[Management of gastrinoma]. / Prise en charge du gastrinome.

Gastrinoma is a very rare tumor leading to gastrin hypersecretion and characterised by Zollinger-Ellisson syndrome (ZES) i.e. severe gastric and duodenal ulceration and profuse diarrhea. This disease can be sporadic or familial within a multiple endocrine neoplasia type 1 (MEN-1) syndrome. Diagnosis is based on hypergastrinemia/hypercholrhydria. Tumors are usually located in the duodeno-pancreas. Preoperative tumor location by CT, echoendoscopy and fibroscopy is not always possible because of the small size of the lesion that are frequently multiple. The aim of gastrinoma treatment is 1/to control the hormonal hypersecretion 2/to remove the neoplasm when it is possible. Surgery is the only chance to cure. Gastrinoma is a slow-growing tumor, and overall survival is good with a median survival above 10years and a 5-year survival above 80 % in surgically resected patients. Recurrence is frequent, a biochemical recurrence is observed in 65 % of cases and morphological recurrence in 40 % of patients at 2years. Metastases are associated with a dismal prognosis.

Causes of death and prognostic factors in multiple endocrine neoplasia type 1: a prospective study: comparison of 106 MEN1/Zollinger-Ellison syndrome patients with 1613 literature MEN1 patients with or without pancreatic endocrine tumors.

Multiple endocrine neoplasia type 1 (MEN1) is classically characterized by the development of functional or nonfunctional hyperplasia or tumors in endocrine tissues (parathyroid, pancreas, pituitary, adrenal). Because effective treatments have been developed for the hormone excess state, which was a major cause of death in these patients in the past, coupled with the recognition that nonendocrine tumors increasingly develop late in the disease course, the natural history of the disease has changed. An understanding of the current causes of death is important to tailor treatment for these patients and to help identify prognostic factors; however, it is generally lacking.To add to our understanding, we conducted a detailed analysis of the causes of death and prognostic factors from a prospective long-term National Institutes of Health (NIH) study of 106 MEN1 patients with pancreatic endocrine tumors with Zollinger-Ellison syndrome (MEN1/ZES patients) and compared our results to those from the pooled literature data of 227 patients with MEN1 with pancreatic endocrine tumors (MEN1/PET patients) reported in case reports or small series, and to 1386 patients reported in large MEN1 literature series. In the NIH series over a mean follow-up of 24.5 years, 24 (23%) patients died (14 MEN1-related and 10 non-MEN1-related deaths). Comparing the causes of death with the results from the 227 patients in the pooled literature series, we found that no patients died of acute complications due to acid hypersecretion, and 8%-14% died of other hormone excess causes, which is similar to the results in 10 large MEN1 literature series published since 1995. In the 2 series (the NIH and pooled literature series), two-thirds of patients died from an MEN1-related cause and one-third from a non-MEN1-related cause, which agrees with the mean values reported in 10 large MEN1 series in the literature, although in the literature the causes of death varied widely. In the NIH and pooled literature series, the main causes of MEN1-related deaths were due to the malignant nature of the PETs, followed by the malignant nature of thymic carcinoid tumors. These results differ from the results of a number of the literature series, especially those reported before the 1990s. The causes of non-MEN1-related death for the 2 series, in decreasing frequency, were cardiovascular disease, other nonendocrine tumors > lung diseases, cerebrovascular diseases. The most frequent non-MEN1-related tumor deaths were colorectal, renal > lung > breast, oropharyngeal. Although both overall and disease-related survival are better than in the past (30-yr survival of NIH series: 82% overall, 88% disease-related), the mean age at death was 55 years, which is younger than expected for the general population.Detailed analysis of causes of death correlated with clinical, laboratory, and tumor characteristics of patients in the 2 series allowed identification of a number of prognostic factors. Poor prognostic factors included higher fasting gastrin levels, presence of other functional hormonal syndromes, need for >3 parathyroidectomies, presence of liver metastases or distant metastases, aggressive PET growth, large PETs, or the development of new lesions.The results of this study have helped define the causes of death of MEN1 patients at present, and have enabled us to identify a number of prognostic factors that should be helpful in tailoring treatment for these patients for both short- and long-term management, as well as in directing research efforts to better define the natural history of the disease and the most important factors determining long-term survival at present.

Impact of lymphadenectomy on survival after surgery for sporadic gastrinoma.

BACKGROUND: The study was undertaken to determine prognostic factors and the value of systematic lymphadenectomy on survival in sporadic gastrinoma. METHODS: Patients with sporadic gastrinoma who underwent initial surgery during a 21-year period in two tertiary referral centres were analysed retrospectively with respect to clinical characteristics, operative procedures and outcome. RESULTS: Forty-eight patients with a median age of 52 (range 22-73) years were analysed. Some 18 patients had pancreatic and 26 had duodenal gastrinomas, whereas the primary tumour remained unidentified in four patients. After a median postoperative follow-up of 83 (range 3-296) months, 20 patients had no evidence of disease, 13 patients were alive with disease, 11 patients had died from the disease and four had died from unrelated causes. In 41 patients who underwent potentially curative surgery, systematic lymphadenectomy with excision of more than ten lymph nodes resulted in a higher rate of biochemical cure after surgery than no or selective lymphadenectomy (13 of 13 versus 18 of 28 patients; P = 0·017), with a trend towards prolonged disease specific survival (P = 0·062) and disease-free survival (P = 0·120), and a reduced risk of death (0 of 13 versus 7 of 24 patients; P = 0·037). Negative prognostic factors for disease specific survival were pancreatic location (P = 0·029), tumour size equal to or larger than 25 mm (P = 0·003), Ki-67 index more than 5 per cent (P < 0·001), preoperative gastrin level 3000 pg/ml or more (P = 0·003) and liver metastases (P < 0·001). Sex, age, type of surgery and presence of lymph node metastases had no influence on disease free or disease specific survival. CONCLUSION: In sporadic gastrinoma, systematic lymphadenectomy during initial surgery may reduce the risk of persistent disease and improve survival.

Value of surgery in patients with negative imaging and sporadic Zollinger-Ellison syndrome.

OBJECTIVES: To address the value of surgery in patients with sporadic Zollinger-Ellison syndrome (ZES) with negative imaging studies. BACKGROUND: Medical control of acid hypersecretion in patients with sporadic ZES is highly effective. This has led to these patients frequently not being sent to surgery, especially if preoperative imaging studies are negative, due, in large part, to existence of almost no data on the success of surgery in this group. METHODS: Fifty-eight prospectively studied patients with sporadic ZES (17% of total studied) had negative imaging studies, and their surgical outcome was compared with 117 patients with positive imaging results. RESULTS: Thirty-five patients had negative imaging studies in the pre-somatostatin receptor scintigraphy (SRS) era, and 23 patients in the post-SRS era. Patients with negative imaging studies had long disease histories before surgery [mean ± SEM (from onset) = 7.9 ± 1 [range, -0.25 to 35 years]) and 25% were followed for 2 or more years from diagnosis. At surgery, gastrinoma was found in 57 of 58 patients (98%). Tumors were small (mean = 0.8 cm, 60% <1 cm). The most common primary sites were duodenal 64%, pancreatic 17%, and lymph node (10%). Fifty percent had a primary-only, 41% primary + lymph node, and 7% had liver metastases. Thirty-five of 58 patients (60%) were cured immediately postoperatively, and at last follow-up [mean = -9.4 years; range, 0.2-22 years], 27 patients (46%) remained cured. During follow-up, 3 patients died, each had liver metastases at surgery. In comparison to positive imaging patients, those with negative imaging studies had lower preoperative fasting gastrin levels; had a longer delay before surgery; more frequently had a small duodenal tumor; less frequently had a pancreatic tumor, multiple tumors, or developed a new lesion postoperatively; and had a longer survival. CONCLUSIONS: Sporadic ZES patients with negative imaging studies are not rare even in the post-SRS period. An experienced surgeon can find gastrinoma in almost every patient (98%) and nearly one half (46%) are cured, a rate similar to patients with positive imaging findings. Because liver metastases were found in 7%, which may have been caused by a long delay in surgery and all the disease-related deaths occurred in this group, surgery should be routinely undertaken early in ZES patients despite negative imaging studies.

Zollinger-Ellison syndrome associated with a history of alcohol abuse: coincidence or consequence?

BACKGROUND: This 47-year observational study suggests that sporadic Zollinger-Ellison (Z-E) syndrome, particularly duodenal wall gastrinomas (DWG), is associated with a history of alcohol abuse. METHODS: Thirty-nine consecutive Z-E patients were followed from 1962 through 2010. The drinking patterns of these patients were assessed and compared with 3,786 community controls. RESULTS: Thirty-five patients had extrapancreatic gastrinomas (34 DWG and/or paraduodenal lymph nodes, 1 antral gastrinoma). Total gastrectomy was done in 24; 9 underwent less extensive operations to remove DWG, and 2 patients had no operations. There were no deaths from tumor progression. Four patients presented with pancreatic gastrinoma (PG) and liver metastasis, all died from tumor progression. Alcohol abuse (>50 g/d) was documented in 81% of patients with DWG and/or paraduodenal lymph nodes. The drinking patterns (drinks per day) of DWG patients were significantly different: DWG vs community control-abstainers, 3% vs 24%; 1-2 drinks, 16% vs 62%; 3-5 drinks, 29% vs 12%; and ≥ 6 drinks, 52% vs 2.5% (P < .01). CONCLUSION: Alcohol abuse is strongly associated with and may be a risk factor for sporadic Z-E with extrapancreatic DWG. Liver metastases and tumor deaths were not observed in this subgroup, supporting the concept that DWG and PG are different tumor entities.

Zollinger-Ellison syndrome: presentation, response to therapy, and outcome.

BACKGROUND: Recent series describing the clinical presentation, response to therapy, and long-term outcome of Zollinger-Ellison syndrome are limited. AIMS: To assess the clinical characteristics and long-term outcome of patients with Zollinger-Ellison syndrome. METHODS: Over a 20-year period, patients with Zollinger-Ellison syndrome were enrolled in a prospective trial evaluating the efficacy of lansoprazole. Following dose stabilization, patients were followed on a 6-monthly basis with interval history, physical examination, endoscopy with gastric biopsies, gastric acid analysis and laboratory studies. RESULTS: 72 patients (mean age 54±12 years, % male 58%, % Caucasian 69%) were prospectively enrolled. The clinical presentation was stereotypical for Zollinger-Ellison syndrome. Symptoms had been reported for a median of 9 years prior to diagnosis. Cross-sectional abdominal imaging was often negative for demonstrable tumour. All patients had gastric acid hypersecretion controlled with variable doses of lansoprazole (median dose 60 mg/day, range 15-480 mg/day). The median survival from the time of diagnosis was 6.6 years; only two of 19 deaths were due to metastatic gastrinoma. CONCLUSIONS: The clinical presentation of Zollinger-Ellison syndrome was similar to prior reports. Acid hypersecretion was controlled in all patients with variable doses of lansoprazole. Long-term survival was principally related to underlying co-morbidity.

Reoperative surgery in sporadic Zollinger-Ellison Syndrome: longterm results.

BACKGROUND: Most patients with Zollinger-Ellison Syndrome (ZES), even those in whom gastrinoma is found and resected at initial operation, will suffer from persistent or recurrent disease in longterm followup. There is currently no consensus about managing patients with recurrent or persistent ZES. Our unit has historically maintained an aggressive approach toward monitoring and reoperation for patients with sporadic ZES. STUDY DESIGN: We performed a review of a consecutive series of patients evaluated and managed at our institution between 1970 and 2007 for ZES. "Biochemical cure" was defined as normal serum gastrin assays and negative imaging studies. Reoperations were performed for elevations in serum gastrin assays and positive findings on imaging studies. RESULTS: Fifty-two patients with sporadic ZES were analyzed. Median followup was 14 years. Among patients with sporadic ZES, 37 patients underwent operative management. The most common operations were resection of duodenal gastrinoma (n=8) and total gastrectomy (n=7). Nine patients underwent 15 reoperations for recurrent or persistent disease. "Biochemical cure" was obtained in four patients (44%) undergoing reoperation for ZES. Three of these patients remained without evidence of recurrence at 4, 9, and 12 years after their curative re-resection. Only one of nine patients who underwent reoperation died of metastatic gastrinoma. CONCLUSIONS: Primary and reoperative surgery in patients with sporadic ZES results in a significant rate of "biochemical cure." In selected patients with recurrent or persistent disease, reoperation for resection of gastrinoma is associated with excellent longterm survival and is warranted.

Surgical aspects of gastrinoma in multiple endocrine neoplasia type 1.

Gastrinoma is the most frequent functional pancreaticoduodenal endocrine tumor in patients with multiple endocrine neoplasia type 1 (MEN1) and one major determinant of mortality in this syndrome. Whether routine surgical exploration should be performed in a patient with MEN1 associated Zollinger-Ellison syndrome (ZES) to possibly reduce the malignant spread and eventually increase survival still remains controversial. There is not only disagreement about the indication for surgical exploration, but also what type of procedure should be performed, since sufficient evidence-based data are not available. The article discusses the available data on treatment strategies of MEN1 associated ZES.

Gastrinoma: sporadic and familial disease.

The physiologic sequelae of a gastrinoma can be well controlled with medical therapy. The role of surgery has shifted from managing acid hyper-secretion and ulcer complications to preventing metastatic disease and managing symptomatic metastases. With improved methods of imaging for the detection of occult gastrinomas, the prospective evaluation of the role for surgery in altering the natural history of these tumors is now possible.

Surgery and prognosis of duodenal gastrinoma as a duodenal neuroendocrine tumor.

It has become increasingly clear that duodenal gastrinomas are the most common cause of Zollinger-Ellison syndrome (ZES). However, attempts to find these tumors before and during surgery for ZES have had limited success until duodenotomy (opening the duodenum) was described. The routine use of duodenotomy in patients with non-familial gastrinoma increases the number of duodenal tumors found, and the immediate and long-term cure-rate. The increase in cure-rate appears to be secondary to increased detection of small, previously undetectable duodenal gastrinomas. Duodenotomy detects small tumors (<1 cm) in the proximal duodenum. It does not detect more duodenal gastrinomas per patient, nor does it detect tumors in unusual duodenal locations. Duodenotomy decreases the death-rate associated with these tumors. However, it has not affected the rate of development of liver metastases. Duodenotomy is a critical method to find duodenal gastrinomas. It should be routinely performed in all surgery to find and remove gastrinoma for cure of ZES.

Surgical treatment and prognosis of gastrinoma.

Zollinger-Ellison syndrome (ZES) is a clinical syndrome with severe peptic ulcer disease and diarrhea caused by gastric acid hypersecretion secondary to a neuroendocrine tumour that secretes excessive amounts of the hormone gastrin (gastrinoma). Gastrinomas occur in a familial and a sporadic form. Patients with gastrinoma in the familial setting of Multiple Endocrine Neoplasia type 1 (MEN-1) are seldom, if ever, cured of Zollinger-Ellison syndrome by the current non-Whipple operations to remove duodenal and pancreatic gastrinoma. Surgery is currently used in these patients to deal with the malignant nature of pancreatic or duodenal neuroendocrine tumours. Malignant potential is best determined by tumour size. Tumours that are greater than 2 cm in size should be excised. In the sporadic setting, cure occurs in a significant proportion of patients (50%) by surgical resection of gastrinoma. Duodenotomy has improved both the tumour detection rate and the cure rate and should be routinely done. Whipple pancreaticoduodenectomy results in the highest probability of cure in both sporadic and MEN-1 gastrinoma patients as it removes the entire gastrinoma triangle. However, the excellent long-term survival of these patients with lesser operations and the increased operative mortality and long-term morbidity of Whipple make its current role unclear until further studies are done.

A follow-up study of patients with Zollinger-Ellison syndrome in the period 1966-2002: effects of surgical and medical treatments on long-term survival.

AIM: To evaluate the clinical history of a series of patients with Zollinger-Ellison syndrome (ZES) in the period 1966 to 2002, before and after the introduction of the current antisecretive H2 receptor antagonists and proton pump inhibitors into clinical practice. PATIENTS AND METHODS: The study involved 18 ZES patients (9 males; mean age, 43 years; range, 12-70 years), 8 with Type 1 multiple endocrine neoplasia (MEN-1), diagnosed on the basis of standard criteria. We considered the type, number and effectiveness of surgical interventions before and after appropriate treatment, the localization of the gastrinoma, the presence of associated diseases, the causes of death, and the duration of survival. RESULTS: Total gastrectomy (but not antrectomy and vagotomy) and full compliance to antisecretory treatment reduced the number of operations from 29 to 9. One patient was cured (5.5%), whereas relapsing gastrinomas occurred in 4 patients and associated diseases or complications in ten. Death was related to ZES in 5 patients and to other causes in 4. CONCLUSIONS: Curing gastrinoma or appropriately inhibiting gastric acid hypersecretion in ZES patients prevent death and favors long-term survival, regardless of gastrin levels and the size or number of tumors.

[Zollinger-Ellison syndrome]. / Zollinger-Ellison-Syndrom Das gewandelte Verständnis der Chirurgie.

The preoperative localization of gastrinomas often fails despite all modern imaging methods. Therefore, after biochemical confirmation of the diagnosis and exclusion of diffuse metastases, a meticulous surgical exploration including intraoperative ultrasound (IOUS) and duodenal exploration after duodenotomy should be performed. The experienced surgeon will be able to identify more than 90% of the primary tumors. Depending on the localization, excision of the tumor in the duodenal wall or enucleation from the pancreatic head should be performed. If the tumor is localized in the tail of the pancreas, distal pancreatectomy is the treatment of choice. Complete resection of the tumor is the only curative approach for the patients. For MEN-1 gastrinomas a spleen-preserving distal pancreatectomy with enucleation of tumors of the pancreatic head and duodenotomy with excision of duodenal gastrinomas should be performed. If the source of gastrin secretion can be regionalized to the pancreatic head by a preoperative SASI angiography, a pylorus-preserving partial pancreaticoduodenectomy might be the treatment of choice.

Endocrine tumors of the duodenum. A study of 55 cases relative to clinicopathological features and hormone content.

BACKGROUND/AIMS: Study of prognosis of duodenal endocrine tumors. METHODOLOGY: Retrospective study concerned 55 duodenal endocrine tumors discovered in biopsy or surgical specimens. Follow-up records available for 49 patients indicated that inconspicuous associated clinical manifestations were often found subsequently. Seven patients were classified as Zollinger-Ellison syndrome and seven as multiple endocrine neoplasia (6 MEN I and 1 MEN II). RESULTS: Tumors were small (mean 1.28cm) and located preferentially in the first and second part of the duodenum. Fifty-four were well-differentiated and one poorly differentiated. Immunochemistry revealed 30 G-cell tumors (54.6%), 15 D-cell (27.3%), two plurihormonal (EC cell and G cell), and one GRH-cell, whereas seven could not be classified. Fifteen patients died (five in relation to their disease). Twenty-one had metastases (liver, nodes, lung), eight of whom are still alive. CONCLUSIONS: Eighty-eight percent of duodenal endocrine tumors were gastrinomas, small plurifocal tumors and somatostatinomas preferentially located in the ampullar region and diagnosed because of hematemesis or icterus. Size is an important prognostic factor in determining whether surgery is required. The prognosis is better for D- and G-cell tumors than pancreatic endocrine tumors. Duodenal endocrine tumors in multiple endocrine neoplasia have a good prognosis, but can be associated with pancreatic plurihormonal tumors and metastases.

Does the use of routine duodenotomy (DUODX) affect rate of cure, development of liver metastases, or survival in patients with Zollinger-Ellison syndrome?

OBJECTIVE: To determine whether routine use of duodenotomy (DUODX) alters cure rate, survival, or development of liver metastases in 143 patients (162 operations) with Zollinger-Ellison syndrome (ZES) without MEN1. SUMMARY BACKGROUND DATA: DUODX has been shown to increase the detection of duodenal gastrinomas, but it is unknown if it alters rate of cure, liver metastases, or survival. Data from our prospective studies of surgery in ZES allow us to address this issue because DUODX was not performed before 1987, whereas it was routinely done after 1987. METHODS: All patients with sporadic ZES (non-MEN1) undergoing surgery for possible cure without a prior DUODX from November 1980 to June 2003 were included. Patients had preoperative computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound; if unclear, angiography and somatostatin receptor scintigraphy since 1994. At surgery, all had the same standard ZES operation and were assessed immediately postoperatively, at 3 to 6 months, and yearly for cure (fasting gastrin, secretin test. and imaging studies). RESULTS: A DUODX was performed in 79 patients (94 operations), and no DUODX was performed in 64 patients (68 operations), with 10 patients having both (no DUODX, then a DUODX later). Gastrinoma was found in 98% with DUODX compared with 76% with no DUODX (P < 0.00001). Duodenal gastrinomas were found more frequently with DUODX (62% vs. 18%; P < 0.00001), whereas pancreatic, lymph node, and other primary gastrinomas occurred similarly. Six of the 10 patients with 2 operations had a duodenal tumor found with DUODX during a second operation that was missed in the first operation without DUODX. Both the immediate postoperative cure rate (65% vs. 44%; P = 0.010) and long-term cure rate at last follow-up (8.8 +/- 0.4 years; range, 0.1 to 21.5) (52% vs. 26%; P = 0.0012) were significantly greater with a DUODX than without. In patients without pancreatic tumors or liver metastases at surgery, both the rate of developing liver metastases (6% vs. 9.5%) and the disease-related death rate (0% vs. 2%) were low and not significantly different in patients with or without a DUODX. CONCLUSIONS: These results demonstrate that routine use of DUODX increases the short-term and long-term cure rate due to the detection of more duodenal gastrinomas. The rate of development of hepatic metastases and/or disease-related mortality in patients without pancreatic tumors is low, and no effect of DUODX on these parameters was seen. Duodenotomy (DUODX) should be routinely performed during all operations for cure of sporadic ZES.

Morbidity and mortality of aggressive resection in patients with advanced neuroendocrine tumors.

BACKGROUND: There is considerable controversy about the treatment of patients with malignant advanced neuroendocrine tumors of the pancreas and duodenum. Aggressive surgery remains a potentially efficacious antitumor therapy but is rarely performed because of its possible morbidity and mortality. HYPOTHESIS: Aggressive resection of advanced neuroendocrine tumors can be performed with acceptable morbidity and mortality rates and may lead to extended survival. DESIGN: The medical records of patients with advanced neuroendocrine tumors who underwent surgery between 1997 and 2002 by a single surgeon at the University of California, San Francisco, were reviewed in an institutional review board-approved protocol. MAIN OUTCOME MEASURES: Surgical procedure, pathologic characteristics, complications, mortality rates, and disease-free and overall survival rates were recorded. Disease-free survival was defined as no tumor identified on radiological imaging studies and no detectable abnormal hormone levels. Proportions were compared statistically using the Fisher exact test. Kaplan-Meier curves were used to estimate survival rates. RESULTS: Twenty patients were identified (11 men and 9 women). Of these, 10 (50%) had gastrinoma, 1 had insulinoma, and the remainder had nonfunctional tumors; 2 had multiple endocrine neoplasia type 1, and 1 had von Hippel-Lindau disease. The mean age was 55 years (range, 34-72 years). In 10 patients (50%), tumors were thought to be unresectable according to radiological imaging studies because of multiple bilobar liver metastases (n = 6), superior mesenteric vein invasion (n = 3), and extensive nodal metastases (n = 1). Tumors were completely removed in 15 patients (75%). Surgical procedures included 8 proximal pancreatectomies (pancreatoduodenectomy or whipple procedure), 3 total pancreatectomies, 9 distal pancreatectomies, and 3 tumor enucleations from the pancreatic head. Superior mesenteric vein reconstruction was done in 3 patients. Liver resections were done in 6 patients, and an extended periaortic node dissection was performed in 1. The spleen was removed in 11 patients, and the left kidney was removed as a result of tumor metastases in 2. Eighteen patients had primary pancreatic tumors, and 2 had duodenal tumors; 2 patients with multiple endocrine neoplasia type 1 had both pancreatic and duodenal tumors. The mean tumor size was 8 cm (range, 0.5-23 cm). Of the patients, 14 (70%) had lymph node metastases and 8 (40%) had liver metastases. The mean postoperative hospital stay was 11.5 days (range, 6-26 days). Six patients (30%) had postoperative complications. There was a significantly greater incidence of pancreatic fistulas with enucleations compared with resections (P =.04). There were no operative deaths. The mean follow-up period was 19 months (range, 1-96 months); 18 patients (90%) are alive, 2 died of progressive tumor, and 12 (60%) are disease-free. The actuarial overall survival rate is 80% at 5 years, and disease-free survival rates indicate that all tumors will recur by the 7-year follow-up visit. CONCLUSIONS: Aggressive surgery including pancreatectomy, splenectomy, superior mesenteric vein reconstruction, and liver resection can be done with acceptable morbidity and low mortality rates for patients with advanced neuroendocrine tumors. Although survival rates following surgery are excellent, most patients will develop a recurrent tumor. These findings suggest that conventional contraindications to surgical resection, such as superior mesenteric vein invasion and nodal or distant metastases, should be reconsidered in patients with advanced neuroendocrine tumors.

Zollinger-Ellison syndrome in the era of effective acid suppression: are we unknowingly growing tumors?

Effective medical therapy of gastric hypersecretion in Zollinger-Ellison syndrome may delay the diagnosis of gastrinoma. To examine the impact of effective medical therapy on the surgical treatment of gastrinoma we reviewed the records of 108 patients diagnosed between 1948 and 1998 at a single institution. Minimum follow-up was 5 years. The experience was divided into four periods: I, 1955-1965-initial recognition, n = 11; II, 1966-1975-increasing recognition, n = 27; III, 1976-1985-widespread application of gastrin radioimmunoassay, n = 21; and IV, 1986-1998-widespread use of effective medical therapy, n = 49. There was no significant difference in age or sex in the groups. Gastric surgery was less common in period IV (37% compared with 86% to 100% in previous periods) as was total gastrectomy (6% compared with 43% to 78%; P <0.0001). Tumor resection was attempted in a similar percentage of patients in each group (57% to 67%). The incidence of metastatic disease in period III was 19% (P = 0.034 versus period I, 45%, period II, 56%, and period IV, 55%). The 5-year disease-free survival increased in period III to 29% (P = 0.001 versus period I, 0%, period II, 4%, and period IV, 2%). The results support the effectiveness of acid suppressive therapy by H2 antagonists and proton pump inhibitors as evidenced by the decrease in gastric surgery. However, in the era of effective medical therapy, the surgeon sees the patient with more advanced disease and 5-year cure is less likely. Physicians must maintain a high index of suspicion for this disease and not mask a potential malignancy with prolonged control of acid-related symptoms without taking steps to diagnose gastrinoma.

[Neuroendocrine tumors of the stomach. Surgery therapy and prognosis]. / Neuroendokrine Tumore des Magens. Chirurgische Therapie und Prognose.

Gastric carcinoid tumors are rare lesions characterized by hypergastrinemia that arise from enterochromaffin-like (ECL) cells of the stomach. A classification system distinguishing three types of gastric carcinoid tumors has been proposed: 1) tumors related to chronic atrophic gastritis, 2) tumors associated with Zollinger-Ellison syndrome, and 3) sporadic lesions. It is apparent that hypergastrinemia-associated gastric carcinoids show a rather benign biological behavior. Normo-gastrinemic sporadic lesions, on the other hand, require an aggressive surgical management. We report seven patients with gastric neuroendocrine tumors ("carcinoids"), who underwent surgical treatment in our department between 1988 and 2000. Surgical therapy included total gastrectomy with D2 lymphadenectomy in two cases with type I tumors and for one patient with type III tumor. One patient with a type II tumor was treated by distal subtotal gastrectomy and another by antrectomy. A local excision was performed on one patient with type I tumor. After a mean follow-up of 8 years, 5 of 7 patients are alive without recurrence.

Comparison of surgical results in patients with advanced and limited disease with multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome.

OBJECTIVE: To determine the role of surgery in patients with Zollinger-Ellison syndrome (ZES) and multiple endocrine neoplasia type 1 (MEN1) with either limited or advanced pancreatic endocrine tumors (PETs). SUMMARY BACKGROUND DATA: The role of surgery in patients with MEN1 and ZES is controversial. There have been numerous previous studies of surgery in patients with PETs; however, there are no prospective studies on the results of surgery in patients with advanced disease. METHODS: Eighty-one consecutive patients with MEN1 and ZES were assigned to one of four groups depending on the results of imaging studies. Group 1 (n = 17) (all PETs smaller than 2.5 cm) and group 3 (n = 8) (diffuse liver metastases) did not undergo surgery. All patients in group 2A (n = 17; single PET 2.5-6 cm [limited disease]) and group 2B (n = 31; two or more lesions, 2.5 cm in diameter or larger, or one lesion larger than 6 cm) underwent laparotomy. Tumors were preferably removed by simple enucleation, or if not feasible resection. Patients were reevaluated yearly. RESULTS: Pancreatic endocrine tumors were found in all patients at surgery, with groups 2A and 2B having 1.7 +/- 0.4 and 4.8 +/- 1 PETs, respectively. Further, 35% of the patients in group 2A and 88% of the patients in group 2B had multiple PETs, 53% and 84% had a pancreatic PET, 53% and 68% had a duodenal gastrinoma, 65% and 71% had lymph node metastases, and 0% and 12% had liver metastases. Of the patients in groups 2A and 2B, 24% and 58% had a distal pancreatectomy, 0% and 13% had a hepatic resection, 0% and 6% had a Whipple operation, and 53% and 68% had a duodenal resection. No patient was cured at 5 years. There were no deaths. The early complication rate, 29%, was similar for groups 2A and 2B. Mean follow-up from surgery was 6.9 +/- 0.8 years, and during follow-up liver metastases developed in 6% of the patients in groups 2A and 2B. Groups 1, 2A, and 2B had similar 15-year survival rates (89-100%); they were significantly better than the survival rate for group 3 (52%). CONCLUSIONS: Almost 40% of patients with MEN1 and ZES have advanced disease without diffuse distant metastases. Despite multiple primaries and a 70% incidence of lymph node metastases, tumor can be removed with no deaths and complication rates similar to those in patients with limited disease. Further, despite previous studies showing that patients with advanced disease have decreased survival rates, in this study the patients with advanced tumor who underwent surgical resection had the same survival as patients with limited disease and patients without identifiable tumor. This suggests that surgical resection should be performed in patients with MEN1 who have ZES and advanced localized PET.