Jeffrey A. Norton

Surgery to cure the Zollinger-Ellison syndrome.

BACKGROUND AND METHODS The role of surgery in patients with the Zollinger-Ellison syndrome is controversial. To determine the efficacy of surgery in patients with this syndrome, we followed 151 consecutive patients who underwent laparotomy between 1981 and 1998. Of these patients, 123 had sporadic gastrinomas and 28 had multiple endocrine neoplasia type 1 with an imaged tumor of at least 3 cm in diameter. Tumor-localization studies and functional localization studies were performed routinely. All patients underwent surgery according to a similar operative protocol, and all patients who had surgery after 1986 underwent duodenotomy. RESULTS The 151 patients underwent 180 exploratory operations. The mean (+/-SD) follow-up after the first operation was 8+/-4 years. Gastrinomas were found in 141 of the patients (93 percent), including all of the last 81 patients to undergo surgery. The tumors were located in the duodenum in 74 patients (49 percent) and in the pancreas in 36 patients (24 percent); however, primary tumors were found in lymph nodes in 17 patients (11 percent) and in another location in 13 patients (9 percent). The primary location was unknown in 24 patients (16 percent). Among the patients with sporadic gastrinomas, 34 percent were free of disease at 10 years, as compared with none of the patients with multiple endocrine neoplasia type 1. The overall 10-year survival rate was 94 percent. CONCLUSIONS All patients with the Zollinger-Ellison syndrome who do not have multiple endocrine neoplasia type 1 or metastatic disease should be offered surgical exploration for possible cure.

Determinants of metastatic rate and survival in patients with zollinger-ellison syndrome: A prospective long-term study

BACKGROUND/AIMS It is unclear whether tumor location, size, or the presence of multiple endocrine neoplasia type 1 (MEN-1) alters metastatic rate and survival in patients with pancreatic endocrine tumors. The purpose of this study was to determine the prognostic factors of survival and metastatic rate in patients with Zollinger-Ellison syndrome (ZES). METHODS Data were analyzed from 185 consecutive patients with ZES who were followed up prospectively. RESULTS Liver metastases were present in 24% of patients and correlated with the size of the primary tumor. Duodenal tumors were smaller than pancreatic tumors. Liver metastases occurred more often (P < 0.00001) with pancreatic than duodenal tumors, whereas the metastatic rate to lymph nodes was not different. Survival of patients with liver but not lymph node metastases was shortened. In patients with sporadic ZES, liver metastases were more common during the initial evaluation and survival was decreased compared with patients with MEN-1; however, during follow-up, an equal percentage of patients with and without MEN-1 developed liver metastases. CONCLUSIONS Survival was primarily determined by the presence of liver metastases. The frequency of liver metastases depends on the size and location of the primary tumor and on the presence of MEN-1 at the initial presentation. Metastases to the lymph nodes do not depend on these factors. A benign and malignant form of ZES exists.

Predictive DNA Testing and Prophylactic Thyroidectomy in Patients at Risk for Multiple Endocrine Neoplasia Type 2A

BackgroundMissense germ-line mutations in the RET protooncogene are associated with multiple endocrine neoplasia type 2A (MEN 2A). Detection of these mutant alleles in kindred members predicts disease inheritance and provides the basis for preventative thyroidectomy. MethodsA polymerase chain reaction (PCR)-based genetic test for the 19 known RET mutations was designed to study 132 members of 7 kindreds with MEN 2A. Haplotypes also were constructed using genetic markers flanking the MEN 2A locus. Plasma calcitonin (CT) concentrations were determined before and after provocative testing. ResultsDirect DNA testing and haplotype analysis showed that 21 of 58 kindred members at risk for disease had inherited a mutation in the RET protooncogene associated with MEN 2A. Plasma CT concentrations were elevated in 9 of the 21 family members, but were normal in 12. After genetic counseling, 13 of the 21 kindred members (6 with normal and seven with elevated plasma CT levels), consented to immediate thyroidectomy. In each patient, the resected thyroid gland showed C-cell hyperplasia with or without medullary thyroid carcinoma. There were no metastases to regional lymph nodes, and postoperative stimulated plasma CT levels were normal. ConclusionThe PCR-based direct DNA test for RET mutations is accurate, rapid, and reproducible. For all 132 individuals evaluated, the results of direct DNA analysis were consistent with haplotype studies. The direct test for mutations in the RET protooncogene is the preferred method for screening MEN 2A kindreds. In family members who have inherited a RET mutation, total thyroidectomy is indicated, regardless of the plasma CT values.

Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research

25–30% of families fulfilling the criteria for hereditary diffuse gastric cancer have germline mutations of the CDH1 (E-cadherin) gene. In light of new data and advancement of technologies, a multidisciplinary workshop was convened to discuss genetic testing, surgery, endoscopy and pathology reporting. The updated recommendations include broadening of CDH1 testing criteria such that: histological confirmation of diffuse gastric criteria is only required for one family member; inclusion of individuals with diffuse gastric cancer before the age of 40 years without a family history; and inclusion of individuals and families with diagnoses of both diffuse gastric cancer (including one before the age of 50 years) and lobular breast cancer. Testing is considered appropriate from the age of consent following counselling and discussion with a multidisciplinary team. In addition to direct sequencing, large genomic rearrangements should be sought. Annual mammography and breast MRI from the age of 35 years is recommended for women due to the increased risk for lobular breast cancer. In mutation positive individuals prophylactic total gastrectomy at a centre of excellence should be strongly considered. Protocolised endoscopic surveillance in centres with endoscopists and pathologists experienced with these patients is recommended for: those opting not to have gastrectomy, those with mutations of undetermined significance, and in those families for whom no germline mutation is yet identified. The systematic histological study of prophylactic gastrectomies almost universally shows pre-invasive lesions including in situ signet ring carcinoma with pagetoid spread of signet ring cells. Expert histopathological confirmation of these early lesions is recommended.

Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management and controversies

Pancreatic endocrine tumors (PETs) can occur as part of 4 inherited disorders, including Multiple Endocrine Neoplasia type 1 (MEN1), von Hippel‐Lindau disease (VHL), neurofibromatosis 1 (NF‐1) (von Recklinghausen disease), and the tuberous sclerosis complex (TSC). The relative frequency with which patients who have these disorders develop PETs is MEN1>VHL>NF‐1>TSC. Over the last few years, there have been major advances in the understanding of the genetics and molecular pathogenesis of these disorders as well in the localization and the medical and surgical treatment of PETs in such patients. The study of PETs in these disorders not only has provided insights into the possible pathogenesis of sporadic PETs but also has presented several unique management and treatment issues, some of which are applicable to patients with sporadic PETs. Therefore, the study of PETs in these uncommon disorders has provided valuable insights that, in many cases, are applicable to the general group of patients with sporadic PETs. In this article, these areas are reviewed briefly along with the current state of knowledge of the PETs in these disorders, and the controversies that exist in their management are summarized briefly and discussed. Cancer 2008;113(7 suppl):1807–43. Published 2008 American Cancer Society.

Localization of Insulinomas to Regions of the Pancreas by Intra-arterial Stimulation with Calcium

Despite the introduction of sophisticated cross-sectional imaging techniquescomputed tomography, magnetic resonance imaging, and ultrasonographythe localization of insulinomas smaller than 2 cm remains a problem. In our previous experience [1], these noninvasive methods of localization had sensitivities of 17% (computed tomography), 25% (magnetic resonance imaging), and 26% (ultrasonography). Our results may have been biased because most patients have negative results on noninvasive imaging studies before referral to the National Institutes of Health. Of the invasive localization techniques, pancreatic arteriography visualized 35% of small (<2 cm) insulinomas. The success of portal venous sampling does not depend on tumor size, and this method localized insulinomas in 77% of patients. However, percutaneous portal venous sampling requires special skills and experience and is associated with slight but significant morbidity [2]. We have developed a technique with which one can localize insulinomas before surgery by stimulating the release of insulin using selective intra-arterial injections of calcium gluconate as a secretagogue and then measuring insulin levels in the right hepatic vein. The results in our first 9 patients were promising [3, 4], and we have since studied an additional 16 patients with surgically proven insulinomas. We present the results of arterial stimulation and venous sampling in these 25 patients studied over the past 4 years. Methods Diagnosis of insulin-secreting islet cell tumor was based on the development of symptomatic hypoglycemia (blood glucose level, <40 mg/100 mL) with inappropriate plasma insulin levels during prolonged fasting. Ten of the patients were men and 15 were women; their average age was 43 years (range, 24 to 72 years). Five patients had had previous unsuccessful explorations of the pancreas, and 3 had had distal pancreatectomy during these explorations. Two patients had multiple endocrine neoplasia type I.1;0 Most of the 25 patients had had computed tomography (n = 23), magnetic resonance imaging (n = 21), and ultrasonography (n = 22) before having arteriography with calcium stimulation. The first 9 patients had portal venous sampling, but this procedure was not done in the other 16 patients because analysis showed that calcium stimulation provided similar information with less morbidity. This decision was supported by the similar sensitivities of portal venous sampling and intra-arterial secretin stimulation in our patients with the Zollinger-Ellison syndrome [5, 6]. Computed tomography (done using a 9800 HiLite, General Electric, Milwaukee, Wisconsin) was done with 5-mm contiguous sections through the pancreas during the bolus injection of 130 mL of iodinated contrast material (iopamidol [Isovue 300, Bristol-Myers Squibb, Princeton, New Jersey]) at 2 mL per second. Magnetic resonance imaging was done using a 0.5-Tesla scanner (Picker, Highland Heights, Ohio) with 10-mm thick axial T1-weighted (repetition time [TR]/echo time [TE] = 300/10) and short inversion time inversion recovery (STIR) (TR/TI [inversion time]/TE = 1800-2200/100/30) sequences. Gadopentetate dimeglumine (Magnevist, Berlex Lab, Wayne, New Jersey) was not given. Ultrasonography was done using a 3.5- or 5-MHz phased-array sector transducer (Acuson, Mountain View, California). Pancreatic arteriography was done by selectively injecting nonionic contrast agent (Isovue 300) into the gastroduodenal, splenic, and superior mesenteric arteries. Care was taken to position the catheter at the origin of these vessels so that major pancreatic arteries originating proximally from these vessels, such as the dorsal pancreatic and pancreatic magna arteries, would be perfused. Selective arteriography of the dorsal pancreatic and pancreatic magna arteries was occasionally done, but we did not infuse calcium into these small pancreatic branches because we feared that doing so might increase the risk for pancreatitis. After each selective arteriogram, calcium gluconate 10% (Lyphomed, Rosemont, Illinois), diluted with saline to a volume of 5 mL, was injected into the selectively catheterized artery at a dose of 0.025 mEq Ca++/kg body weight. Blood samples (5 mL) for insulin determination were obtained from the right (n = 25) and left (n = 17) hepatic veins before and 30, 60, and 120 seconds after calcium infusion. Specimens from the hepatic veins were placed on ice, and plasma was separated in a refrigerated centrifuge and stored at 20C until insulin levels were measured by radioimmunoassay. Samples were obtained from the left as well as the right hepatic vein in the first 17 patients because of concern that an insulinoma in the body or tail of the pancreas might be overlooked if splenic venous effluent streamed into the left hepatic lobe. However, it is more difficult to place and maintain a catheter in the left than in the right hepatic vein. To determine whether diagnostic elevations of insulin levels were ever seen only in the left hepatic vein, we compared insulin levels in the right and left hepatic veins in a subset of 10 patients whose insulinomas were in the pancreatic body and tail. The insulinomas ranged in size from 6 to 25 mm (average, 15 mm). Twelve were located to the right of the superior mesenteric artery (pancreatic head and neck), and 13 were located to the left (pancreatic body and tail). All tumors of the head and neck were enucleated. Tumors of the body and tail were removed by enucleation (n = 5) or distal pancreatectomy (n = 8). Intraoperative ultrasonography (10-MHz transducer, Diasonics, Santa Clara, California) was done in each patient to visualize the tumor, to identify major pancreatic and biliary ducts adjacent to the tumor, and to direct the pancreatic incision for enucleation. All patients were cured. Data Analysis The results of sampling from the right (n = 25) and left (n = 17) hepatic veins were plotted for each patient. Graphs were analyzed by selecting the greatest insulin response in a given vessel in the 30- or 60-second sample after injection. Each patient was coded so that, at the time of analysis, the observers were unaware of the results of any other localizing studies or of the location of the tumor at surgery. A response after calcium infusion into the gastroduodenal or superior mesenteric artery localized the adenoma to the head and neck of the pancreas; a response after splenic artery injection localized the adenoma to the body and tail of the pancreas. A response to calcium stimulation usually involved a single artery (Figure 1). When both the gastroduodenal and superior mesenteric arteries showed a response to calcium stimulation, the insulinoma was presumed to be located to the right of the superior mesenteric artery (pancreatic head and neck) (Figure 2). When no vessel was clearly dominant, the response was considered nonlocalizing (Figure 3). Figure 1. Typical sampling results from a patient with an insulinoma in the pancreatic tail. top bottom Figure 2. In a patient with an insulinoma of the pancreatic head, greater than twofold gradients were seen after calcium injection into both the gastroduodenal and superior mesenteric arteries, with higher elevations in the gastroduodenal artery (top). bottom Figure 3. The only nondiagnostic study in the last 20 cases shows elevated insulin levels in the splenic and gastroduodenal arteries. The sensitivity of calcium stimulation in all 25 patients was calculated and compared with the sensitivity of the noninvasive imaging studies (computed tomography, magnetic resonance imaging, and ultrasonography) and arteriography. Specificity was irrelevant because all patients in the series had proven insulinomas. In the 9 patients who had portal venous sampling, the sensitivity of calcium stimulation was compared with the sensitivity of portal venous sampling. To determine whether it was necessary to sample the left hepatic vein, we compared the maximum insulin levels in the right and the left hepatic veins and the ratio of insulin levels in the hepatic vein with those in the peripheral vein in a subset of 10 patients with insulinomas of the body and tail. Results The results of all localization studies are summarized in Table 1. A response to calcium stimulationthat is, a greater than twofold elevation of insulin levels in the right or left hepatic vein on the 30- or 60-second samplesoccurred in all 25 patients. Calcium stimulation with venous sampling correctly predicted the site of the insulinoma in 22 of 25 patients (sensitivity, 88% [95% CI, 68% to 97%]). In 2 of the 3 patients with false localizations, responses to gastroduodenal and splenic artery injections occurred in the presence of a tumor in the proximal body of the pancreas (Figure 3); in the third patient, a response to a superior mesenteric artery injection occurred in the presence of a tumor in the proximal body. All patients who had a positive response to splenic artery injection only had insulinomas of the body or tail. Two of the three false localizations occurred in our first 5 patients; only one false localization occurred among our last 20 patients. Table 1. Results of Localization Studies in 25 Patients with Surgically Proven Insulinomas In the nine patients who had both portal venous sampling and calcium stimulation, portal venous sampling correctly localized six insulinomas (sensitivity, 67%), and calcium stimulation correctly localized seven insulinomas (sensitivity, 78%). Among 10 patients with surgically proven insulinomas of the body and tail of the pancreas, the maximum insulin levels in response to calcium stimulation were higher in the right than in the left hepatic vein in 8 patients and were equal in the right and left hepatic veins in 1 patient (103 U/mL compared with 107 U/mL [739 pmol/L compared with 768 pmol/L]). Only 1 patient with an insulinoma of the pancreatic body had a higher insulin level in the left than in the right hepatic vein (148 U/L compa

Lethality of Multiple Endocrine Neoplasia Type I

Abstract. The lethality of the endocrine tumors associated with multiple endocrine neoplasia type I (MEN-I), particularly the pancreatic islet cell tumors, has been controversial. We evaluated the cause and age of death in MEN-I kindreds. Our database contains 34 distinct kindreds with 1838 members. Reliable death data are available for 103 people (excluding accidents and age < 18 years). We compared survival curves of MEN-I patients who died from causes related to MEN-I with those from MEN-I carriers who died from a nonendocrine cause and unaffected kindred members. We also compared ages of death between affected and unaffected members of MEN-I kindreds. Of 59 MEN-I-affected patients, 27 died directly of MEN-I-specific illness and 32 of non-MEN-I causes. The MEN-I-specific deaths occurred at a younger age (median 47 years) than either MEN-I patients whose death was from some nonendocrine cause (median 60 years,p < 0.02) or than all kindred members who did not die of MEN-I disease (median 55 years,p < 0.05). The causes of death of the MEN-I patients included islet cell tumor (n= 12), ulcer disease (n= 6), hypercalcemia/uremia (n= 3), carcinoid tumor (n= 6), and nonendocrine malignancies (n= 9). There was no difference in survival between MEN-I carriers and unaffected kindred members. Of our MEN-I patients, 46% died from causes related to their endocrine tumors after a median age of 47 years, which was younger than family members who did not die from these tumors. Pancreatic islet cell tumors were the most common cause of death of MEN-I patients. Management of kindreds with MEN-I should include an aggressive screening program with early therapeutic intervention when a tumor is identified.

Thyroid Cancer: A Lethal Endocrine Neoplasm

This conference focuses on the controversies about managing thyroid cancer, emphasizing the possibility that the treatment of patients with potentially fatal thyroid cancer may be improved. Although the mortality rate from thyroid cancer is low, it is the highest among cancers affecting the endocrine glands (excluding the ovary). Exposure to radiation during childhood in the 1930s and 1940s increased the incidence of but not the mortality from thyroid cancer, because these tumors are mainly papillary cancers developing in young adults. These rates may change as the exposed cohort ages. Risk factors that increase mortality include older patient age and the growth characteristics of the tumor at diagnosis, the presence of distant metastases, and cell type (for example, the tall-cell variants of papillary cancer, follicular cancer [to be distinguished from the more benign follicular variant of papillary cancer], medullary cancer, and anaplastic cancer). Local metastases in lymph nodes do not seem to increase the risk for death from papillary cancer, but they do increase the risk for death from follicular and medullary cancer. In the latter, mortality is decreased by the early detection and treatment of patients with the familial multiple endocrine neoplasia syndrome 2a. There are excellent tumor markers for differentiated cancer of the parafollicular and of the follicular cells (serum calcitonin and serum thyroglobulin levels, respectively). Measuring the calcitonin level allows early diagnosis of familial medullary cancer, whereas measuring the thyroglobulin level, although useful only after total thyroidectomy, allows early recognition of recurrence or metastases of papillary or follicular cancer. Initial surgery, protocols for follow-up, and the use of radioiodine for the ablation of any residual thyroid and the treatment of metastatic cancer are discussed. Because these tumors resist currently available chemotherapy regimens, possible ways to increase the effectiveness of radioiodine therapy are considered as are new approaches to treatment.

Resolved and Unresolved Controversies in the Surgical Management of Patients With Zollinger-Ellison Syndrome

Objective:Highlight unresolved controversies in the management of Zollinger-Ellison syndrome (ZES). Summary Background Data:Recent studies have resolved some of the previous controversies including the surgical cure rate in patients with and without Multiple Endocrine Neoplasia-type1 (MEN1), the biological behavior of duodenal and pancreatic gastrinomas, role of imaging studies to localize tumor, and gastrectomy to manage acid output. Methods:Review of the literature based on computer searches in Index Medicus, Pubmed and Ovid. Results:Current controversies as identified in the literature include the role of endoscopic ultrasound (EUS), surgery in ZES patients with MEN1, pancreaticoduodenectomy (Whipple procedure), lymph node primary gastrinoma, parietal cell vagotomy, reoperation and surgery for metastatic tumor, and the use of minimally invasive surgical techniques to localize and remove gastrinoma. Conclusions:It is hoped that future studies will focus on these issues to improve the surgical management of ZES patients.

Gemcitabine Chemotherapy and Single-Fraction Stereotactic Body Radiotherapy for Locally Advanced Pancreatic Cancer

PURPOSE Fractionated radiotherapy and chemotherapy for locally advanced pancreatic cancer achieves only modest local control. This prospective trial evaluated the efficacy of a single fraction of 25 Gy stereotactic body radiotherapy (SBRT) delivered between Cycle 1 and 2 of gemcitabine chemotherapy. METHODS AND MATERIALS A total of 16 patients with locally advanced, nonmetastatic, pancreatic adenocarcinoma received gemcitabine with SBRT delivered 2 weeks after completion of the first cycle. Gemcitabine was resumed 2 weeks after SBRT and was continued until progression or dose-limiting toxicity. The gross tumor volume, with a 2-3-mm margin, was treated in a single 25-Gy fraction by Cyberknife. Patients were evaluated at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT. RESULTS All 16 patients completed SBRT. A median of four cycles (range one to nine) of chemotherapy was delivered. Three patients (19%) developed local disease progression at 14, 16, and 21 months after SBRT. The median survival was 11.4 months, with 50% of patients alive at 1 year. Patients with normal carbohydrate antigen (CA)19-9 levels either at diagnosis or after Cyberknife SBRT had longer survival (p <0.01). Acute gastrointestinal toxicity was mild, with 2 cases of Grade 2 (13%) and 1 of Grade 3 (6%) toxicity. Late gastrointestinal toxicity was more common, with five ulcers (Grade 2), one duodenal stenosis (Grade 3), and one duodenal perforation (Grade 4). A trend toward increased duodenal volumes radiated was observed in those experiencing late effects (p = 0.13). CONCLUSION SBRT with gemcitabine resulted in comparable survival to conventional chemoradiotherapy and good local control. However, the rate of duodenal ulcer development was significant.