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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Endocrine tumors of the pancreas

, M.D. and , M.D.

Department of General and Endocrine Surgery, University Hospital, Lille, France

Introduction

Endocrine tumors of the pancreas (ETP) or islet cell tumors are rare lesions, the incidence of which is estimated to be less than 1 per 100,000 person-years. These tumors are fascinating both for their dramatic and sometimes puzzling initial clinical presentation, and their excellent outcome when recognized early on and correctly addressed. Surgeons should therefore be well aware of the optimal modalities of management of ETP. The scarcity of these tumors precludes any classical controlled clinical trials, therefore guidelines for the management of ETP must rely on comprehensive prospective cohort studies from referral centers and literature reviews. This overview underlines the crucial issues of the management of ETP, only mentioning gastrinoma which is treated elsewhere in this book.

Pathology

ETP are slow growing differentiated neoplasms characterized by the expression of genes encoding for various regulatory peptides normally present in the mature pancreas or during its ontogeny. ETP are classified as functioning or non functioning according to the type and level of their hormonal secretion (1). Among functioning ETP, insulinomas (50%) and gastrinomas (30%) are the most frequent; tumors secreting vasoactive intestinal peptide (VIPomas), glucagon (glucagonomas), and somatostatin (somatostatinomas) are much rarer (5–10%); and those secreting growth-hormone-releasing factor (GHRH), adrenocorticotropic hormone (ACTH) or corticotropin-releasing factor (CRF), and parathyroid hormone related peptide (PTHrp) are anecdotal. Conversely, at least 15% of ETP are non functioning or secrete non clinically active peptides such as human pancreatic polypeptide (PPomas). All ETP are further characterized by the tissue expression of neuron specific enolase (NSE), synaptophysin, and chromogranin A. With the exception of insulinomas, most ETP also express somatostatin membrane receptors. The common origin of the different pancreatic cellular types from the pluripotent endodermal cells of the primitive foregut accounts for the eventful distribution of ETP not only within the pancreas but also in adjacent structures such as the duodenum (2). Most functioning ETP are small (0.5–5 cm) and well demarcated neoplasms, with a white-gray to pinkish-brown color and firm consistency. Because of their more insidious growth, glucagonomas, PPomas and non-functioning ETP are generally much larger, with a local or distant invasion at the time of diagnosis. The proliferation of isolated pancreatic islet cells, arising from the pluripotent ductal cells (nesidioblastosis) is also frequently observed in the vicinity of ETP tumors. In the neonate, diffuse pancreatic nesidioblastosis can cause overt clinical hypoglycemia in the absence of any tumoral process (3), but this condition is exceedingly rare in adults.

With the exception of insulinomas, ETP are frequently malignant as characterized by vascular invasion, gross infiltration of adjacent organs, and synchronous or metachronous nodal or distant metastases. In some cases, the diagnosis of malignancy is made only several years after resection of an apparently benign tumor, by the outcome of metastases.

Apparently sporadic in most cases, ETP arise in 10–20% in the context of a multiple endocrine neoplasia type 1 (MEN 1) or Wermer's syndrome, due to an inherited autosomal defect in the menin gene, a tumor suppressor gene mapping to chromosome 11q13 (4). ETP are then generally associated with parathyroid or anterior pituitary neoplasms, and eventually carcinoid or adrenal tumors. In that genetic setting, ETP are often multiple and may simultaneously secrete different peptides. Interestingly, somatic mutations of the menin gene are also found in one third of sporadic ETP.

Symptom recognition

Functioning ETP may provoke various symptoms according to the nature of the secreted peptide (table I). The crucial issue of ETP management is undoubtedly to evoke the diagnosis before symptoms become obvious or life threatening. Most ETP related symptoms are indeed very poorly specific. Proper diagnosis, depending on the physician awareness, is frequently delayed for months to years since their first appearance. Abrupt onset of ETP is exceedingly rare and a careful screening of the preceding years will reveal premonitory signs in most cases.

Table I. Characteristics of various endocrine tumors of the pancreas.

Table I

Characteristics of various endocrine tumors of the pancreas.

Insulinoma occurs generally in adults within their third to fifth decade. Hypoglycemia may induce signs related both to an insufficient supply of glucose to the brain (neuroglycopenia) and to the counterregulatory autonomic nervous and endocrine reaction (5). Symptoms associated with neuroglycopenia are almost constant in patients with an insulinoma. They include various transient non focal events such as apathy, dizziness, confusion, tiredness, or behavioral disturbances. Initially isolated and fluctuating, these symptoms frequently lead to erroneous neuropsychiatric diagnosis. In some cases, diplopia or other temporary or permanent focal neurological deficits may be observed. Profound hypoglycemia can lead to seizures, coma and even death if left untreated. Counterregulatory reaction symptoms include anxiety, sweating, palpitation, blurred vision, nausea, an hunger. Autonomic nervous signs are less frequent than those associated with neuroglycopenia, probably due to the progressive decrease of the counterregulatory reaction induced by chronic hypoglycemia. Conversely to various other conditions causing hypoglycemia, organic hypoglycemia associated with insulinomas is classically characterized by the Whipple triad; symptoms occur preferentially during fasting or exertion, they are associated with low blood sugar (< 45 mg/dl), and are relieved by the administration of glucose. It is finally noteworthy that most patients with insulinomas progressively develop overeating habits to prevent symptom occurrence. Excess weight is frequent at diagnosis.

In patients with a gastrinoma, diarrhea is generally the first symptom to appear, lasting frequently several years before diagnosis becomes recognized. Due to the overflow of gastropancreatic secretions, diarrhea is generally watery and disappears with gastric suction. Atypical gastroduodenal ulcer disease is generally the hallmark to diagnosis. Any peptic ulcer disease should suggest the presence of a gastrinoma when recurring or persisting after adequate medical or surgical treatment, being initially severe and complicated, or arising in multiple or unusual locations especially within the jejunum.

Most glucagonomas arise in mature patients, beyond the fifth decade. The corresponding syndrome is coined by diabetes, weight loss and a pathognomonic cutaneous rash: the necrolytic migratory erythema (6). This typical skin lesion involves most often the lower extremities and groins and is characterized by a red, scaling and migratory rash, associated with an intense pruritus. Present in 90% of cases, these skin lesions are indirectly caused by the hyperglucagonemia and may be due to a zinc or aminoacid deficiency. Diabetes, related to glucagon oversecretion, is present in most cases and may require insulin therapy. Hypercatabolism is responsible for an almost constant weight loss which may be profound and lead to cachexia. Advanced stages of the syndrome are also characterized by frequent deep vein thrombosis and pulmonary embolism.

Endocrine cholera associated with VIPomas is characterized by a profuse watery diarrhea and hypochlorydria. This secretory type diarrhea is secondary to a massive jejunal net secretion of water and electrolytes. The stool volume frequently exceeds three liters a day and is not modified by fasting nor by gastric suction. Muscle weakness is due to hypokaliemia, hypercalcemia and hypomagnesemia, which may also cause tetany and lead to progressive protrusion. In rare cases, severe electrolyte imbalance may cause sudden death.

Generally observed around the fifth decade, somatostatinoma causes a syndrome characterized by mild diabetes, steatorrhea, and gallbladder disease. Glucose intolerance is moderate in most cases, rarely requiring insulin therapy. This impairment is a result of a combination of somatostatin inhibitory effects on insulin, glucagon, and growth hormone secretion. Cholelithiasis is almost constant and secondary to the bile stasis induced by the inhibition of gallbladder contraction. Diarrhea with steatorrhea is secondary to the combined effects of somatostatin on pancreatic exocrine secretion and intestinal motility. Secondary weight loss is also common. In most instances, this syndrome has not been previously recognized and somatostatinomas are found incidentally during preoperative imaging or exploring the abdomen for routine cholecystectomy.

Non functioning tumors or tumors secreting non active peptides (PPomas) remain clinically silent until they reach a noticeable size and provoke symptoms by tumor mass effects. They may then be revealed by epigastric pain, dyspepsia, and jaundice. Other circumstances of diagnosis include upper gastrointestinal bleeding, recurrent pancreatitis, palpable mass or hepatomegaly, and cachexia in case of advanced disease. Silent ETP may also eventually be discovered incidentally by abdominal imaging for another cause or during screening in a MEN 1 patient.

Confirm the diagnosis

Confirmation of the diagnosis of a functioning ETP is generally straightforward, relying on the demonstration of an abnormally elevated circulating level of the corresponding hormone. Since peptides are particularly sensitive to physical and enzymatic degradation, one should be particularly aware of the specific sampling and storing conditions necessary for the accurate measurement of each of them.

The diagnosis of insulinoma relies on the documentation of simultaneous low blood sugar and inappropriate serum insulin levels. With time, many patients progressively develop a hypoglycemia unawareness and support surprisingly well even the lowest blood sugar levels. Insulinoma secretion being generally intermittent, a prolonged fasting test, bringing on an hypoglycemic episode and allowing detection of a concomitant inappropriate insulin level is often necessary to confirm the diagnosis. Most patients with an insulinoma experience hypoglycemia before 24 hours of fasting and virtually all do before 72 hours (5). The need for stimulation tests such as tolbutamide infusion to demonstrate an abnormal insulin secretion remains the exception and should question the diagnosis. Beside insulin, insulinoma cells are also secreting a high proportion of proinsulin and intermediate insulin precursors which are not recognized by specific immunoradiometric assays for insulin. Serum C-peptide and proinsulin, or total immunoreactive insulin should therefore also be measured with appropriate assays when suspecting an insulinoma. The last essential issue before concluding the diagnosis is to rule out factitious hypoglycemia, a non exceptional and potentially misleading situation (5). Careful clinical assessment is mandatory to rule out self administration of exogenous insulin or hypoglycemic oral medications, particularly in female patients from the medical community or relatives of diabetic patients. C-peptide and sulfonylurea serum levels should be measured in equivocal cases.

Basal acid output and serum fasting gastrin levels are elevated in most but not all patients with gastrinomas (7). On the other hand, various conditions can be associated with hypergastrinemia despite normal or elevated gastric acid secretion (antral G-cell hyperplasia, retained antrum, short bowel syndrome, gastric outlet obstruction, renal failure). Conversely, the paradoxical elevation of both serum gastrin and gastric acid secretion two minutes after the infusion of secretin is a unique feature of gastrinomas. This secretin test should be performed prior to surgery in every patient with ETP in a MEN 1 setting, to detect an associated gastrinoma and eventually modify the surgical strategy (8).

Fasting serum glucagon, VIP, and plasma somatostatin can be measured with the appropriate radioimmunological assays when their hypersecretion is suspected.

When the diagnosis of ETP is suspected in the absence of any functional syndrome, serum PP should be measured in fasting and postprandial serum before ruling out a functioning tumor. Chromogranin A, a secretory protein exclusively present in neuronal and neuroendocrine cell granules may also be measured in serum to confirm neuroendocrine function in equivocal cases (9). Since most ETP express somatostatin receptors, scintigraphy with a radiolabelled somatostatin analogue (octreotide) can also be used to confirm the neuroendocrine nature of a non functioning pancreatic tumor detected by conventional imaging (10).

Ruling out a genetic setting

The natural history of ETP and their management are dramatically modified if they occur in a genetic setting. Classical multiple endocrine syndrome is initially present in only a small fraction of patients with germline mutation of the menin gene and ETP can be the first symptomatic lesion (11). It is therefore of prominent importance to rule out the diagnosis of MEN 1 before treatment of an ETP is considered. When arising in a patient from a known MEN 1 family, the genetic origin of ETP is obvious. The diagnosis of MEN 1 is also very likely in cases of previous pancreatic, parathyroid, or pituitary disease in the patient's kindred. Clinical assessment should therefore include a careful search for a family history of kidney stones, gastroduodenal ulcer disease, cerebral, cervical or major abdominal surgery, and precocious death of unknown cause. In absence of any family history, the association of ETP with parathyroid or pituitary disease should be routinely screened out respectively by the measurement of intact parathyroid hormone (PTH) and serum calcium, and serum prolactin and insulin-growth factor 1 (IGF 1), even in asymptomatic patients. Diagnosis of MEN 1 should also be considered when ETP arise in young patients. Since multiple secretion of ETP is frequent in MEN 1, serum insulin, proinsulin, glucagon, PP, gastrin, and chromogranin A should be routinely performed to detect other duodenal/pancreatic tumors (12). Early diagnosis of ETP can even be enhanced in MEN 1 patients by measuring serum PP and gastrin after a standard meal stimulation (12).

When a reasonable suspicion of MEN 1 is raised, the diagnosis can be confirmed by genetic testing for germline mutations in the menin gene, at institutions where the test is available. If positive, this diagnosis should lead to patient's first degree relatives screening and appropriate counseling (4).

Localization of the tumors

When the presence of a functioning TEP has been firmly demonstrated by biochemical testing, tumor imaging is not a prerequisite for surgical abdominal exploration. Preoperative imaging of ETP should be considered only to guide the management by ruling out distant metastases and facilitate surgery when showing duodenal or pancreatic lesions, and/or regional abnormal lymph nodes.

The classical non invasive morphological studies such as abdominal ultrasound, (helical) CT-scan, and MRI have a poor sensitivity for the smallest lesions. They are therefore of little help for insulinomas and gastrinomas, except for detecting liver metastases. Conversely, for large non functioning tumors they are useful in assessing the local invasion of adjacent structures and estimate their resectability.

The excellent overall performances of two recent remarkable non-invasive localization studies: endoscopic ultrasonography (EUS) (13) and somatostatin receptor scintigraphy (SRS) (14) led to their rapid widespread and general acceptance as initial studies for imaging ETP (15). When performed by experienced endoscopists, EUS accurately predicts both the site and the size of most neuroendocrine tumors. As illustrated in figure 1 this technique may guide the surgeon toward both the primary tumor and the metastatic lymph nodes. If including a comprehensive exploration of the entire duodenum and the first jejunal loop, sensitivity of EUS for small pancreatic tumors such as insulinomas is excellent (16), and even the detection of minute duodenal tumors is possible (17). On the other hand, the positive predictive value of EUS is not absolute and pancreatic resection for a non palpable intrapancreatic tumor diagnosed by preoperative EUS would appear unwise without confirmation by intraoperative ultrasonography. The value of preoperative SRS has been well documented in various types of ETP especially for gastrinomas (18), and to a lesser extent for insulinomas (16). The results of SRS does not depend on size or location of the tumor but on the presence of type 2 somatostatin receptors. One of the major advantages of SRS is its high specificity for neuroendocrine tumors (10). It is also noteworthy that a positive SRS is highly suggestive of efficacy of hormonal inhibition by octreotide (19) and eventually of therapeutic use of radiolabelled somatostatin analogues (20). SRS is also generally considered to be an excellent tool to detect metastases in patients with advanced disease (18), but the detection of occult metastases may be impaired by its physiological hepatic uptake.

Figure 1. Somatostatin receptor scintigraphy (A) and endoscopic ultrasonography (B) are the initial non invasive studies of choice for the localization of small endocrine tumors of the pancreas and their potential lymph node metastases.

Figure 1

Somatostatin receptor scintigraphy (A) and endoscopic ultrasonography (B) are the initial non invasive studies of choice for the localization of small endocrine tumors of the pancreas and their potential lymph node metastases. The arrows indicates the (more...)

The last available technique is the functional localization of the tumor (s) by hormonal measurement in the supra-hepatic veins after selective intraarterial stimulation of tumor secretion, as proposed for gastrinomas (21) and insulinomas (22). These techniques however do not localize the tumor but rather regionalize the source of hypersecretion. Invasive and demanding, they should be reserved for the most difficult cases, when other techniques have remained negative.

Treatment

Optimal management of ETP must pursue two goals: controlling the symptoms and prolonging survival by eradicating the tumoral process. Surgery is the only modality which addresses satisfactorily both issues. For benign sporadic ETP such as most insulinomas, surgery allows definitive cure in more than 90% of cases (23). When correctly treated, many malignant ETP have an indolent clinical course and survival is often measured in years or decades.

Complete surgical resection of the tumors is an independent determinant of overall survival (24, 25) and surgery should remain the mainstay of ETP treatment. Nevertheless urgent need for operation is exceptional. Most patients are now operated on only after stabilization of the symptoms and comprehensive preoperative work-up. Numerous drugs are available to control the symptoms associated with excess hormone production. Adequate diet and diazoxide treatment can control hypoglycemia in most insulinoma cases. Proton pump inhibitors have revolutionized the treatment of hypergastrinemia and virtually eliminated the need for acid reduction gastric surgery. But the major breakthrough in the medical management of ETP has been the use of somatostatin analogues, octreotide and lanreotide and their long lasting forms which decrease hormonal secretion of ETP (26). These drugs have only few adverse effects such as digestive discomfort upon treatment initiation, reduced glucose tolerance, and increase incidence of cholesterol gallstones. Subcutaneous administration of 150–300 μg of octreotide per day ameliorates many of the symptoms related with excess hormone production (27). Clinical effects of octreotide may be dramatic, especially for VIPomas and glucagonomas.

Surgical strategy

Preoperative preparation should include pneumococcal vaccination in case a splenectomy becomes necessary, routine mechanical bowel preparation, and broad spectrum antibioprophylaxis, especially if a duodenotomy is considered. Except in thin patients, a bilateral subcostal or transverse laparotomy seems preferable to allow sufficient access to the abdomen. The state of the art operation (28) starts by a standardized and meticulous abdominal exploration, with exhaustive visual inspection and palpation from the inframesocolic area to the supramesocolic area, including the liver. An extended Kocher's maneuver is then performed, liberating the duodenum up to the level of the superior mesenteric vein to allow adequate mobilization of the head and the uncinate process of the pancreas. After opening the lesser sac from the hepatic to the splenic flexure, the posterior aspect of the tail is dissected free. The whole pancreatic gland can then be explored with bimanual palpation and intraoperative ultrasonography (IOUS), allowing the detection of 90–100% of solitary pancreatic tumors (29). In patients with documented hypergastrinemia, routine lymph node clearance within the gastrinoma triangle is performed, and operative endoscopy with duodenum transillumination and duodenotomy are mandatory to find minute submucosal duodenal lesions (28). Any detectable pancreatic tumor and potentially involved lymph nodes should then be resected when deemed feasible. Enucleation, which preserves the normal pancreas and spleen, is the preferred option for benign tumors when found at a distance to the pancreatic duct by IOUS, such as most insulinomas (23). For lesions within the left pancreas, when malignancy is likely or enucleation may risk duct injury, a formal pancreatic resection is the preferred option, eventually associated with a splenectomy. For large and frequently malignant tumors such as glucagonomas, VIPomas, somatostatinomas and nonfunctioning ETP, a formal resection is the only choice but the problem is often its feasibility. Whipple operation is often necessary for large tumors arising in the head and uncinate. Also proposed by some authors to ensure complete tumoral resection of gastrinomas (30), duodenopancreatectomy is exceptionally performed for Zollinger-Ellison, generally treated with limited resection of duodenal or pancreatic tumors and lymph node clearance (28). In absence of any palpable mass, blind pancreatectomy should not be done without preoperative localization or at least functional regionalization of the secreting tumor. For the exceptional patients with hypoglycemia caused by diffuse nesidioblastosis, an extended distal pancreatectomy may be curative (31). In selected cases, the completeness of surgical removal of functioning ETP can be assessed with intraoperative hormone measurement in systemic and portal blood (21, 31). When complete resection is not achievable, surgical debulking of the tumors can facilitate their postoperative management and prolong survival. When functioning ETP are associated with liver metastases, those accessible to reasonable liver resection should be synchronously excised. Cholecystectomy should always be considered in patients with advanced disease to prevent cholelithiasis associated with long lasting octreotide therapy. Laparoscopic pancreatic resection seems technically feasible for apparently benign and sporadic ETP but is still experimental (32).

In the setting of a MEN 1, the pancreatic disease is often multifocal or diffuse, and preoperative localization is rarely exhaustive. For these patients, a fine balance must be struck between totally removing the gross tumor and limiting prophylactic resection to prevent endocrine and exocrine pancreatic insufficiency. The best surgical option consists of enucleation of any head or uncinate tumors and distal pancreatectomy. In patients with proven hypergastrinemia, the operation should also include a routine duodenotomy and peripancreatic node clearance (8). Early pancreatic surgery in patients with MEN 1 is now widely accepted, except in gastrinomas for which controversies persist (33). In case of associated parathyroid disease, subtotal parathyroidectomy and thymectomy should be performed first, eventually immediately before pancreatic surgery.

The most common complication after pancreatic surgery for ETP is pancreatic fistula. Even in the most experienced hands, fistulas occurs in up to 10–20% of patients with insulinomas, especially after enucleation (23). Conservative treatment with prolonged drainage, somatostatin analogues and eventually low-dose pancreatic radiotherapy is sufficient in most cases. The prophylactic role of routine postoperative administration of somatostatin analogues already demonstrated in various pancreatic diseases remains to be established for ETP (34).

Advanced disease

As many as 50% of the patients with ETP have already developed metastases at diagnosis. Conversely to nodal involvement, the presence of liver metastases is the major determinant of survival in patients with ETP (24, 25, 33). Various techniques have therefore been proposed to treat these patients with the aim of both diminishing the clinical symptoms associated with hormonal secretion and prolonging survival. Combining these modalities, the median survival of patients with advanced ETP often exceed several years. Unfortunately, evidence based guidelines are lacking to define the optimal management of advanced ETP. No randomized controlled therapeutic trial is available to support the aggressive treatment of these slow growing tumors. Furthermore the interpretation of most retrospective or cohort studies reported in the literature is complicated by the absence of a clear TNM classification for ETP, the simultaneous inclusion of midgut carcinoid tumors which have a much better prognosis than ETP (35), and the lack of strict treatment protocols running for long periods of time.

Surgical resection of liver metastases may benefit to patients with limited liver involvement. When more than 90% of the tumor volume can be safely resected, aggressive surgical resection results in long-term relief of symptoms and prolong survival (36).

When unresectable metastases are progressing, various alternative modalities may be contemplated. In the absence of any conclusive evidence, the preferential choice of one of these methods is debatable and the association or the sequential use of multiple modalities is frequent. A given technique may not be pursued if tumor reduction can not be demonstrated after two treatment cycles. Somatostatin analogues are widely used to control the symptoms in patients with advanced disease, although their frequently evoked antiproliferative effect has never been demonstrated for ETP (26). Disrupting blood supply to the neoplastic cells by repeated hepatic ischemia obtained by embolization or by a temporary mechanical occlusion of the hepatic artery may slower tumor growth, at the price of a significant morbidity (37). For the tumors expressing somatostatin receptors, treatment with high doses of radiolabelled somatostatin analogues may result in tumor shrinkage (20). Because of its serious adverse effects, chemotherapy should be reserved for patients in which the disease continues to progress after failure of less invasive techniques. The most efficient chemotherapy protocols associate streptozotocin with fluorouracil or doxorubicin (38). The low response rate and the high incidence of side effects have limited the use of interferon for metastastic ETP (39).

When the liver disease is still progressing after the resection of the primary tumor and the failure of all other techniques, total hepatectomy and liver transplantation may eventually be considered, although its results for ETP are far less encouraging than for carcinoid tumors (40).

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Bookshelf ID: NBK6889

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