinoid tumors. In one autopsy report, it was suggested that nonfunctioning pancreatic islet cell tumors occur in approximately 1% of subjects.” Functional islet cell tumors occur in one per thousand autopsy subjects. In surgical series, nonfunctioning pancreatic islet cell tumors are reported to comprise approximately 15% to 20% of all pancreatic endocrine tumors removed,5-7 and in a recent large pathologic series, approximately 36% of resected pancreatic tumors were endocrine tumors.’ PATHOLOGIC
FEATURES
Pancreatic islet cell tumors share a number of common pathologic features. These tumors are believed to ori inate from cells that are part of the neuroendocrine cell system? ‘, f‘, l2 These cells share cytochemical properties with carcinoid tumors, medullary carcinoma of the thyroid, melanoma, and pheochromocytoma, and have been called APLJDoma &nine Precursor Uptake and Decarboxylationl. Islet cell tumors are composed of monotonous sheets of small round cells with uniform nuclei and cytoplasm. Mitotic figures are unusual. Under electron microscopy, these tumors demonstrate dense granules that contain secretory products including peptides, neuronspecific enolase, amines, synaptophysin, and chromogranin-A.8’ 13, I4 Thus these pancreatic neuroendocrine tumors are clearly multihormonal when examined by specific immunologic staining techniques. In most series, more than 50% of all pancreatic islet cell tumors contain more than one hormone defined by immunocytochemisw.8, 15-20 In insulinomas, for example, glucagon has been detected in 0% to 44% of tumors, somatostatin in 0% to 18%, gastrin in 3% to ll%, pancreatic polypeptide in 18% to 39%, and adrenocorticotropic C u r r Probl S u r g , F e b r u a r y 1 9 9 4
91
hormone (ACTH) in 11% .13, l8 The most common accessory hormone is pancreatic polypeptide (PP), which has been identified in as man as 39% of insulinomas, 67% of glucagonomas, and 75% of VIPomas.3’ Y’ In most instances, only one peptide is secreted into the circulation; however, in other instances numerous peptides can be measured in the circulation. At present, it is not clear why patients with a certain pancreatic endocrine tumor only have symptoms characteristic of one of these many peptides, especially when the tumor contains multiple peptides on immunocytochemistry. Possible hypotheses include the following: (1) only one peptide is released into the circulation; (2) some peptides released are able to antagonize symptoms caused by the other peptides that are present; or (3) only one of the peptides is biologically active, and the remainder are precursor hormones . Because most patients with pancreatic islet cell tumors are now living longer as therapy becomes more effective, the development of a secondary symptomatic pancreatic hormone may become evident.“’ ” One recent study indicates that secondary symptomatic pancreatic hormone secretion is common, occurring in 8% of patients, during a mean follow-up of 2 years.” Another study suggests it is uncommon, occurring in only 2% of patients with ZollingerEllison syndrome (ZES) followed up for 11 years.l’ This condition may be common in patients with malignant tumors. Patients with gastrinoma who have evidence of ACTH secretion appear to have a more malignant course.21 Because of the frequent presence of multiple hormones by immunocytochemistry in tumor specimens, it is not possible to determine by immunocytochemical techniques which of the hormones is responsible for the symptoms and syndrome in an individual patient. Therefore immunocytochemistry is not useful in categorizing an individual tumor as an insulinoma or gastrlnoma. However, it can provide some evidence to suggest what type of tumor an individual tumor is. For example, if an individual islet cell tumor has 80% of its cells positive for gastrln, most likely it will be a gastrinoma?s In general, microscopic pathologic description of pancreatic endocrine tumors has failed to predict the growth pattern of a specific tumor and is not able to determine whether an individual islet cell tumor is cancerous.’ In addition, no clear correlation exists between the histologic pattern of an islet cell tumor and the type of associated clinical syndrome.’ Pancreatic endocrine tumors may express the o-chain and -chain of human chorionic gonadotropin” and chromogranin-A.2 B S o m e authors suggest that each of these markers is a good indicator of malignancy.22’23 However, at present, the only clear determination of malignancy is surgical detection of metastatic tumor either in lymph nodes or the liver.’ Gross invasion of blood vessels and surrounding pancreas or infiltration into adjacent organs is another indicator of malignancy, but this sign is less certain than 92
Cum- Probl Surg. February 1994
the presence of distant metastatic disease. Therefore it is not clear what proportion of pancreatic islet cell tumors is cancerous. The benign nature of an individual tumor can be determined only by careful long-term follow-up studies. In general, less than 10% of insulinomas are cancerous, approximately 60% of gastrinomas are malignant, and 50% to 90% of all other islet cell tumors are malignant.1 The size of an individual islet cell tumor does not correlate with the severity of the hormonally mediated symptoms. However, a correlation does exist between the size of the tumor and the occurrence of [email protected]’ 24 Insulinomas, like gastrinomas, are generally small tumors (<2 cm)?’ Glucagonomas, somatostatinomas, pancreatic polypeptide (PPlomas, and other islet cell tumors are frequently larger at the time of detection (>5 cm).“” Most primary pancreatic endocrine tumors are solitary, encapsulated, and within the pancreas. However, islet cell tumors can occur in the duodenum and other locations besides the pancreas.26‘28 When metastatic disease occurs, it commonly is seen at diagnosis with either peripancreatic lymph node involvement or evidence of liver metastases.” Late in the course of the disease, metastases to lung, bone, and even heart may be identified. Pancreatic endocrine tumors occur in either a nonfamilial (sporadic) form or in a familial form associated with MEN-l. MEN-l is inherited as an autosomal dominant disorder and is characterized by tumors of the parathyroid glands, pancreas, and pituitary. It is associated with a defect on chromosome 11.l’ 3o Recently, two patients with MEN-l and insulinoma have been shown to possess the same constitutional gene defect and a deletion on chromosome 11. Similar defects have been identified in other pancreatic endocrine tumors in patients with MEN-1 .31 The chromosomal defects in insulinoma in patients with MEN-l are in contrast to patients with sporadic islet cell tumors, where homozygous inactivation of the MEN-l gene does not develop .31 The exact proportion of patients with pancreatic islet cell tumors who manifest MEN-l varies in different series from less than 5% to 25%.17 The recognition that an islet cell tumor is part of the MEN-l syndrome is important because patients with MEN-l always have multiple pancreatic islet cell tumors.32 Furthermore, screening of other family members for various features of the syndrome is indicated. Functional islet cell tumors are the second most frequent abnormality in MEN-l patients and are found in approximately 80% of these individuals. Gastrinomas, insulinomas, glucagonomas, and VIPomas occur in a decreasing incidence in that order, with gastrinomas occurring in 54% of patients and insulinomas in 20% of patients with MEN-1.33 Almost all insulinomas occur in the pancreas.“, 341 35 Glucagonomas generally occur within the pancreas and most commonly in the pancreatic body and tai1?4’ 36 In contrast to insulinomas and gluCurr Probl Surg,
February 1994
93
cagonomas, gastrinomas can occur within the duodenumz6-” and the pancreas.37’ 38 Approximately 50% of gastrinomas have recently been identified in the duodenal ~al1.2~, “, 38 VIPomas are usually in the pancreas” 3s; however, the VIPoma syndrome has been reported in association with pheochromocytoma or carcinoid tumor of the intestine.40’ 41 Somatostatinomas, like gastrinomas, may be extrapancreatic. In a recent review of 48 primary somatostatinomas, 56% were in the pancreas and 44% were in the duodenum or jejunum.42 Similar to glucagonomas, somatostatinomas usually are large (>5 cm) at the time of presentation.42 Only primary insulinomas and gastrinomas are small at the time of presentation, frequently less than 2 cm.25’ “, 38 Nonfimctioning pancreatic islet cell tumors and PPomas are usually greater than 5 cm in diameterP3’ 44 Other less common functioning islet cell tumors, such as those secreting GRF, parathyroidhormonelike (PTH-like) factor, or ACTH, are usually large tumors located within the pancreas.21’ 431 44 In addition to MEN-l syndrome, recent studies suggest that pancreatic islet cell tumors are found in a higher frequency in patients with von Recklinghausen’s disease,4547 von Hippel Lindau syndrome,48 and tuberous sclerosis.4s In patients with von Recklinghausen’s disease, duodenal somatostatinomas and gastrinomas have been reported?5-47 In patients with von Hippel Lindau syndrome, as many as 17% of patients have pancreatic endocrine tumors, including both adenomas and carcinomas. However, it is unusual for these tumors to be functional, and only one patient had a clinical hormonal syndrome in this series. In one series, patients with tuberous sclerosis had an incidence of insulinoma and nonfunctional pancreatic islet cell tumor.
SURGICAL PRINCIPLES
The goal of operation in patients with islet cell tumors is to identify, stage, and remove all tumor. The surgeon should remove all tumor in a manner that allows the mortality and morbidity of surgery to be less than the natural history of the tumor. The surgeon must know the natural history and pathologic condition of the islet cell tumor, the expected outcome of the surgical procedure, the expected survival with the tumor resected, the immediate and long-term complication rate, and the availability of alternative medical treatments to manage the disease. Most experts recommend that patients with islet cell tumor should undergo surgery because any islet cell tumor may be malignant, medical management can only control the signs and symptoms, and tumor resection is the only potentially curative treatment. Therefore each patient with biochemical evidence of an islet cell tumor should undergo complete radiologic assessment of the extent of disease to 94
Curr Probl Surg, February ww
determine the feasibility of surgery. During the radiologic evaluation, medical management should be used to ameliorate symptoms resulting from excessive hormone secretion. It is clear that in some patients with islet cell tumors (such as gastrinoma5’ and VIPoma41) advances in medical control of the hormone production has improved the surgical outcome and has reduced the operative complication rate. Many variables associated with an individual patient impact on the surgical outcome. These variables include the extent of disease on preoperative imaging studies, the location of the primary tumor (within the pancreas or duodenum), the exact area of the pancreas involved (head or tail), the presence of liver or other distant metastases and whether they are resectable, the occurrence of the islet cell tumor in a familial or a sporadic setting, and the simultaneous occurrence of other medical conditions that limit the ability of a patient to undergo major surgery. Success need not be defined as cure of the hormonal syndrome. Success may involve decreased medication requirement, decreased symptoms, and increased survival. In individual patients, clear benefits may be difficult to quantitate. Nonetheless, it is clear that islet cell tumors may be malignant, that surgery is an effective way to stage the true extent of disease accurately, and that surgery may cure patients even with metastatic islet cell tumor.51’ 52
PREOPERATIVE MANAGEMENT Diagnosis
Patients with functional islet cell tumors have symptoms resulting from uncontrolled excessive hormone secretion. The symptoms and signs for each islet cell tumor are listed in Table 1. Patients with nonfunctional islet cell tumors usually have symptoms related to a pancreatic mass (pain, intestinal bleeding, or obstruction).43S 53 As with most other endocrine tumors, the diagnosis of functional islet cell tumors is made biochemically by the immunologic detection of elevated plasma levels of a hormone. The exact diagnostic criteria for each type of islet cell tumor are listed in Table 2. It is necessary to obtain an unequivocal biochemical diagnosis before performing invasive localization studies.
Medical Management of Hormonal Symptoms
After diagnosis, the physician must attempt to ameliorate the signs and symptoms of excessive hormone secretion. Medical management has been facilitated by new drugs that reduce the levels of circulating hormone (e.g., octreotide541 or inhibit specific effects (antigastric acid hypersecretion [e.g., ranitidine?5 famotidineF6 a n d omeprazole57~5sl). CurrProblSur~
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96
TABLE
2. Diagnostic criteria for neuroendocnne tumors
Tumor type
Test
Results
Gastrinoma
Fasting gastrin Basal acid output
Elevated gastrin (>lOO pg/mlJ Elevated basal acid output 1X5 mEq/hourJ Elevated gastrin (>200 pgmll Symptoms of hypoglycemia Elevated insulin (Xi @J/ml) Decreased glucose (<40 mgdl) Elevated C peptide 1X.7 ng/mlJ Elevated percentage proinsulin (>30% 1 Elevated VIP (>250 pgml) Elevated glucagon (>500 pgml) Elevated somatostatin Elevated GRF Elevated cortisol Elevated ACTH Failure to suppress Failure to increase Elevated calcium Undetectable PTH Elevated PTH-like factor Elevated neurotensin
Insulinoma
VIPoma Glucagonoma Somatostatinoma GRFoma ACTHoma
PTH-like tumor
Neurotensinoma
Secretin test 72 hour fast
Fasting VIP Fasting glucagon Fasting somatostatin Fasting GRF Urinary free corns01 Plasma ACTH Dexamethasone CRH Calcium PfH PTH-like factor Fasting neurotensin
C/W, Corticotmpin-releasing hormone.
Localization The next step in the management of patients with biochemical evidence of an islet cell tumor is tumor localization. Unfortunately, radiologic procedures to image an islet cell tumor often fail. In fact, 50% of patients with insulinoma or gastrinoma will have no tumor identified despite invasive localization studies.25J 38, ” Published reports of recent studies including endoscopic ultrasonography, octreotide scan, and selective angiography with the administration of secretago e s suggest that a greater proportion of tumors can be localized6P-64 (Table 31. Furthermore, either infusion computed tomography (CT) or magnetic resonance imaging (MRI) can determine the presence of liver metastases with precision (80% 1 .65S 66 In patients with CT or MRI evidence of unresectable metastatic disease, biopsy confirmation of tumor is necessary before starting treatmentl’ 67 Andersen68 found that percutaneous biopsy correctly diagnosed the presence of metastatic neoplasm within the liver in 17 of 19 patients (89%) with pancreatic islet cell tumor. A 93% accuracy rate of CTguided aspiration biopsy has been observed in patients with CT evidence of liver disease.68 The use of ‘“lI-labeled octreotide has demonstrated that islet cell tumors can be imaged on the basis of the presence of functional so96
Corr Probl Sorg,
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TABLE 3.
Preoperative localization of neuruendocrine tumors of the pancreas and duodenum ”
Noninvasive Ultrasonography Octreotide radioimaging CT MRI Invasive Endoscopic ultrasonography Selective angiography Portal venous sampling Provocative angiography’ ‘Secretin
True positives (%I
Reference
43 21 60 35
10 18 26 9
(23) (861 (43) 1261
25,37 64,282 25,65 25,66
38 70 92 17
31 39 60 11
(82) (56) (761 (65)
63 25,283 25,76,211 61,62
for gastrinoma and calcium for insulinoma.
matostatin receptors.64, “, 7o Between 60% and 90% of gastrinomas and insulinomas have been correctly imaged. Endoscopic ultrasonography is another new modality to localize islet cell tumors.63 The procedure is performed by passing an endoscope through the stomach and duodenum. A balloon is inflated with saline solution, and a 5 to 10 MHz transducer is used to scan the pancreas and duodenal wall. Islet cell tumors within the body and tail of the pancreas are imaged with the transducer in the stomach. Islet cell tumors within the head of the pancreas or the duodenum are imaged with the transducer in the duodenum. Islet cell tumors are imaged as sonolucent mass lesions by ultrasonography. Approximately 80% of islet cell tumors were correctly identified in one recent rep~rt.~~ Apparently, islet cell tumors within the pancreatic tail are difficult to image (Table 3). Invasive islet cell tumor localization studies include selective arteriography and portal venous sampling. Selective angiography identifies an islet cell tumor by its appearance as a blush resulting from increased vascularity.71 Although it is one of the most reliable and sensitive imaging studies, in recent reports angiography was found to identify less than 50% of islet cell tumorsz5, “, 73 When injected directly into the artery that supplies the gastrinoma, secretin produces a quick rapid rise in hepatic venous levels of gastrin, which suggests that the gastrinoma is within the portion of the pancreas perfused by the injected artery.“’ 74, 75 In patients with insulinoma, intraarterial calcium can be injected to obtain similar information.61 A more tedious and invasive method to obtain regional localization is transhepatic portal venous sampling of the portal vein and its tributaries for elevated hormone concentrations. This procedure requires that the radiologist pass a catheter across the liver into the portal vein and its branches and collecting multiple blood samples Curr Probl Surg,
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97
for hormone. Theoretically, the closer the catheter gets to the tumor, the greater the venous hormone concentration. A 50% increment in hormone concentration in a selective vein that drains into either the splenic vein, the superior mesenteric vein, or the portal vein localizes the tumor to the head, body, or tail of the pancreas.76 Portal venous sampling correctly localizes 73% of gastrinomas76 and w%‘~ of insulinomas (Table 3). Multiple Endocrine Neoplasia The surgeon should obtain a careful family history for the presence of familial endocrine tumors. The familial syndrome most commonly associated with islet cell tumors is MEN-l. This syndrome is inherited as an autosomal dominant trait, and a genetic defect exists on chromosome 11.l’ 3o The most common islet cell tumor in patients with MEN-l is gastrinoma; the second most common tumor is insulinoma, but these patients may also have any other islet cell tumor.77-7s Other endocrine tumors in patients with MEN-l include primary hyperparathymidism caused by hyperplasia,77 and pituitary adenoma, commonly a pro1actinoma.l Patients with MEN-l also have a higher incidence of thyroid adenoma, adrenocortical tumors, carcinoid tumors, and lipomas.’ Patients with MEN-l generally have evidence of primary hyperparathyroidism before the islet cell tumor syndrome.77 In patients with islet cell tumors, the presence of MEN-l should be excluded by questioning about family history, by measuring serum levels of calcium, and by examining for other evidence of MEN-l (lipomas, elevated prolactin level). The management of patients with islet cell tumors in the presence of MEN-l is controversial and will be considered in a separate section. Preoperative Preparation Patients who are scheduled for exploration for an islet cell tumor require evaluation of cardiac, pulmonary, renal, coagulation, hematologic, and hepatic functions. Pneumococcal vaccine is given in case a splenectomy is necessary. Splenectomy may be part of subtotal or distal pancreatectomy. A mechanical bowel preparation with a strong cathartic is performed in case tumor excision requires a concomitant bowel resection or in case the bowel is injured. Broad-spectrum perioperative antibiotics such as second-generation cephalosporins are used for prophylaxis against surgical infection.80
OPERATIVE
MANAGEMENT
The choice of incision depends on body habitus. In patients who are thin, a midline incision is preferred. In patients who are obese or 98
Cur-r
Probl Surg,
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have a wide costal margin, a bilateral subcostal incision is more useful. A fixed upper abdominal retractor will improve exposure. Careful examination and palpation of all abdominal organs are necessary. Initial attention is focused on the liver and ovaries. Metastatic islet cell tumors are commonly firm nodules in the liver. Prim trinomas can occur in unusual locations such as the ovary. s?%ay; primary ovarian cystadenocarcinoma is identified,” then a total abdominal hysterectomy and bilateral salpingo-oophorectomy is indicated. After careful palpation and inspection of the liver, uterus, and ovaries, the entire small intestine is examined. Gastrinomas have been identified in either lymph nodes or the wall of the first portion of the jejunum.37’ 83 Finally, the colon is also palpated. To expose the pancreas; the lesser sac is opened by dividing the gastrocolic ligament. The ligaments attaching the hepatic and splenic flexures to the liver and spleen are divided to mobilize the colon out of the operative work space. The head of the pancreas is mobilized by dividing the attachments of the duodenum to the retroperitoneum (Kocher maneuver). This procedure allows palpation of the head of the pancreas between the thumb and forefinger as well as partial visualization of the posterior head of the pancreas. The body and tail of the pancreas are mobilized by dividing along the inferior and posterior border. It may be necessary to divide the splenic ligaments and rotate the spleen out of the retroperitoneum to carefully palpate the tail of the pancreas. Once the pancreas is mobilized, the entire gland should be palpated carefully between the thumb and forefinger. Islet cell tumors of the pancreas may be impossible to locate by palpation alone, especially in the pancreatic head.” Therefore the use of intraoperative ultrasonography to improve operative identitication of islet cell tumors has become a standard procedure. A 7.5 to 10 MHz transducer is preferred because of short focal length and high resolution.85 A 5 MHz transducer is used for the liver because of better depth of penetration. A color flow unit allows accurate detection of intrahepatic and intrapancreatic blood vessels, including determination of veins and arteries based on flow characteristics. Color flow Doppler also aids in assessing the relationship of islet cell tumors to major ducts, which are sonolucent tubular structures without blood flow. Intraoperative ultrasonography is performed by the operating surgeon in conjunction with an ultrasonographer. The peritoneum is iilled with saline solution to improve the quality of the images. The operative lights are dimmed to minimize glare. Masses are scanned in planes (longitudinal and transverse) to determine the relationship between imaged masses and other structures.86 Islet cell tumors are uniform sonolucent masses seen on ultrasound scan (Fig. 1). Ultrasonographic detection of islet cell tumors is aided by the uniCurr Probl Surg,
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99
FIG. 1. lntraoperative ultrasound appearance of a typical islet cell tumor (gastrinoma). The tumor IS sonolucent compared with the surrounding pancreas, which is more echogenlc. The margin between the tumor and the pancreas IS discrete, with an echogenic rim around the entire tumor. (From Norton JA, et al. Ann Surg 1988;207:160-8.) 100
Curr Probl Sorg,
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form echo-dense background of the pancreas and the liver. Numerous reports have demonstrated that intraoperative ultrasonography greatly yy$g detection of islet cell tumors within the pancreas.63’ 73* This technique is able to image nearly all pancreatic insulinomas and gastrinomas correctly, including tumors that are not palpable (Table 4). However, intraoperative ultrasonography is less useful in the detection of duodenal gastrinomas, which is explained by the fact that the duodenum is composed of solid, liquid, and gas and does not have the same uniform background as the pancreas. Small sonolucent islet cell tumors are less visible against a nonuniform background. Intraoperative ultrasonography is a tool for the surgeon. It is an extension of palpation because it allows looking into an organ without incising it. This feature is extremely valuable in the pancreas because it reduces unnecessary incisions into the gland that result in complications such as fistulas, pancreatitis, and pseudocyst. Exploration of the duodenum may be a critical component of islet cell tumor surgery. Many patients with ZES have a small duodenal wall islet cell tumor as a cause of excessive gastrin secretion.“’ 38 The duodenum has been the most frequent site of missed gastrinomas.27, 37,38 Techniques to facilitate operative detection of duodenal wall tumors are important in patients with ZES. Intraoperative endoscopy with transillumination of the duodenum improves detection of duodenal wall gastrinomagl (Table 4). During the operation, an endoscope is passed orally into the duodenum after complete exposure of the duodenum. The endoscopist looks for mucosal irregularities or outgrowing mass lesions within the wall of the duodenum that may occur as a result of intramural gastrinomas (Fig. 2). With the use of transillumination, intramural tumors are identifiable as an opaque density within the bowel walls2 (Fig. 3). Other authors suggest that extensive duodenotomy is the best method to find duodenal wall tuTABLE
4. Results of new intraoaerative methods to identifv neuroendocrine tumors
Type of tumor Pancreatic Insulinoma Gastrinoma Duodenal Gastrinoma
Method
”
Intraoperative ultrasonography Intraoperative ultrasonography
101
89 (881
73, 84, 87-90, 264
34
31 (91)
87, 89, 92, 284
Palpation Intraoperative ultrasonography Endoscopy and transilhtmination Duodenectomy
31 31
19 (61) 8 126)
92 92
31
20 164)
92
31
31 (1001
92
Curr Probl Sur5 February 1994
No. true positives (W 1
Reference
101
FIG.
2. Endoscopic view of duodenal gastrinoma. Side-viewing endoscope is passed into second portion of the duodenum, and gastrinoma is visible as a mass lesion (arrow).
morsz7 This method allows visualization and open palpation for nodules.27 A recent study demonstrated that duodenotomy was better than transillumination and was the single best method to locate duodenal tumors, identifying tumors not seen by transilluminationg2 Two methods are available to remove a pancreatic islet cell tumor: enucleation or resection. Enucleation refers to simple excision of the tumor. Enucleation is acceptable for islet cell tumors that are benign. Insulinoma is usually benign, and enucleation results in long-term cures (Table 51. Enucleation is preferred for insulinoma because enucleation preserves vital organs such as the pancreas and spleen. The exact determination of the relationship of the tumor to the pancreatic duct is important before removing an islet cell tumor. A ductal injury during dissection may result in considerable morbidity, including pancreatic fistula, abscess, and pseudocyst. The proximity of the tumor to the duct is best determined intraoperatively by ultrasonography. If no clear margin exists between the tumor and the duct, a distal pancreatectomy and splenectomy are preferable. The higher malignancy rate of other types of islet cell tumors, such as 102
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FIG. 3.
Operative surgeon’s view of duodenal gastrinoma that appears as a focal light defect during transillumination of duodenum.
TABLE 5.
Neuroendocrine
NeuruendocrIne Insulinoma
Total Gastrinoma
Total
tumor identification and cure rate’
tumor n 396 36 25
73 11 125 209
No. with tumor identified (%I
No. cured (I)
394 (991 3 6 (100) 24 (96) 45 (100) 499 (99) 57 178) 1 0 191) 101 (81) 168 (80)
394 (99) 3 5 197) 2 4 (96) 45 (100) 499 4 2 (58) 9 (82) 3 2 (26) 83 (40)
Reference 103 73 25 102 38 167 177
‘Cure rate refer8 to the immediate cure rate. Actual long-term GyearJ cure rate in gastrinoma patients may decrease by 50%. Cum Probl Surg, February 1994
103
gastrinoma, somatostatinoma, and glucagonoma, suggests that a pancreatic resection is indicated especially if preservation of the pancreatic head and duodenum can be achieved.s3’94 Gastrinomas within the head of the pancreas or duodenum are simply excised instead of performing a pancreaticoduodenectomy (Whipple procedure). Excision has been associated with excellent long-term ~utvival.~~ Therefore the choice of procedure to remove an islet cell tumor is based on the normal structures that may be sacrificed, operative death and complication rate, type of tumor, expected malignancy rate, and projected quality and length of life. POSTOPERATlVE
MANAGEMENT
The complications of surgery for islet cell tumors may be the result of major surgery or the result of removing an islet cell tumor from the pancreas or duodenum. Complications associated with major abdominal surgery include atelectasis, ileus, and infections. Complications associated with surgery to remove an islet cell tumor include pancreatitis, pancreatic fistula, pseudocyst, abscess, and duodenal leak (Table 6). Postoperative control of pancreatic exocrine drainage is achieved by insertion of large drains whenever a pancreatic incision is necessary. Closed suction drains should be used. Amylase concentrations of the drainage can be measured to determine that the collected fluid is from the pancreas. The drains must be lefi in place until the patient is eating regular food and the drainage is minimal (less than 20 ml/day). A low-fat diet is used to reduce pancreatic drainage. An H,receptor antagonist such as ranitidine or famotidine will decrease stomach acid and pancreatic exocrine secretion. In patients in whom excessive drainage of amylase-rich fluid persists (>250 ml/day), total parenteral nutrition will reduce the amount of drainage and promote healing. In addition, it has also been reported that patients with pancreatic and intestinal fistulas will benefit from octreotide to reduce the amount of drainage.54’ ” A recent study from Germany of patients undergoing pancreatic resection for adenocarcinoma and pancreatitis demonstrated a reduced complication and mortality rate with the use of octreotide.g6 However, another study in patients undergoing TABLE 6.
Morbidity and mortality of neuroendocrine tumor surgery
Location of tumor Multicenter Pancreas Duodenum
pancreas
n
No. with morbidity (W 1
No. with mortality (WI
Reference
419 49
132 (32) 7 (14)’
10 (2) 0 (0)
103 x,97
35
6 (17)t
0 (0)
92
*Incarcerated hernia (n = l), pancreatic fistia (n = 3), pseudocyst (n = 11, and abscess (II = 21. tPancreatitis (n = 21, duodenal leak (n = l), abscess (n = 21, and bowel obstruction In = 1).
104
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February 1994
resection of islet cell tumors failed to detect a benefits7 A major difference in these two studies is that octreotide was started pmoperatively in the study that detected a benefit and was only given postoperatively in the study that failed to demonstrate an effect. Although the data are conflicting, octreotide may be useful to reduce complications of pancreatic surgery when administered both preoperatively and after pancreatic surgery. INSLJLINOMA Endogenous hyperinsulinism was the first syndrome of excessive pancreatic hormone secretion to be identified. The first description of tumor-induced hyperinsulinism came from the Mayo Clinic in 1927. The tumor was a malignant insulinoma with multiple liver metastases. It was biopsied but not resected. Roscoe Graham in Toronto is credited with the first successful surgical removal of an insulinoma in 1929. Evarts Graham of Barnes Hospital in St. Louis successfully enucleated a tiny (5 mm) insulinoma in 1931. This procedure was identical to enucleation performed today. In 1935, Whipple grouped 32 patients who had insulinoma and proposed the classic triad of diagnostic features. Whipple’s diagnostic triad includes the following: (1) symptoms of hypoglycemia while fasting, (2) blood glucose levels less than 50 m#dl, and (3) relief of symptoms after administration of g1ucose.s8 SMMPTOMS
Inswlinoma must be considered in the differential diagnosis of neuroglycopenic symptoms seen while fasting.“’ “, loo Most patients with insulinoma have hypoglycemic symptoms for years before diagnosis .” The mean length of time from the onset of symptoms to diagnosis is 2 years, and some patients have had symptoms for 6 years. There is a higher incidence of insulinoma in women?5S 35, s”,101-104 Neuroglycopenic symptoms include anxiety, dizziness, obtundation, or confusion during a period of fasting. Seizures related to hypoglycemiaz5 and psychosis will develop in 30% of patients. Most patients have documented weight gain?” lo2 The diagnosis of insulinoma may become more apparent when the patient reduces food intake in an effort to lose weight. DLAGNOSIS
If a patient has hypoglycemia while fasting, a hospitalized fast with measurement of blood levels of insulin and glucose is indicated to rule out insulinoma. The finding of an inappropriately elevated seCurr Probl Surg, February 1994
106
rum level of insulin for the level of glucose establishes the diagnosis of insulinoma.ss The patient is allowed noncaloric beverages and is observed at frequent intervals. Blood levels of glucose and insulin are measured every 6 hours during the fast. The fast is continued for a maximum of 72 hours or until neuroglycopenic symptoms are observed (Fig. 4). Symptoms include shaking, diaphoresis, obtundation, confusion, and seizures. At that point, blood levels of insulin, glucose, C peptide, and proinsulin are drawn, and the fast is terminated. Symptoms of hypoglycemia will develop in two thirds of individuals with insulinoma before 24 hours of fasting, and symptoms will develop in the remainder before 72 hoursz5 Hypoglycemia is defined as a level of blood glucose less than 40 mgdl. However, symptoms will develop in a few patients (16%) with insulinoma when the blood glucose is approximately 45 m#dlz5 (Fig. 4). Each patient with insulinoma (100% 1 will have inappropriately elevated plasma levels of insulin G-5 @J/ml) at the time of documented symptoms and hypogly-
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FIG. 4. Hours of fast (left panel) and serum levels of glucose and insulin (right panel) at termination of the fast resulting from neuroglycopenic symptoms in 25 patients with proven insulinoma. Each number represents a patient. One patient (No. 12) had two separate fasts. Symptoms developed in 57% of patients by 24 hours and in 88% by 48 hours. Shaded area indicates normal levels of insulin. Each patient (100%) had elevated serum levels of insulin at the conclusion of the fast (>5 )IU/ml). Each patient had hypoglycemia (~50 mg/ dl), and 23 of 26 patients had blood glucose levels less than 40 mg/dl. (From Doherty GM, et al. Surgery 1991; 110:989-97.) 106
Curr Probl Surg February 1994
cemia25 (Fig. 4). The ratio of blood insulin to glucose (>0.4) may be used as another diagnostic criterion for insulinoma.102 Twenty-one of 23 patients (91%) with insulinoma have elevated blood levels of C peptide (>1.7 rig/ml) at the conclusion of the fast25”05,106 (Fig. 5). Eighty percent of patients with insulinoma will have elevated proportions of proinsulin ~~~~~~~~~~~~~~~~ lo8 (Fig. 51, and it may be a marker of a malignant tumor.“’ Proinsulin is an insulin precursor. Patients with greater proportions of proinsulin are able to undergo longer fasts with fewer symptoms because proinsulin is biologically less active.25 Several suppression and stimulation tests are available for the diagnosis of insulinoma.” Stimulation tests include the administration of tolbutamide, calcium, glucagon, or leucine and the measurement of increased insulin levels after each of these agents. Similarly, other investigators have used either porcine or fish insulin, which fails to change plasma levels of C peptide or human insulin in patients with insulinoma but will suppress levels in normal individuals.105’106 In most patients, suppression or stimulation tests are not necessary to diagnose insulinoma. One cause of hypoglycemia or pseudo-hypoglycemia is surreptia
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FIG. 5. Serum levels of C peptide (left panel) and percentage of proinsulin (right panel) at termination of a fast in 25 patients with insulinoma for patients shown in Figure 4. Shaded areas indicate normal levels of C peptide and percentage of proinsulin. Twenty-three of 25 patients (92%) had elevated C peptide levels. Twenty-one of 25 patients (84%) had elevated percentage of proinsulin. (From Doherty GM, et al. Surgery 1991 ;110:989-97.) Curr Prohi
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tious or factitious hypoglycemia.1og Young women with access to insulin, such as nurses or individuals with diabetic relatives, are at high risk. Patients with factitious hypoglycemia have low levels of C peptide and normal proinsulin levels, and antiinsulin antibodies may be present?” ‘OS Mass spectroscopy can detect minute levels of sulfonylurea in the blood of patients taking oral hypoglycemic drugs. These patients may undergo unnecessary surgery, including pancreatic resection.10s Despite accurate diagnosis and confrontation, the long-term prognosis of patients with factitious hypoglycemia remains poor, and only one third return to productive life.‘Og CONTROL OF HYPOGLYCEMIA
After the diagnosis is established, hypoglycemic symptoms are avoided primarily through medical means. The diet is modified to increase the frequency of meals, including possibly setting the alarm clock to awaken for a meal during the night.” Cornstarch can be added to slow the absorption of food and to prevent hypoglycemic troughs. Drugs are indicated to increase fasting glucose levels. Diazoxide is helpful in approximately 60% of patients.” Because it can cause operative hypotension, diazoxide should be discontinued 1 week before surgery. Calcium channel blockers may also be useful.11o Octreotide, the long-acting somatostatin analogue, has been effective in the management of hypoglycemia in infants with nesidioblastosis, but it is not as effective in adults with insulinoma.41’ “‘a 11’ This agent may be useful in an occasional patient; some investigators have reported long-term control of hypoglycemia with octreotide.113’ ‘14 In general, the long-term medical management of hypoglycemia has been ineffective, and the best results have been obtained with surgical excision.” RADIOGRAPHIC
LOCALIZATION
Localization studies tc image or localize the tumor to a region of the pancreas can be divided into noninvasive and invasive imaging or localizing studies. These studies may provide exact images of the tumor, or they may suggest the area of the pancreas that contains the tumor and allow the surgeon to focus on that region with intraoperative techniques or remove the region if a tumor is not identified during surgery. Abdominal ultrasonography is the least invasive, least expensive, and least sensitive method to localize insulinoma.25’ 71,115 The truepositive rate is between 20% and 40% .“, 71, ‘I5 CT with intravenous contrast demonstrates an insulinoma as a dense blush”, 71, 768 lo’, I’5 because the islet cell tumor has increased vascularity. MRI images .108
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small insulinomas as bright spots on the T, weighted imagesz5, ‘15 It appears from initial studies that MRI is comparable to CT. Octreotide scan has been used to image insulinomas on the basis of the density of somatostatin receptors6 ’ ‘O However, because insulinomas do not have a high number of somatostatin receptors, labeled octreotide is not always useful in the imaging of insulinoma. This technique images only 60% of insulinomas. Selective angiography, which images insulinoma on the basis of increased blood supply, is the single best study.71*116 Some authors have suggested that nearly 90% of insulinomas can be identified.l16 However, in recent reports, only 50% of insulinomas are identified.25 A tumor that is able to be imaged is usually correct because few false positive results are seen. Controversy exists among surgeons as to whether regional localization is necessary for patients who do not have insulinoma identified on imaging studies. We have suggested and demonstrated that in those patients portal venous sampling can be very helpful, and it pinpoints the exact area with the insulinoma in 75% of patients” (Fig. 61. Van Heerden and colleaguesl” have recently described 20 similar patients who underwent successful surgery without venous sampling. Both groups used intraoperative ultrasonography and were convinced that it was helpful. Venous sampling of the portal vein and its tributaries for levels of insulin has been the single most informative stud?’ “I 118-121 (Fig. 6). It does not provide precise imaging of the tumor, but it can provide localization of the insulinoma to the head, body, or tail in 75% of patients. A catheter is placed through the liver into the portal vein, and numerous blood samples are taken to measure insulin levels from selective veins that drain into the portal vein or one of the two major tributaries (superior mesenteric and splenic vein). A 50% increment in insulin concentration from the levels in a peripheral vein indicates that the insulinoma is in the part of the pancreas where the step-up occurred. Portal venous sampling is expensive, and it may result in complications such as intraperitoneal bleeding or hemobilia. A new study called calcium angiography appears to be able to determine which region of the pancreas contains the insulinoma.61 This study is similar to the secretin arteriography, which is as effective as portal venous sampling for the localization of gastrinomas.6z’ 74, 75 The radiologist performs pancreatic arteriography and identifies which arteries perfuse different areas in the pancreas. Sequentially, in three separate studies, calcium is injected into different arteries, and plasma samples are obtained from the hepatic veins for insulin concentrations. If the artery that supplies the region with the insulinoma is injected with calcium, a rapid, marked rise in hepatic vein insulin levels occurs in the samples taken 30 seconds after calcium injection. An initial report demonstrates that calcium angiography can reliably determine the location of the insulinoma. Whether it will CurrProblSurg,
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109
Peripheral insulin = 56 $/ml
SMV
FIG. 6.
Portal venous sampling for insulin concentrations in patient with insulinoma in pancreatic tail. A catheter is passed through the liver and down the portal vein (PI/) and its tributaries (SV, splenic vein: IMV, inferior mesenteric vein; SMV, superior mesenteric vein; IPDV, inferior pancreaticoduodenal vein; S/WV, superior pancreaticoduodenal vein) to localize insulinoma. Serum insulin levels are measured at each site. Intraoperative ultrasonography and palpation failed to identify an insulinoma in this patient. A distal pancreatectomy was performed solely on the basis of marked insulin step-up (305 pU/ml) in the splenic vein. Pathologic analysis confirmed the presence of a 1 cm insulinoma in pancreatic tail. (From Norton JA, et al. Ann Surg 1990;212:615-20.)
be as sensitive as portal venous sampling is not yet clear. Endoscopic ultrasonography has also been reported to identify correctly 80% of islet cell tumors.63 Islet cell tumors within the head of the pancreas are imaged more often because the study is usually performed with the endoscope and transducer in the duodenum. However, tumors within the tail of the pancreas may also be imaged with the endoscope in the stomach. EXPLOR4TION
FOR INSULINOMA
Insulinomas are rare tumors, and few surgeons will have vast experience with the intraoperative management of patients with these 110
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tumors. Experience is important because in most patients with insulinoma the preoperative imaging studies are negative and the tumor is small and difficult to, detect. Furthermore, misadventures during operations on the pancreas are complicated by pancreatitis, fistula, abscess, and pseudocyst. Before undertaking exploration for insulinoma, the surgeon must have a firm conviction of the diagnosis. Medical management of hypoglycemia should have been attempted to determine the necessity of insulinoma resection. Many patients will be poorly controlled or will not tolerate the medicines to ameliorate the hypoglycemia. In those patients, a greater urgency exists for operative removal of an insulinoma. Careful questioning and testing should have been performed tq determine whether the patient has MEN-l. The management of insulinoma in MEN-l is different and will be discussed separately. The surgeon should examine and review all of the information on localization available on the patient. If the tumor is imaged on either CT or angiography, the surgeon must be able either to confirm or deny that the insulinoma is present where the study suggests. If there is accurate regional localization and no tumor is identified intraoperatively (Fig. 6), then the surgeon knows that resection of that specific area of the pancreas will include the tumor and correct the hypoglycemia. Finally, even in p.atients with inconclusive localizing information, an experienced surgeon can usually identify and resect the insulinoma.84’ “’ Insulinomas are small (<2 cm1 solid tumors that are located within the parenchyma of the pancreas.z5’ 35, 102,103, lz3 Insulinomas are uniformly distributed throughout the entire pancreasz5’ 35, ‘02, lo3, lz3 (Fig. 7). Other islet cell tumors such as gastrinoma are commonly identified in extrapancreatic locations within the wall of the duodenum38 and pccur more commonly in the pancreatic head or duodenum.lz4 Insulinomas have been found‘only rarely in extrapancreatic locations associated with ectopic pancreas.25J 350 lo’, lo3* lz3 Unlike gastrinomas, which are usual1 malignant,19 g3 insulinomas are most often benign.25, 35,102,103,1 Y3 A confusing entity in adult patients with hypoglycemia is nesidioblastosis.‘02’125 This diagnosis implies a diffuse nodular enlargement of the entire pancreas, and near total pancreatectomy is reported to be the procedure of choice.“02,‘25 However, recent studies suggest that nesidioblastosis is not a true pathologic entity in adults.lz5 The surgeon should operate on the assumption that each patient has a solitary small insulinoma that must be found and removed for control of hypoglycemia.25 This point is controversial, and some authors contend that nesidioblastosis is a pathologic entity in adults.“’ However, we have not encountered this condition in 35 consecutive adult patients with sporadic insulinoma. Each individual had a small, identifiable insulinoma. The goal of surgery for patients with insulinoma is to find and reCurr Probl Surg,
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FIG. 7. Location of 24 sporadic insulinomas that were successfully removed in 25 con-
secutive patients with insulinoma. Each number represents a patient’s tumor. Numbers within circles indicate location of tumors that were found only by intraoperative ultrasonography. Seven tumors were found only by intraoperative ultrasonography, and six of these were within the pancreatic head. One tumor (No. 17, square) was found only by resection after portal venous sampling (Fig. 6). That tumor was not identifiable by palpation or intraoperative ultrasonography. Note that the insulinomas are uniformly distributed throughout the entire pancreas. (From Doherty GM, et al. Surgery 1991;110:989-97.)
move all tumor safely. Because these tumors are nearly always benign and small, the primary operative difficulty is precise localization. After excellent exposure of the pancreas, the search for the insulinoma is undertaken. Occasionally it is necessary to divide the splenic ligaments to mobilize the spleen completely for meticulous examination of the pancreatic tail. Three methods are used to identify insulinoma. The first method is visualization. Insulinomas appear as a reddish-brown, cherrylike tumor because of increased vascularity. However, on direct inspection most insulinomas are not visible because the tumor is buried within the pancreas. Therefore visualization has limited use. The second operative method used to identify insulinoma is palpation. Insulinomas feel firm and nodular compared with the surrounding pancreas. Palpation is more difficult in patients who have had prior surgery or who drink alcohol because the pancreas loses its soft consistency. Palpation is less useful for pancreatic insulinomas within the pancreatic head because it is thicker and therefore a small tumor may be indistinguishablez5 (Fig. 7). Careful a l ation can be used to find some insulinomas that are not visible. !v “, 27 The best method for operative detection of insulinomas is intraoperative ultrasonography.73’ 84S “, ‘I5 Insulinoma, like other islet cell tumors, appear sonolucent compared with the more echo-dense normal pancreas (Fig. 8). Intraoperative ultrasonography becomes an extension of palpation, and the surgeon can confirm or refute specific areas of the pancreas that may feel firm.“’ a9 Further112
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QJi&
8mm
%7sulinoma Pancreas
FIG. 8. lntraoperative ultrasonography of 8 mm insulinoma overlying the portal vein in a patient who had previously undergone blind, unsuccessful subtotal pancreatic resection, Intraoperative ultrasonography was performed with a 10 MHz transducer. The tumor (between fwo arrows) was sonolucent compared with the more echo-dense pancreatic head. (From Norton JA, et al. Ann Surg 1990;212:615-20.) Cur-r
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more, intraoperative ultrasonography is able to determine the relationship of the tumor to the pancreatic duct, the superior mesenteric vein, and other vital structures so that the surgeon can plan the safest route to remove the tumor (Fig. 8). The surgeon should use the information obtained by intraoperative ultrasonography to plan the method and route of tumor removal. Because small, typical insulinomas are benign, surgery should be designed to remove only the tumor without removing adjacent pancreas and spleen. Insulinomas within the pancreatic head are enucleated. Insulinomas within the body or tail of the pancreas are either enucleated or resected by a distal or subtotal pancreatectomy on the basis of the relationship between the tumor and the pancreatic duct. Some investigators recommend resection of progressively more and more pancreas with intraoperative on-line measurement of blood glucose levels to determine when and if the insulinoma has been removed.‘28-131 This procedure is mentioned to condemn it. As stated, the goal of surgery is not to blindly resect more and more pancreas but to identity the tumor accurately so that it alone can be removed. The presence of malignancy in insulinoma, although uncommon, can occur,51’ ‘1’S 13’ and the surgeon must carefully evaluate adjacent lymph nodes and the liver for the presence of disease. Intraoperative ultrasonography also may be helpful in assessing the liver. If a patient has limited resectable metastatic islet cell tumor, most surgeons familiar with these patients recommend resection of metastatic disease either at the same or a subsequent procedure. Results of surgery for insulinoma demonstrate that most patients with this tumor are cured by surgical resection of the tumor73'90'102,103,126,127 (Table 5). In our experience with 25 consecutive patients with biochemical evidence of insulinoma and no evidence of MEN-l, 96% were cured of hyperinsulinism at initial operation.25 Some operative complications occurred, but no patient experienced long-term morbidity from the surgery (Table 6). INSULINOMA AND MULTIPLE ENDOCRINE NEOPLASLA TYPE 2
Approximately 10% of patients with hyperinsulinism will have MEN-1.33 Insulinoma is the second most common functional islet cell tumor of the pancreas in patients with this familial syndrome. The presence of MEN-l may be determined by careful questioning about family history and searching for other manifestations of the syndrome. Ascertaining the serum levels of calcium, prolactin, and pancreatic polypeptide44,133, 134 may be useful in attempting to determine the presence of MEN-l. The pancreas of patients with MEN-l always has multiple islet cell tumors7” 135 and recent studies suggest that the duodenum also has 114
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multiple neuroendocrine tumorsz6 However, careful immunoperoxidase staining of these tumors suggests that the duodenal tumors may more likely be gastrinomasz6 and that the pancreatic tumors may more likely be insulinomas.“’ I35 Another important fact is that larger tumors may be malignant, and 50% in one small study had evidence of spread to either lymph nodes or the liver.33 Because of multiple islet cell tumors, either portal venous sampling for insulin or calcium arteriography to localize the specific area of the pancreas that contains the insulinoma will help determine which area to resect.33’ lzl However, in our experience, patients with MEN-l and insulinoma usually have a dominant islet cell tumor able to be imaged that is responsible for the excessive insulin secretion (Fig. 9). Because patients with MEN-l always have multiple islet cell tumors, we try to resect the area of the pancreas that is suggested by the preoperative portal venous sampling or the calcium angiogram as containing the insulinoma.33,121 Patients with MEN-l and insulinoma usually have an islet cell tumor that is able to be imaged by CT, MBI, or angiographf3’ 13’ (Fig. 9). The imaged tumor is located in the same region of the pancreas that has excessive insulin production. Furthermore, we can usually identify other small islet cell tumors.” If the dominant tumor is present within the body or tail of the pancreas, a subtotal or distal pancreatectomy is recommended. If the dominant islet cell tumor is within the pancreatic head, enucleation
FIG.
9. CT scan of a dominant insulinoma in a patient with MEN-l. Arrow depicts a 6 cm mass in the pancreatic tail that was resected with resolution of hypennsulinism. This tumor was malignant, with vascular lnvaslon and spread to regional lymph nodes. curr Probl surg, Fehnmy 1994
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is attempted. A pancreaticoduodenectomy may be indicated if a large localized islet cell tumor cannot be enucleated. Despite the fact that these patients have multiple islet cell tumors and that some of the islet cell tumors may be malignant, patients with insulinoma and MEN-l are usually freed of the hypoglycemia after surgical resection (Fig. 101. Careful long-term follow-up is required because recurrent hyperinsulinism may develop by either the occurrence of another pancreatic insulinoma or the development of metastatic disease from the original tumor. Repeat surgical resection may be indicated for recurrent hyperinsulinism in patients with MEN-l if the procedure can be performed safely with acceptable morbidity and mortality. Although the management of hyperinsulinism in patients with MEN-l may be both complex and confusing, proper recognition of the syndrome helps to determine the correct surgical approach and produces an excellent outcome in most patients33”35 (Fig. 10). ZOLLINGER-ELLISON SYNDROME In 1955, Zollinger and Ellison were the first to describe the association of life-threatening peptic ulcer disease, gastric acid hyper-
FIG. 10. Results of resection of islet cell tumor in patients with MEN-l and either insulinoma or VlPoma and an unusual patient with MEN-2 and gastrinoma. Unlike the situation in patients with MEN-l and gastrinoma, each of these patients had complete reversal of biochemical parameters and symptoms of disease after surgical resection of islet cell tumor. The two patients with insulinoma each had normalization of fasting levels of insulin and glucose after tumor resection (center). Similar results were noted in one patient with MEN-l and VlPoma (right) and one patient with MEN-2 and gastrinoma (left). (From Sheppard BC, et al. Surgery 1989;106:1108-118.) 116
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secretion, and a pancreatic islet cell tumor. They suggested that the tumor produced a factor that caused the ulcer diathesis. The peptic ulcer disease was so severe that each patient required multiple operations and eventually total gastrectomy to stop acid secretion and control symptoms.136 In 1960, Gregory and colleagues13’ extracted a peptide from tumors of patients with ZES and noted that it was similar to the antral hormone gastrin. Subsequently, it was determined that the peptide was indeed gastrin.138’ 13’ With the development of specific and sensitive immunoassays for gastrin, it has been shown that patients with ZES have elevated levels of gastrin in the serum and tumor.14’ The gastrin immunoassay is now the major tool for diagnosis .141 Although the prevalence is not known, studies suggest that gastrinoma will develop in approximately 0.5 to 1 per million population.2’ 142, l43 Most studies suggest that it is the second most common islet cell tumor,” 143 but one study indicates it the most common.‘4z It is the most common functional pancreatic neoplasm in patients with MEN-1,26,33,68,77,144-147and approximately 20% of patients with ZES will have MEN-l (Table 1). Despite these facts, gastrinomas are a rare source of eptic ulcer disease, causing less than 1% of all duodenal ulcers.14 P
SYMPTOMS
ZES occurs more commonly in men than women, and the mean age at presentation is approximately 45 years. However, patients with ZES as part of MEN-l usually have peptic ulcer disease in the third decade of life.33’ 14’ Pain in the epigastrium is the most common symptom, and approximately 90% of patients have evidence of duodenal ulcer disease at the time of diagnosis.38’ 150-152 Most of the symptoms of patients with ZES am caused by the gastric acid hypersecretion. *‘, 51J 68, 148 Therefore either medical or surgical control of the acid hypersecretion abolishes all symptoms.l” 5’S 5sJ 153-155 Most patients have epigastric pain and indigestion that are alleviated by eating. Diarrhea and weight loss are also common (40% 1. Twenty percent of patients will complain only of diarrhea, which is caused by gastric acid hypersecretion3” 14’ When the acid hypersecmtion is controlled either surgically or medically, the diarrhea will resolve, and the serum levels of gastrin will not change.17’ 58J *T3, ls4 Esophagitis may occur in a significant proportion of patients, and 30% have dysphagia. Stricture and perforation of the esophagus have recently been described as an unrecognized complication of ZES.l’” In recent studies of 122 patients with ZES, esophageal symptoms and endoscopic abnormalities were present in approximately 60% of patientsl”’ Is8 High serum levels of gastrin also cause parietal cell hyCur-r
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, with changes resulting from the trophic effects of gasAs the tumor progresses, symptoms related to tumor burden may develop ? 43, 16’ Initially, most patients with ZES had atypical peptic ulcer disease associated with multiple ulcers, ulcers in unusual locations, and failed acid-reducing surgical procedures.136s 16’ Although atypical or recurrent peptic ulcer disease suggest ZES, most patients today have typical peptic ulcer disease, and some patients (approximately 20%) do not have ulcer disease.38 The availability of reliable radioimmunoassays for gastrin has improved the ability to diagnose ZES and may account for the earlier diagnosis and fewer complications of this disease in patients today. Nevertheless, often a long history (6 to 9 years) of significant peptic ulcer disease has existed before the diagnosis of ZES,38, lz4*’ 3 and 30% to 40% of patients have had failed surgery before the correct diagnosis.38 Between 7% and 30% of patients will have perforation of the duodenum or jejunum as a presenting problem.157 Whenever considering an operation for peptic ulcer disease, the surgeon should measure fasting serum levels of gastrin to exclude ZES. In patients with ZES and MEN-l, primary hyperparathyroidism is usually evident at the time of diagnosis of ZES.68’ 77, I49 These patients may have symptoms related to both conditions. Studies suggest that management of the peptic ulcer disease is facilitated by successful management of the hyperparathyroidism77 (see section on MEN-l and ZES). PATHOLOGIC
FEATURES
Until recently, most series reported that most gastrinomas occurred within the pancreas itself.15” I62 Furthermore, gastrinomas were uniformly distributed throughout the pancreas.‘“4’ 165 Although duodenal wall gastrinomas were originally described in 1958 by Oberhelman and co11eagues,166 these tumors were thought to be rare, occurring in less than 20% of cases.164’ 165 According to recent series, both of these perceptions are incorrect. It has now been demonstrated that nearly all gastrinomas are found within an area centered around the ancreatic head and duodenum, the gastrinoma teangle.27, 38, 1B4, 167-169 Additionally, the duodenum and not the pancreas may be the most common location for a primary tumor.27’ 38, 1’S Some investigators suggest that duodenal gastrinomas are less commonly malignant than ancreatic gastrinomas, with only a 36% incidence of metastases.17 F Other investigators have demonstrated that the malignancy rate for duodenal gastrinomas is similar to pancreatic gastrinomas.38 Gastrinomas may originate at other sites, includ118
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ing the liver, stomach, jejunum, mesentery, spleen, and ovary. 37, 82,148, 171,172 Adding to the confusion about ‘primary gastrinomas,” several independent groups have described a “lymph node” primary gastrinoma.83’ 16’, 173 Although these tumors are uncommon, some patients have been cured after resection of gastrinomas within lymph nOdeS~'~63,16',173 Whether these tumors represent primary or metastatic gastrinomas will be determined with long-term follow-up because some authors suggest that these patients actually have occult duodenal wall primary gastrinomas that were missed.z7’ 38 At present, it is unclear whether these are primary or metastatic tumors. Because delta or gastrin-producing neuroendocrine cells are present within the duodenum and not the pancreas, some authors believe that pancreatic gastrinomas are ectopic and more malignant than duodenal tumors.133 However, recent studies suggest that the malignant potential of duodenal wall gastrinomas is identical to pancreatic tumorsz8 Metastases are present in more than one half of patients with duodenal tumors.28 Furthermore, the disease-free interval for patients with duodenal wall tumors is shorter than for pancreatic tumors.38 Therefore the metastatic potential of gastrinoma does not differ on the basis of primary location, In early studies, approximately 60% of .patients had liver metastases at diagnosis of ZES.162, 165’ ” Currently, approximately one third of patients have liver invo1vement.38’ 68, 145, 14’ Gastrinoma spreads to the regional lymph nodes and liver. Some patients have had widely disseminated disease at death with involvement of the lungs, bone, heart, and adrenal gland.‘61, 175, 176 Despite the presence of distant disease, gastrinomas are slow growing. Patients with distant metastatic disease may survive for years. Patients with unresectable liver metastases have a 5-year survival rate between 20% and 42% and a lo-year survival rate between 0% and 30%“’ 38J 165 (Fig. 11). Possibly the tumor biology of patients who have distant disease at diagnosis is more aggressive than that of patients with localized disease at diagnosis. In early series when most patients were seen after many years of symptoms, gastrinomas were identified in nearly every patient (81% to 94w~~'36,162,177 However, with the development of an earlier diagnosis based on serum levels of gastrin, tumors were found in only 50% of pa~~en~s~37~51~163~176~181 Most recently, with the development of improved operative methods to detect duodenal astrinomas, tumor has been found in nearly every patient.“, 38z 75, 1 84, 168, I” Approximately 20% of patients with ZES also have MEN1.26,3 , 71, 77,144 The islet cell tumors in patients with MEN-l are always multiple.7sJ la2 Furthermore, recent studies also indicate that these patients have multiple duodenal tumors that are positive for gastrin.26J27 Immunocytochemical studies of the islet cell tumors in Curr Probl Surg,
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NO TUMOR FOUND o RESECTED AND CURED m RESECTED BUT NOT CURED o DISTANT DISEASE l
0.0
0
I 50
I 100
1 150
MONTHS
FIG. 11. Survival of patients with ZES from day of diagnosis. Patients were divided into four groups on the basis of preoperative evaluation, operative findings, and initial postoperative evaluation: patients who had metastatic disease at diagnosis (n = 18) patients who had no tumor found at surgery (n = 16) patients who had tumor resected and were disease free (cured) (n = 42), and patients who had all tumor resected but were not disease free (n = 15). No differences were observed among the three groups with localized gastrinoma. The group with distant disease had a significantly shorter survival time than all other patient groups @I < 0.001). (From Norton JA, et al. Ann Surg 1992;215:8-18.)
patients with MEN-l have demonstrated that not all tumors produce gastrin and that multiple hormones may be made by the same tumor.26J 7s Despite the fact that these patients have multiple islet cell tumors and that each tumor may produce more than one hormone, it is unusual for patients with MEN-l to have serum evidence of excessive production of more than one islet cell hormone.26’ 33 DIAGNOSIS
The original diagnostic criteria for ZES have been modified since the development of the immunoassay for gastrin. Zollinger and Ellison136 described patients with severe gastric acid hypersecretion, unrelenting peptic ulcer disease, and a pancreatic islet cell tumor. Currently, only two of the three original criteria are necessary for the diagnosis.s3 Approximately 30% to 40% of patients with ZES do not have evidence of peptic ulcer disease.38’ 68 Forty percent of patients have duodenal tumors instead of pancreatic tumors.388 68 The diagnosis to130
Curr Probl SW-~, February 1994
day is dependent on the presence of gastric acid hypersecretion I>15 mEq/L in patients who have not had surgery or 5 mEq/L in patients with prior ulcer surgery5o,183 1 and elevated fasting levels of gastrin (>loo pg/ml).93> 124,146,181 The diagnosis of ZES must be excluded in patients with peptic ulcer disease or secretory diarrhea. It should also be considered in patients with severe esophagitis. ZES may be the underlining cause of duodenal ulcer disease that does not heal with appropriate doses of histamine receptor antagonists.50’ ls3 ZES must be excluded before performing operations for duodenal ulcer disease. This determination can be accomplished readily by measuring gastric pH and fasting serum level of gastrin68’ s3J 168 (Table 2). The diagnosis of ZES is dependent on both the fasting serum level of gastrin and the acid outpuL3’, 51J s3 All ulcer medications must be discontinued before these measurements. Basal acid output is the amount of titratable acid secreted during a timed interval. It is obtained by neutralizing the collected gastric contents with sodium hydroxide (1 N NaOH). The amount of added base in milliequivalents required to achieve a neutral ph equals the amount of acid in the sample. A simpler qualitative method is to measure the pH of the collected sample. Patients with ZES usually have a gastric pH level less than or equal to 2, but the level must be less than or equal to 4. The fasting serum level of gastrin is elevated in all patients (>lOO p#ml). Patients with achlorhydria or hypochlorhydria may have falsely elevated serum levels of gastrin. Conditions that give false positive gastrin levels include gastritis, gastric cancer, pernicious anemia, prior vagotomy, retained gastric antrum, s3, ~8, ls4 and failure to discontinue antacid medications. If a patient has both elevated fasting serum levels of gastrin and elevated basal acid output, the diagnosis of ZES is confirmed. False positive conditions may be excluded by the use of a secretin stimulation test. Provocative tests are useful in the diagnosis of ZES. The most studied agents are secretin,185’ 186 calcium,186-188 and protein meal.17sJ 18’ In the secretin test, fasting serum levels of gastrin are measured before and at 2, 5, 10, and 20 minutes after 2 U/kg secretin administered intravenously. A result consistent with ZES is a greater than 200 pg/ml increment in the serum gastrin leve1.185, 186 Calcium gluconate is infused over a 3-hour period at a dose of 54 mgkg/hour, and blood levels of gastrin and calcium are measured at 30-minute intervals. A positive result is an increment in the gastrin level of greater than 395 Pkw.lS6, lS8 With a standard 40 gm protein meal test, serum levels of gastrin are measured at -15, 0, 30, 60, and 90 minutes. Patients with ZES will not have an increment in gastrin over basal levels.‘7s For the diagnosis of ZES,18s the most useful tests are the measurement of fasting serum levels of gastrin and the basal acid output, which are positive in 100% of patients with the syndrome (Table 21, Cum Probl Surg,
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191
and the secretin test, which is positive in 85% of patients.18’ The calcium infusion test and protein meal test are no longer indicated. Similar results are obtained in patients with ZES as part of MEN-1y3, 77 In patients who have had gastrinoma resected for potential cure of ZES, secretin-stimulated gastrin levels are the most sensitive indicator of recurrent or persistent disease.37’ lgo Abnormal secretin tests occur before any other indicator of recurrent disease. Imaging studies are not necessary unless the secretin test becomes abnormal.18sJ lso CONTROL OF ACID SECRETION
The most important first maneuver in the management of patients with ZES is to eliminate the gastric acid hypersecretions3 With the use of cimetidine alone, patients commonly fail medical management of acid output. However, with the use of ranitidine, famotidine, and omeprazole, it is now easy to control acid hypersecretion in all patients with ZES.38 The acid secretion must be measured and maintained at less than 10 mEq/hour if the patient has had no prior acid reduction surgery and less than 5 mEq/hour if prior ulcer surgery has been performed5’, 183 (Fig. 12). Symptomatic improvement and endoscopic evidence of healin although desired, are not adequate indicators of acid contro1.50’1 3 With these guidelines, more than 150 consecutive patients in three recent series have had peptic ulcer disease healed without complications .38, 5o, Ia3 Each patient has reported complete resolution of all symptoms, including pain and diarrhea. Furthermore, each patient has experienced weight gain when acid output was controlled. Experience has indicated that the amount of antisecretory medication can vary from patient to patient and in the same patient at different times. Anticholinergic drugs alone were not potent enough to control acid, but they potentiated the ude of cimetidine in patients with ZES.“’ The potency of new histamine receptor antagonists (ranitidine38, s3 and famotidine154) has improved acid control. The dose of medication and the dosing interval were able to be reduced as more potent agents became available. The appropriate daily dosages of Hz-receptor antagonists are cimetidine, 6 gm; ranitidine, 2 gm; and famotidine, 0.3 gm.38 Despite the implementation of more potent H,-receptor antagonists, simple control of acid secretion was not possible until the use of omeprazole~57-59'155,192-194 Omeprazole is administered only once or twice daily. The usual dose is 80 mgday, and the range of doses varies between 60 and 120 mg/day. The use of omeprazole has been a concern to some investigators because long-term administration is associated with carcinoid tumors of the stomach.‘48 These studies hypothesize that the carcinoid tumors result from enterochromaffin 122
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1 1 0I-
loo
,-
90 80 ‘;: f f
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60
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50 40
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10
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-
-
-
-
-
-CONTROL - - LEVEL
it 2.5
CIMETIDINE
3
4
(mg/kg/hrt
FIG.
12. Titration to control acid secretion in patient with ZES by continuous infusion of intravenous cimetidine. The patient’s basal acid output was more than 100 mEq/hour. The dose of cimetidine was increased in a stepwise fashion until acid output was less than 10 mEq/hour. Similar acid titrations were performed with ranitidine and famotidine. In general, the ranitidine dose was 33% of the cimetidine dose, and the famotidine dose was 5% of the cimetidine dose. (From Fraker DL, et al. Surgery 1988;104:1054-63.)
cell hyperplasia that is due to drug-induced achlorhydria and hypergastrinemia.148’1g5-1g8 The long-term effects of omeprazole in patients with ZES await future reports. It is approved by the Food and Drug Administration for control of acid in patients with ZES and is the drug of choice for this indication. Because of the dramatic efficacy of omeprazole, surgery (total gastrectomy) to control acid hypersecretion is not indicated. The control of acid hypersecretion should not be forgotten during the preoperative and postoperative periods. The intravenous prepaCurr Probl Surg, February 1994
123
ration of omeprazole is not approved for patient use. Continuous intravenous infusion of either cimetidine or ranitidine at doses that keep the acid secretion in the safe limits described are effective16’ (Fig. 12). After removal of a gastrinoma, when can the antiacid medication be discontinued? Despite the fact that some authors suggest stopping medication immediately,1gg approximately 50% of patients will still secrete excessive acid because of increased parietal cell mass 16’, ‘O”, ‘01 (Fig. 13). Therefore antiacid medication should be continued until it is established by measurement that the patient has a normal basal acid output. Finally, in patients with MEN-l, ZES, and primary hyperparathyroidism, surgery to control the primary hyper-
I151151
113/161
121/361
NO RESECTION
RESECTED CURED
7ESECTEO
OPERATIVE
OUTCOME
FIG. 13. Percentage of patients with persistently elevated basal acid output
(BAO) (>lO mEq/hour) at 3 to 6 months after surgery for gastrinoma. Forty percent (8 of 20) of patients who had gastrinoma resected and appeared to be biochemically cured (normal serum level of gastrin and negative secretin test) still had elevated basal acid output, presumably resulting from hypertrophied parietal cell mass. (From Fraker DL, et al. Surgery 1988;104:1054-63.)
124
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parathyroidism usually reduces the amount of medication necessary to control the acid output.” RALIZOGRAPHZC LOCALIZATION
Accurate tumor staging and localization are critical during the preoperative assessment of patients with ZES51, 68, g3 In reported studies* between 13% and 50% of patients with ZES have metastatic disease to the liver at the time of diagnosis. Therefore preoperative imaging studies should include an accurate and careful assessment of the liver. Ultrasonography,66’ ‘03 CT,65, 204-206 and MR166, I”, “’ have been reported to be useful in im$ng gastrinoma.65’ 66 Labeled octreotide scan may also be effective. ’ 6s Selective angiography,lzo’ 2o8 selective angiography with secretin stimulation,62, 74, 758 2os, 210 portal venous sampling for gastrin,76’ 1208 211, 212 and endoscopic ultrasonographf113 may be useful for localizing gastrinoma. Ultrasonography has low sensitivity for imaging gastrinoma66 (Table 3). CT detects no tumors less than 1 cm, 30% of tumors between 1 and 3 cm, and all tumors greater than 3 cm. Overall, CT successfully images 50% of tumors.652 14’* 204-206 MRI is similar to CT but has the potential of being more useful. Gastrinomas are very bright on either T, or stir sequences. Gadolinium may further enhance the sensitivity of ~~.66,175,207
Selective angiography is the best imaging study to identify primary and metastatic astrinoma.120’ 2o8 This technique has a sensitivity of 40% to 60%4’ 38, 8” and provides accurate localization with few false positive results (Table 3). However, it seldom identifies duodenal wall gastrinomas?” ” The combination of selective angiography and secretin has increased the sensitivity to 75%.74 As part of the angiographic procedure, secretin is injected into arteries, and hepatic vein levels of gastrin are measured. When the artery that is perfusing the gastrinoma is injected, an early peak of gastrin levels is observed in the hepaticvein.62'74,'6,209,210 Furthermore, an association exists between a gradient after gastroduodenal artery injection and duodenal gastrinomas?14 Imamura and colleagues75 advocated a pancreaticoduodenectomy if no tumor is found and the secretin study indicates that the gastrinoma is within the pancreatic head. This strategy is not generally recommended because the survival of patients with localized gastrinoma in whom no tumor is identified or in whom the tumor is simply excised is excellent (Fig. 11). Portal venous sampling also provides regional localization and may be one of the single best localization studies.21s This study is the most invasive and is associated with complications including hemoperito*References37,38,93,124,150,153,163,168,202 Curr Probl SW,,
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neum, hemobilia, and pain in about 20% of individualszl’ It appears to provide similar localization information to secretin angiograPhY.6z, 76, 212 Because secretin angiography is less invasive and may image the tumor, portal venous sampling is no longer recommended. The final study is endoscopic ultrasonography.213 preliminary data suggest that islet cell tumors are identified by this technique.63,213 However, it has not been determined that this study can identify small, difficult-to-image duodenal gastrinomas. These tumors are common (40% 1and are seldom identified by any study.“, 28* 630 ” Intraoperative ultrasonography has had difficulty imaging tiny duodenal wall tumors.63, 8s Endoscopic ultrasonography may not be able to distinguish small duodenal gastrinomas unless the surgeon is willing to accept some false positive findings. In summary, patients with ZES should undergo either CT or MBI to rule out liver metastatic disease and identify the primary tumor. If more precise localization is desired, selective angiography coupled with secretin may identify the tumor or the region of the pancreas in which the tumor is localized. The surgeon should remember that occult tumors will most likely be located within the astrinoma triangle that includes the wall of the duodenum.“’ 38812 #’ 168 Portal venous sampling for gastrin is no longer indicated.76’ “‘, ‘I2 Octreotide scanning and endoscopic ultrasonography appear promising, but their exact roles await further study. EXPLORATION FOR GASTRINOMA
Since the syndrome was originally described in 1955, the major surgical intervention in patients with ZES was total gastrectomy. 136J150, 15’, *” However, this procedure did not affect the basic disease process, the tumor. Zollinger and others162, 1658 “‘, ‘16 noted that the malignant potential of the tumor was the major determinant of survival. Tumor resection may result in cure or improved surViVd.38, 124, 16’S 168, “I Therefore today the goal of surgery has shifted from total gastrectomyl”” 165J “‘, 216 (i.e., resection of the end organ) to resection of the gastrinoma.38’ 16’ It is important to control the gastric acid hypersecretion in the perioperative period by continuous infusion of either cimetidine or ranitidine, selecting a dosage that decreases the acid output to the safe range16’ (Fig. 12). Initially, a complete general exploration of the entire abdomen is performed. Ovarian gastrinomas have been repofiedl’2, 217-219as well as gastrinomas near the ligament of Treitz and within the greater omentum.37’ “’ The color of a gastrinoma is usually reddish blue, but occasionally it may be white. Some surgeons have used selective injection of methylene blue into the gastroduodenal artery during exploration to identify small, blue-staining duodenal wall tumors.220 Any suspicious nodule should be excised. Care126
Curr Probl Surg February 1994
ful palpation and visualization of the liver is performed, with any superficial lesion removed by excisional biopsy. Exposure of the pancreas is critica13’, 124 A Kocher maneuver is performed to mobilize the duodenum and the head of the pancreas out of the retroperitoneum. The inferior border of the body and tail of the pancreas is also incised. Intraoperative ultrasonography is performed after complete exposure and palpation” (Fig. 1). Intraoperative endoscopy with transillumination of the duodenum is performed next” (Fig. 3). After transillumination, duodenotomy is performed in all patients.” The ability of each intraoperative maneuver to find duodenal and pancreatic gastrinoma is summarized in Table 4. Duodenal tumors were frequently missed before efforts to improve the operative detection rate.38 The prevalence of duodenal tumors decreases as the surgeon progresses distally in the duodenum (Fig. 141. Transillumination clearly improves identitlcation of duodenal wall tumors; if a tumor is identified, this technique allows placement of the duodenotomy in a location where the tumor can be completely excised (Fig. 3). Duodenotomy is a true advancement because it facilitates identification of gastrinomas on the medial wall. These tumors abut the
FIG. 14. Location of 24 duodenal gastrinomas in patients with ZES. Seventeen tumors were in the first portion, five were in the second, and two were in the third. (From Thorn AK. et al. Surgery 1991;i 10:1086-93.) Curr Probl Sur5 February 1994
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pancreas and are not transilluminated. Medial wall gastrinomas may be near either the ampulla or the pancreatic duct. The surgeon must accurately identify the ducts before removing a medial wall tumor. It may be helpful to thread a cholangiocatheter through the cystic duct into the common duct and duodenum to identity the ampulla of Vater. The orifice of the pancreatic duct may be identified by administering secretin intravenously, which is followed rapidly by pancreatic exocrine secretion. Duodenal wall tumors are firm to palpation. A tumor nodule may be small (between 2 and 5 mm). Tumors are more often within the proximal duodenum (Fig. 14). Although duodenal gastrinomas originate within the submucosa, they almost always dimple or raise the mucosaz8’ 63 (Fig. 2). The tumors may appear multiple because they can spread along submucosal lymphatits. Excision of tumors requires a full-thickness elliptical excision of the duodenum. The longitudinal duodenal incision should be closed transversely. Systematic sampling of anterior and posterior lymph nodes around the head of the pancreas, the common bile duct, and the celiac axis should be performed?‘, ‘St 38, lz4 Abnormal nodes often appear normal. Whenever a nodule is removed from either within or near the pancreas, the pathologist should be asked whether the tumor is within a lymph node. If a tumor is found within a lymph node, careful attention should be directed to the duodenum because a primary tumor may have been missed. If a gastrinoma is identified within the body or tail of the pancreas (which is unusual), the tumor should be resected by distal or subtotal pancreatectomy and splenectomy.2’ Primary gastrinomas within the head of the pancreas are enucleated. It appears from recent studies that two distinct populations of tumoral behavior exist based on location of the primary gastrinoma. Tumors to the right of the superior mesenteric artery are more common and behave in a more benign manner. Rarer tumors to the left of the superior mesenteric artery are more malignant and have a poorer prognosis and less successful cure rate.221 Liver metastases should be resected with negative margins if all tumor can be removed and the resection can be accomplished safely. Some surgeons still advocate total gastrectomy for ZES because patients cannot afford medications or do not comply with prescriptions.f53 Other authors recommend parietal cell vagotomy to reduce the dose of H,-receptor antagonists.222 We do not recommend any procedure to reduce acid secretion, and because of the efficacy of omeprazole, most experts agree. Current results from different institutions demonstrate that with increased awareness of duodenal tumors, gastrinoma can be found in nearly every patient with the condition2” 38,168, XI (Table 5). If all tumor is removed, the immediate postoperative cure rate varies from 40% to go%27,38,168,169 (Table 5). Furthermore, the mortality rate is 128
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095, and the morbidity rate is between 10% and 17%~~ (Table 6). Careful long-term follow-up indicates that nearly 50% of patients who initially are free of disease will have recurrence by 6 years3’ (Fig. 15). Furthermore, a curative resection results in decreased parietal cell mass and slow reduction of acid output to normal levels. Fifty percent of patients have normal gastric acid secretion at 3 months postoperatively, and additional patients experience a further decrease in acid output as the parietal cell mass decreases.“‘With this approach, no patient with local disease at diagnosis has died of tumor progression at long-term follow-up3s (Fig. 11). No complication of the gastric acid hypersecretion or the medication taken to control it has developed. The data suggest that the most important component in the treatment of the tumoral process is the surgeon.“’ 38J 16’ The use of extensive studies of localization did not improve the operative detection rate; only the addition of operative methods to explore the duodenum better improved tumor detection?” 28, 638 S’S lz4 METASTMES
The management of liver metastases is controversial. Many patients with liver metastases are without symptoms as long as gastric acid 1 .o
0.9 ; LL 2
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$
0.6
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0.5 0.4
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!
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l
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ALL PATIENTS
sb
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MONTHS
FIG. 15. Time to recurrence of ZES in patients initially disease free by surgery. Disease free is defined as no evidence of tumor on imaging studies, normal fasting gastrin level, and negative provocative test (n = 42). (From Norton JA, et al. Ann Surg 1992;215:8-18.) CurrPmblSurg,
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hypersecretion is treated effectivelyY3 Other patients die of malignant dissemination despite control of acid hypersecretion.2” “‘, 16’ The best chemotherapy, including doxorubicin, 5fluorouracil, and streptozotocin, results in a 40% response rate, but there are no complete responses, considerable toxicity exists, and no apparent impact on smvival is seen67~223-225 (Fig. 11, distant disease). Interferon-o has been advocated for these patients, but it is associated with a severe flulike syndrome and produces only a few partial responses?61 The antitumor effects of octreotide are few, and its use in patients with ZES is limited because effective oral drugs to control gastric acid secretion are available.41, ‘I2 The lack of epective antitumor treatment besides surgery and the fact that Zollinger had reported long-term survivors in patients with resected liver metastases led us to attempt to resect distant gastrinoma?’ We have resected distant islet cell tumor including liver metastases in 15 patients5’ The study was not randomized, so the results are difficult to interpret. However, it appears that patients with solitary localized metastatic disease benefit most from this aggressive surgical approach; none of these patients have died from disease, and most have had prolonged disease-free survival. However, despite complete surgical resection and initial biochemical cure, most patients have recurrent disease with long-term follow-up. No deaths from operations occurred, and an acceptable complication rate was observed.52 Other authors have reported similar results.43’ 53 These studies suggest that aggressive resection of localized liver metastatic gastrinoma is indicated and should be attempted. GASTRINOMA AND MULTIPLE ENDOCRINE NEOPLASLA TYPE 1
The management of patients with ZES in the presence of MEN-l is controversial. Malagelada and co11eagues144 from the Mayo Clinic suggest that in this setting gastrinoma is seldom malignant, no patients are cured, and surgery is not indicated. Thompson and col~eagues27,215,226,227 from the University of Michigan suggest that some patients with MEN-l and ZES are cured because portal venous sampling for gastrin can be used to determine which islet cell tumor is the gastrinoma. We reported a contradictory result in five patients with ZES and MEN-l who underwent surgery after portal venous samplirig.33 No patient was cured despite the fact that each patient had an islet cell tumor removed from the exact area of the pancreas suggested by portal venous sampling. Controversy exists because results from different reputable institutions are dissimilar. Patients with MEN-1 usually have primary hyperparathyroidism before ZEST7, 14’ Patients with ZES should have serum levels of calcium measured. If the calcium level is elevated, then serum levels of parathyroid hor130
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mone (PTH) should also be determined. If the patient has evidence of both primary hyperparathyroidism and ZES, the presence of MEN-l is confirmed. These patients should also have an MRI of the sella and determination of serum levels of prolactin to exclude the presence of a prolactinoma. If a prolactinoma is present, careful determination of visual fields is necessary to exclude bitemporal hemianopsia. It has been demonstrated that surgery directed at the primary hyperparathytoidism improves the ZES14’ (Fig. 16). Because these patients have parathyroid hyperplasiazz8 and a high incidence of recurrent hyperparathyroidism (40% to 8O%),22s four-gland parathyroidectomy with immediate autograft is recommended. Furthermore, supernumerary glands or fragments of abnormal parathyroid tissue are often present within the thymus; therefore cervical thymectomy is also indicated.230 Reversal of primary hyperparathyroidism has had dramatic effects on the manifestations of ZES in these patients (Fig. 16). Most patients have gastric acid medications reduced and a decrease in serum levels of gastrin (Fig. 16). In one series, 2 of 10 patients no longer had any biochemical evidence of ZES after parathyroidectomy.77 Patients with MEN-l and ZES may have multiple pancreatic and duodenal islet cell tumorsz6, 7g, ls2 Studies of resected pancreatic specimens have demonstrated that the pancreas of patients with MEN-l has multiple macroscopic and microscopic islet cell tumors7’ It is not clear which tumor is responsible for the gastrin production.33 Furthermore, a recent study demonstrated that these patients also have duodenal wall islet cell tumors that stain positive for gastrin. The study of Pipeleers-Marichal and colleaguesz6 may provide a clue to the location of the missed gastrinoma in patients with MEN-l and ZES. Thompsoi?’ recently described 11 patients with MEN-l who were apparently cured of ZES by tumor resection from the duodenum. Islet cell tumors in patients with MEN-l may be more malignant than previously thought. In patients with MEN-l and CT or angiographic evidence of islet cell tumor, 50% of patients have tumor metastases at surgery.33 Furthermore, certain family histories suggest that relatives have died from metastatic, malignant islet cell tumor. Importantly, few patients with MEN-l have been cured of ZES by islet cell tumor resection even with the use of portal vein samplin93'"8,78,93,178 (Fig. 16). Recently, however, by removing duodenal and pancreatic gastrinomas, we also have cured three patients with MEN-l and ZES. This result supports other reports2151 z7 and suggests that extensive focus on the duodenum may improve the surgical cure rate for patients with MEN-l as it does for patients with sporadic tumors. On the basis of these considerations, we recommend surgical correction of the primary hyperparathyroidism as the initial procedure77 Curr Probl Surg, February 1994
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30
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FIG. 16. Impact of successful parathyroidectomy and islet cell tumor resection on serum levels of gastrin in patients with hyperparathyroidism. ZES, and MEN-l. Upper panel demonstrates change in level of fasting serum gastrin concentration after parathyroidectomy followed by successful islet cell tumor resection. Lower panel demonstrates change in level of fasting serum gastrin concentration after islet cell tumor resection followed by parathyroidectomy. In each patient the parathyroidectomy had a greater impact on the serum levels of gastrin than the islet cell tumor resection. (From Sheppard BC, et al. Surgery 1989;106:1108-118.)
(Fig. 161. The gastric acid hypersecretion must be controlled in a manner similar to patients with sporadic gastrinoma. The use of surgery to cure the patient with MEN-l of ZES appears unlikely at this time.33’ 68, “* g3, “’ However, surgery is indicated to control a potentially malignant islet cell tumor. Imaged pancreatic tumors within the pancreatic head are enucleated. Imaged tumors within the body or tail are resected by subtotal or distal pancreatectomy (Fig. 9). During surgery, the duodenum should be explored with transillumination and duodenotomy. Previously missed duodenal wall gastrinomas may account for the inability to cure patients with MEN-l and ZES. If the gastrinoma is not in the pancreas (as seems probable from the negative results that have been published33J 68J “, g3,178), then the tumor may be in the duodenum. Exploration of the duodenum may be the critical step for cure of ZES in patients with MEN-l. UNUSUAL ISLET CELL TUMORS
The less common pancreatic islet cell tumors include VIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma, PPoma, and nonfunctional tumors.231’ 232 Patients with these tumors have either a syndrome of symptoms related to excessive hormone secretion WIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHomal or the mass of the tumor at diagnosis. Unusual islet cell tumors are more malignant in nature than gastrinoma or insulinoma43’ g43 231J 233 (Table 11, yet these tumors have a better prognosis than other abdominal solid tumors. The goal of surgery is to free the patient of the hormonally mediated syndrome and to excise a potentially malignant tumor. These patients usually have evidence by CT or MRI of a pancreatic or duodenal tumor. The surgical problem is not tumor localization but rather the feasibility of tumor resection. WSOACTM!? INTESTINAL PEPTIDE-SECRETING TUMORS
The VIPoma is an endocrine tumor generally located in the pancreas that secretes excessive amounts of VIP that cause a distinct syndrome characterized by large-volume diarrhea, hypokalemia, and hypochlorhydria (Table 1). This condition is also called the VernerMorrison syndrome because of the oeal description in 1958 by these two authors of pancreatic cholera, and the WDHA syndrome (watery diarrhea, hypokalemia, and achlorhydria)?35 \ierner and Morrison reported two patients who died from watery diarrhea, hypokalemia, and nephropathy associated with a noninsulin-secreting pancreatic islet cell tumor. The diarrhea is large in volume (>l L/day) and secretory, which means that it persists during fasting.236’237 Hypokalemia is present in nearly every patient and is caused by excesCurrProblSurg,
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sive potassium losses in the diarrhea fluid.238, 23g Hypochlorhydria is found in 75% of patients with VIPoma syndrome and is due to the inhibitory effect of VIP on gastric acid secretion.237’ 240 Flushing is present in a small number of patients and may be caused by vasodilatory effects of VIP.237 Hyperglycemia is detected in 25% to 50% of patients and is related to a glycogenolytic effect of VIP?36 Hypercalcemia is reported in 25% to 76% of patients with VIPoma.237 A small number of patients have VIPoma in conjunction with MEN-l (Fig. 101, but this fact does not explain the high incidence of hypercalcemia associated with these tumors. The definitive diagnosis of VIPoma requires the triad of severe secretory diarrhea, elevated fasting serum levels of VIP, and a pancreatic islet cell tumor. In most patients with VIPoma, the fasting stool output is greater than 3 L/day, and the diagnosis is excluded if the stool output is less than 700 ml/day. The normal fasting plasma VIP concentration is less than 190 p#ml. The fasting plasma VIP concentration should be determined at the same time that diarrhea is present. The mean concentration of fasting plasma VIP levels in 29 patients with VIPoma was 956 pgml with a range of 225 to 1850 pg/ m1.236.237
Once the diagnosis is established, patients with VIPoma require correction of dehydration, hypokalemia, and other metabolic abnormalities. Before octreotide, complete correction of these derangements was usually impossible because the voluminous diarrhea continued. However, octreotide therapy dramatically reduces serum levels of VIP, diminishes the diarrhea and dehydration, and allows rapid restoration of body potassium.3s,241 Octreotide therapy has simplified the preoperative management of VIPoma patients. GLUCAGONOMA Glucagonomas are islet cell tumors of the pancreas that secrete excessive amounts of glucagon and cause a unique syndrome characterized by skin rash, type II diabetes, malnutrition, weight loss, and anemia (Table 1). In 1963, Roger Unger extracted glucagon from four islet cell tumors found at autopsy. In 1966, McGavran and colleaguesz4’ at Barnes Hospital in St. Louis reported a patient with diabetes mellitus, a skin rash, anemia, and a pancreatic carcinoma with liver metastases. Polk biopsied this tumor in 1964. Subsequently, the patient was found to have high plasma levels of glucagon. Mallinson and colleagues243 associated glucagonoma with a specific skin rash and described nine patients with dermatitis, diabetes mellitus, weight loss, hypoaminoacidemia, anemia, and a glucagon-producing tumor of the pancreas. Norton and colleague? demonstrated that in one patient the rash was due to markedly decreased plasma levels of amino acids. 134
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The peak age of incidence in patients with the glucagonoma syndrome is 50 to 60 years. The characteristic skin rash associated with glucagonoma is called necrop migratory erythema and is pathognomonic of this tumor.245J ’ 6 Hypoaminoacidemia occurs in most patients, and levels can vary with the intensity of the diseaseF4’ Diabetes mellitus and glucose intolerance are among the most frequent findings in these patients. However, a number of patients do not have glucose intolerance.248 Diabetes mellitus is a much less constant feature of the syndrome than is the hypoaminoacidemia. Weight loss is common and may be profound. Thromboembolic phenomena are more common in patients with the glucagonoma syndrome.248 Deep venous thrombosis and pulmonary emboli have been reported to occur and can cause death. The diagnosis of glucagonoma is made by measuring elevated plasma levels of glucagon. In almost all patients with glucagonoma, the plasma glucagon concentration is elevated (>150 pg/mU. It is suggested that a plasma glucagon concentration greater than 1000 pg/ml is diagnostic of glucagonoma. Preoperative preparation of patients with glucagonoma involves control of the diabetes, treatment of any complications of venous thrombosis, and improvement of the nutritional status, which will usually correct and heal the rash. Total parenteral nutrition with added insulin has been one form of effective therapy.244 Recently, octreotide has been used to reduce plasma levels of glucagon and improve the nutritional status.z41 SOMATOSTATINOMA
Somatostatinomas are endocrine tumors of the pancreas or duodenum that secrete excessive amounts of somatostatin, causing a distinct syndrome characterized by type II diabetes, cholelithiasis, and steatorrhea (Table 1). Somatostatin, or growth hormone release inhibiting hormone, was discovered in the hypothalamus in 19i’3. In 1977, the first two cases of somatostatinoma were reported by Ganda and colleagues24s and Larsson and colleagues.250 Initially, it was thought that the somatostatinoma syndrome consisted of diabetes, cholelithiasis, weight loss, and anemia. Diarrhea, steatorrhea, and hypochlorhydria were described later.251 Somatostatin is a major inhibitory peptide that inhibits the release of most other hormones. It has direct effects on a number of gastrointestinal functions, inhibiting acid secretion, pancreatic enzyme secretion, and intestinal absorption. It decreases gut motility and gastrointestinal transit time. Patients with pancreatic or intestinal somatostatinomas are usually about 50 years of age and are evenly divided between men and women.252 Initial symptoms include diabetes, gallbladder disease, and steatorrhea. Diabetes mellitus or glucose intolerance is reported to occur in 60% of patients. Cholelithiasis occurs in 70% of patients. CurrProblSurg,
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Diarrhea and steatorrhea are reported in between 30% and 68% of patients. In some patients, the severity of the diarrhea and steatorrhea correlates with the size and degree of metastatic spread of the tumor and improves with tumor resection. Hypochlorhydria is present in between 33% and 53% of patients. Hypochlorhydria occurs in 86% of patients with pancreatic and 17% of patients with intestinal somatostatinomas. Weight loss is common in patients with somatostatinomas and may result from the diarrhea and malabsorption In most instances, somatostatinomas have been discovered incidentally. The tumor is usually discovered at the time of cholecystectomy or during routine imaging studies performed because of abdominal pain, bleeding, or diarrhea. Once discovered, the tumors are identified as somatostatinomas either by demonstrating elevated tissue concentrations of somatostatin or an increased number of D cells by immunocytochemistry or by showing evidence of increased plasma concentrations of somatostatin-like immunoreactivity. The early diagnosis of somatostatinoma may be possible with greater awareness and reliable assays for the determination of somatostatin in the blood. Presently, these assays are complicated by the need for extraction of the plasma and are not widely available. GROWTH HORMONE-RELEASING FACTOR-SECRETING TUMORS
GRFomas are neuroendocrine tumors that secrete excessive amounts of GRF and cause acromegaly. GRFomas were first described in 1982 .253’ 254 GRF is a peptide originally isolated from pancreatic islet cell tumors253 and is similar in structure to VIP.253,254 GRFomas have been reported to occur in the lung (bronchus), pancreas, jejunum, adrenal gland, and retroperitoneum, in decreasing frequency.255 The most common symptom is acromegaly. Patients usually have a large pancreatic islet cell tumor (>6 cm) that is metastatic in 30% of patients at the time of diagnosis. Nearly 50% of patients have associated ZES, and one third have MEN-l. GRFoma may be suspected in a patient with acromegaly and a pancreatic mass or hepatic metastases or with peptic ulcer disease.253-255 The diagnosis should be considered in any patient with acromegaly and ZES or acromegaly and MEN-l. The diagnosis can be confirmed by performing a plasma assay for GRF and a CT of the abdomen to identify a pancreatic or hepatic mass. ALIRENOCORTICOTROPIC
HORMONE-SECRETING TUMORS
Cushing’s syndrome associated with a pancreatic islet cell tumor that secretes ACTH always occurs in patients with an islet cell 136
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tumor that secretes another peptide and causes another syndrome. Cushing’s disease may occur in patients with MEN-l and ZES, but it is due to pituitary production of ACTH. The hypercortisolism in these patients is usually mild and clinically insigniIicant.z56 Cushing’s syndrome has also been reported in a number of cases of sporadic ZES, and in one recent prospective study it was present in 5% of all cases.256 In patients with the sporadic form of ZES, the symptoms of Cushing’s syndrome are severe and usually occur in patients with metastatic disease; in addition, the Cushing’s syndrome is due to ectopic production of ACTH. These patients usually respond poorly to chemotherapy and have a poor prognosis. The occurrence of Cushing’s syndrome only as a clinical manifestation of a pancreatic endocrine tumor is rare but almost always is associated with a metastatic malignant tumor. In our experience, patients with ACTH-producing islet cell tumors, unlike patients with ACTH-producing bronchial or thymic tumors, are not amenable to surgical cure (Fig. 17). Bilateral adrenalectomy is often indicated in these patients to control the severe signs and symptoms of hypercortisolism.‘l
Legend Bronchus 0 Thymus W Pancreas .
0 . 0 It
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I
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FIG. 17. Disease-free survival of three groups of patients with ectopic ACTH syndrome: bronchial carcinoid (closed circles), thymic carcinoid (open circles), and pancreatic islet cell tumors (closed squares). Unlike patients with bronchial or thymic carcinoid tumors, no patients with ectopic ACTH syndrome caused by a pancreatic islet cell tumor were able to be rendered disease free. (From Zeiger MA, et al. Surgery 1992;112:994-1001.) Curr
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PARATHYROID
HORMONELIKE-SECRETING TUMORS
Severe hypercalcemia rarely has been reported to be the result of a pancreatic islet cell tumor releasing PTH-like immunoreactive factor*257, 258 Hypercalcemia associated with pancreatic islet cell tumors has also been reported to be the result of the release of other substances. In most cases, the pancreatic tumor is malignant and has spread to the liver at the time of diagnosis. NEUROTENSlNOMA
Pancreatic neurotensinomas have been described.25s’ “’ Neurotensin is a peptide extracted from the bovine brain and the human gastrointestinal tract.25s Neurotensin can cause hypotension, tachycardia, cyanosis, pancreatic secretion, intestinal motility, and small intestinal secretion.25s Patients with neurotensinomas have diarrhea with hypokalemia, weight loss, diabetes, cyanosis, hypotension, and flushing. Patients can be cured by tumor resection and have responded to chemotherapy.25s’ 260 Some authors have questioned whether a separate neurotensinoma exists. Patients with VIPoma and gastrinoma have been found to have elevated plasma levels of neurotensin. At present, it is unclear whether a separate syndrome exists. PANCREATIC POLYPEPTIDE TUMORS AND NONFUNCTIONING ISLET CELL TUMORS
PPomas and nonfunctioning pancreatic islet cell tumors are tumors that either secrete excessive amounts of pancreatic polypeptide (PPoma) or do not function (nonfunctioning) and usually cause symptoms resulting from tumor mass. These tumors diifer from other islet cell tumors because symptoms are not due to secreted hormones.261 These tumors are diagnosed when the patient has cachexia, abdominal pain, or hepatomegaly. Patients commonly have metastatic endocrine tumor at the time of diagnosis. Despite the fact that infusions of PP into animals have been shown to have numerous effects, patients with PPomas do not have symptoms as a result of the increased plasma levels of PP. Typically, the patient with a PPoma or nonfimctioning pancreatic endocrine tumor has abdominal pain or jaundice or is without symptoms. Nonfunctioning pancreatic endocrine tumors or PPomas are usually not differentiated from other malignant tumors of the pancreas before biopsy. Recent studies suggest that plasma marker 7B2 may be a good indicator of nonfunctional pancreatic islet cell tumors.262 Tumors are often discovered incidentally during other operative procedures.2”1 Any patient with a long survival period (>5 years) and sus138
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petted metastatic pancreatic adenocarcinoma may have a nonfimctioning islet cell tumor or PPoma. Typically, these tumors are large when diagnosed (>5 cm) and almost all are malignant (70% to 92% ) T3 Nonfunctioning pancreatic endocrine tumors are differentiated from PPomas by the results of the plasma PP assay. At present, no data suggest that PPomas or nonfunctioning pancreatic endocrine tumors differ in biological behavior from functioning islet cell tumoB.264, 26.5 However, recognizing a tumor to be a PPoma may be clinically important because plasma PP levels may be used to monitor the results of antitumor therapies such as surgical resection or chemotherapy. SUMMARY
Unusual neuroendocrine tumors of the pancreas and duodenum as well as nonfunctional tumors are more malignant than either gastrinomas or insulinomas.43’ s4, 231S233 Despite this fact, these tumors may have a better prognosis than other intraabdominal solid malignancies. Therefore, if the entire extent of tumor can be resected and the patient is otherwise healthy, major operative procedures (including pancreaticoduodenectomy, liver lobectomy, subtotal pancreatectomy, and splenectomy) may be indicated.“’ 43, 52, 13’ Furthermore, in patients with some rare tumors associated with severe symptoms that are poorly controlled medically, such as somatostatinoma, glucagonoma, PTH-like tumors, and ACTHoma, major surgery to debulk tumor or to remove end organs (e.g., adrenal gland in patients with ACTHoma) may be necessary.36, “, s4 Therefore aggressive surgery has an important role in the therapy of these patients and is the only potentially curative treatment. MULTIPLE ENDOCRINE NEOPIASIA TYPE 1
A significant proportion of patients with neuroendocrine tumors of the pancreas and duodenum also have MEN-l. Correct management of neuroendocrine tumors in these patients is unclear and controversial.33~ 144 Certain points must be remembered before developing a therapeutic plan. First, careful analysis of resected pancreatic specimens from patients with MEN-l demonstrates that these patients always have multiple macroscopic and microscopic islet cell tumors.7s Recent studies suggest that these patients may also have multiple neuroendocrine tumors within the duodenum.26 Because of the presence of multiple islet cell tumors within the pancreas and duodenum, it is never clear which tumor is responsible for producing the hormonal syndrome of an individual patient.33’ 78, ‘41 Furthermore, although older studies suggested that the neuroendocrine tuCurrProblSur5
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mors in patients with MEN-l rarely were malignant,144 recent studies suggest that these tumors may be as malignant as sporadic neuroendocrine tumors.33’ “’ The presence of other endocrinopathies such as primary hyperparathyroidism in patients with MEN-l may affect the symptoms related to the islet cell tumor.” Therefore surgery to eliminate the p r i m ark hyperparathyroidism may improve control of the islet cell tumor’ (Fig. 16). The results of most studies in patients with MEN-l and ZES indicate that despite resection of islet cell tumors, the effect on the biochemical parameters of ZES is minima133’ lz6, z6 (Fig. 16). Some authors suggest that portal venous sampling for gastrin may identify which area of the pancreas contains gastrinoma.215 However, other studies indicate that resection of a neuroendocrine tumor from the exact region with the gradient failed to reduce serum levels of gastrin33 (Fig. 16). In most patients with MEN-l and biochemical evidence of an islet cell tumor, an identifiable tumor mass on either CT scan or MRI is obselved33 (Fig. 9). At exploration, 55% of these patients have local or distant metastases, and few patients, if any, are cured of gastrinoma.33’ 135 In contrast, patients with MEN-l with either insulinoma or VIPoma can be relieved of the hormonal syndrome by resection of tumor (Fig. 10). A case report of a rare patient with MEN-2 and gastrinoma indicates that this patient underwent a complete remission after resection of a pancreatic gastrinomaz67 (Fig. 10). Other authors have reported a similar result in a patient with MEN-l and metastatic gastrinoma.2”8 The poor results in patients with MEN-l and ZES after islet cell tumor resection are different from the outcome of surgery to correct the primary hyperparathyroidism.77 After parathyroidectomy, patients have definite improvement in the biochemical parameters of ZES, and approximately 20% of patients no longer have any biochemical evidence of ZES” (Fig. 16). In patients with MEN-l, primary hyperparathyroidism, and ZES, surgery to remove the abnormal hyperplastic parathyroid glands is recommended before surgery directed at the islet cell tumor.” The proper procedure is either a 3X-gland or 4gland parathyroidectomy with immediate autograft because patients with MEN-l and primary hyperparathytoidism have &gland hyperplasia. For patients with biochemical evidence of ZES and MEN-l, surgery is indicated when an islet cell tumor is identified on imaging studies (Fig. 9). Because patients with ZES and MEN-l usually have multiple pancreatic and neuroendocrine tumors, a resection is indicated, including the portion of the gland with the imaged tumor. Therefore, if the tumor is in the body or tail of the pancreas, a subtotal pancreatectomy is recommended. If an islet cell tumor is identified in the pancreatic head, simple enucleation is most often performed. If the tumor is localized to the head of the pancreas and cannot be enucleated, pancreaticoduodenectomy may be necessary. Intraoperative ultrasonography 140
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is used to identify and enucleate any additional tumors not pmsent within the resected specimen. Transillumination and duodenotomy are used to identify and resect neuroendocrine tumors within the wall of the duodenum. Most patients with islet cell tumors and MEN-l have a large dominant tumor within either the body or tail of the pancreas (Fig. 9). This tumor can usually be resected without performing a proximal pancreaticoduodenectomy. The goal of the operation is to remove the potentially malignant tumor. Patients with MEN-l and insulinoma or VIPoma are similar at diagnosis. Although some patients with MEN-l and insulinoma are not curable,z6y’270 most patients are cured of the hypoglycemia by tumor resection3” In conclusion, in patients with MEN-l, hyperparathyroidism, and ZES, the primary hyperparathyroidism should be treated first. Similarly, surgery in these patients is indicated to remove tumor with the hope of limiting the tumoral process. In patients with MEN-l and insulinoma or VIPoma, tumor resection is indicated for potential cure. METASTATIC ISLET CELL TUMORS
Distant metastatic disease will develop in approximately 30% to 50% of patients with neuroendocrine tumors. Surgical procedures to remove distant disease appear to be beneficial and are the only potentially curative form of treatment. Furthermore, resection may increase survival and improve symptoms. Malignant neuroendocrine tumors generally spread from either the pancreas or duodenum to lymph nodes and the liver?3 Select patients may be candidates for complete resection of all tumor for cure or noncurative debulking of the tumor mass to prolong survival.zg~27* Patients with metastatic islet cell tumors have been treated with chemotherapy (primarily 5-FU, adriamycin, and streptozotocin272 or combinations of these drugs272-274 1, immunotherapy (with interferona 275-277), chemoembolization therapy for liver metastases,z78’ 27s and octreotide to suppress or inhibit tumor progression.280~ “I Each of these treatments has been associated with tumor response, but none has produced a complete response or evidence of cure. Only surgical resection has produced biochemical and imaging evidence of complete remission.2s’ 51 In patients with metastatic insulinoma,51’ 13’ approximately 30% of patients can undergo complete resection. Nearly 50% of patients undergoing resection have evidence of complete biochemical remission. Patients with metastatic insulinoma who cannot undergo resection have a median survival of only 11 months. Debulking surgery extends the median survival to 4 years,13’ but incomplete resection does not improve the ability to control hypoglycemia. Aggressive resection of CurrProblSur~
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all metastatic tumor appears to improve the quality and duration of life, and a number of patients are cured. Subtotal resection is less beneficial and is attempted only if most tumor can be removed. Patients with metastatic gastrinoma have a 5-year survival rate between 20% and 40%” s3 (Fig. 11). A number of patients with metastatic gastrinoma can undergo resection for long-term benefit and potential cm-e.29 In three separate series, the resectability rate was 36%.= In an initial evaluation of 10 patients with metastatic gastrinoma,” 5 underwent resection for potential cure. Of the five patients, four had resections and two were initially cured?’ Long-term follow-up of patients with metastatic gastrinoma suggest that all patients will eventually experience recurrence and that patients with limited metastatic disease will enjoy the best disease-free survi~al~~ Symptoms can be well controlled with omeprazole?s2 Patients with ACTH-producing gastrinoma usually have concomitant severe Cushing’s syndrome at diagnosis. In these patients, excellent pa&ation of symptoms can be achieved by bilateral adrenalectomy?l Select patients with metastatic glucagonoma have had amelioration of the characteristic rash, malnutrition, thrombosis, and hypoaminoacidemia by tumor resection?6 Similar results have been reported in patients with metastatic VIPoma.282 Therefore aggressive surgery to resect primary and metastatic neuroendocrine tumors is indicated if the patient is in good condition and all gross tumor is resected. Subtotal resections may be indicated in patients whose symptoms resulting from hormonal hypersecretion are poorly controlled with medications. However, debulking of tumor has not provided good results in alI patients. REFERENCES 1. Norton JA, Doppman JL, Jensen RT. Cancer of the endocrine system. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncologv. Philadelphia: Lippincott, 1989:1269-1344. 2. Buchanan KD, Johnston CF, O’Hare MMT, et al. Neuroendocrine tumors: a European view. Am J Med 1986$1(suppl 68):14-23. 3. Jensen RT, Norton JA. Pancreatic endocrine tumors. In: Yamada T, Alpers DH, Owyang C, Powell DW, Silvenstein FE, eds. Textbook of gastroentemlogy. Philadelphia: Lippincott, 1991:1912. 4. Stadil F, Stage JG. The Zollinger-Ellison syndrome. Clin Endocrinol Metab, 1979; 9:433. 5. Dent RB, van Heerden JA, Weiland LH. Nonfunctioning islet cell tumors, Ann Surg 1981;193:185-93. 6. Bmder LE, Carter SK. Pancreatic islet cell carcinoma: clinical features of 52 patients. Ann Intern Med 1973;79:101. 7. Bmughan TA, Leslie JD, Soto JM, Hennann RE. Pancreatic islet cell tumors. Surgery 1986;99:671. 8. Koppel G, Heitz PU. Pancreatic endocrine tumors. Path01 Res Pratt 1988;183:155. 142
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9. Bolande RP. The neurocrestopathies: a unifying concept of disease arising from neural crest maldevelopment. Hum Path01 1974;5:409. 10. Weil C. Gastroenteropancreatic endocrine tumors. Klin Wochenschr 1985;63:433. 11. Pearse HGE. The APUD concept and hormone production. Clin Endocrinol Metab 1980;9211. 12. Pearse AGE, Tabor ‘IT. Embryology of the diifuse neuroendocrine system and its relationship to the common peptides. Fed Proc 1979;38:2288. 13. Heitz PU, Kasper M, Polak JM, Kloppel G. Pancreatic endocrine tumors. Hum Path01 1982;13263. 14. Solcia E, Capella C, Fiocca R, Cornaggia M, Bosi F. The gastroenteropancreatic endocrine system and related tumors. Gastroenterol Clin North Am 1989;18:671-93. 15. Mukai K, Greider MH, Grotting JC, Rosai J. Retrospective study of 77 pancreatic endocrine tumors using the immunoperoxidase method. Am J Surg Path01 1982;6:387. 16. Creutzfeldt W. Endocrine tumors of the pancreas: clinical and morphological patterns. In: Fitzgerald PS, Morrison AB, eds. The pancreas. Baltimore: Williams &. Wilkins, 1980:208. 17. Jensen RT, Gardner JD. Gastrinoma. In: Go VLW, Brooks FA, DiMagno EP, Gardner JD, Lebenthal E, Scheele GA, eds. The exocrine pancreas: biology, pathobiology and disease. New York: Raven Press, 1992. 18. Larsson LI, Grimelius L, Hakanson R, et al. Mixed endocrine pancreatic tumors producing several peptide hormones. Am J Path01 197.5;79271. 19. Chiang HC, O’Dorisio TM, Huang SC, et al. Multiple hormone elevations in patients with Zollinger-Ellison syndrome: prospective study of clinical significance and of development of a second symptomatic pancreatic endocrine tumor syndrome. Gastroentemlogv 1990;99:1565. 20. Wynick D, Williams SJ, Bloom SR. Symptomatic secondary hormone syndromes in patients with malignant pancreatic endocrine tumors. N Engl J Med 1988;319:605-10. 21. Zeiger MA, Pass HI, Doppman JD, et al. Surgical strategy in the management of non-small cell ectopic adrenocorticotmpic hormone syndrome. Surgery 1992;112994-1001. 22. Kahn CR, Rosen SW, Weintraub BD, et al. Ectopic production of chorionic gonadotropin and its subunits by islet cell tumors: a specific marker for malignancy. N Engl J Med 1977;297:565. 23. O’Connor DT, Deftos LI. Secretion of chmmogranin A by peptide-producing endocrine neoplasms. N Engl J Med 1986;314:1145-51. 24. Boden G. Glucagonomas and insulinomas. Gastmenteml Clin North Am 1989;18:831. 25. Doherty GM, Doppman JL, Shawker TH, Eastman RC, Gorden P, Norton JA. Results of a prospective strategy to diagnose, localize and resect insulinoma. Surgery 1991;110:989-97. 26. Pipeleers-Marichal M, Somers G, Willems G, et al. Gastrinomas in the duodenums of patients with multiple endocrine neoplasic type 1 and the Zollinger-Ellison syndrome. N Engl J Med 1990;322:723-7. 27. Thompson NW, Vinik AI, Eckhauser FE. Micmgastrinomas of the duodenum. Ann Surg 1989;209:396-404. 28. Thorn AK, Norton JA, Axiotis CA, Jensen RT. Location, incidence and malignant potential of duodenal gastrinomas. Surgery 1991;110:1086-93. 29. Norton JA, Sugarbaker PH, Doppman JL, et al. Aggressive resection of metaCurr P r o b l
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management of patients with Zoliinger-Ellison syndrome. Gastroenterology 1988;94294-9. 51. Fraker DL, Norton JA. The role of surgery in the management of islet cell tumors. Gastroenteml Clin North Am 1989;18:805-30. 52. Catty S, Jensen RT, Norton JA. Prospective study of aggressive resection of metastatic pancreatic endocrine tumors. Surg 1992;112:1024-32. 53. Thompson GB, van Heerden JA, Grant CS, Carney JA, Ilstrup DM. Islet cell carcinomas of the pancreas: a twenty-year experience. Surgery 1988; 104:1011-7. 54. Gorden P, Comi RJ, Maton PN, Go VLW. Somatostatin and somatostatin analogue (SMS 201-995) in treatment of hormone-secreting tumors of the pituitary and gastmintestinal tract and non-neoplastic diseases of the gut. Ann Intern Med 1989;110:35-50. 55. Jensen RT, Collen MJ, McArthur KE, et al. Comparison of the effectiveness of ranitidine and cimetidine in inhibiting acid secretion in patients with gastric hypersecretoty states. Am J Med 1984;7790-105. 56. Vinayek R, Howard JM, Maton PN, et al. Famotidine in the therapy of gastric hypersecretory states. Am J Med 1986;81:49-59. 57. Vinayek R, Frucht H, London JF, et al. Intravenous omeprazole in patients with Zollinger-Ellison syndrome undergoing surgery. Gastmentemlogv 1990;99:10-6. 58. Maton PN, Vinayek R, Frucht H, et al. Long term efficacy and safety of omeprazole in patients with Zollinger-Ellison syndrome: a prospective study. Gastmentemlogy 1989;97:827-36. 59. Vinayek R, Amantea MA, Maton PN, Fruchet H, Gardner JD, Jensen RT. Pharmacokinetics of oral and intravenous omeprazole in patients with ZollingerEllison syndrome. Gastmentemlogy 1991;101:138-47. 60. Doherty GM, Norton JA. Preoperative and intraoperative localization of gastrinomas. Probl Gen Surg I990;7:521-32. 61. Doppman JL, Miller DL, Chang R, Gorden P, Norton JA. Insulinomas localization with selective intraarterial injection of calcium. Radiologv 1991;178:237-41. 62. Doppman JL, Miller DL, Chang R, et al. Gastrinomas: localization by means of selective intraarterial injection of secretin. Radiologv 1990;17425-9. 63. Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med 1992;326:1721-6. 64. VanEyck CHJ, Bruining HA, Reubi JC, Bakker WH, Oei HY, Krenning EP, Lamperts SWJ. Use of isotope-labelled somatostatin analogs for visualization of islet cell tumors. World J Surg 1993;17:444-7. 65. Wank SA, Doppman HL, Miller DL, et al. Prospective study of the ability of computerized axial tomography to localize gastrinomas in patients with Zollinger-Ellison syndrome. Gastmentemlogy 1987;92:905-12. 66. Frucht H, Doppman JL, Norton JA, et al. MR imaging of gastrinomas: comparison with computed tomography, angiography and ultrasound. Radiolo g y 1989;171:713-7. 67. von Schrenck T, Howard JM, Doppman JL, et al. Prospective study of chemotherapy in patients with metastatic gastrinoma. Gastmenterology 1988;94:1326-34. 68. Andersen DK. Current diagnosis and management of Zollinger-Ellison syndrome. Ann Surg 1989;210:685-703. 69. Lamberts SW, Bakker WH, Reubi JC, Krenning EP. Somatostatin receptor imaging in the localization of endocrine tumors. N Engl J Med 1990;323:1246-9. 70. Lamberts SW, Hofland LJ, van Koetsveld PM, et al. Parallel in vivo and in Curr Prohl Surg,
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vitro detection of functional somatostatin receptors in human endocrine tumors: consequences with regard to diagnosis, localization and therapy. .I Clin Endocrinol Metab 1990;31:566-73. 71. Fraker DL, Norton JA. Localization and resection of insulinomas and gastrinomas. JAMA 1988;259:3601-5. 72. Gabber AK, Reading CC, Charboneau JW, et al. Localization of pancreatic insulinoma: comparison of pre- and intraoperative US with CT and angiography. Radiology 1988;166:405-8. 73. Grant CS, van Heerden J, Charboneau JW, James EM, Reading CC. Insulinoma: the value of intraoperative ultrasonography. Arch Surg 1988;123:843-8. 74. Imamura M, Takahaski K, Adachi H, et al. Usefulness of selective arterial secretin injection test for localization of gastrinoma in the Zollinger-Ellison syndrome. Ann Surg 1987;205:230-9. 75. Imamura M, Takashi MP, Isobe Y, Hattori Y, Satomura K, Tobe T. Curative resection of multiple gastrinomas aided by selective arterial secretin injection and intraoperative secretin test. Ann Surg 1989210:710-5. 76. Cherner JA, Doppman JL, Norton JA, et al. Prospective assessment of selective venous sampling for gastrin to localize gastrinomas. Ann Intern Med 1986;105:841-7. 77. Norton JA, Cornelius MJ, Doppman JL, Maton PN, Gardner JD, Jensen RT. Effect of parathymidectomy in patients with hyperparathymidism and Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1: a prospective study. Surgery 1987;102:958-66. 78. van Heerden JA, Smith SL, Miller LT. Management of the Zollinger-Ellison syndrome in patients with multiple endocrine neoplasia type I. Surgery 1986;100:971-7. 79. Thompson NW, Lloyd RV, Nishiyama RH, et al. MEN I pancreas: a histological and immunohistochemical study. World J Surg 1984;8:561-74. 80. Norton JA. Surgical treatment of islet cell tumors with special emphasis on operative ultrasound. In: Mignon M, Jensen RT, eds. Endocrine tumors of the pancreas: recent advances. Frontiers of Gastrointestinal Research. Karger and Base1 (in press). 81. Sawicki MP, Howard TJ, Dalton M, Stabile BE, Passaro F. The dichotomous distribution of gastrinomas. Arch Surg 1990;125:1584-7. 82. Maton PN, Macken SM, Norton JA, Gardner JD, O’Dorisio TM, Jensen RT. Ovarian carcinoma as a cause of Zollinger-Ellison syndrome. Gastroentemlo@ 1989;97:464-7. 83. Friesen SR. Are “aberrant nodal gastrinomas” pathogenetically similar to “lateral aberrant thyroid” nodules? Surgery 1990;107:236-8. 84. Norton JA, Shawker TH, Doppman JL, et al. Localization and surgical treatment of occult insulinomas. Ann Surg 1990;212:615-20. 85. Cromack DT, Norton JA, Sigel B, Shawker TH, Doppman JL, Maton PN, Jensen RT. The use of high-resolution intraoperative ultrasound to localize gastrinomas: an initial report of a prospective study. World J Surg 1987;11:648-53. 86. Sigel B, Coelho JCLJ, Nyhos LM, et al. Detection of pancreatic tumors by ultrasound during surgery. Arch Surg 1982;177:1058-61. 87. Klotter HJ, Ruckert K, Kummerle F, Rothmund M. The use of intraoperative sonography in endocrine tumors of the pancreas. World J Surg 1987;11:63541. 88. Angelini L, Bezzi M, Tucci G, et al. The ultrasonic detection of insulinomas during surgical exploration of the pancreas. World J Surg 1987;11:642-7. 146
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with hypercalcemia: complete remission 5 years after surgical excision and chemotherapy. Am J Gastroenteml 1991;86:635. 258. Arps H, Dietel M, Schulz A, Janzarik H, Kloppel G. Pancreatic endocrine carcinoma with ectopic PTH-production and paraneoplastic hypercalcaemia. Virchows Arch 1986;408:497. 259. Blackburn AM, Bryant MG, Adrian TE, Bloom SR. Pancreatic tumors produce neurotensin. J Clin Endocrinol Metab 1981;52:820. 260. Shulkes A, Boden R, Cook I, et al. Characterization of a pancreatic tumor containing vasoactive intestinal peptide, neurotensin and pancreatic polypeptide. J Clin Endocrinol Metab 1984;58:41. 261. Kent RB, van Heerden JA, Weiland LH. Nonfunctioning islet cell tumors. Ann Surg 1981;193:185. 262. Iguchi H, Yasuda D, Yamada Y, et al. 7B2, a possible marker for nonfunctioning pancreatic islet cell tumor. Horm ,Metab Res 1991;23:486-9. 263. Eckhauser FE, Cheung PS, Vinik AI, et al. Nonfunctioning malignant neutoendocrine tumors of the pancreas. Surgery 1986;100:978. 264. VonKatesh S, Ordonoz NG, Ajani J, et al. Islet cell carcinoma of the pancreas: a study of 98 patients. Cancer 1990;65:354. 265. Lin TH, Zhu Y, Lui QI, et al. Nonfunctioning pancreatic endocrine tumors: an immunohistochemical and electron microscopic analysis of 26 cases. Path01 Res Pratt 1992;188:191. 266. Akerstrom G, Johansson H, Grama D. Surgical treatment of endocrine pancreatic lesions in MEN-l. Acta Oncol 1991;30:541-5. 267. Maton PN, Norton JA, Nieman L, Doppman JL, Gardner JD, Jensen RT. Multiple endocrine neoplasia type 2 with Zollinger-Ellison syndrome caused by a solitary pancreatic gastrinoma. JAMA 1989;262:535-7. 268. Cherner JA, Sawyers JL. Benefit of resection of metastatic gastrinoma in multiple endocrine neoplasia type I. Gastroenterology 1992;102:1049-53. 269. Rasbach DA, van Heerden JA, Telander RL, et al. Surgical management of hyperinsulinism in the multiple endocrine neoplasia, type I syndrome. Arch Surg 1985;120584-9. 270. Demure MJ, Klonoff DC, Karam JH, Duh QY, Clark OH. Insulinomas associated with multiple endocrine neoplasia type I: the need for a different approach. Surgery 1991;110:998-1005. 271. McEntee GP, Nagorney DM, Kvols LK et al. Cytoreductive hepatic surgery for neuroendocdne tumors. Surgery lSSO;lO8:lOSl-6. 272. Moertel CG, Hanley JA, Johnson LA. Streptozotocin alone compared with streptozotocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med 1980;303:1189. 273. Moertel CG, Hanley JA. Combination chemotherapy trials in metastatic carcinoid and malignant carcinoid syndrome. Cancer Clin Trials 1979;2:327. 274. Moertel CG, Kvols LK, O’Connell MJ, Rubin J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Cancer 1991;68227. 275. Oberg K, Ericksson B, Norheim I. Interferon treatment of nemoendocrine gut tumors. J Clin Oncol 1987;6:80. 276. Oberg K, Lindstrom H, Alm G, Lundquist G. Successful treatment of therapyresistant pancreatic cholera with human leukocyte interferon. Lancet 198.5;1:725. 277. Oberg K, Norheim I, Lind E, et al. Treatment of malignant carcinoid tumors with human leukocyte interferon: long term results. Cancer Treat Rev 1986;70:1297-1304. 278. Moertel CG. An odyssey in the land of small tumors. J Clin Oncol 1987;5:1502-22. CurrProblSurg,
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279. Moertel CG, May GR, Martin JK, et al. Sequential hepatic artery occlusion and chemotherapy for metastatic carcinoid tumor and islet cell carcinoma. Proc Amer Sot Clin Oncol 1985;4:80. 280. Arnold R, Benning R, Neuhaus C, Rolwage M, Trautmann PW. Gastroenteropancreatic endocrine tumors: effect of sandostatin on tumor growth. [The German Sandostatic Study Group.1 Metabolism 1992;41:116-8. 281. Oberg K; ,Norheim I, Theodorsson E. Treatment of malignant carcinoid tumors with a long-acting somatostatin analogue octreotide. Acta Oncol 1991;30503-7. 2 8 2 . Norton JA, Doherty GM, Farker DL. Surgery for endocrine tumors of the pancreas. In: Liang V, Go W, Gurder JD, et al., eds. Biology, pathobiology, and disease. New York: Raven Press, Ltd., 1993:1009-94. 283. Lamberts SW, Reubi JC, Krenning EP. Somatostatin receptor imaging in the diagnosis and treatment of neuroendocrine tumors. J Steroid Biochem Mol 1992;43:185-8. 284. Maton PN, Miller DL, Doppman HL, et al. Role of selective angiography in the management of Zollinger-Ellison syndrome. Gastroenterologv 1987;92:913-9. 285. Sigel B, Machi J, Ramos JR, Duarte B, Donahue J. The role of imaging ultrasound during pancreatic surgery. Ann Surg 1984;200:486-93.
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INTRODUCTION
Endocrine neoplasms of the pancreas are classified primarily according to the clinical syndrome that patients manifest (Table 1). In each instance, the principal clinical manifestations of the tumor are due to the uncontrolled excessive release of peptide hormones into the circulation. These hormones occur naturally and are important in mediating various physiologic processes. However, in patients with pancreatic endocrine tumors, the release and secretion of these hormones are not under normal physiologic regulation. Because of extremely high levels of hormones, characteristic signs and symptoms develop (Table 11. Different types of pancreatic endocrine tumors share several features in common, including pathologic characteristics, natural history, management considerations, radiographic localization studies, occurrence in familial syndromes, and propensity to metastasize. Effective therapy of patients with pancreatic endocrine tumors requires treatment of the signs and symptoms of excessive hormone production and the malignant nature of the tumor itself. In this monograph, the common features of islet cell tumors are discussed first, and the distinctive features of individual tumors are described subsequently. Special attention is given to neuroendocrine tumors as part of multiple endocrine neoplasia type 1 (MEN-11 and metastatic islet cell tumors. PREVALENCE
Endocrine tumors of the pancreas are rare, with an incidence of less than 10 per million population per year.” 2 Insulinomas are the most common islet cell tumor, with a prevalence of approximately 1 per million population per year, and gastrinomas are the second most common islet cell tumor, with an incidence of 0.1 to 0.4 per million population per year.3 Some authors suggest that gastrinomas may be as common as insulinomas, with a relative frequency of each of one to three per million population per year.4 Gastrinomas are the most Curr Pmbl Surg, February 1994
89
Neumtensinoma
mH-like-oma
GRFoma ACTHoma
Somatostatinoma
Insulinoma VIPoma Glucagonoma
Rare
1 in 5 million
Neumtensin
Pancreatic polypeptide, neuron-specific enolase
RalX?
WH-like
factor
RalX RaN?
4 in 5 million Rare Rare
2 in 5 million
GRF ACTH
Somatostatin
Insulin VIP Glucagon
Ulcer pain Diarrhea EsophagItis Hypoglycemia Watery diarrhea Rash Weight loss Malnutrition Diabetes Cholelithiasis Steatorrhea Acmmegaly cushing’s syndrome Hypercalcemia Bone pain Hypotension Tachycardia Malabsorption Cyanosis Pain Gastrointestinal bleeding Mass
Gastrinoma
Incidence
100
100
100
100 100
100
80-100 100 98-100
52-87
-
100
-
>99
100
30 100
7 -
50
50
>99 85 >99
15 -
62
38
60
>80
100
30 100
70
5 40 70
50
High
-
-
Occasional
5 Occasional Occasional
18-24
Percentage Percentage with with metastases MEN-l
tumors
Percentage of Tumors identified Percentage in Percentage in at surgery duodenum pancreas
Location
or symptoms, hormone, prevalence, and pathologic features of pancreatic or duodenal neuruendocdne
Signs or symptoms Hormone
Signs
Name of tumor
TABLE 1.
common functional islet cell tumor in patients with MEN-l, and insulinomas are the second most common functional islet cell tumor in these patients. The remaining pancreatic endocrine tumors occur in less than 0.2 per million population per year. Only 100 patients with glucagonoma have been reported worldwide; 21 cases of intestinal somatostatinoma, 27 cases of pancreatic somatostatinomas, and even fewer vasoactive intestinal peptide-secreting tumors WIPomas) and growth hormone-releasing factor-secreting tumors (GRFomas) have been described.5-s The best data on the relative frequency of various islet cell tumors is from Ireland, where an average incidence of 3.6 cases per million population per year has been documented.’ Insulinomas were the most common islet cell tumor, twice as common as gastrinomas, eight times as common as VIPomas, seventeen times as common as glucagonomas, and as common as nonfunctional islet cell tumors (Table 1). Somatostatinomas were rare, with no cases reported.’ In this series, all pancreatic endocrine tumors combined were approximately equal to the incidence of carcinoid tumors. In one autopsy report, it was suggested that nonfunctioning pancreatic islet cell tumors occur in approximately 1% of subjects.” Functional islet cell tumors occur in one per thousand autopsy subjects. In surgical series, nonfunctioning pancreatic islet cell tumors are reported to comprise approximately 15% to 20% of all pancreatic endocrine tumors removed,5-7 and in a recent large pathologic series, approximately 36% of resected pancreatic tumors were endocrine tumors.’ PATHOLOGIC
FEATURES
Pancreatic islet cell tumors share a number of common pathologic features. These tumors are believed to ori inate from cells that are part of the neuroendocrine cell system? ‘, f‘, l2 These cells share cytochemical properties with carcinoid tumors, medullary carcinoma of the thyroid, melanoma, and pheochromocytoma, and have been called APLJDoma &nine Precursor Uptake and Decarboxylationl. Islet cell tumors are composed of monotonous sheets of small round cells with uniform nuclei and cytoplasm. Mitotic figures are unusual. Under electron microscopy, these tumors demonstrate dense granules that contain secretory products including peptides, neuronspecific enolase, amines, synaptophysin, and chromogranin-A.8’ 13, I4 Thus these pancreatic neuroendocrine tumors are clearly multihormonal when examined by specific immunologic staining techniques. In most series, more than 50% of all pancreatic islet cell tumors contain more than one hormone defined by immunocytochemisw.8, 15-20 In insulinomas, for example, glucagon has been detected in 0% to 44% of tumors, somatostatin in 0% to 18%, gastrin in 3% to ll%, pancreatic polypeptide in 18% to 39%, and adrenocorticotropic C u r r Probl S u r g , F e b r u a r y 1 9 9 4
91
hormone (ACTH) in 11% .13, l8 The most common accessory hormone is pancreatic polypeptide (PP), which has been identified in as man as 39% of insulinomas, 67% of glucagonomas, and 75% of VIPomas.3’ Y’ In most instances, only one peptide is secreted into the circulation; however, in other instances numerous peptides can be measured in the circulation. At present, it is not clear why patients with a certain pancreatic endocrine tumor only have symptoms characteristic of one of these many peptides, especially when the tumor contains multiple peptides on immunocytochemistry. Possible hypotheses include the following: (1) only one peptide is released into the circulation; (2) some peptides released are able to antagonize symptoms caused by the other peptides that are present; or (3) only one of the peptides is biologically active, and the remainder are precursor hormones . Because most patients with pancreatic islet cell tumors are now living longer as therapy becomes more effective, the development of a secondary symptomatic pancreatic hormone may become evident.“’ ” One recent study indicates that secondary symptomatic pancreatic hormone secretion is common, occurring in 8% of patients, during a mean follow-up of 2 years.” Another study suggests it is uncommon, occurring in only 2% of patients with ZollingerEllison syndrome (ZES) followed up for 11 years.l’ This condition may be common in patients with malignant tumors. Patients with gastrinoma who have evidence of ACTH secretion appear to have a more malignant course.21 Because of the frequent presence of multiple hormones by immunocytochemistry in tumor specimens, it is not possible to determine by immunocytochemical techniques which of the hormones is responsible for the symptoms and syndrome in an individual patient. Therefore immunocytochemistry is not useful in categorizing an individual tumor as an insulinoma or gastrlnoma. However, it can provide some evidence to suggest what type of tumor an individual tumor is. For example, if an individual islet cell tumor has 80% of its cells positive for gastrln, most likely it will be a gastrinoma?s In general, microscopic pathologic description of pancreatic endocrine tumors has failed to predict the growth pattern of a specific tumor and is not able to determine whether an individual islet cell tumor is cancerous.’ In addition, no clear correlation exists between the histologic pattern of an islet cell tumor and the type of associated clinical syndrome.’ Pancreatic endocrine tumors may express the o-chain and -chain of human chorionic gonadotropin” and chromogranin-A.2 B S o m e authors suggest that each of these markers is a good indicator of malignancy.22’23 However, at present, the only clear determination of malignancy is surgical detection of metastatic tumor either in lymph nodes or the liver.’ Gross invasion of blood vessels and surrounding pancreas or infiltration into adjacent organs is another indicator of malignancy, but this sign is less certain than 92
Cum- Probl Surg. February 1994
the presence of distant metastatic disease. Therefore it is not clear what proportion of pancreatic islet cell tumors is cancerous. The benign nature of an individual tumor can be determined only by careful long-term follow-up studies. In general, less than 10% of insulinomas are cancerous, approximately 60% of gastrinomas are malignant, and 50% to 90% of all other islet cell tumors are malignant.1 The size of an individual islet cell tumor does not correlate with the severity of the hormonally mediated symptoms. However, a correlation does exist between the size of the tumor and the occurrence of [email protected]’ 24 Insulinomas, like gastrinomas, are generally small tumors (<2 cm)?’ Glucagonomas, somatostatinomas, pancreatic polypeptide (PPlomas, and other islet cell tumors are frequently larger at the time of detection (>5 cm).“” Most primary pancreatic endocrine tumors are solitary, encapsulated, and within the pancreas. However, islet cell tumors can occur in the duodenum and other locations besides the pancreas.26‘28 When metastatic disease occurs, it commonly is seen at diagnosis with either peripancreatic lymph node involvement or evidence of liver metastases.” Late in the course of the disease, metastases to lung, bone, and even heart may be identified. Pancreatic endocrine tumors occur in either a nonfamilial (sporadic) form or in a familial form associated with MEN-l. MEN-l is inherited as an autosomal dominant disorder and is characterized by tumors of the parathyroid glands, pancreas, and pituitary. It is associated with a defect on chromosome 11.l’ 3o Recently, two patients with MEN-l and insulinoma have been shown to possess the same constitutional gene defect and a deletion on chromosome 11. Similar defects have been identified in other pancreatic endocrine tumors in patients with MEN-1 .31 The chromosomal defects in insulinoma in patients with MEN-l are in contrast to patients with sporadic islet cell tumors, where homozygous inactivation of the MEN-l gene does not develop .31 The exact proportion of patients with pancreatic islet cell tumors who manifest MEN-l varies in different series from less than 5% to 25%.17 The recognition that an islet cell tumor is part of the MEN-l syndrome is important because patients with MEN-l always have multiple pancreatic islet cell tumors.32 Furthermore, screening of other family members for various features of the syndrome is indicated. Functional islet cell tumors are the second most frequent abnormality in MEN-l patients and are found in approximately 80% of these individuals. Gastrinomas, insulinomas, glucagonomas, and VIPomas occur in a decreasing incidence in that order, with gastrinomas occurring in 54% of patients and insulinomas in 20% of patients with MEN-1.33 Almost all insulinomas occur in the pancreas.“, 341 35 Glucagonomas generally occur within the pancreas and most commonly in the pancreatic body and tai1?4’ 36 In contrast to insulinomas and gluCurr Probl Surg,
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93
cagonomas, gastrinomas can occur within the duodenumz6-” and the pancreas.37’ 38 Approximately 50% of gastrinomas have recently been identified in the duodenal ~al1.2~, “, 38 VIPomas are usually in the pancreas” 3s; however, the VIPoma syndrome has been reported in association with pheochromocytoma or carcinoid tumor of the intestine.40’ 41 Somatostatinomas, like gastrinomas, may be extrapancreatic. In a recent review of 48 primary somatostatinomas, 56% were in the pancreas and 44% were in the duodenum or jejunum.42 Similar to glucagonomas, somatostatinomas usually are large (>5 cm) at the time of presentation.42 Only primary insulinomas and gastrinomas are small at the time of presentation, frequently less than 2 cm.25’ “, 38 Nonfimctioning pancreatic islet cell tumors and PPomas are usually greater than 5 cm in diameterP3’ 44 Other less common functioning islet cell tumors, such as those secreting GRF, parathyroidhormonelike (PTH-like) factor, or ACTH, are usually large tumors located within the pancreas.21’ 431 44 In addition to MEN-l syndrome, recent studies suggest that pancreatic islet cell tumors are found in a higher frequency in patients with von Recklinghausen’s disease,4547 von Hippel Lindau syndrome,48 and tuberous sclerosis.4s In patients with von Recklinghausen’s disease, duodenal somatostatinomas and gastrinomas have been reported?5-47 In patients with von Hippel Lindau syndrome, as many as 17% of patients have pancreatic endocrine tumors, including both adenomas and carcinomas. However, it is unusual for these tumors to be functional, and only one patient had a clinical hormonal syndrome in this series. In one series, patients with tuberous sclerosis had an incidence of insulinoma and nonfunctional pancreatic islet cell tumor.
SURGICAL PRINCIPLES
The goal of operation in patients with islet cell tumors is to identify, stage, and remove all tumor. The surgeon should remove all tumor in a manner that allows the mortality and morbidity of surgery to be less than the natural history of the tumor. The surgeon must know the natural history and pathologic condition of the islet cell tumor, the expected outcome of the surgical procedure, the expected survival with the tumor resected, the immediate and long-term complication rate, and the availability of alternative medical treatments to manage the disease. Most experts recommend that patients with islet cell tumor should undergo surgery because any islet cell tumor may be malignant, medical management can only control the signs and symptoms, and tumor resection is the only potentially curative treatment. Therefore each patient with biochemical evidence of an islet cell tumor should undergo complete radiologic assessment of the extent of disease to 94
Curr Probl Surg, February ww
determine the feasibility of surgery. During the radiologic evaluation, medical management should be used to ameliorate symptoms resulting from excessive hormone secretion. It is clear that in some patients with islet cell tumors (such as gastrinoma5’ and VIPoma41) advances in medical control of the hormone production has improved the surgical outcome and has reduced the operative complication rate. Many variables associated with an individual patient impact on the surgical outcome. These variables include the extent of disease on preoperative imaging studies, the location of the primary tumor (within the pancreas or duodenum), the exact area of the pancreas involved (head or tail), the presence of liver or other distant metastases and whether they are resectable, the occurrence of the islet cell tumor in a familial or a sporadic setting, and the simultaneous occurrence of other medical conditions that limit the ability of a patient to undergo major surgery. Success need not be defined as cure of the hormonal syndrome. Success may involve decreased medication requirement, decreased symptoms, and increased survival. In individual patients, clear benefits may be difficult to quantitate. Nonetheless, it is clear that islet cell tumors may be malignant, that surgery is an effective way to stage the true extent of disease accurately, and that surgery may cure patients even with metastatic islet cell tumor.51’ 52
PREOPERATIVE MANAGEMENT Diagnosis
Patients with functional islet cell tumors have symptoms resulting from uncontrolled excessive hormone secretion. The symptoms and signs for each islet cell tumor are listed in Table 1. Patients with nonfunctional islet cell tumors usually have symptoms related to a pancreatic mass (pain, intestinal bleeding, or obstruction).43S 53 As with most other endocrine tumors, the diagnosis of functional islet cell tumors is made biochemically by the immunologic detection of elevated plasma levels of a hormone. The exact diagnostic criteria for each type of islet cell tumor are listed in Table 2. It is necessary to obtain an unequivocal biochemical diagnosis before performing invasive localization studies.
Medical Management of Hormonal Symptoms
After diagnosis, the physician must attempt to ameliorate the signs and symptoms of excessive hormone secretion. Medical management has been facilitated by new drugs that reduce the levels of circulating hormone (e.g., octreotide541 or inhibit specific effects (antigastric acid hypersecretion [e.g., ranitidine?5 famotidineF6 a n d omeprazole57~5sl). CurrProblSur~
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96
TABLE
2. Diagnostic criteria for neuroendocnne tumors
Tumor type
Test
Results
Gastrinoma
Fasting gastrin Basal acid output
Elevated gastrin (>lOO pg/mlJ Elevated basal acid output 1X5 mEq/hourJ Elevated gastrin (>200 pgmll Symptoms of hypoglycemia Elevated insulin (Xi @J/ml) Decreased glucose (<40 mgdl) Elevated C peptide 1X.7 ng/mlJ Elevated percentage proinsulin (>30% 1 Elevated VIP (>250 pgml) Elevated glucagon (>500 pgml) Elevated somatostatin Elevated GRF Elevated cortisol Elevated ACTH Failure to suppress Failure to increase Elevated calcium Undetectable PTH Elevated PTH-like factor Elevated neurotensin
Insulinoma
VIPoma Glucagonoma Somatostatinoma GRFoma ACTHoma
PTH-like tumor
Neurotensinoma
Secretin test 72 hour fast
Fasting VIP Fasting glucagon Fasting somatostatin Fasting GRF Urinary free corns01 Plasma ACTH Dexamethasone CRH Calcium PfH PTH-like factor Fasting neurotensin
C/W, Corticotmpin-releasing hormone.
Localization The next step in the management of patients with biochemical evidence of an islet cell tumor is tumor localization. Unfortunately, radiologic procedures to image an islet cell tumor often fail. In fact, 50% of patients with insulinoma or gastrinoma will have no tumor identified despite invasive localization studies.25J 38, ” Published reports of recent studies including endoscopic ultrasonography, octreotide scan, and selective angiography with the administration of secretago e s suggest that a greater proportion of tumors can be localized6P-64 (Table 31. Furthermore, either infusion computed tomography (CT) or magnetic resonance imaging (MRI) can determine the presence of liver metastases with precision (80% 1 .65S 66 In patients with CT or MRI evidence of unresectable metastatic disease, biopsy confirmation of tumor is necessary before starting treatmentl’ 67 Andersen68 found that percutaneous biopsy correctly diagnosed the presence of metastatic neoplasm within the liver in 17 of 19 patients (89%) with pancreatic islet cell tumor. A 93% accuracy rate of CTguided aspiration biopsy has been observed in patients with CT evidence of liver disease.68 The use of ‘“lI-labeled octreotide has demonstrated that islet cell tumors can be imaged on the basis of the presence of functional so96
Corr Probl Sorg,
February 1994
TABLE 3.
Preoperative localization of neuruendocrine tumors of the pancreas and duodenum ”
Noninvasive Ultrasonography Octreotide radioimaging CT MRI Invasive Endoscopic ultrasonography Selective angiography Portal venous sampling Provocative angiography’ ‘Secretin
True positives (%I
Reference
43 21 60 35
10 18 26 9
(23) (861 (43) 1261
25,37 64,282 25,65 25,66
38 70 92 17
31 39 60 11
(82) (56) (761 (65)
63 25,283 25,76,211 61,62
for gastrinoma and calcium for insulinoma.
matostatin receptors.64, “, 7o Between 60% and 90% of gastrinomas and insulinomas have been correctly imaged. Endoscopic ultrasonography is another new modality to localize islet cell tumors.63 The procedure is performed by passing an endoscope through the stomach and duodenum. A balloon is inflated with saline solution, and a 5 to 10 MHz transducer is used to scan the pancreas and duodenal wall. Islet cell tumors within the body and tail of the pancreas are imaged with the transducer in the stomach. Islet cell tumors within the head of the pancreas or the duodenum are imaged with the transducer in the duodenum. Islet cell tumors are imaged as sonolucent mass lesions by ultrasonography. Approximately 80% of islet cell tumors were correctly identified in one recent rep~rt.~~ Apparently, islet cell tumors within the pancreatic tail are difficult to image (Table 3). Invasive islet cell tumor localization studies include selective arteriography and portal venous sampling. Selective angiography identifies an islet cell tumor by its appearance as a blush resulting from increased vascularity.71 Although it is one of the most reliable and sensitive imaging studies, in recent reports angiography was found to identify less than 50% of islet cell tumorsz5, “, 73 When injected directly into the artery that supplies the gastrinoma, secretin produces a quick rapid rise in hepatic venous levels of gastrin, which suggests that the gastrinoma is within the portion of the pancreas perfused by the injected artery.“’ 74, 75 In patients with insulinoma, intraarterial calcium can be injected to obtain similar information.61 A more tedious and invasive method to obtain regional localization is transhepatic portal venous sampling of the portal vein and its tributaries for elevated hormone concentrations. This procedure requires that the radiologist pass a catheter across the liver into the portal vein and its branches and collecting multiple blood samples Curr Probl Surg,
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for hormone. Theoretically, the closer the catheter gets to the tumor, the greater the venous hormone concentration. A 50% increment in hormone concentration in a selective vein that drains into either the splenic vein, the superior mesenteric vein, or the portal vein localizes the tumor to the head, body, or tail of the pancreas.76 Portal venous sampling correctly localizes 73% of gastrinomas76 and w%‘~ of insulinomas (Table 3). Multiple Endocrine Neoplasia The surgeon should obtain a careful family history for the presence of familial endocrine tumors. The familial syndrome most commonly associated with islet cell tumors is MEN-l. This syndrome is inherited as an autosomal dominant trait, and a genetic defect exists on chromosome 11.l’ 3o The most common islet cell tumor in patients with MEN-l is gastrinoma; the second most common tumor is insulinoma, but these patients may also have any other islet cell tumor.77-7s Other endocrine tumors in patients with MEN-l include primary hyperparathymidism caused by hyperplasia,77 and pituitary adenoma, commonly a pro1actinoma.l Patients with MEN-l also have a higher incidence of thyroid adenoma, adrenocortical tumors, carcinoid tumors, and lipomas.’ Patients with MEN-l generally have evidence of primary hyperparathyroidism before the islet cell tumor syndrome.77 In patients with islet cell tumors, the presence of MEN-l should be excluded by questioning about family history, by measuring serum levels of calcium, and by examining for other evidence of MEN-l (lipomas, elevated prolactin level). The management of patients with islet cell tumors in the presence of MEN-l is controversial and will be considered in a separate section. Preoperative Preparation Patients who are scheduled for exploration for an islet cell tumor require evaluation of cardiac, pulmonary, renal, coagulation, hematologic, and hepatic functions. Pneumococcal vaccine is given in case a splenectomy is necessary. Splenectomy may be part of subtotal or distal pancreatectomy. A mechanical bowel preparation with a strong cathartic is performed in case tumor excision requires a concomitant bowel resection or in case the bowel is injured. Broad-spectrum perioperative antibiotics such as second-generation cephalosporins are used for prophylaxis against surgical infection.80
OPERATIVE
MANAGEMENT
The choice of incision depends on body habitus. In patients who are thin, a midline incision is preferred. In patients who are obese or 98
Cur-r
Probl Surg,
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have a wide costal margin, a bilateral subcostal incision is more useful. A fixed upper abdominal retractor will improve exposure. Careful examination and palpation of all abdominal organs are necessary. Initial attention is focused on the liver and ovaries. Metastatic islet cell tumors are commonly firm nodules in the liver. Prim trinomas can occur in unusual locations such as the ovary. s?%ay; primary ovarian cystadenocarcinoma is identified,” then a total abdominal hysterectomy and bilateral salpingo-oophorectomy is indicated. After careful palpation and inspection of the liver, uterus, and ovaries, the entire small intestine is examined. Gastrinomas have been identified in either lymph nodes or the wall of the first portion of the jejunum.37’ 83 Finally, the colon is also palpated. To expose the pancreas; the lesser sac is opened by dividing the gastrocolic ligament. The ligaments attaching the hepatic and splenic flexures to the liver and spleen are divided to mobilize the colon out of the operative work space. The head of the pancreas is mobilized by dividing the attachments of the duodenum to the retroperitoneum (Kocher maneuver). This procedure allows palpation of the head of the pancreas between the thumb and forefinger as well as partial visualization of the posterior head of the pancreas. The body and tail of the pancreas are mobilized by dividing along the inferior and posterior border. It may be necessary to divide the splenic ligaments and rotate the spleen out of the retroperitoneum to carefully palpate the tail of the pancreas. Once the pancreas is mobilized, the entire gland should be palpated carefully between the thumb and forefinger. Islet cell tumors of the pancreas may be impossible to locate by palpation alone, especially in the pancreatic head.” Therefore the use of intraoperative ultrasonography to improve operative identitication of islet cell tumors has become a standard procedure. A 7.5 to 10 MHz transducer is preferred because of short focal length and high resolution.85 A 5 MHz transducer is used for the liver because of better depth of penetration. A color flow unit allows accurate detection of intrahepatic and intrapancreatic blood vessels, including determination of veins and arteries based on flow characteristics. Color flow Doppler also aids in assessing the relationship of islet cell tumors to major ducts, which are sonolucent tubular structures without blood flow. Intraoperative ultrasonography is performed by the operating surgeon in conjunction with an ultrasonographer. The peritoneum is iilled with saline solution to improve the quality of the images. The operative lights are dimmed to minimize glare. Masses are scanned in planes (longitudinal and transverse) to determine the relationship between imaged masses and other structures.86 Islet cell tumors are uniform sonolucent masses seen on ultrasound scan (Fig. 1). Ultrasonographic detection of islet cell tumors is aided by the uniCurr Probl Surg,
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99
FIG. 1. lntraoperative ultrasound appearance of a typical islet cell tumor (gastrinoma). The tumor IS sonolucent compared with the surrounding pancreas, which is more echogenlc. The margin between the tumor and the pancreas IS discrete, with an echogenic rim around the entire tumor. (From Norton JA, et al. Ann Surg 1988;207:160-8.) 100
Curr Probl Sorg,
February 1994
form echo-dense background of the pancreas and the liver. Numerous reports have demonstrated that intraoperative ultrasonography greatly yy$g detection of islet cell tumors within the pancreas.63’ 73* This technique is able to image nearly all pancreatic insulinomas and gastrinomas correctly, including tumors that are not palpable (Table 4). However, intraoperative ultrasonography is less useful in the detection of duodenal gastrinomas, which is explained by the fact that the duodenum is composed of solid, liquid, and gas and does not have the same uniform background as the pancreas. Small sonolucent islet cell tumors are less visible against a nonuniform background. Intraoperative ultrasonography is a tool for the surgeon. It is an extension of palpation because it allows looking into an organ without incising it. This feature is extremely valuable in the pancreas because it reduces unnecessary incisions into the gland that result in complications such as fistulas, pancreatitis, and pseudocyst. Exploration of the duodenum may be a critical component of islet cell tumor surgery. Many patients with ZES have a small duodenal wall islet cell tumor as a cause of excessive gastrin secretion.“’ 38 The duodenum has been the most frequent site of missed gastrinomas.27, 37,38 Techniques to facilitate operative detection of duodenal wall tumors are important in patients with ZES. Intraoperative endoscopy with transillumination of the duodenum improves detection of duodenal wall gastrinomagl (Table 4). During the operation, an endoscope is passed orally into the duodenum after complete exposure of the duodenum. The endoscopist looks for mucosal irregularities or outgrowing mass lesions within the wall of the duodenum that may occur as a result of intramural gastrinomas (Fig. 2). With the use of transillumination, intramural tumors are identifiable as an opaque density within the bowel walls2 (Fig. 3). Other authors suggest that extensive duodenotomy is the best method to find duodenal wall tuTABLE
4. Results of new intraoaerative methods to identifv neuroendocrine tumors
Type of tumor Pancreatic Insulinoma Gastrinoma Duodenal Gastrinoma
Method
”
Intraoperative ultrasonography Intraoperative ultrasonography
101
89 (881
73, 84, 87-90, 264
34
31 (91)
87, 89, 92, 284
Palpation Intraoperative ultrasonography Endoscopy and transilhtmination Duodenectomy
31 31
19 (61) 8 126)
92 92
31
20 164)
92
31
31 (1001
92
Curr Probl Sur5 February 1994
No. true positives (W 1
Reference
101
FIG.
2. Endoscopic view of duodenal gastrinoma. Side-viewing endoscope is passed into second portion of the duodenum, and gastrinoma is visible as a mass lesion (arrow).
morsz7 This method allows visualization and open palpation for nodules.27 A recent study demonstrated that duodenotomy was better than transillumination and was the single best method to locate duodenal tumors, identifying tumors not seen by transilluminationg2 Two methods are available to remove a pancreatic islet cell tumor: enucleation or resection. Enucleation refers to simple excision of the tumor. Enucleation is acceptable for islet cell tumors that are benign. Insulinoma is usually benign, and enucleation results in long-term cures (Table 51. Enucleation is preferred for insulinoma because enucleation preserves vital organs such as the pancreas and spleen. The exact determination of the relationship of the tumor to the pancreatic duct is important before removing an islet cell tumor. A ductal injury during dissection may result in considerable morbidity, including pancreatic fistula, abscess, and pseudocyst. The proximity of the tumor to the duct is best determined intraoperatively by ultrasonography. If no clear margin exists between the tumor and the duct, a distal pancreatectomy and splenectomy are preferable. The higher malignancy rate of other types of islet cell tumors, such as 102
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FIG. 3.
Operative surgeon’s view of duodenal gastrinoma that appears as a focal light defect during transillumination of duodenum.
TABLE 5.
Neuroendocrine
NeuruendocrIne Insulinoma
Total Gastrinoma
Total
tumor identification and cure rate’
tumor n 396 36 25
73 11 125 209
No. with tumor identified (%I
No. cured (I)
394 (991 3 6 (100) 24 (96) 45 (100) 499 (99) 57 178) 1 0 191) 101 (81) 168 (80)
394 (99) 3 5 197) 2 4 (96) 45 (100) 499 4 2 (58) 9 (82) 3 2 (26) 83 (40)
Reference 103 73 25 102 38 167 177
‘Cure rate refer8 to the immediate cure rate. Actual long-term GyearJ cure rate in gastrinoma patients may decrease by 50%. Cum Probl Surg, February 1994
103
gastrinoma, somatostatinoma, and glucagonoma, suggests that a pancreatic resection is indicated especially if preservation of the pancreatic head and duodenum can be achieved.s3’94 Gastrinomas within the head of the pancreas or duodenum are simply excised instead of performing a pancreaticoduodenectomy (Whipple procedure). Excision has been associated with excellent long-term ~utvival.~~ Therefore the choice of procedure to remove an islet cell tumor is based on the normal structures that may be sacrificed, operative death and complication rate, type of tumor, expected malignancy rate, and projected quality and length of life. POSTOPERATlVE
MANAGEMENT
The complications of surgery for islet cell tumors may be the result of major surgery or the result of removing an islet cell tumor from the pancreas or duodenum. Complications associated with major abdominal surgery include atelectasis, ileus, and infections. Complications associated with surgery to remove an islet cell tumor include pancreatitis, pancreatic fistula, pseudocyst, abscess, and duodenal leak (Table 6). Postoperative control of pancreatic exocrine drainage is achieved by insertion of large drains whenever a pancreatic incision is necessary. Closed suction drains should be used. Amylase concentrations of the drainage can be measured to determine that the collected fluid is from the pancreas. The drains must be lefi in place until the patient is eating regular food and the drainage is minimal (less than 20 ml/day). A low-fat diet is used to reduce pancreatic drainage. An H,receptor antagonist such as ranitidine or famotidine will decrease stomach acid and pancreatic exocrine secretion. In patients in whom excessive drainage of amylase-rich fluid persists (>250 ml/day), total parenteral nutrition will reduce the amount of drainage and promote healing. In addition, it has also been reported that patients with pancreatic and intestinal fistulas will benefit from octreotide to reduce the amount of drainage.54’ ” A recent study from Germany of patients undergoing pancreatic resection for adenocarcinoma and pancreatitis demonstrated a reduced complication and mortality rate with the use of octreotide.g6 However, another study in patients undergoing TABLE 6.
Morbidity and mortality of neuroendocrine tumor surgery
Location of tumor Multicenter Pancreas Duodenum
pancreas
n
No. with morbidity (W 1
No. with mortality (WI
Reference
419 49
132 (32) 7 (14)’
10 (2) 0 (0)
103 x,97
35
6 (17)t
0 (0)
92
*Incarcerated hernia (n = l), pancreatic fistia (n = 3), pseudocyst (n = 11, and abscess (II = 21. tPancreatitis (n = 21, duodenal leak (n = l), abscess (n = 21, and bowel obstruction In = 1).
104
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resection of islet cell tumors failed to detect a benefits7 A major difference in these two studies is that octreotide was started pmoperatively in the study that detected a benefit and was only given postoperatively in the study that failed to demonstrate an effect. Although the data are conflicting, octreotide may be useful to reduce complications of pancreatic surgery when administered both preoperatively and after pancreatic surgery. INSLJLINOMA Endogenous hyperinsulinism was the first syndrome of excessive pancreatic hormone secretion to be identified. The first description of tumor-induced hyperinsulinism came from the Mayo Clinic in 1927. The tumor was a malignant insulinoma with multiple liver metastases. It was biopsied but not resected. Roscoe Graham in Toronto is credited with the first successful surgical removal of an insulinoma in 1929. Evarts Graham of Barnes Hospital in St. Louis successfully enucleated a tiny (5 mm) insulinoma in 1931. This procedure was identical to enucleation performed today. In 1935, Whipple grouped 32 patients who had insulinoma and proposed the classic triad of diagnostic features. Whipple’s diagnostic triad includes the following: (1) symptoms of hypoglycemia while fasting, (2) blood glucose levels less than 50 m#dl, and (3) relief of symptoms after administration of g1ucose.s8 SMMPTOMS
Inswlinoma must be considered in the differential diagnosis of neuroglycopenic symptoms seen while fasting.“’ “, loo Most patients with insulinoma have hypoglycemic symptoms for years before diagnosis .” The mean length of time from the onset of symptoms to diagnosis is 2 years, and some patients have had symptoms for 6 years. There is a higher incidence of insulinoma in women?5S 35, s”,101-104 Neuroglycopenic symptoms include anxiety, dizziness, obtundation, or confusion during a period of fasting. Seizures related to hypoglycemiaz5 and psychosis will develop in 30% of patients. Most patients have documented weight gain?” lo2 The diagnosis of insulinoma may become more apparent when the patient reduces food intake in an effort to lose weight. DLAGNOSIS
If a patient has hypoglycemia while fasting, a hospitalized fast with measurement of blood levels of insulin and glucose is indicated to rule out insulinoma. The finding of an inappropriately elevated seCurr Probl Surg, February 1994
106
rum level of insulin for the level of glucose establishes the diagnosis of insulinoma.ss The patient is allowed noncaloric beverages and is observed at frequent intervals. Blood levels of glucose and insulin are measured every 6 hours during the fast. The fast is continued for a maximum of 72 hours or until neuroglycopenic symptoms are observed (Fig. 4). Symptoms include shaking, diaphoresis, obtundation, confusion, and seizures. At that point, blood levels of insulin, glucose, C peptide, and proinsulin are drawn, and the fast is terminated. Symptoms of hypoglycemia will develop in two thirds of individuals with insulinoma before 24 hours of fasting, and symptoms will develop in the remainder before 72 hoursz5 Hypoglycemia is defined as a level of blood glucose less than 40 mgdl. However, symptoms will develop in a few patients (16%) with insulinoma when the blood glucose is approximately 45 m#dlz5 (Fig. 4). Each patient with insulinoma (100% 1 will have inappropriately elevated plasma levels of insulin G-5 @J/ml) at the time of documented symptoms and hypogly-
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FIG. 4. Hours of fast (left panel) and serum levels of glucose and insulin (right panel) at termination of the fast resulting from neuroglycopenic symptoms in 25 patients with proven insulinoma. Each number represents a patient. One patient (No. 12) had two separate fasts. Symptoms developed in 57% of patients by 24 hours and in 88% by 48 hours. Shaded area indicates normal levels of insulin. Each patient (100%) had elevated serum levels of insulin at the conclusion of the fast (>5 )IU/ml). Each patient had hypoglycemia (~50 mg/ dl), and 23 of 26 patients had blood glucose levels less than 40 mg/dl. (From Doherty GM, et al. Surgery 1991; 110:989-97.) 106
Curr Probl Surg February 1994
cemia25 (Fig. 4). The ratio of blood insulin to glucose (>0.4) may be used as another diagnostic criterion for insulinoma.102 Twenty-one of 23 patients (91%) with insulinoma have elevated blood levels of C peptide (>1.7 rig/ml) at the conclusion of the fast25”05,106 (Fig. 5). Eighty percent of patients with insulinoma will have elevated proportions of proinsulin ~~~~~~~~~~~~~~~~ lo8 (Fig. 51, and it may be a marker of a malignant tumor.“’ Proinsulin is an insulin precursor. Patients with greater proportions of proinsulin are able to undergo longer fasts with fewer symptoms because proinsulin is biologically less active.25 Several suppression and stimulation tests are available for the diagnosis of insulinoma.” Stimulation tests include the administration of tolbutamide, calcium, glucagon, or leucine and the measurement of increased insulin levels after each of these agents. Similarly, other investigators have used either porcine or fish insulin, which fails to change plasma levels of C peptide or human insulin in patients with insulinoma but will suppress levels in normal individuals.105’106 In most patients, suppression or stimulation tests are not necessary to diagnose insulinoma. One cause of hypoglycemia or pseudo-hypoglycemia is surreptia
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FIG. 5. Serum levels of C peptide (left panel) and percentage of proinsulin (right panel) at termination of a fast in 25 patients with insulinoma for patients shown in Figure 4. Shaded areas indicate normal levels of C peptide and percentage of proinsulin. Twenty-three of 25 patients (92%) had elevated C peptide levels. Twenty-one of 25 patients (84%) had elevated percentage of proinsulin. (From Doherty GM, et al. Surgery 1991 ;110:989-97.) Curr Prohi
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February lYY4
107
tious or factitious hypoglycemia.1og Young women with access to insulin, such as nurses or individuals with diabetic relatives, are at high risk. Patients with factitious hypoglycemia have low levels of C peptide and normal proinsulin levels, and antiinsulin antibodies may be present?” ‘OS Mass spectroscopy can detect minute levels of sulfonylurea in the blood of patients taking oral hypoglycemic drugs. These patients may undergo unnecessary surgery, including pancreatic resection.10s Despite accurate diagnosis and confrontation, the long-term prognosis of patients with factitious hypoglycemia remains poor, and only one third return to productive life.‘Og CONTROL OF HYPOGLYCEMIA
After the diagnosis is established, hypoglycemic symptoms are avoided primarily through medical means. The diet is modified to increase the frequency of meals, including possibly setting the alarm clock to awaken for a meal during the night.” Cornstarch can be added to slow the absorption of food and to prevent hypoglycemic troughs. Drugs are indicated to increase fasting glucose levels. Diazoxide is helpful in approximately 60% of patients.” Because it can cause operative hypotension, diazoxide should be discontinued 1 week before surgery. Calcium channel blockers may also be useful.11o Octreotide, the long-acting somatostatin analogue, has been effective in the management of hypoglycemia in infants with nesidioblastosis, but it is not as effective in adults with insulinoma.41’ “‘a 11’ This agent may be useful in an occasional patient; some investigators have reported long-term control of hypoglycemia with octreotide.113’ ‘14 In general, the long-term medical management of hypoglycemia has been ineffective, and the best results have been obtained with surgical excision.” RADIOGRAPHIC
LOCALIZATION
Localization studies tc image or localize the tumor to a region of the pancreas can be divided into noninvasive and invasive imaging or localizing studies. These studies may provide exact images of the tumor, or they may suggest the area of the pancreas that contains the tumor and allow the surgeon to focus on that region with intraoperative techniques or remove the region if a tumor is not identified during surgery. Abdominal ultrasonography is the least invasive, least expensive, and least sensitive method to localize insulinoma.25’ 71,115 The truepositive rate is between 20% and 40% .“, 71, ‘I5 CT with intravenous contrast demonstrates an insulinoma as a dense blush”, 71, 768 lo’, I’5 because the islet cell tumor has increased vascularity. MRI images .108
Curr Probl Surg,
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small insulinomas as bright spots on the T, weighted imagesz5, ‘15 It appears from initial studies that MRI is comparable to CT. Octreotide scan has been used to image insulinomas on the basis of the density of somatostatin receptors6 ’ ‘O However, because insulinomas do not have a high number of somatostatin receptors, labeled octreotide is not always useful in the imaging of insulinoma. This technique images only 60% of insulinomas. Selective angiography, which images insulinoma on the basis of increased blood supply, is the single best study.71*116 Some authors have suggested that nearly 90% of insulinomas can be identified.l16 However, in recent reports, only 50% of insulinomas are identified.25 A tumor that is able to be imaged is usually correct because few false positive results are seen. Controversy exists among surgeons as to whether regional localization is necessary for patients who do not have insulinoma identified on imaging studies. We have suggested and demonstrated that in those patients portal venous sampling can be very helpful, and it pinpoints the exact area with the insulinoma in 75% of patients” (Fig. 61. Van Heerden and colleaguesl” have recently described 20 similar patients who underwent successful surgery without venous sampling. Both groups used intraoperative ultrasonography and were convinced that it was helpful. Venous sampling of the portal vein and its tributaries for levels of insulin has been the single most informative stud?’ “I 118-121 (Fig. 6). It does not provide precise imaging of the tumor, but it can provide localization of the insulinoma to the head, body, or tail in 75% of patients. A catheter is placed through the liver into the portal vein, and numerous blood samples are taken to measure insulin levels from selective veins that drain into the portal vein or one of the two major tributaries (superior mesenteric and splenic vein). A 50% increment in insulin concentration from the levels in a peripheral vein indicates that the insulinoma is in the part of the pancreas where the step-up occurred. Portal venous sampling is expensive, and it may result in complications such as intraperitoneal bleeding or hemobilia. A new study called calcium angiography appears to be able to determine which region of the pancreas contains the insulinoma.61 This study is similar to the secretin arteriography, which is as effective as portal venous sampling for the localization of gastrinomas.6z’ 74, 75 The radiologist performs pancreatic arteriography and identifies which arteries perfuse different areas in the pancreas. Sequentially, in three separate studies, calcium is injected into different arteries, and plasma samples are obtained from the hepatic veins for insulin concentrations. If the artery that supplies the region with the insulinoma is injected with calcium, a rapid, marked rise in hepatic vein insulin levels occurs in the samples taken 30 seconds after calcium injection. An initial report demonstrates that calcium angiography can reliably determine the location of the insulinoma. Whether it will CurrProblSurg,
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109
Peripheral insulin = 56 $/ml
SMV
FIG. 6.
Portal venous sampling for insulin concentrations in patient with insulinoma in pancreatic tail. A catheter is passed through the liver and down the portal vein (PI/) and its tributaries (SV, splenic vein: IMV, inferior mesenteric vein; SMV, superior mesenteric vein; IPDV, inferior pancreaticoduodenal vein; S/WV, superior pancreaticoduodenal vein) to localize insulinoma. Serum insulin levels are measured at each site. Intraoperative ultrasonography and palpation failed to identify an insulinoma in this patient. A distal pancreatectomy was performed solely on the basis of marked insulin step-up (305 pU/ml) in the splenic vein. Pathologic analysis confirmed the presence of a 1 cm insulinoma in pancreatic tail. (From Norton JA, et al. Ann Surg 1990;212:615-20.)
be as sensitive as portal venous sampling is not yet clear. Endoscopic ultrasonography has also been reported to identify correctly 80% of islet cell tumors.63 Islet cell tumors within the head of the pancreas are imaged more often because the study is usually performed with the endoscope and transducer in the duodenum. However, tumors within the tail of the pancreas may also be imaged with the endoscope in the stomach. EXPLOR4TION
FOR INSULINOMA
Insulinomas are rare tumors, and few surgeons will have vast experience with the intraoperative management of patients with these 110
Curr ProblSurg, February 19%
tumors. Experience is important because in most patients with insulinoma the preoperative imaging studies are negative and the tumor is small and difficult to, detect. Furthermore, misadventures during operations on the pancreas are complicated by pancreatitis, fistula, abscess, and pseudocyst. Before undertaking exploration for insulinoma, the surgeon must have a firm conviction of the diagnosis. Medical management of hypoglycemia should have been attempted to determine the necessity of insulinoma resection. Many patients will be poorly controlled or will not tolerate the medicines to ameliorate the hypoglycemia. In those patients, a greater urgency exists for operative removal of an insulinoma. Careful questioning and testing should have been performed tq determine whether the patient has MEN-l. The management of insulinoma in MEN-l is different and will be discussed separately. The surgeon should examine and review all of the information on localization available on the patient. If the tumor is imaged on either CT or angiography, the surgeon must be able either to confirm or deny that the insulinoma is present where the study suggests. If there is accurate regional localization and no tumor is identified intraoperatively (Fig. 6), then the surgeon knows that resection of that specific area of the pancreas will include the tumor and correct the hypoglycemia. Finally, even in p.atients with inconclusive localizing information, an experienced surgeon can usually identify and resect the insulinoma.84’ “’ Insulinomas are small (<2 cm1 solid tumors that are located within the parenchyma of the pancreas.z5’ 35, 102,103, lz3 Insulinomas are uniformly distributed throughout the entire pancreasz5’ 35, ‘02, lo3, lz3 (Fig. 7). Other islet cell tumors such as gastrinoma are commonly identified in extrapancreatic locations within the wall of the duodenum38 and pccur more commonly in the pancreatic head or duodenum.lz4 Insulinomas have been found‘only rarely in extrapancreatic locations associated with ectopic pancreas.25J 350 lo’, lo3* lz3 Unlike gastrinomas, which are usual1 malignant,19 g3 insulinomas are most often benign.25, 35,102,103,1 Y3 A confusing entity in adult patients with hypoglycemia is nesidioblastosis.‘02’125 This diagnosis implies a diffuse nodular enlargement of the entire pancreas, and near total pancreatectomy is reported to be the procedure of choice.“02,‘25 However, recent studies suggest that nesidioblastosis is not a true pathologic entity in adults.lz5 The surgeon should operate on the assumption that each patient has a solitary small insulinoma that must be found and removed for control of hypoglycemia.25 This point is controversial, and some authors contend that nesidioblastosis is a pathologic entity in adults.“’ However, we have not encountered this condition in 35 consecutive adult patients with sporadic insulinoma. Each individual had a small, identifiable insulinoma. The goal of surgery for patients with insulinoma is to find and reCurr Probl Surg,
Fehuary 1994
111
I
9 8 o
14
@@
; 19
117) 20
24
FIG. 7. Location of 24 sporadic insulinomas that were successfully removed in 25 con-
secutive patients with insulinoma. Each number represents a patient’s tumor. Numbers within circles indicate location of tumors that were found only by intraoperative ultrasonography. Seven tumors were found only by intraoperative ultrasonography, and six of these were within the pancreatic head. One tumor (No. 17, square) was found only by resection after portal venous sampling (Fig. 6). That tumor was not identifiable by palpation or intraoperative ultrasonography. Note that the insulinomas are uniformly distributed throughout the entire pancreas. (From Doherty GM, et al. Surgery 1991;110:989-97.)
move all tumor safely. Because these tumors are nearly always benign and small, the primary operative difficulty is precise localization. After excellent exposure of the pancreas, the search for the insulinoma is undertaken. Occasionally it is necessary to divide the splenic ligaments to mobilize the spleen completely for meticulous examination of the pancreatic tail. Three methods are used to identify insulinoma. The first method is visualization. Insulinomas appear as a reddish-brown, cherrylike tumor because of increased vascularity. However, on direct inspection most insulinomas are not visible because the tumor is buried within the pancreas. Therefore visualization has limited use. The second operative method used to identify insulinoma is palpation. Insulinomas feel firm and nodular compared with the surrounding pancreas. Palpation is more difficult in patients who have had prior surgery or who drink alcohol because the pancreas loses its soft consistency. Palpation is less useful for pancreatic insulinomas within the pancreatic head because it is thicker and therefore a small tumor may be indistinguishablez5 (Fig. 7). Careful a l ation can be used to find some insulinomas that are not visible. !v “, 27 The best method for operative detection of insulinomas is intraoperative ultrasonography.73’ 84S “, ‘I5 Insulinoma, like other islet cell tumors, appear sonolucent compared with the more echo-dense normal pancreas (Fig. 8). Intraoperative ultrasonography becomes an extension of palpation, and the surgeon can confirm or refute specific areas of the pancreas that may feel firm.“’ a9 Further112
Cur-r
Probl Sur5 February 1994
QJi&
8mm
%7sulinoma Pancreas
FIG. 8. lntraoperative ultrasonography of 8 mm insulinoma overlying the portal vein in a patient who had previously undergone blind, unsuccessful subtotal pancreatic resection, Intraoperative ultrasonography was performed with a 10 MHz transducer. The tumor (between fwo arrows) was sonolucent compared with the more echo-dense pancreatic head. (From Norton JA, et al. Ann Surg 1990;212:615-20.) Cur-r
hobl SW& February 1994
113
more, intraoperative ultrasonography is able to determine the relationship of the tumor to the pancreatic duct, the superior mesenteric vein, and other vital structures so that the surgeon can plan the safest route to remove the tumor (Fig. 8). The surgeon should use the information obtained by intraoperative ultrasonography to plan the method and route of tumor removal. Because small, typical insulinomas are benign, surgery should be designed to remove only the tumor without removing adjacent pancreas and spleen. Insulinomas within the pancreatic head are enucleated. Insulinomas within the body or tail of the pancreas are either enucleated or resected by a distal or subtotal pancreatectomy on the basis of the relationship between the tumor and the pancreatic duct. Some investigators recommend resection of progressively more and more pancreas with intraoperative on-line measurement of blood glucose levels to determine when and if the insulinoma has been removed.‘28-131 This procedure is mentioned to condemn it. As stated, the goal of surgery is not to blindly resect more and more pancreas but to identity the tumor accurately so that it alone can be removed. The presence of malignancy in insulinoma, although uncommon, can occur,51’ ‘1’S 13’ and the surgeon must carefully evaluate adjacent lymph nodes and the liver for the presence of disease. Intraoperative ultrasonography also may be helpful in assessing the liver. If a patient has limited resectable metastatic islet cell tumor, most surgeons familiar with these patients recommend resection of metastatic disease either at the same or a subsequent procedure. Results of surgery for insulinoma demonstrate that most patients with this tumor are cured by surgical resection of the tumor73'90'102,103,126,127 (Table 5). In our experience with 25 consecutive patients with biochemical evidence of insulinoma and no evidence of MEN-l, 96% were cured of hyperinsulinism at initial operation.25 Some operative complications occurred, but no patient experienced long-term morbidity from the surgery (Table 6). INSULINOMA AND MULTIPLE ENDOCRINE NEOPLASLA TYPE 2
Approximately 10% of patients with hyperinsulinism will have MEN-1.33 Insulinoma is the second most common functional islet cell tumor of the pancreas in patients with this familial syndrome. The presence of MEN-l may be determined by careful questioning about family history and searching for other manifestations of the syndrome. Ascertaining the serum levels of calcium, prolactin, and pancreatic polypeptide44,133, 134 may be useful in attempting to determine the presence of MEN-l. The pancreas of patients with MEN-l always has multiple islet cell tumors7” 135 and recent studies suggest that the duodenum also has 114
Cur-r
Probl Swg, February 19%
multiple neuroendocrine tumorsz6 However, careful immunoperoxidase staining of these tumors suggests that the duodenal tumors may more likely be gastrinomasz6 and that the pancreatic tumors may more likely be insulinomas.“’ I35 Another important fact is that larger tumors may be malignant, and 50% in one small study had evidence of spread to either lymph nodes or the liver.33 Because of multiple islet cell tumors, either portal venous sampling for insulin or calcium arteriography to localize the specific area of the pancreas that contains the insulinoma will help determine which area to resect.33’ lzl However, in our experience, patients with MEN-l and insulinoma usually have a dominant islet cell tumor able to be imaged that is responsible for the excessive insulin secretion (Fig. 9). Because patients with MEN-l always have multiple islet cell tumors, we try to resect the area of the pancreas that is suggested by the preoperative portal venous sampling or the calcium angiogram as containing the insulinoma.33,121 Patients with MEN-l and insulinoma usually have an islet cell tumor that is able to be imaged by CT, MBI, or angiographf3’ 13’ (Fig. 9). The imaged tumor is located in the same region of the pancreas that has excessive insulin production. Furthermore, we can usually identify other small islet cell tumors.” If the dominant tumor is present within the body or tail of the pancreas, a subtotal or distal pancreatectomy is recommended. If the dominant islet cell tumor is within the pancreatic head, enucleation
FIG.
9. CT scan of a dominant insulinoma in a patient with MEN-l. Arrow depicts a 6 cm mass in the pancreatic tail that was resected with resolution of hypennsulinism. This tumor was malignant, with vascular lnvaslon and spread to regional lymph nodes. curr Probl surg, Fehnmy 1994
115
is attempted. A pancreaticoduodenectomy may be indicated if a large localized islet cell tumor cannot be enucleated. Despite the fact that these patients have multiple islet cell tumors and that some of the islet cell tumors may be malignant, patients with insulinoma and MEN-l are usually freed of the hypoglycemia after surgical resection (Fig. 101. Careful long-term follow-up is required because recurrent hyperinsulinism may develop by either the occurrence of another pancreatic insulinoma or the development of metastatic disease from the original tumor. Repeat surgical resection may be indicated for recurrent hyperinsulinism in patients with MEN-l if the procedure can be performed safely with acceptable morbidity and mortality. Although the management of hyperinsulinism in patients with MEN-l may be both complex and confusing, proper recognition of the syndrome helps to determine the correct surgical approach and produces an excellent outcome in most patients33”35 (Fig. 10). ZOLLINGER-ELLISON SYNDROME In 1955, Zollinger and Ellison were the first to describe the association of life-threatening peptic ulcer disease, gastric acid hyper-
FIG. 10. Results of resection of islet cell tumor in patients with MEN-l and either insulinoma or VlPoma and an unusual patient with MEN-2 and gastrinoma. Unlike the situation in patients with MEN-l and gastrinoma, each of these patients had complete reversal of biochemical parameters and symptoms of disease after surgical resection of islet cell tumor. The two patients with insulinoma each had normalization of fasting levels of insulin and glucose after tumor resection (center). Similar results were noted in one patient with MEN-l and VlPoma (right) and one patient with MEN-2 and gastrinoma (left). (From Sheppard BC, et al. Surgery 1989;106:1108-118.) 116
Cur-r Probl Surg, February 1994
secretion, and a pancreatic islet cell tumor. They suggested that the tumor produced a factor that caused the ulcer diathesis. The peptic ulcer disease was so severe that each patient required multiple operations and eventually total gastrectomy to stop acid secretion and control symptoms.136 In 1960, Gregory and colleagues13’ extracted a peptide from tumors of patients with ZES and noted that it was similar to the antral hormone gastrin. Subsequently, it was determined that the peptide was indeed gastrin.138’ 13’ With the development of specific and sensitive immunoassays for gastrin, it has been shown that patients with ZES have elevated levels of gastrin in the serum and tumor.14’ The gastrin immunoassay is now the major tool for diagnosis .141 Although the prevalence is not known, studies suggest that gastrinoma will develop in approximately 0.5 to 1 per million population.2’ 142, l43 Most studies suggest that it is the second most common islet cell tumor,” 143 but one study indicates it the most common.‘4z It is the most common functional pancreatic neoplasm in patients with MEN-1,26,33,68,77,144-147and approximately 20% of patients with ZES will have MEN-l (Table 1). Despite these facts, gastrinomas are a rare source of eptic ulcer disease, causing less than 1% of all duodenal ulcers.14 P
SYMPTOMS
ZES occurs more commonly in men than women, and the mean age at presentation is approximately 45 years. However, patients with ZES as part of MEN-l usually have peptic ulcer disease in the third decade of life.33’ 14’ Pain in the epigastrium is the most common symptom, and approximately 90% of patients have evidence of duodenal ulcer disease at the time of diagnosis.38’ 150-152 Most of the symptoms of patients with ZES am caused by the gastric acid hypersecretion. *‘, 51J 68, 148 Therefore either medical or surgical control of the acid hypersecretion abolishes all symptoms.l” 5’S 5sJ 153-155 Most patients have epigastric pain and indigestion that are alleviated by eating. Diarrhea and weight loss are also common (40% 1. Twenty percent of patients will complain only of diarrhea, which is caused by gastric acid hypersecretion3” 14’ When the acid hypersecmtion is controlled either surgically or medically, the diarrhea will resolve, and the serum levels of gastrin will not change.17’ 58J *T3, ls4 Esophagitis may occur in a significant proportion of patients, and 30% have dysphagia. Stricture and perforation of the esophagus have recently been described as an unrecognized complication of ZES.l’” In recent studies of 122 patients with ZES, esophageal symptoms and endoscopic abnormalities were present in approximately 60% of patientsl”’ Is8 High serum levels of gastrin also cause parietal cell hyCur-r
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117
, with changes resulting from the trophic effects of gasAs the tumor progresses, symptoms related to tumor burden may develop ? 43, 16’ Initially, most patients with ZES had atypical peptic ulcer disease associated with multiple ulcers, ulcers in unusual locations, and failed acid-reducing surgical procedures.136s 16’ Although atypical or recurrent peptic ulcer disease suggest ZES, most patients today have typical peptic ulcer disease, and some patients (approximately 20%) do not have ulcer disease.38 The availability of reliable radioimmunoassays for gastrin has improved the ability to diagnose ZES and may account for the earlier diagnosis and fewer complications of this disease in patients today. Nevertheless, often a long history (6 to 9 years) of significant peptic ulcer disease has existed before the diagnosis of ZES,38, lz4*’ 3 and 30% to 40% of patients have had failed surgery before the correct diagnosis.38 Between 7% and 30% of patients will have perforation of the duodenum or jejunum as a presenting problem.157 Whenever considering an operation for peptic ulcer disease, the surgeon should measure fasting serum levels of gastrin to exclude ZES. In patients with ZES and MEN-l, primary hyperparathyroidism is usually evident at the time of diagnosis of ZES.68’ 77, I49 These patients may have symptoms related to both conditions. Studies suggest that management of the peptic ulcer disease is facilitated by successful management of the hyperparathyroidism77 (see section on MEN-l and ZES). PATHOLOGIC
FEATURES
Until recently, most series reported that most gastrinomas occurred within the pancreas itself.15” I62 Furthermore, gastrinomas were uniformly distributed throughout the pancreas.‘“4’ 165 Although duodenal wall gastrinomas were originally described in 1958 by Oberhelman and co11eagues,166 these tumors were thought to be rare, occurring in less than 20% of cases.164’ 165 According to recent series, both of these perceptions are incorrect. It has now been demonstrated that nearly all gastrinomas are found within an area centered around the ancreatic head and duodenum, the gastrinoma teangle.27, 38, 1B4, 167-169 Additionally, the duodenum and not the pancreas may be the most common location for a primary tumor.27’ 38, 1’S Some investigators suggest that duodenal gastrinomas are less commonly malignant than ancreatic gastrinomas, with only a 36% incidence of metastases.17 F Other investigators have demonstrated that the malignancy rate for duodenal gastrinomas is similar to pancreatic gastrinomas.38 Gastrinomas may originate at other sites, includ118
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ing the liver, stomach, jejunum, mesentery, spleen, and ovary. 37, 82,148, 171,172 Adding to the confusion about ‘primary gastrinomas,” several independent groups have described a “lymph node” primary gastrinoma.83’ 16’, 173 Although these tumors are uncommon, some patients have been cured after resection of gastrinomas within lymph nOdeS~'~63,16',173 Whether these tumors represent primary or metastatic gastrinomas will be determined with long-term follow-up because some authors suggest that these patients actually have occult duodenal wall primary gastrinomas that were missed.z7’ 38 At present, it is unclear whether these are primary or metastatic tumors. Because delta or gastrin-producing neuroendocrine cells are present within the duodenum and not the pancreas, some authors believe that pancreatic gastrinomas are ectopic and more malignant than duodenal tumors.133 However, recent studies suggest that the malignant potential of duodenal wall gastrinomas is identical to pancreatic tumorsz8 Metastases are present in more than one half of patients with duodenal tumors.28 Furthermore, the disease-free interval for patients with duodenal wall tumors is shorter than for pancreatic tumors.38 Therefore the metastatic potential of gastrinoma does not differ on the basis of primary location, In early studies, approximately 60% of .patients had liver metastases at diagnosis of ZES.162, 165’ ” Currently, approximately one third of patients have liver invo1vement.38’ 68, 145, 14’ Gastrinoma spreads to the regional lymph nodes and liver. Some patients have had widely disseminated disease at death with involvement of the lungs, bone, heart, and adrenal gland.‘61, 175, 176 Despite the presence of distant disease, gastrinomas are slow growing. Patients with distant metastatic disease may survive for years. Patients with unresectable liver metastases have a 5-year survival rate between 20% and 42% and a lo-year survival rate between 0% and 30%“’ 38J 165 (Fig. 11). Possibly the tumor biology of patients who have distant disease at diagnosis is more aggressive than that of patients with localized disease at diagnosis. In early series when most patients were seen after many years of symptoms, gastrinomas were identified in nearly every patient (81% to 94w~~'36,162,177 However, with the development of an earlier diagnosis based on serum levels of gastrin, tumors were found in only 50% of pa~~en~s~37~51~163~176~181 Most recently, with the development of improved operative methods to detect duodenal astrinomas, tumor has been found in nearly every patient.“, 38z 75, 1 84, 168, I” Approximately 20% of patients with ZES also have MEN1.26,3 , 71, 77,144 The islet cell tumors in patients with MEN-l are always multiple.7sJ la2 Furthermore, recent studies also indicate that these patients have multiple duodenal tumors that are positive for gastrin.26J27 Immunocytochemical studies of the islet cell tumors in Curr Probl Surg,
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1994
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NO TUMOR FOUND o RESECTED AND CURED m RESECTED BUT NOT CURED o DISTANT DISEASE l
0.0
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I 50
I 100
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FIG. 11. Survival of patients with ZES from day of diagnosis. Patients were divided into four groups on the basis of preoperative evaluation, operative findings, and initial postoperative evaluation: patients who had metastatic disease at diagnosis (n = 18) patients who had no tumor found at surgery (n = 16) patients who had tumor resected and were disease free (cured) (n = 42), and patients who had all tumor resected but were not disease free (n = 15). No differences were observed among the three groups with localized gastrinoma. The group with distant disease had a significantly shorter survival time than all other patient groups @I < 0.001). (From Norton JA, et al. Ann Surg 1992;215:8-18.)
patients with MEN-l have demonstrated that not all tumors produce gastrin and that multiple hormones may be made by the same tumor.26J 7s Despite the fact that these patients have multiple islet cell tumors and that each tumor may produce more than one hormone, it is unusual for patients with MEN-l to have serum evidence of excessive production of more than one islet cell hormone.26’ 33 DIAGNOSIS
The original diagnostic criteria for ZES have been modified since the development of the immunoassay for gastrin. Zollinger and Ellison136 described patients with severe gastric acid hypersecretion, unrelenting peptic ulcer disease, and a pancreatic islet cell tumor. Currently, only two of the three original criteria are necessary for the diagnosis.s3 Approximately 30% to 40% of patients with ZES do not have evidence of peptic ulcer disease.38’ 68 Forty percent of patients have duodenal tumors instead of pancreatic tumors.388 68 The diagnosis to130
Curr Probl SW-~, February 1994
day is dependent on the presence of gastric acid hypersecretion I>15 mEq/L in patients who have not had surgery or 5 mEq/L in patients with prior ulcer surgery5o,183 1 and elevated fasting levels of gastrin (>loo pg/ml).93> 124,146,181 The diagnosis of ZES must be excluded in patients with peptic ulcer disease or secretory diarrhea. It should also be considered in patients with severe esophagitis. ZES may be the underlining cause of duodenal ulcer disease that does not heal with appropriate doses of histamine receptor antagonists.50’ ls3 ZES must be excluded before performing operations for duodenal ulcer disease. This determination can be accomplished readily by measuring gastric pH and fasting serum level of gastrin68’ s3J 168 (Table 2). The diagnosis of ZES is dependent on both the fasting serum level of gastrin and the acid outpuL3’, 51J s3 All ulcer medications must be discontinued before these measurements. Basal acid output is the amount of titratable acid secreted during a timed interval. It is obtained by neutralizing the collected gastric contents with sodium hydroxide (1 N NaOH). The amount of added base in milliequivalents required to achieve a neutral ph equals the amount of acid in the sample. A simpler qualitative method is to measure the pH of the collected sample. Patients with ZES usually have a gastric pH level less than or equal to 2, but the level must be less than or equal to 4. The fasting serum level of gastrin is elevated in all patients (>lOO p#ml). Patients with achlorhydria or hypochlorhydria may have falsely elevated serum levels of gastrin. Conditions that give false positive gastrin levels include gastritis, gastric cancer, pernicious anemia, prior vagotomy, retained gastric antrum, s3, ~8, ls4 and failure to discontinue antacid medications. If a patient has both elevated fasting serum levels of gastrin and elevated basal acid output, the diagnosis of ZES is confirmed. False positive conditions may be excluded by the use of a secretin stimulation test. Provocative tests are useful in the diagnosis of ZES. The most studied agents are secretin,185’ 186 calcium,186-188 and protein meal.17sJ 18’ In the secretin test, fasting serum levels of gastrin are measured before and at 2, 5, 10, and 20 minutes after 2 U/kg secretin administered intravenously. A result consistent with ZES is a greater than 200 pg/ml increment in the serum gastrin leve1.185, 186 Calcium gluconate is infused over a 3-hour period at a dose of 54 mgkg/hour, and blood levels of gastrin and calcium are measured at 30-minute intervals. A positive result is an increment in the gastrin level of greater than 395 Pkw.lS6, lS8 With a standard 40 gm protein meal test, serum levels of gastrin are measured at -15, 0, 30, 60, and 90 minutes. Patients with ZES will not have an increment in gastrin over basal levels.‘7s For the diagnosis of ZES,18s the most useful tests are the measurement of fasting serum levels of gastrin and the basal acid output, which are positive in 100% of patients with the syndrome (Table 21, Cum Probl Surg,
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191
and the secretin test, which is positive in 85% of patients.18’ The calcium infusion test and protein meal test are no longer indicated. Similar results are obtained in patients with ZES as part of MEN-1y3, 77 In patients who have had gastrinoma resected for potential cure of ZES, secretin-stimulated gastrin levels are the most sensitive indicator of recurrent or persistent disease.37’ lgo Abnormal secretin tests occur before any other indicator of recurrent disease. Imaging studies are not necessary unless the secretin test becomes abnormal.18sJ lso CONTROL OF ACID SECRETION
The most important first maneuver in the management of patients with ZES is to eliminate the gastric acid hypersecretions3 With the use of cimetidine alone, patients commonly fail medical management of acid output. However, with the use of ranitidine, famotidine, and omeprazole, it is now easy to control acid hypersecretion in all patients with ZES.38 The acid secretion must be measured and maintained at less than 10 mEq/hour if the patient has had no prior acid reduction surgery and less than 5 mEq/hour if prior ulcer surgery has been performed5’, 183 (Fig. 12). Symptomatic improvement and endoscopic evidence of healin although desired, are not adequate indicators of acid contro1.50’1 3 With these guidelines, more than 150 consecutive patients in three recent series have had peptic ulcer disease healed without complications .38, 5o, Ia3 Each patient has reported complete resolution of all symptoms, including pain and diarrhea. Furthermore, each patient has experienced weight gain when acid output was controlled. Experience has indicated that the amount of antisecretory medication can vary from patient to patient and in the same patient at different times. Anticholinergic drugs alone were not potent enough to control acid, but they potentiated the ude of cimetidine in patients with ZES.“’ The potency of new histamine receptor antagonists (ranitidine38, s3 and famotidine154) has improved acid control. The dose of medication and the dosing interval were able to be reduced as more potent agents became available. The appropriate daily dosages of Hz-receptor antagonists are cimetidine, 6 gm; ranitidine, 2 gm; and famotidine, 0.3 gm.38 Despite the implementation of more potent H,-receptor antagonists, simple control of acid secretion was not possible until the use of omeprazole~57-59'155,192-194 Omeprazole is administered only once or twice daily. The usual dose is 80 mgday, and the range of doses varies between 60 and 120 mg/day. The use of omeprazole has been a concern to some investigators because long-term administration is associated with carcinoid tumors of the stomach.‘48 These studies hypothesize that the carcinoid tumors result from enterochromaffin 122
CurrF'rc~blSurg,
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1 1 0I-
loo
,-
90 80 ‘;: f f
70
g
60
k! Y VJ cl 2
50 40
30
20
10
0
-
-
-
-
-
-CONTROL - - LEVEL
it 2.5
CIMETIDINE
3
4
(mg/kg/hrt
FIG.
12. Titration to control acid secretion in patient with ZES by continuous infusion of intravenous cimetidine. The patient’s basal acid output was more than 100 mEq/hour. The dose of cimetidine was increased in a stepwise fashion until acid output was less than 10 mEq/hour. Similar acid titrations were performed with ranitidine and famotidine. In general, the ranitidine dose was 33% of the cimetidine dose, and the famotidine dose was 5% of the cimetidine dose. (From Fraker DL, et al. Surgery 1988;104:1054-63.)
cell hyperplasia that is due to drug-induced achlorhydria and hypergastrinemia.148’1g5-1g8 The long-term effects of omeprazole in patients with ZES await future reports. It is approved by the Food and Drug Administration for control of acid in patients with ZES and is the drug of choice for this indication. Because of the dramatic efficacy of omeprazole, surgery (total gastrectomy) to control acid hypersecretion is not indicated. The control of acid hypersecretion should not be forgotten during the preoperative and postoperative periods. The intravenous prepaCurr Probl Surg, February 1994
123
ration of omeprazole is not approved for patient use. Continuous intravenous infusion of either cimetidine or ranitidine at doses that keep the acid secretion in the safe limits described are effective16’ (Fig. 12). After removal of a gastrinoma, when can the antiacid medication be discontinued? Despite the fact that some authors suggest stopping medication immediately,1gg approximately 50% of patients will still secrete excessive acid because of increased parietal cell mass 16’, ‘O”, ‘01 (Fig. 13). Therefore antiacid medication should be continued until it is established by measurement that the patient has a normal basal acid output. Finally, in patients with MEN-l, ZES, and primary hyperparathyroidism, surgery to control the primary hyper-
I151151
113/161
121/361
NO RESECTION
RESECTED CURED
7ESECTEO
OPERATIVE
OUTCOME
FIG. 13. Percentage of patients with persistently elevated basal acid output
(BAO) (>lO mEq/hour) at 3 to 6 months after surgery for gastrinoma. Forty percent (8 of 20) of patients who had gastrinoma resected and appeared to be biochemically cured (normal serum level of gastrin and negative secretin test) still had elevated basal acid output, presumably resulting from hypertrophied parietal cell mass. (From Fraker DL, et al. Surgery 1988;104:1054-63.)
124
CurrProblSurg,
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parathyroidism usually reduces the amount of medication necessary to control the acid output.” RALIZOGRAPHZC LOCALIZATION
Accurate tumor staging and localization are critical during the preoperative assessment of patients with ZES51, 68, g3 In reported studies* between 13% and 50% of patients with ZES have metastatic disease to the liver at the time of diagnosis. Therefore preoperative imaging studies should include an accurate and careful assessment of the liver. Ultrasonography,66’ ‘03 CT,65, 204-206 and MR166, I”, “’ have been reported to be useful in im$ng gastrinoma.65’ 66 Labeled octreotide scan may also be effective. ’ 6s Selective angiography,lzo’ 2o8 selective angiography with secretin stimulation,62, 74, 758 2os, 210 portal venous sampling for gastrin,76’ 1208 211, 212 and endoscopic ultrasonographf113 may be useful for localizing gastrinoma. Ultrasonography has low sensitivity for imaging gastrinoma66 (Table 3). CT detects no tumors less than 1 cm, 30% of tumors between 1 and 3 cm, and all tumors greater than 3 cm. Overall, CT successfully images 50% of tumors.652 14’* 204-206 MRI is similar to CT but has the potential of being more useful. Gastrinomas are very bright on either T, or stir sequences. Gadolinium may further enhance the sensitivity of ~~.66,175,207
Selective angiography is the best imaging study to identify primary and metastatic astrinoma.120’ 2o8 This technique has a sensitivity of 40% to 60%4’ 38, 8” and provides accurate localization with few false positive results (Table 3). However, it seldom identifies duodenal wall gastrinomas?” ” The combination of selective angiography and secretin has increased the sensitivity to 75%.74 As part of the angiographic procedure, secretin is injected into arteries, and hepatic vein levels of gastrin are measured. When the artery that is perfusing the gastrinoma is injected, an early peak of gastrin levels is observed in the hepaticvein.62'74,'6,209,210 Furthermore, an association exists between a gradient after gastroduodenal artery injection and duodenal gastrinomas?14 Imamura and colleagues75 advocated a pancreaticoduodenectomy if no tumor is found and the secretin study indicates that the gastrinoma is within the pancreatic head. This strategy is not generally recommended because the survival of patients with localized gastrinoma in whom no tumor is identified or in whom the tumor is simply excised is excellent (Fig. 11). Portal venous sampling also provides regional localization and may be one of the single best localization studies.21s This study is the most invasive and is associated with complications including hemoperito*References37,38,93,124,150,153,163,168,202 Curr Probl SW,,
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neum, hemobilia, and pain in about 20% of individualszl’ It appears to provide similar localization information to secretin angiograPhY.6z, 76, 212 Because secretin angiography is less invasive and may image the tumor, portal venous sampling is no longer recommended. The final study is endoscopic ultrasonography.213 preliminary data suggest that islet cell tumors are identified by this technique.63,213 However, it has not been determined that this study can identify small, difficult-to-image duodenal gastrinomas. These tumors are common (40% 1and are seldom identified by any study.“, 28* 630 ” Intraoperative ultrasonography has had difficulty imaging tiny duodenal wall tumors.63, 8s Endoscopic ultrasonography may not be able to distinguish small duodenal gastrinomas unless the surgeon is willing to accept some false positive findings. In summary, patients with ZES should undergo either CT or MBI to rule out liver metastatic disease and identify the primary tumor. If more precise localization is desired, selective angiography coupled with secretin may identify the tumor or the region of the pancreas in which the tumor is localized. The surgeon should remember that occult tumors will most likely be located within the astrinoma triangle that includes the wall of the duodenum.“’ 38812 #’ 168 Portal venous sampling for gastrin is no longer indicated.76’ “‘, ‘I2 Octreotide scanning and endoscopic ultrasonography appear promising, but their exact roles await further study. EXPLORATION FOR GASTRINOMA
Since the syndrome was originally described in 1955, the major surgical intervention in patients with ZES was total gastrectomy. 136J150, 15’, *” However, this procedure did not affect the basic disease process, the tumor. Zollinger and others162, 1658 “‘, ‘16 noted that the malignant potential of the tumor was the major determinant of survival. Tumor resection may result in cure or improved surViVd.38, 124, 16’S 168, “I Therefore today the goal of surgery has shifted from total gastrectomyl”” 165J “‘, 216 (i.e., resection of the end organ) to resection of the gastrinoma.38’ 16’ It is important to control the gastric acid hypersecretion in the perioperative period by continuous infusion of either cimetidine or ranitidine, selecting a dosage that decreases the acid output to the safe range16’ (Fig. 12). Initially, a complete general exploration of the entire abdomen is performed. Ovarian gastrinomas have been repofiedl’2, 217-219as well as gastrinomas near the ligament of Treitz and within the greater omentum.37’ “’ The color of a gastrinoma is usually reddish blue, but occasionally it may be white. Some surgeons have used selective injection of methylene blue into the gastroduodenal artery during exploration to identify small, blue-staining duodenal wall tumors.220 Any suspicious nodule should be excised. Care126
Curr Probl Surg February 1994
ful palpation and visualization of the liver is performed, with any superficial lesion removed by excisional biopsy. Exposure of the pancreas is critica13’, 124 A Kocher maneuver is performed to mobilize the duodenum and the head of the pancreas out of the retroperitoneum. The inferior border of the body and tail of the pancreas is also incised. Intraoperative ultrasonography is performed after complete exposure and palpation” (Fig. 1). Intraoperative endoscopy with transillumination of the duodenum is performed next” (Fig. 3). After transillumination, duodenotomy is performed in all patients.” The ability of each intraoperative maneuver to find duodenal and pancreatic gastrinoma is summarized in Table 4. Duodenal tumors were frequently missed before efforts to improve the operative detection rate.38 The prevalence of duodenal tumors decreases as the surgeon progresses distally in the duodenum (Fig. 141. Transillumination clearly improves identitlcation of duodenal wall tumors; if a tumor is identified, this technique allows placement of the duodenotomy in a location where the tumor can be completely excised (Fig. 3). Duodenotomy is a true advancement because it facilitates identification of gastrinomas on the medial wall. These tumors abut the
FIG. 14. Location of 24 duodenal gastrinomas in patients with ZES. Seventeen tumors were in the first portion, five were in the second, and two were in the third. (From Thorn AK. et al. Surgery 1991;i 10:1086-93.) Curr Probl Sur5 February 1994
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pancreas and are not transilluminated. Medial wall gastrinomas may be near either the ampulla or the pancreatic duct. The surgeon must accurately identify the ducts before removing a medial wall tumor. It may be helpful to thread a cholangiocatheter through the cystic duct into the common duct and duodenum to identity the ampulla of Vater. The orifice of the pancreatic duct may be identified by administering secretin intravenously, which is followed rapidly by pancreatic exocrine secretion. Duodenal wall tumors are firm to palpation. A tumor nodule may be small (between 2 and 5 mm). Tumors are more often within the proximal duodenum (Fig. 14). Although duodenal gastrinomas originate within the submucosa, they almost always dimple or raise the mucosaz8’ 63 (Fig. 2). The tumors may appear multiple because they can spread along submucosal lymphatits. Excision of tumors requires a full-thickness elliptical excision of the duodenum. The longitudinal duodenal incision should be closed transversely. Systematic sampling of anterior and posterior lymph nodes around the head of the pancreas, the common bile duct, and the celiac axis should be performed?‘, ‘St 38, lz4 Abnormal nodes often appear normal. Whenever a nodule is removed from either within or near the pancreas, the pathologist should be asked whether the tumor is within a lymph node. If a tumor is found within a lymph node, careful attention should be directed to the duodenum because a primary tumor may have been missed. If a gastrinoma is identified within the body or tail of the pancreas (which is unusual), the tumor should be resected by distal or subtotal pancreatectomy and splenectomy.2’ Primary gastrinomas within the head of the pancreas are enucleated. It appears from recent studies that two distinct populations of tumoral behavior exist based on location of the primary gastrinoma. Tumors to the right of the superior mesenteric artery are more common and behave in a more benign manner. Rarer tumors to the left of the superior mesenteric artery are more malignant and have a poorer prognosis and less successful cure rate.221 Liver metastases should be resected with negative margins if all tumor can be removed and the resection can be accomplished safely. Some surgeons still advocate total gastrectomy for ZES because patients cannot afford medications or do not comply with prescriptions.f53 Other authors recommend parietal cell vagotomy to reduce the dose of H,-receptor antagonists.222 We do not recommend any procedure to reduce acid secretion, and because of the efficacy of omeprazole, most experts agree. Current results from different institutions demonstrate that with increased awareness of duodenal tumors, gastrinoma can be found in nearly every patient with the condition2” 38,168, XI (Table 5). If all tumor is removed, the immediate postoperative cure rate varies from 40% to go%27,38,168,169 (Table 5). Furthermore, the mortality rate is 128
CurrProblSurg,
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095, and the morbidity rate is between 10% and 17%~~ (Table 6). Careful long-term follow-up indicates that nearly 50% of patients who initially are free of disease will have recurrence by 6 years3’ (Fig. 15). Furthermore, a curative resection results in decreased parietal cell mass and slow reduction of acid output to normal levels. Fifty percent of patients have normal gastric acid secretion at 3 months postoperatively, and additional patients experience a further decrease in acid output as the parietal cell mass decreases.“‘With this approach, no patient with local disease at diagnosis has died of tumor progression at long-term follow-up3s (Fig. 11). No complication of the gastric acid hypersecretion or the medication taken to control it has developed. The data suggest that the most important component in the treatment of the tumoral process is the surgeon.“’ 38J 16’ The use of extensive studies of localization did not improve the operative detection rate; only the addition of operative methods to explore the duodenum better improved tumor detection?” 28, 638 S’S lz4 METASTMES
The management of liver metastases is controversial. Many patients with liver metastases are without symptoms as long as gastric acid 1 .o
0.9 ; LL 2
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$
0.6
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0.5 0.4
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0.3
Lg
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0.7
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!
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l
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ALL PATIENTS
sb
100 I
MONTHS
FIG. 15. Time to recurrence of ZES in patients initially disease free by surgery. Disease free is defined as no evidence of tumor on imaging studies, normal fasting gastrin level, and negative provocative test (n = 42). (From Norton JA, et al. Ann Surg 1992;215:8-18.) CurrPmblSurg,
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hypersecretion is treated effectivelyY3 Other patients die of malignant dissemination despite control of acid hypersecretion.2” “‘, 16’ The best chemotherapy, including doxorubicin, 5fluorouracil, and streptozotocin, results in a 40% response rate, but there are no complete responses, considerable toxicity exists, and no apparent impact on smvival is seen67~223-225 (Fig. 11, distant disease). Interferon-o has been advocated for these patients, but it is associated with a severe flulike syndrome and produces only a few partial responses?61 The antitumor effects of octreotide are few, and its use in patients with ZES is limited because effective oral drugs to control gastric acid secretion are available.41, ‘I2 The lack of epective antitumor treatment besides surgery and the fact that Zollinger had reported long-term survivors in patients with resected liver metastases led us to attempt to resect distant gastrinoma?’ We have resected distant islet cell tumor including liver metastases in 15 patients5’ The study was not randomized, so the results are difficult to interpret. However, it appears that patients with solitary localized metastatic disease benefit most from this aggressive surgical approach; none of these patients have died from disease, and most have had prolonged disease-free survival. However, despite complete surgical resection and initial biochemical cure, most patients have recurrent disease with long-term follow-up. No deaths from operations occurred, and an acceptable complication rate was observed.52 Other authors have reported similar results.43’ 53 These studies suggest that aggressive resection of localized liver metastatic gastrinoma is indicated and should be attempted. GASTRINOMA AND MULTIPLE ENDOCRINE NEOPLASLA TYPE 1
The management of patients with ZES in the presence of MEN-l is controversial. Malagelada and co11eagues144 from the Mayo Clinic suggest that in this setting gastrinoma is seldom malignant, no patients are cured, and surgery is not indicated. Thompson and col~eagues27,215,226,227 from the University of Michigan suggest that some patients with MEN-l and ZES are cured because portal venous sampling for gastrin can be used to determine which islet cell tumor is the gastrinoma. We reported a contradictory result in five patients with ZES and MEN-l who underwent surgery after portal venous samplirig.33 No patient was cured despite the fact that each patient had an islet cell tumor removed from the exact area of the pancreas suggested by portal venous sampling. Controversy exists because results from different reputable institutions are dissimilar. Patients with MEN-1 usually have primary hyperparathyroidism before ZEST7, 14’ Patients with ZES should have serum levels of calcium measured. If the calcium level is elevated, then serum levels of parathyroid hor130
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mone (PTH) should also be determined. If the patient has evidence of both primary hyperparathyroidism and ZES, the presence of MEN-l is confirmed. These patients should also have an MRI of the sella and determination of serum levels of prolactin to exclude the presence of a prolactinoma. If a prolactinoma is present, careful determination of visual fields is necessary to exclude bitemporal hemianopsia. It has been demonstrated that surgery directed at the primary hyperparathytoidism improves the ZES14’ (Fig. 16). Because these patients have parathyroid hyperplasiazz8 and a high incidence of recurrent hyperparathyroidism (40% to 8O%),22s four-gland parathyroidectomy with immediate autograft is recommended. Furthermore, supernumerary glands or fragments of abnormal parathyroid tissue are often present within the thymus; therefore cervical thymectomy is also indicated.230 Reversal of primary hyperparathyroidism has had dramatic effects on the manifestations of ZES in these patients (Fig. 16). Most patients have gastric acid medications reduced and a decrease in serum levels of gastrin (Fig. 16). In one series, 2 of 10 patients no longer had any biochemical evidence of ZES after parathyroidectomy.77 Patients with MEN-l and ZES may have multiple pancreatic and duodenal islet cell tumorsz6, 7g, ls2 Studies of resected pancreatic specimens have demonstrated that the pancreas of patients with MEN-l has multiple macroscopic and microscopic islet cell tumors7’ It is not clear which tumor is responsible for the gastrin production.33 Furthermore, a recent study demonstrated that these patients also have duodenal wall islet cell tumors that stain positive for gastrin. The study of Pipeleers-Marichal and colleaguesz6 may provide a clue to the location of the missed gastrinoma in patients with MEN-l and ZES. Thompsoi?’ recently described 11 patients with MEN-l who were apparently cured of ZES by tumor resection from the duodenum. Islet cell tumors in patients with MEN-l may be more malignant than previously thought. In patients with MEN-l and CT or angiographic evidence of islet cell tumor, 50% of patients have tumor metastases at surgery.33 Furthermore, certain family histories suggest that relatives have died from metastatic, malignant islet cell tumor. Importantly, few patients with MEN-l have been cured of ZES by islet cell tumor resection even with the use of portal vein samplin93'"8,78,93,178 (Fig. 16). Recently, however, by removing duodenal and pancreatic gastrinomas, we also have cured three patients with MEN-l and ZES. This result supports other reports2151 z7 and suggests that extensive focus on the duodenum may improve the surgical cure rate for patients with MEN-l as it does for patients with sporadic tumors. On the basis of these considerations, we recommend surgical correction of the primary hyperparathyroidism as the initial procedure77 Curr Probl Surg, February 1994
131
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24
30
36
Months
Months
FIG. 16. Impact of successful parathyroidectomy and islet cell tumor resection on serum levels of gastrin in patients with hyperparathyroidism. ZES, and MEN-l. Upper panel demonstrates change in level of fasting serum gastrin concentration after parathyroidectomy followed by successful islet cell tumor resection. Lower panel demonstrates change in level of fasting serum gastrin concentration after islet cell tumor resection followed by parathyroidectomy. In each patient the parathyroidectomy had a greater impact on the serum levels of gastrin than the islet cell tumor resection. (From Sheppard BC, et al. Surgery 1989;106:1108-118.)
(Fig. 161. The gastric acid hypersecretion must be controlled in a manner similar to patients with sporadic gastrinoma. The use of surgery to cure the patient with MEN-l of ZES appears unlikely at this time.33’ 68, “* g3, “’ However, surgery is indicated to control a potentially malignant islet cell tumor. Imaged pancreatic tumors within the pancreatic head are enucleated. Imaged tumors within the body or tail are resected by subtotal or distal pancreatectomy (Fig. 9). During surgery, the duodenum should be explored with transillumination and duodenotomy. Previously missed duodenal wall gastrinomas may account for the inability to cure patients with MEN-l and ZES. If the gastrinoma is not in the pancreas (as seems probable from the negative results that have been published33J 68J “, g3,178), then the tumor may be in the duodenum. Exploration of the duodenum may be the critical step for cure of ZES in patients with MEN-l. UNUSUAL ISLET CELL TUMORS
The less common pancreatic islet cell tumors include VIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma, PPoma, and nonfunctional tumors.231’ 232 Patients with these tumors have either a syndrome of symptoms related to excessive hormone secretion WIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHomal or the mass of the tumor at diagnosis. Unusual islet cell tumors are more malignant in nature than gastrinoma or insulinoma43’ g43 231J 233 (Table 11, yet these tumors have a better prognosis than other abdominal solid tumors. The goal of surgery is to free the patient of the hormonally mediated syndrome and to excise a potentially malignant tumor. These patients usually have evidence by CT or MRI of a pancreatic or duodenal tumor. The surgical problem is not tumor localization but rather the feasibility of tumor resection. WSOACTM!? INTESTINAL PEPTIDE-SECRETING TUMORS
The VIPoma is an endocrine tumor generally located in the pancreas that secretes excessive amounts of VIP that cause a distinct syndrome characterized by large-volume diarrhea, hypokalemia, and hypochlorhydria (Table 1). This condition is also called the VernerMorrison syndrome because of the oeal description in 1958 by these two authors of pancreatic cholera, and the WDHA syndrome (watery diarrhea, hypokalemia, and achlorhydria)?35 \ierner and Morrison reported two patients who died from watery diarrhea, hypokalemia, and nephropathy associated with a noninsulin-secreting pancreatic islet cell tumor. The diarrhea is large in volume (>l L/day) and secretory, which means that it persists during fasting.236’237 Hypokalemia is present in nearly every patient and is caused by excesCurrProblSurg,
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sive potassium losses in the diarrhea fluid.238, 23g Hypochlorhydria is found in 75% of patients with VIPoma syndrome and is due to the inhibitory effect of VIP on gastric acid secretion.237’ 240 Flushing is present in a small number of patients and may be caused by vasodilatory effects of VIP.237 Hyperglycemia is detected in 25% to 50% of patients and is related to a glycogenolytic effect of VIP?36 Hypercalcemia is reported in 25% to 76% of patients with VIPoma.237 A small number of patients have VIPoma in conjunction with MEN-l (Fig. 101, but this fact does not explain the high incidence of hypercalcemia associated with these tumors. The definitive diagnosis of VIPoma requires the triad of severe secretory diarrhea, elevated fasting serum levels of VIP, and a pancreatic islet cell tumor. In most patients with VIPoma, the fasting stool output is greater than 3 L/day, and the diagnosis is excluded if the stool output is less than 700 ml/day. The normal fasting plasma VIP concentration is less than 190 p#ml. The fasting plasma VIP concentration should be determined at the same time that diarrhea is present. The mean concentration of fasting plasma VIP levels in 29 patients with VIPoma was 956 pgml with a range of 225 to 1850 pg/ m1.236.237
Once the diagnosis is established, patients with VIPoma require correction of dehydration, hypokalemia, and other metabolic abnormalities. Before octreotide, complete correction of these derangements was usually impossible because the voluminous diarrhea continued. However, octreotide therapy dramatically reduces serum levels of VIP, diminishes the diarrhea and dehydration, and allows rapid restoration of body potassium.3s,241 Octreotide therapy has simplified the preoperative management of VIPoma patients. GLUCAGONOMA Glucagonomas are islet cell tumors of the pancreas that secrete excessive amounts of glucagon and cause a unique syndrome characterized by skin rash, type II diabetes, malnutrition, weight loss, and anemia (Table 1). In 1963, Roger Unger extracted glucagon from four islet cell tumors found at autopsy. In 1966, McGavran and colleaguesz4’ at Barnes Hospital in St. Louis reported a patient with diabetes mellitus, a skin rash, anemia, and a pancreatic carcinoma with liver metastases. Polk biopsied this tumor in 1964. Subsequently, the patient was found to have high plasma levels of glucagon. Mallinson and colleagues243 associated glucagonoma with a specific skin rash and described nine patients with dermatitis, diabetes mellitus, weight loss, hypoaminoacidemia, anemia, and a glucagon-producing tumor of the pancreas. Norton and colleague? demonstrated that in one patient the rash was due to markedly decreased plasma levels of amino acids. 134
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The peak age of incidence in patients with the glucagonoma syndrome is 50 to 60 years. The characteristic skin rash associated with glucagonoma is called necrop migratory erythema and is pathognomonic of this tumor.245J ’ 6 Hypoaminoacidemia occurs in most patients, and levels can vary with the intensity of the diseaseF4’ Diabetes mellitus and glucose intolerance are among the most frequent findings in these patients. However, a number of patients do not have glucose intolerance.248 Diabetes mellitus is a much less constant feature of the syndrome than is the hypoaminoacidemia. Weight loss is common and may be profound. Thromboembolic phenomena are more common in patients with the glucagonoma syndrome.248 Deep venous thrombosis and pulmonary emboli have been reported to occur and can cause death. The diagnosis of glucagonoma is made by measuring elevated plasma levels of glucagon. In almost all patients with glucagonoma, the plasma glucagon concentration is elevated (>150 pg/mU. It is suggested that a plasma glucagon concentration greater than 1000 pg/ml is diagnostic of glucagonoma. Preoperative preparation of patients with glucagonoma involves control of the diabetes, treatment of any complications of venous thrombosis, and improvement of the nutritional status, which will usually correct and heal the rash. Total parenteral nutrition with added insulin has been one form of effective therapy.244 Recently, octreotide has been used to reduce plasma levels of glucagon and improve the nutritional status.z41 SOMATOSTATINOMA
Somatostatinomas are endocrine tumors of the pancreas or duodenum that secrete excessive amounts of somatostatin, causing a distinct syndrome characterized by type II diabetes, cholelithiasis, and steatorrhea (Table 1). Somatostatin, or growth hormone release inhibiting hormone, was discovered in the hypothalamus in 19i’3. In 1977, the first two cases of somatostatinoma were reported by Ganda and colleagues24s and Larsson and colleagues.250 Initially, it was thought that the somatostatinoma syndrome consisted of diabetes, cholelithiasis, weight loss, and anemia. Diarrhea, steatorrhea, and hypochlorhydria were described later.251 Somatostatin is a major inhibitory peptide that inhibits the release of most other hormones. It has direct effects on a number of gastrointestinal functions, inhibiting acid secretion, pancreatic enzyme secretion, and intestinal absorption. It decreases gut motility and gastrointestinal transit time. Patients with pancreatic or intestinal somatostatinomas are usually about 50 years of age and are evenly divided between men and women.252 Initial symptoms include diabetes, gallbladder disease, and steatorrhea. Diabetes mellitus or glucose intolerance is reported to occur in 60% of patients. Cholelithiasis occurs in 70% of patients. CurrProblSurg,
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Diarrhea and steatorrhea are reported in between 30% and 68% of patients. In some patients, the severity of the diarrhea and steatorrhea correlates with the size and degree of metastatic spread of the tumor and improves with tumor resection. Hypochlorhydria is present in between 33% and 53% of patients. Hypochlorhydria occurs in 86% of patients with pancreatic and 17% of patients with intestinal somatostatinomas. Weight loss is common in patients with somatostatinomas and may result from the diarrhea and malabsorption In most instances, somatostatinomas have been discovered incidentally. The tumor is usually discovered at the time of cholecystectomy or during routine imaging studies performed because of abdominal pain, bleeding, or diarrhea. Once discovered, the tumors are identified as somatostatinomas either by demonstrating elevated tissue concentrations of somatostatin or an increased number of D cells by immunocytochemistry or by showing evidence of increased plasma concentrations of somatostatin-like immunoreactivity. The early diagnosis of somatostatinoma may be possible with greater awareness and reliable assays for the determination of somatostatin in the blood. Presently, these assays are complicated by the need for extraction of the plasma and are not widely available. GROWTH HORMONE-RELEASING FACTOR-SECRETING TUMORS
GRFomas are neuroendocrine tumors that secrete excessive amounts of GRF and cause acromegaly. GRFomas were first described in 1982 .253’ 254 GRF is a peptide originally isolated from pancreatic islet cell tumors253 and is similar in structure to VIP.253,254 GRFomas have been reported to occur in the lung (bronchus), pancreas, jejunum, adrenal gland, and retroperitoneum, in decreasing frequency.255 The most common symptom is acromegaly. Patients usually have a large pancreatic islet cell tumor (>6 cm) that is metastatic in 30% of patients at the time of diagnosis. Nearly 50% of patients have associated ZES, and one third have MEN-l. GRFoma may be suspected in a patient with acromegaly and a pancreatic mass or hepatic metastases or with peptic ulcer disease.253-255 The diagnosis should be considered in any patient with acromegaly and ZES or acromegaly and MEN-l. The diagnosis can be confirmed by performing a plasma assay for GRF and a CT of the abdomen to identify a pancreatic or hepatic mass. ALIRENOCORTICOTROPIC
HORMONE-SECRETING TUMORS
Cushing’s syndrome associated with a pancreatic islet cell tumor that secretes ACTH always occurs in patients with an islet cell 136
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tumor that secretes another peptide and causes another syndrome. Cushing’s disease may occur in patients with MEN-l and ZES, but it is due to pituitary production of ACTH. The hypercortisolism in these patients is usually mild and clinically insigniIicant.z56 Cushing’s syndrome has also been reported in a number of cases of sporadic ZES, and in one recent prospective study it was present in 5% of all cases.256 In patients with the sporadic form of ZES, the symptoms of Cushing’s syndrome are severe and usually occur in patients with metastatic disease; in addition, the Cushing’s syndrome is due to ectopic production of ACTH. These patients usually respond poorly to chemotherapy and have a poor prognosis. The occurrence of Cushing’s syndrome only as a clinical manifestation of a pancreatic endocrine tumor is rare but almost always is associated with a metastatic malignant tumor. In our experience, patients with ACTH-producing islet cell tumors, unlike patients with ACTH-producing bronchial or thymic tumors, are not amenable to surgical cure (Fig. 17). Bilateral adrenalectomy is often indicated in these patients to control the severe signs and symptoms of hypercortisolism.‘l
Legend Bronchus 0 Thymus W Pancreas .
0 . 0 It
0
I
I
I
I
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FIG. 17. Disease-free survival of three groups of patients with ectopic ACTH syndrome: bronchial carcinoid (closed circles), thymic carcinoid (open circles), and pancreatic islet cell tumors (closed squares). Unlike patients with bronchial or thymic carcinoid tumors, no patients with ectopic ACTH syndrome caused by a pancreatic islet cell tumor were able to be rendered disease free. (From Zeiger MA, et al. Surgery 1992;112:994-1001.) Curr
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PARATHYROID
HORMONELIKE-SECRETING TUMORS
Severe hypercalcemia rarely has been reported to be the result of a pancreatic islet cell tumor releasing PTH-like immunoreactive factor*257, 258 Hypercalcemia associated with pancreatic islet cell tumors has also been reported to be the result of the release of other substances. In most cases, the pancreatic tumor is malignant and has spread to the liver at the time of diagnosis. NEUROTENSlNOMA
Pancreatic neurotensinomas have been described.25s’ “’ Neurotensin is a peptide extracted from the bovine brain and the human gastrointestinal tract.25s Neurotensin can cause hypotension, tachycardia, cyanosis, pancreatic secretion, intestinal motility, and small intestinal secretion.25s Patients with neurotensinomas have diarrhea with hypokalemia, weight loss, diabetes, cyanosis, hypotension, and flushing. Patients can be cured by tumor resection and have responded to chemotherapy.25s’ 260 Some authors have questioned whether a separate neurotensinoma exists. Patients with VIPoma and gastrinoma have been found to have elevated plasma levels of neurotensin. At present, it is unclear whether a separate syndrome exists. PANCREATIC POLYPEPTIDE TUMORS AND NONFUNCTIONING ISLET CELL TUMORS
PPomas and nonfunctioning pancreatic islet cell tumors are tumors that either secrete excessive amounts of pancreatic polypeptide (PPoma) or do not function (nonfunctioning) and usually cause symptoms resulting from tumor mass. These tumors diifer from other islet cell tumors because symptoms are not due to secreted hormones.261 These tumors are diagnosed when the patient has cachexia, abdominal pain, or hepatomegaly. Patients commonly have metastatic endocrine tumor at the time of diagnosis. Despite the fact that infusions of PP into animals have been shown to have numerous effects, patients with PPomas do not have symptoms as a result of the increased plasma levels of PP. Typically, the patient with a PPoma or nonfimctioning pancreatic endocrine tumor has abdominal pain or jaundice or is without symptoms. Nonfunctioning pancreatic endocrine tumors or PPomas are usually not differentiated from other malignant tumors of the pancreas before biopsy. Recent studies suggest that plasma marker 7B2 may be a good indicator of nonfunctional pancreatic islet cell tumors.262 Tumors are often discovered incidentally during other operative procedures.2”1 Any patient with a long survival period (>5 years) and sus138
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petted metastatic pancreatic adenocarcinoma may have a nonfimctioning islet cell tumor or PPoma. Typically, these tumors are large when diagnosed (>5 cm) and almost all are malignant (70% to 92% ) T3 Nonfunctioning pancreatic endocrine tumors are differentiated from PPomas by the results of the plasma PP assay. At present, no data suggest that PPomas or nonfunctioning pancreatic endocrine tumors differ in biological behavior from functioning islet cell tumoB.264, 26.5 However, recognizing a tumor to be a PPoma may be clinically important because plasma PP levels may be used to monitor the results of antitumor therapies such as surgical resection or chemotherapy. SUMMARY
Unusual neuroendocrine tumors of the pancreas and duodenum as well as nonfunctional tumors are more malignant than either gastrinomas or insulinomas.43’ s4, 231S233 Despite this fact, these tumors may have a better prognosis than other intraabdominal solid malignancies. Therefore, if the entire extent of tumor can be resected and the patient is otherwise healthy, major operative procedures (including pancreaticoduodenectomy, liver lobectomy, subtotal pancreatectomy, and splenectomy) may be indicated.“’ 43, 52, 13’ Furthermore, in patients with some rare tumors associated with severe symptoms that are poorly controlled medically, such as somatostatinoma, glucagonoma, PTH-like tumors, and ACTHoma, major surgery to debulk tumor or to remove end organs (e.g., adrenal gland in patients with ACTHoma) may be necessary.36, “, s4 Therefore aggressive surgery has an important role in the therapy of these patients and is the only potentially curative treatment. MULTIPLE ENDOCRINE NEOPIASIA TYPE 1
A significant proportion of patients with neuroendocrine tumors of the pancreas and duodenum also have MEN-l. Correct management of neuroendocrine tumors in these patients is unclear and controversial.33~ 144 Certain points must be remembered before developing a therapeutic plan. First, careful analysis of resected pancreatic specimens from patients with MEN-l demonstrates that these patients always have multiple macroscopic and microscopic islet cell tumors.7s Recent studies suggest that these patients may also have multiple neuroendocrine tumors within the duodenum.26 Because of the presence of multiple islet cell tumors within the pancreas and duodenum, it is never clear which tumor is responsible for producing the hormonal syndrome of an individual patient.33’ 78, ‘41 Furthermore, although older studies suggested that the neuroendocrine tuCurrProblSur5
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mors in patients with MEN-l rarely were malignant,144 recent studies suggest that these tumors may be as malignant as sporadic neuroendocrine tumors.33’ “’ The presence of other endocrinopathies such as primary hyperparathyroidism in patients with MEN-l may affect the symptoms related to the islet cell tumor.” Therefore surgery to eliminate the p r i m ark hyperparathyroidism may improve control of the islet cell tumor’ (Fig. 16). The results of most studies in patients with MEN-l and ZES indicate that despite resection of islet cell tumors, the effect on the biochemical parameters of ZES is minima133’ lz6, z6 (Fig. 16). Some authors suggest that portal venous sampling for gastrin may identify which area of the pancreas contains gastrinoma.215 However, other studies indicate that resection of a neuroendocrine tumor from the exact region with the gradient failed to reduce serum levels of gastrin33 (Fig. 16). In most patients with MEN-l and biochemical evidence of an islet cell tumor, an identifiable tumor mass on either CT scan or MRI is obselved33 (Fig. 9). At exploration, 55% of these patients have local or distant metastases, and few patients, if any, are cured of gastrinoma.33’ 135 In contrast, patients with MEN-l with either insulinoma or VIPoma can be relieved of the hormonal syndrome by resection of tumor (Fig. 10). A case report of a rare patient with MEN-2 and gastrinoma indicates that this patient underwent a complete remission after resection of a pancreatic gastrinomaz67 (Fig. 10). Other authors have reported a similar result in a patient with MEN-l and metastatic gastrinoma.2”8 The poor results in patients with MEN-l and ZES after islet cell tumor resection are different from the outcome of surgery to correct the primary hyperparathyroidism.77 After parathyroidectomy, patients have definite improvement in the biochemical parameters of ZES, and approximately 20% of patients no longer have any biochemical evidence of ZES” (Fig. 16). In patients with MEN-l, primary hyperparathyroidism, and ZES, surgery to remove the abnormal hyperplastic parathyroid glands is recommended before surgery directed at the islet cell tumor.” The proper procedure is either a 3X-gland or 4gland parathyroidectomy with immediate autograft because patients with MEN-l and primary hyperparathytoidism have &gland hyperplasia. For patients with biochemical evidence of ZES and MEN-l, surgery is indicated when an islet cell tumor is identified on imaging studies (Fig. 9). Because patients with ZES and MEN-l usually have multiple pancreatic and neuroendocrine tumors, a resection is indicated, including the portion of the gland with the imaged tumor. Therefore, if the tumor is in the body or tail of the pancreas, a subtotal pancreatectomy is recommended. If an islet cell tumor is identified in the pancreatic head, simple enucleation is most often performed. If the tumor is localized to the head of the pancreas and cannot be enucleated, pancreaticoduodenectomy may be necessary. Intraoperative ultrasonography 140
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is used to identify and enucleate any additional tumors not pmsent within the resected specimen. Transillumination and duodenotomy are used to identify and resect neuroendocrine tumors within the wall of the duodenum. Most patients with islet cell tumors and MEN-l have a large dominant tumor within either the body or tail of the pancreas (Fig. 9). This tumor can usually be resected without performing a proximal pancreaticoduodenectomy. The goal of the operation is to remove the potentially malignant tumor. Patients with MEN-l and insulinoma or VIPoma are similar at diagnosis. Although some patients with MEN-l and insulinoma are not curable,z6y’270 most patients are cured of the hypoglycemia by tumor resection3” In conclusion, in patients with MEN-l, hyperparathyroidism, and ZES, the primary hyperparathyroidism should be treated first. Similarly, surgery in these patients is indicated to remove tumor with the hope of limiting the tumoral process. In patients with MEN-l and insulinoma or VIPoma, tumor resection is indicated for potential cure. METASTATIC ISLET CELL TUMORS
Distant metastatic disease will develop in approximately 30% to 50% of patients with neuroendocrine tumors. Surgical procedures to remove distant disease appear to be beneficial and are the only potentially curative form of treatment. Furthermore, resection may increase survival and improve symptoms. Malignant neuroendocrine tumors generally spread from either the pancreas or duodenum to lymph nodes and the liver?3 Select patients may be candidates for complete resection of all tumor for cure or noncurative debulking of the tumor mass to prolong survival.zg~27* Patients with metastatic islet cell tumors have been treated with chemotherapy (primarily 5-FU, adriamycin, and streptozotocin272 or combinations of these drugs272-274 1, immunotherapy (with interferona 275-277), chemoembolization therapy for liver metastases,z78’ 27s and octreotide to suppress or inhibit tumor progression.280~ “I Each of these treatments has been associated with tumor response, but none has produced a complete response or evidence of cure. Only surgical resection has produced biochemical and imaging evidence of complete remission.2s’ 51 In patients with metastatic insulinoma,51’ 13’ approximately 30% of patients can undergo complete resection. Nearly 50% of patients undergoing resection have evidence of complete biochemical remission. Patients with metastatic insulinoma who cannot undergo resection have a median survival of only 11 months. Debulking surgery extends the median survival to 4 years,13’ but incomplete resection does not improve the ability to control hypoglycemia. Aggressive resection of CurrProblSur~
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all metastatic tumor appears to improve the quality and duration of life, and a number of patients are cured. Subtotal resection is less beneficial and is attempted only if most tumor can be removed. Patients with metastatic gastrinoma have a 5-year survival rate between 20% and 40%” s3 (Fig. 11). A number of patients with metastatic gastrinoma can undergo resection for long-term benefit and potential cm-e.29 In three separate series, the resectability rate was 36%.= In an initial evaluation of 10 patients with metastatic gastrinoma,” 5 underwent resection for potential cure. Of the five patients, four had resections and two were initially cured?’ Long-term follow-up of patients with metastatic gastrinoma suggest that all patients will eventually experience recurrence and that patients with limited metastatic disease will enjoy the best disease-free survi~al~~ Symptoms can be well controlled with omeprazole?s2 Patients with ACTH-producing gastrinoma usually have concomitant severe Cushing’s syndrome at diagnosis. In these patients, excellent pa&ation of symptoms can be achieved by bilateral adrenalectomy?l Select patients with metastatic glucagonoma have had amelioration of the characteristic rash, malnutrition, thrombosis, and hypoaminoacidemia by tumor resection?6 Similar results have been reported in patients with metastatic VIPoma.282 Therefore aggressive surgery to resect primary and metastatic neuroendocrine tumors is indicated if the patient is in good condition and all gross tumor is resected. Subtotal resections may be indicated in patients whose symptoms resulting from hormonal hypersecretion are poorly controlled with medications. However, debulking of tumor has not provided good results in alI patients. REFERENCES 1. Norton JA, Doppman JL, Jensen RT. Cancer of the endocrine system. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncologv. Philadelphia: Lippincott, 1989:1269-1344. 2. Buchanan KD, Johnston CF, O’Hare MMT, et al. Neuroendocrine tumors: a European view. Am J Med 1986$1(suppl 68):14-23. 3. Jensen RT, Norton JA. Pancreatic endocrine tumors. In: Yamada T, Alpers DH, Owyang C, Powell DW, Silvenstein FE, eds. Textbook of gastroentemlogy. Philadelphia: Lippincott, 1991:1912. 4. Stadil F, Stage JG. The Zollinger-Ellison syndrome. Clin Endocrinol Metab, 1979; 9:433. 5. Dent RB, van Heerden JA, Weiland LH. Nonfunctioning islet cell tumors, Ann Surg 1981;193:185-93. 6. Bmder LE, Carter SK. Pancreatic islet cell carcinoma: clinical features of 52 patients. Ann Intern Med 1973;79:101. 7. Bmughan TA, Leslie JD, Soto JM, Hennann RE. Pancreatic islet cell tumors. Surgery 1986;99:671. 8. Koppel G, Heitz PU. Pancreatic endocrine tumors. Path01 Res Pratt 1988;183:155. 142
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9. Bolande RP. The neurocrestopathies: a unifying concept of disease arising from neural crest maldevelopment. Hum Path01 1974;5:409. 10. Weil C. Gastroenteropancreatic endocrine tumors. Klin Wochenschr 1985;63:433. 11. Pearse HGE. The APUD concept and hormone production. Clin Endocrinol Metab 1980;9211. 12. Pearse AGE, Tabor ‘IT. Embryology of the diifuse neuroendocrine system and its relationship to the common peptides. Fed Proc 1979;38:2288. 13. Heitz PU, Kasper M, Polak JM, Kloppel G. Pancreatic endocrine tumors. Hum Path01 1982;13263. 14. Solcia E, Capella C, Fiocca R, Cornaggia M, Bosi F. The gastroenteropancreatic endocrine system and related tumors. Gastroenterol Clin North Am 1989;18:671-93. 15. Mukai K, Greider MH, Grotting JC, Rosai J. Retrospective study of 77 pancreatic endocrine tumors using the immunoperoxidase method. Am J Surg Path01 1982;6:387. 16. Creutzfeldt W. Endocrine tumors of the pancreas: clinical and morphological patterns. In: Fitzgerald PS, Morrison AB, eds. The pancreas. Baltimore: Williams &. Wilkins, 1980:208. 17. Jensen RT, Gardner JD. Gastrinoma. In: Go VLW, Brooks FA, DiMagno EP, Gardner JD, Lebenthal E, Scheele GA, eds. The exocrine pancreas: biology, pathobiology and disease. New York: Raven Press, 1992. 18. Larsson LI, Grimelius L, Hakanson R, et al. Mixed endocrine pancreatic tumors producing several peptide hormones. Am J Path01 197.5;79271. 19. Chiang HC, O’Dorisio TM, Huang SC, et al. Multiple hormone elevations in patients with Zollinger-Ellison syndrome: prospective study of clinical significance and of development of a second symptomatic pancreatic endocrine tumor syndrome. Gastroentemlogv 1990;99:1565. 20. Wynick D, Williams SJ, Bloom SR. Symptomatic secondary hormone syndromes in patients with malignant pancreatic endocrine tumors. N Engl J Med 1988;319:605-10. 21. Zeiger MA, Pass HI, Doppman JD, et al. Surgical strategy in the management of non-small cell ectopic adrenocorticotmpic hormone syndrome. Surgery 1992;112994-1001. 22. Kahn CR, Rosen SW, Weintraub BD, et al. Ectopic production of chorionic gonadotropin and its subunits by islet cell tumors: a specific marker for malignancy. N Engl J Med 1977;297:565. 23. O’Connor DT, Deftos LI. Secretion of chmmogranin A by peptide-producing endocrine neoplasms. N Engl J Med 1986;314:1145-51. 24. Boden G. Glucagonomas and insulinomas. Gastmenteml Clin North Am 1989;18:831. 25. Doherty GM, Doppman JL, Shawker TH, Eastman RC, Gorden P, Norton JA. Results of a prospective strategy to diagnose, localize and resect insulinoma. Surgery 1991;110:989-97. 26. Pipeleers-Marichal M, Somers G, Willems G, et al. Gastrinomas in the duodenums of patients with multiple endocrine neoplasic type 1 and the Zollinger-Ellison syndrome. N Engl J Med 1990;322:723-7. 27. Thompson NW, Vinik AI, Eckhauser FE. Micmgastrinomas of the duodenum. Ann Surg 1989;209:396-404. 28. Thorn AK, Norton JA, Axiotis CA, Jensen RT. Location, incidence and malignant potential of duodenal gastrinomas. Surgery 1991;110:1086-93. 29. Norton JA, Sugarbaker PH, Doppman JL, et al. Aggressive resection of metaCurr P r o b l
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