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© 2001 American Society for Clinical Oncology Prognostic Value of Initial Fasting Serum Gastrin Levels in Patients With Zollinger-Ellison SyndromeFrom the Surgery Branch and Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute; Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases; and Department of Diagnostic Radiology, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD. Address reprint requests to H. Richard Alexander, MD, FACS, Surgery Branch, Center for Cancer Research, National Cancer Institute, Bldg 10, Rm 2B07, National Institutes of Health, Bethesda, MD 20892; email: richard_alexander{at}nih.gov
PURPOSE: To assess the value of the initial fasting serum gastrin (FSG) at presentation in patients with Zollinger-Ellison Syndrome (ZES) in predicting primary tumor characteristics and survival. PATIENTS AND METHODS: A total of 239 patients were treated for ZES between December 1981 and September 1998, with a mean follow-up of 9.1 ± 0.6 years. At initial evaluation, 86 patients (36%) had mild (0 to 499 pg/mL), 61 (25.5%) had moderate (500 to 1,000 pg/mL), and 92 (38.5%) had severe (> 1,000 pg/mL) elevations in FSG. Primary tumor location and size, presence of lymph node or hepatic metastases, and survival were analyzed based on the level of initial FSG. RESULTS: In patients with sporadic ZES, but not in those with multiple endocrine neoplasia type 1 (MEN-1) and ZES, there was a significant relationship between the level of initial FSG and tumor size and location of primary tumor, frequency of lymph node and liver metastases, and survival. The median 5- and 10-year survival decreased with increasing initial FSG (P < .001) in patients with sporadic ZES; MEN-1 patients lived longer than sporadic ZES patients (P = .012), and survival in this group was not associated with the level of initial FSG. Multivariate analysis showed that factors independently associated with death from disease in patients with sporadic ZES were liver metastases (P = .0001), a pancreatic site (P = .0027), and primary tumor size (P = .011) but not initial FSG (P > .30). CONCLUSION: The severity of FSG at presentation is associated with size and site of tumor and the presence of hepatic metastases, factors that are significant independent predictors of outcome. The level of FSG at presentation may be useful in planning the nature and extent of the initial evaluation and management in patients with sporadic ZES.
ZOLLINGER AND ELLISON first described the syndrome of a pancreatic islet cell tumor associated with fulminant peptic ulcer disease in 1955.1 Originally, the management of Zollinger-Ellison syndrome (ZES) consisted of total gastrectomy to palliate the sequelae of severe gastric acid hypersecretion,2 but in the 1970s it became possible to control the ulcer diathesis in ZES patients with H2 histamine antagonists such as cimetidine.3 Since the 1980s, agents that block the H+-K+-adenosine triphosphate pump, such as omeprazole, have been routinely used. Both of these agents have been demonstrated to effectively control gastric acid hypersecretion in 100% of patients in most series.4 Therefore, the current goal of operation in patients with ZES is attempted curative resection of the gastrinoma, primarily to control the malignant potential of the tumor. With current preoperative imaging techniques and careful operative exploration, gastrinoma can be identified and resected in more than 95% of patients.5-7 However, in patients with sporadic ZES undergoing operation with curative intent, the 5- and 10-year disease-free survival rates are only 40% and 34%, respectively.8 The most important diagnostic test for patients with ZES is an elevated fasting serum gastrin (FSG) in the presence of gastric acid hypersecretion after discontinuation of acid reduction medications.9 More than 99% of patients with ZES have an elevated (> 100 pg/mL) FSG. However, hypergastrinemia can also be present after massive small bowel resection or secondary to gastric outlet obstruction, antral G-cell hyperplasia, Helicobacter pylori infection, or retained gastric antrum after gastrectomy. An FSG greater than 1,000 pg/mL is virtually diagnostic of ZES, but approximately 68% of patients with ZES will have only a moderate elevation of FSG between 100 and 1,000 pg/mL.10 In these patients, a secretin stimulation test will help distinguish between ZES and other conditions.11 It is not known whether the level of FSG at the initial presentation in patients with ZES has important or useful prognostic information with respect to the location or size of the gastrinoma, the overall disease burden (including the presence of regional lymph node or occult hepatic metastases), and survival. In patients with medullary thyroid cancer, the level of pretreatment basal or stimulated calcitonin has well-established prognostic information and predicts disease burden and outcome in patients undergoing operation with curative intent.12 The malignant nature of gastrinoma is highlighted by the fact that less than half of patients with sporadic ZES and virtually none with multiple endocrine neoplasia type 1 (MEN-1) and ZES undergoing operation with curative intent are cured.8 Lymph node metastases are identified in approximately half of the patients at the time of operation, and the presence of hepatic metastases is associated with only a 50% 5-year survival rate.13 To date, only a normal postoperative FSG and secretin stimulation test have been shown to significantly and independently correlate with long-term (5 or more years) biochemical cure rate in ZES patients after resection with curative intent.14 Furthermore, recent studies show that, in approximately 25% of patients, the disease pursues an aggressive course with the development of liver metastases, which are the leading determinant of shortened survival.13,15 The purpose of this study was to determine whether the degree of FSG elevation in ZES patients at presentation has significant predictive value with respect to tumor location and size or is a significant prognostic factor with respect to the incidence of regional lymph node or liver metastases and survival in patients undergoing resection with curative intent.
Between December 1981 and September 1998, we identified 239 patients from a prospectively maintained database who underwent evaluation for ZES. Patients were referred to the National Institutes of Health (NIH) in Bethesda, MD, for evaluation and treatment of ZES on an approved institutional protocol. Patients were initially evaluated with FSG and acid secretory studies such as basal acid output and maximal acid output. All diagnostic studies were performed when patients were not receiving any antisecretory therapy to eliminate confounding influences of these agents. The diagnosis of ZES was established if two of the following three criteria were met: (1) elevated FSG (more than 100 pg/mL), (2) basal acid output (more than 15 mEq/h or more than 5 mEq/h in patients with history of a previous acid reduction operation), and (3) an incremental increase in serum gastrin after stimulation tests (more than 200 pg/mL after secretin or 395 pg/mL after calcium). The diagnosis of MEN-1 in study patients was made based on a family history compatible with the syndrome and the presence of associated endocrinopathies that occur in MEN-1. The initial evaluation also included standard imaging studies to identify the location and extent of disease. The tests routinely include abdominal ultrasonography, abdominal computed tomography, and selective hepatic, gastroduodenal, splenic, and superior mesenteric angiography as previously described.8,16 Additionally, beginning in 1987, patients underwent magnetic resonance imaging of the abdomen, and from January 1988, many patients underwent secretin stimulation angiography with the collection of blood from the main hepatic veins for gastrin concentrations after selective intra-arterial injection of secretin as previously described.17,18 Finally, beginning in 1994, all patients underwent somatostatin receptor scintigraphy.19
The FSG level used for analysis was the mean of the initial values (n In the absence of unresectable metastatic disease on imaging studies, all patients with sporadic disease underwent a standardized operation and resection of all identifiable disease.20 Patients with ZES with MEN-1 underwent a standardized operation if a tumor greater than 3 cm in diameter was imaged as described previously.8,21 Briefly, using a bilateral subcostal incision or a midline abdominal incision, an initial complete abdominal exploration was performed, including the small and large intestines and pelvis. The omentum and liver were explored, including intraoperative ultrasound of both lobes of the liver. After this, the entire pancreas and parts of the duodenum were exposed via the lesser sac and a Kocher maneuver. The pancreas was completely evaluated by inspection, palpation, and intraoperative ultrasound. Additionally, the peripancreatic, periportal, and celiac nodes were evaluated in a similar manner. Beginning in 1988, all patients had undergone a systematic exploration of the duodenum; this included external palpation, intraoperative endoscopy with transillumination, and exploratory duodenotomy.22 An attempt was then made to remove all identifiable disease by excision or enucleation. All patients were followed-up with biochemical and imaging studies at regular intervals. Patients underwent evaluation of FSG and secretin stimulation within the first week postoperatively and then 3 to 6 months after operation. After this, patients were followed-up yearly with functional and imaging studies to determine whether they were biochemically free of disease or had recurrent or persistent disease. Patients were defined as disease-free if the FSG level was normal, the secretin provocative test was negative, and all imaging studies were negative.8,23 Patients who were initially disease-free but in whom there was subsequent development of abnormalities consistent with ZES were defined as having recurrent disease. Persistent disease was defined as continued abnormalities of biochemical or imaging studies with no period of normalization after the initial operation. Survival curves were plotted using the method of Kaplan and Meier. The association between survival and various potential risk factors was analyzed by the likelihood ratio test of the multivariate Cox proportional hazards regression model. Statistical analyses of the FSG data were performed using the Cochran-Armitage test, the Fisher-Freeman-Halton test and the Kendall’s tau-b test. The choice of statistical test was made based on the number of categories and if there was inherent ordering in the categories being analyzed.
A total of 239 patients (139 male and 100 female) were evaluated and treated for ZES at the NIH in the study period (Table 1). The mean age was 46.1 years, with a range of 11 to 70 years. For the purpose of analysis, patients were classified into groups based on the level of initial FSG, including mild (0 to 499 pg/mL, n = 86, 36%), moderate (500 to 1,000 pg/mL, n = 61, 25.5%) or severe ( > 1,000 pg/mL, n = 92, 38.5%) hypergastrinemia. The majority of patients (78%) had sporadic ZES.
Of the 239 patients, 60 (25%) had proven liver metastases either initially or sometime during the follow-up period. The follow-up period was a mean of 9.1 ± 0.6 years (range, 0.1 to 33.6 years), with 72% of the patients followed-up yearly for greater than 5 years. In evaluating the serum FSG levels of these patients, there was a significant correlation between the initial FSG and the presence of liver metastases (Table 2). The number of patients with liver metastases increased as the serum FSG level increased from mild to moderate to severe (14% to 20% to 39%, respectively). When the analysis was performed separating sporadic from MEN-1 ZES patients, the significance of the correlation became even stronger for sporadic ZES (P = .00005) and was eliminated in patients with ZES with MEN-1 (P = .35).
To evaluate the extent of disease present at operation, we divided patients into groups based on the location(s) of tumor(s) at exploration—ie, no tumor found, primary tumor only, or liver and/or lymph node metastases. These data (Table 3) demonstrate several interesting trends. Of the 12 patients who did not have a tumor identified during operation, eight had a preoperative FSG of less than 500 pg/mL, and the percentage of patients who had no tumor identified at operation decreased significantly in the higher gastrin categories (P = .036). Similarly, the percentage of patients who had only a primary tumor also progressively decreased significantly (P < .0001) as the initial FSG level increased from mild to moderate to severe (53% to 34% to 21%, respectively). On the other hand, there was a significant (P < .00001) increase in the number of patients with metastatic disease to either the liver or lymph nodes as the magnitude of the initial FSG increased (Table 3). In particular, as the serum FSG level increased from mild to severe, the incidence of lymph node and/or liver metastases increased from 35% to 76%. The majority of patients in the moderate and severe FSG groups (62% and 76%) had metastatic disease at exploration.
Next, we examined the relationship between tumor size and the initial FSG levels. In this analysis, tumor size was grouped as 1 cm in diameter or smaller, 1.1 to 3 cm, and greater than 3 cm. In patients with an initial FSG less than 500 pg/mL, the majority (54%) of tumors were 1 cm or smaller (Table 4). There was a significant increase in the proportion of patients with tumors larger than 3 cm as the FSG level increased (21% to 30% to 49%, respectively), as well as a corresponding decrease in the frequency of patients with tumors smaller than 1 cm with increasing FSG (Table 4). Again, these associations were seen only in patients with sporadic ZES and not those with MEN-1–associated ZES, most likely owing to the selective nature in which patients with ZES and MEN-1 were offered operation.
The majority (61%) of patients with FSG less than 500 pg/mL had primary tumors located in the duodenum, whereas 47% of patients with the largest elevations in FSG had a pancreatic primary (Table 5). There was a significant association between increasing frequency of pancreatic tumors with increasing initial FSG (15% to 35% to 47%, respectively). The decreasing frequency of duodenal tumors as the severity of FSG increased (61% to 43% to 31%, respectively) was also significant. Because a high proportion of patients with ZES and MEN-1 have duodenal primary tumors, the correlation was only significant for patients with sporadic ZES.
Next, we evaluated the relationship between survival and the initial FSG. There were a total of 41 deaths (17%) during a follow-up period of 9.1 ± 0.6 years (range, 0.1 to 33.5 years). Ranitidine or omeprazole effectively controlled gastric acid hypersecretion as assessed by regularly performed gastric analyses in all patients in this series, and all deaths from disease were due to the malignant progression of tumor. Only four deaths (10%) occurred in patients with MEN-1, whereas the other 37 deaths occurred in sporadic ZES patients. MEN-1 patients had a significantly longer survival than patients with sporadic ZES (P = .012), but there was no difference in survival in MEN-1 patients when analyzed based on the initial FSG (P = .068). However, when outcome in sporadic ZES patients was analyzed based on the level of the initial hypergastrinemia, there was a significant correlation between survival and initial FSG levels (Fig 1, P = .0006). The median 5- and 10-year survival decreased with increasing FSG levels (Table 6).
Multivariate analysis showed that factors independently associated with death from disease in patients with sporadic ZES were liver metastases, a pancreatic site, and tumor size larger than 3 cm, but not initial FSG (P > .30). The estimated relative risk of death from disease was 5.0 (P = .0001) for liver metastases, 5.9 (P = .0027) for a pancreatic site, and 3.1 (P = .011) for tumor size larger than 3 cm. In patients with sporadic ZES, the significant association between initial FSG determined at presentation and multiple independent prognostic factors identified only with subsequent imaging studies or at operation supports its value in providing predictive information with respect to tumor size, location, presence of metastases, and survival.
We advocate that patients who have been biochemically diagnosed with ZES undergo imaging studies to determine the extent of disease. In the absence of diffuse metastases, those with sporadic ZES and those with MEN-1 who have a tumor present on imaging studies of at least 3 cm in diameter should undergo a standard abdominal exploration with attempted resection of all disease.8,24 Using this approach, we have achieved 5- and 10-year disease-free survival rates (defined as normal FSG, normal secretin stimulation test, and negative imaging studies) in 40% and 34% of patients with sporadic ZES, respectively.8 Although none of the patients with ZES and MEN-1 had long-term cure after operation, the overall disease-specific mortality in all patients was less than 5%, highlighting the indolent nature of tumor progression in this population. In the absence of biochemical cure, up to 70% of patients have a significant amelioration in the biochemical severity of their disease after surgery.25,26 The benefit of operation and resection of gastrinoma with curative intent has not been definitively established. In one retrospective series comparing patients who underwent operation with curative intent to a cohort who received medical management and observation, the incidence of hepatic metastases was significantly lower in those who underwent surgery.27 However, conclusions drawn from this experience are limited by the fact that there were no prospectively established selection criteria to determine which treatment was offered to individuals in each group. Previous studies have been inconclusive with respect to the value of serum gastrin as a predictor of disease extent, with one showing no correlation and another showing a correlation with the presence of metastatic disease.28,29 The results of these studies were primarily limited by small numbers of patients, limited follow-up, and lack of regular, thorough evaluations for follow-up tumor extent. No studies have evaluated FSG as a predictor of primary tumor location or primary tumor size. The present study was designed to determine the possible predictive value of the initial FSG level for these parameters. Because a large number of patients were studied (n = 239), the follow-up period was long (up to 30 years), and all patients had yearly biochemical studies and imaging evaluations with a least three modalities (computed tomography, magnetic resonance imaging, and ultrasound), our results do not have these limitations. At present there are no reliable means of predicting the rate of tumor progression in a given patient. Recent studies indicate that 75% of patients with ZES will have a benign clinical course, with tumors increasing in size slowly over time and with limited metastatic potential.13,15 In contrast, 25% of patients have gastrinomas that pursue an aggressive course with progressive tumor growth and the development of liver metastases. Any study that provides predictive information on tumor extent, location, or the subsequent biologic behavior of the tumor with respect to its potential to metastasize and shorten survival would be of benefit in determining the appropriate initial imaging paradigm or guiding the nature of an operation to resect disease. For example, after initial diagnosis a large number of imaging studies (including ultrasound, computed tomography, magnetic resonance imaging, somatostatin-receptor scintigraphy, endoscopic ultrasound, and angiography with or without selective intra-arterial calcium stimulation) are available in staging patients with ZES, and each has certain limitations and advantages.9,23 The extent of preoperative imaging necessary in ZES patients is not known but, in patients with high initial FSG levels, a more extensive preoperative evaluation would seem justified to identify possible lymph node or liver metastases. At operation we routinely perform a systematic evaluation of the pancreas, duodenum, regional lymph nodes, and liver using inspection, palpation, intraoperative ultrasound, endoscopic duodenal transillumination, and duodenotomy to identify and extirpate all disease.8,14,22 Our experience indicates that almost half of all ZES patients undergoing operation will have a gastrinoma in the duodenum, that the average size is less than 1 cm, that the majority will not be localized to the duodenum on preoperative imaging studies, and that the most sensitive method for identifying these lesions is duodenotomy.8,22 Because of the rarity of this condition, it is likely that the systematic intraoperative search for a gastrinoma, particularly duodenal lesions, may be done with different degrees of diligence by various individuals. If the initial FSG is only mildly elevated, one should be prepared to use intraoperative endoscopic duodenal transillumination and duodenotomy to identify a possible duodenal primary tumor. More than 60% of patients with mild FSG levels (ie, < 500 pg/mL) had a primary tumor in the duodenum, and only 35% had metastatic disease on exploration. In the event of a more severe elevation in FSG, intraoperative ultrasound may be important to identify a primary pancreatic tumor or liver metastases. In patients who had an FSG more than 1,000 pg/mL, 47% had a primary tumor in the pancreas and 76% had liver and/or lymph node metastases, the latter of which portends a worse survival in ZES patients.13 The correlation between initial FSG and both the site and size of the primary tumor may be explained in part, but not completely, by previous observations that larger tumors are more commonly found in the pancreas.13 With respect to site of primary disease, duodenal tumors are generally smaller than 1 cm,30 whereas pancreatic gastrinomas tend to be larger.13 However, duodenal tumors are as frequently associated with lymph node metastases8 so that the correlation between site of primary and FSG levels is not necessarily secondary to associated lymph node metastases in patients with pancreatic primary tumors. The selective criteria used for operation in patients with ZES and MEN-1 requiring a tumor larger than 3 cm be present on imaging studies for exploration likely accounted for the failure to find prognostic information with respect to FSG and primary tumor size and location in any patients with MEN-1. These data are comparable to those previously established by Wells et al31 in patients with medullary carcinoma of the thyroid using preoperative basal serum calcitonin (CT) levels. They demonstrated that patients with the highest preoperative CT levels had the worst prognosis and that a markedly elevated CT level was associated with a high incidence of regional lymph node metastases31 and a larger primary tumor size.32 In this study, we have shown that the degree of elevation in initial FSG levels at presentation is also an important factor in predicting location and size of tumor and frequency of metastases to regional lymph nodes and liver for patients with sporadic ZES. On multivariate analysis, these parameters were independent prognostic parameters significantly associated with disease-specific survival. Therefore, the initial FSG, which is easily obtained at diagnosis, is valuable in providing predictive information with respect to location and extent of disease and survival.
1. Zollinger RM, Ellison EH: Primary peptic ulceration of the jejunum associated with islet cell tumors of the pancreas. Ann Surg 142: 709-728, 1955[Medline] 2. Thompson JC, Lewis BG, Wiener I, et al: The role of surgery in the Zollinger-Ellison syndrome. Ann Surg 197: 594-607, 1983[Medline] 3. Jensen RT, Collen MJ, McArthur KE, et al: Comparison of the effectiveness of ranitidine and cimetidine in inhibiting acid secretion in patients with gastric hypersecretory states. Am J Med 77: 90-105, 1984[Medline] 4. Frucht H, Maton P, Jensen RT: The use of omeprazole in patients with Zollinger-Ellison syndrome. Dig Dis Sci 36: 405-408, 1991[Medline] 5. Howard TJ, Zinner MJ, Stabile BE, et al: Gastrinoma excision for cure. Ann Surg 211: 9-14, 1990[Medline] 6. Fedorak IJ, Ko TC, Gordon D, et al: Localization of islet cell tumors of the pancreas: A review of current techniques. Surgery 113: 242-249, 1993[Medline] 7. Zeiger MA, Shawker TH, Norton JA: Use of intraoperative ultrasonography to localize islet cell tumors. World J Surg 17: 448-454, 1993[Medline]
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Norton JA, Fraker DL, Alexander HR, et al: Surgery to cure the Zollinger-Ellison syndrome. N Engl J Med 341: 635-644, 1999 9. Alexander HR Jr, Jensen RT, Doppman JL: Pancreatic Endocrine Tumors, in Torosian M (ed): Integrated Cancer Management: Surgery Medical Oncology and Radiation Oncology. New York, NY: Marcel Dekker, 1999, pp 241-268 10. Frucht H, Howard JM, Slaff JF: Secretin and calcium provocative tests in patients with Zollinger-Ellison syndrome: A prospective study. Ann Intern Med 111: 713-722, 1989 11. Wolfe MM, Jensen RT: Zollinger-Ellison syndrome: Current concepts in diagnosis and management. N Engl J Med 317: 1200-1209, 1987[Abstract] 12. Cance WG, Wells SA Jr: Multiple endocrine neoplasia type IIa. Curr Probl Surg 22: 1-56, 1985[Medline] 13. Weber HC, Venzon DJ, Fishbein VA, et al: Determinants of metastatic rate and survival in patients with Zollinger-Ellison syndrome (ZES): A prospective long-term study. Gastroenterology 108: 1637-1649, 1995[Medline] 14. Alexander HR, Bartlett DL, Venzon DJ, et al: Analysis of factors associated with long-term (five or more years) cure in patients undergoing operation for Zollinger-Ellison syndrome. Surgery 124: 1160-1166, 1998[Medline]
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Yu F, Venzon DJ, Serrano J, et al: Prospective study of the clinical course, prognostic factors, causes of death, and survival in patients with long-standing Zollinger-Ellison syndrome. J Clin Oncol 17: 615-630, 1999 16. Maton PN, Miller DL, Doppman HL, et al: Role of selective angiography in the management of Zollinger-Ellison syndrome. Gastroenterology 92: 913-919, 1987[Medline]
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Doppman JL, Miller DL, Chang R, et al: Gastrinomas: Localization by means of selective intraarterial injection of secretin. Radiology 174: 25-29, 1990 18. Thom AK, Norton JA, Doppman JL, et al: A prospective study of the use of intraarterial secretin injection and portal venous sampling to localize duodenal gastrinomas. Surgery 112: 1002-1008, 1992[Medline]
19.
Gibril F, Reynolds JC, Doppman JL, et al: Somatostatin receptor scintigraphy: Its sensitivity compared with that of other imaging methods in detecting primary and metastatic gastrinomas—A prospective study. Ann Intern Med 125: 26-34, 1996 20. Fraker DL, Alexander HR: The surgical approach to endocrine tumors of the pancreas. Semin Gastrointest Dis 6: 102-113, 1995[Medline] 21. MacFarlane MP, Fraker DL, Alexander HR, et al: A prospective study of surgical resection of duodenal and pancreatic gastrinomas. Surgery 118: 973-980, 1995[Medline] 22. Sugg SL, Norton JA, Fraker DL, et al: A prospective study of intraoperative methods to diagnose and resect duodenal gastrinomas. Ann Surg 218: 2-138, 1993 23. Alexander HR, Fraker DL, Norton JA, et al: Prospective study of somatostatin receptor scintigraphy and its effect on operative outcome in patients with Zollinger-Ellison syndrome. Ann Surg 228: 228-238, 1998[Medline] 24. Harmon JW, Norton JA, Collen MJ: Removal of gastrinomas for control of Zollinger-Ellison syndrome. Ann Surg 200: 396-404, 1984[Medline] 25. Norton JA, Doppman JL, Jensen RT: Curative resection in Zollinger-Ellison syndrome: Results of a 10 year prospective study. Ann Surg 215: 8-18, 1992[Medline] 26. Norton JA, Doppman JL, Collen MJ, et al: Prospective study of gastrinoma localization and resection in patients with Zollinger-Ellison syndrome. Ann Surg 204: 468-479, 1986[Medline] 27. Fraker DL, Norton JA, Alexander HR, et al: Surgery in Zollinger-Ellison syndrome alters the natural history of gastrinoma. Ann Surg 220: 320-330, 1994[Medline] 28. Kothary PC, Fabri PJ, Gower W, et al: Evaluation of NH2-terminus gastrins in gastrinoma syndrome. J Endocrinol Metab 62: 970-974, 1986[Abstract] 29. Bardram L: Progastrin in serum from Zollinger-Ellison patients: An indicator of malignancy? Gastroenterology 98: 1420-1426, 1990[Medline] 30. Thom AK, Norton JA, Axiotis CA, et al: Location, incidence and malignant potential of duodenal gastrinomas. Surgery 110: 1086-1093, 1991[Medline] 31. Wells SA Jr, Baylin SG, Leight GS, et al: The importance of early diagnosis in patients with hereditary medullary thyroid carcinoma. Ann Surg 195: 595-599, 1982[Medline] 32. Wells SA Jr, Baylin SB, Gann DW, et al: Medullary thyroid carcinoma: Relationship of method of diagnosis to pathological staging. Ann Surg 188: 377-383, 1978[Medline] Submitted May 25, 2000; accepted March 16, 2001. This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
3) obtained at the NIH before any surgical or other antitumor treatment. We determined which of the 239 patients in the prospectively maintained database had liver metastases on presentation. This included patients with preoperatively or intraoperatively diagnosed liver metastases. The extent of disease and primary tumor site were determined for the 189 patients (79%) who underwent a full abdominal exploration. Extent of disease in patients was classified as no tumor identified, a primary tumor only located at exploration, or the presence of liver and/or lymph node metastases. For evaluation of tumor site, patients were placed into groups with pancreatic, duodenal, or other tumors. This analysis was based on 149 patients in whom only one primary site was identified at operation. Finally, tumor size was determined by in situ measurement of the tumor in the largest diameter and the patients were categorized as having a tumor less than 1 cm, 1.1 to 2.9 cm, or greater than 3 cm according to the diameter of the largest tumor. There were 197 patients who had one known tumor size that was measured and correlated with the initial FSG. 
