A report of a gastrinoma localized preoperatively by endoscopic ultrasound only and a review of the approach to imaging in Zollinger-Ellison syndrome

The addition of somatostatin receptor scintigraphy and endoscopic ultrasound to the preoperative assessment of patients with Zollinger-Ellison syndrome has improved the ability to localize gastrinomas. We report a patient with Zollinger-Ellison syndrome with a gastrinoma localized preoperatively by endoscopic ultrasound only. We review the literature regarding the sensitivity of somatostatin receptor scintigraphy and endoscopic ultrasound and discuss the approach to imaging in Zollinger-Ellison syndrome.     

Added value of gastrin receptor scintigraphy in comparison to somatostatin receptor scintigraphy in patients with carcinoids and other neuroendocrine tumours

Gastrin receptor scintigraphy (GRS) is a new imaging method primarily developed for the detection of metastases of medullary thyroid carcinoma (MTC). As gastrin-binding CCK(2) receptors are also expressed on a variety of other neuroendocrine tumours (NET), we compared GRS to somatostatin receptor scintigraphy (SRS) in patients with NET. SRS and GRS were performed within 21 days in a series of 60 consecutive patients with NET. GRS was directly compared with SRS. If lesions were visible on GRS but not detectable by SRS, other imaging modalities (MRI, CT) and follow-up were used for verification. Of the 60 evaluable patients, 51 had carcinoid tumours, 3 gastrinomas, 2 glucagonomas, 1 insulinoma and 3 paragangliomas. The overall tumour-detection rate was 73.7% for GRS and 82.1% for SRS. In the 11 patients with negative SRS, GRS was positive in 6 (54.5%). Based on the number of tumour sites detected and the degree of uptake, GRS performed better than SRS in 13 patients (21.7%), equivalent images were obtained in 18 cases (30.0%) and SRS performed better in 24 (40.0%) cases. In six of the SRS positive patients, 18 additional sites of tumour involvement could be detected. Overall, GRS detected additional tumour sites in 20% of the patients. Localisation of the primary tumours or their functional status had no influence on the outcome of imaging. GRS should be performed in selected patients as it may provide additional information in patients with NET with equivocal or absent somatostatin uptake.     

Nuclear medicine in the detection, staging and treatment of gastrointestinal carcinoid tumours

Carcinoid tumours belong to the family of neuroendocrine tumours with a capacity to take up and concentrate amines and precursors as well as peptides, and can thereby be detected by nuclear medicine techniques. These rare tumours are difficult to diagnose at earlier stages because of small size and multiplicity. Computed tomography (CT) and magnetic resonance imaging (MRI) are mostly of benefit for detection of larger primary tumours (1-3 cm) and liver and lymph-node metastases. A majority of carcinoid tumours express somatostatin receptors, particularly receptor type 2, and thus somatostatin receptor scintigraphy (SRS) can be used for detection and staging of carcinoid tumours. The detection rate of carcinoid tumours has been reported to be somewhere between 80 and 100% in different studies. The scintigraphy gives a good staging of the disease and detection of unexpected tumour sites, which were not determined by conventional imaging. This method also indicates content of somatostatin receptors, which might indicate efficacy of treatment with octreotide or other somatostatin analogues. Another new non-invasive technique for detection of carcinoid tumours is positron emission tomography (PET). The biological substance for study can be labelled for radioactive imaging with radionuclears, such as (11)C, (15)O and (18)F, with emission of positrons. More than 95% of patients studied displayed high tracer uptake from PET with (11)C-5HTP (5-hydroxytryptophan), which is significantly higher compared to both computer tomography and somatostatin receptor scintigraphy. MIBG has been used for decades to visualize carcinoid tumours, because MIBG is concentrated in the endocrine cells. It was initially developed to detect phaeochromocytomas of the adrenal with reported high sensitivity (87%) and specificity as high as 99%. The method can be used when other methods fail to localize carcinoid tumours and particularly when treatment with (131)I-MIBG is being considered. Tumour-targeted treatment for malignant carcinoid tumour is still investigational, but has become of significant interest with the use of radiolabelled somatostatin analogues. Since a majority of carcinoid tumours present somatostatin receptors and can therefore be visualized in vivo by using radiolabelled somatostatin analogues, it seems logical to try to target these tumours with radioactive substances, not only for visualization but also for treatment. (111)Indium-DTPA-octreotide has been used as the first tumour-targeted treatment, with rather low response rates (in the order of 10-20%) and no significant tumour shrinkage. The second radioactive analogue which has been applied in the clinic is (90)yttrium-DOTA-Tyr3-octreotide, which has given partial and complete remissions in 20-30% of patients. The most significant side-effects have been kidney dysfunction, thrombocytopenia and liver toxicity. The most recent compound is (177)lutetium-DOTA-Tyr3-octreotate, which has been applied by the Rotterdam group and has been reported to give partial remission in about 40% of the patients. In the near future, combined treatment with both (90)yttrium and (177)lutetium coupled to a somatostatin analogue might come into clinical trials. (177)Lutetium may be more effective for smaller tumours whereas (90)yttrium may be more effective for larger tumours.     

Endoscopic ultrasonography and somatostatin receptor scintigraphy in the preoperative localisation of insulinomas and gastrinomas.

BACKGROUND: Endoscopic ultrasonography (EUS) and somatostatin receptor scintigraphy (SRS) can detect a high percentage of gastroenteropancreatic neuroendocrine tumours especially in the upper gastrointestinal tract. The ability of these procedures to localise primary tumour lesions and metastases of gastrinomas and insulinomas was evaluated in comparison with transabdominal ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI). PATIENTS AND METHODS: In a prospective trial, patients with gastrinomas (n = 10) and insulinomas (n = 10) diagnosed by clinical signs and laboratory tests were assessed by EUS, SRS, US, CT and MRI. RESULTS: In 10 patients with gastrinoma and 10 patients with insulinoma, a total of 14 separate primary tumour lesions were histologically confirmed for each of the tumour entities. The mean diameter was 2.1 cm for gastrinomas and 1.5 cm for insulinomas. All insulinomas and nine gastrinoma lesions were located in the pancreas. Three gastrinomas were found in the duodenal wall, one in a periduodenal lymph node, and one in the liver, For gastrinomas, sensitivities were 79% with EUS, 86% with SRS and 29% with CT, US, and MRI. For insulinomas, sensitivities were 93% with EUS, 14% with SRS, 21% with CT and 7% with US and MRI. CONCLUSIONS: EUS is of high value for localising primary lesions of both tumour entities. SRS is a very sensitive procedure for diagnosing of gastrinomas but not insulinomas. CT, US and MRI are primarily useful for visualising metastases.     

Localisation of neuroendocrine tumours of the upper gastrointestinal tract.

In order to localise neuroendocrine tumours of the foregut type (that is, of the stomach, duodenum, and pancreas), 18 patients were studied prospectively by endoscopic ultrasonography, computed tomography, transabdominal ultrasonography, magnetic resonance imaging, and somatostatin receptor scintigraphy. These 18 patients had a total of 25 primary tumour lesions which were verified histologically in tissue obtained by surgery or by ultrasound or endoscopy guided biopsy. Tumours were found in the stomach (n = 1), duodenum (n = 6), pancreas (n = 17), and liver (n = 1). Endoscopic ultrasonography had the highest sensitivity for tumour detection, followed by somatostatin receptor scintigraphy, computed tomography, transabdominal ultrasonography, and magnetic resonance imaging (88%, 52%, 36%, 32%, and 24% respectively). Endoscopic ultrasonography was especially sensitive in tumours smaller than 2 cm in diameter (88% v somatostatin receptor scintigraphy 35%; computed tomography 12%; transabdominal ultrasonography 6%; and magnetic resonance imaging 0%). Of 17 tumours located in the pancreas, endoscopic ultrasonography showed a sensitivity of 94% (somatostatin receptor scintigraphy 47%; computed tomography 47%; transabdominal ultrasonography 41%; and magnetic resonance imaging 29%). Of eight extrapancreatic tumours, six were identified by endoscopic ultrasonography, five by somatostatin receptor scintigraphy, and only one by computed tomography, transabdominal ultrasonography, and magnetic resonance imaging. One neuroendocrine tumour that was not detected by endoscopic ultrasonography was correctly identified by somatostatin receptor scintigraphy. Endoscopic ultrasound allowed correct determination of the tumour size and tumour spread into parapancreatic structures, especially the large vessels (T stage), in all 14 patients operated upon. The lymph node stage (N stage) was correctly determined in 10 of these 14 patients. In summary, endoscopic ultrasonography and somatostatin receptor scintigraphy were the most sensitive imaging methods for the localisation of these tumours and should be used as early diagnostic procedures to accurately stage neuroendocrine tumours of the foregut type.     

Carcinoid syndrome: diagnosis and medical management

Gastro-intestinal carcinoids are slow growing tumors arising from enterochromaffin or Kulchitsky cells. Their clinical presentation depends on what combination of bioactive substances is secreted. Midgut carcinoid can present with the carcinoid syndrome in the presence of liver metastases. Its most typical clinical manifestations include cutaneous flushing and diarrhea. A nonspecific biochemical tumor marker for carcinoid tumors is serum chromogranin A and a specific marker for the carcinoid syndrome is the increased urinary excretion of 5-hydroxy indole acetic acid (5-HIAA). Localizing studies in carcinoid tumors/syndrome are: transabdominal ultrasonography (US), endoscopy, endoscopic US, videocapsule endoscopy, computerized tomography, magnetic resonance imaging, selective abdominal angiography, 111In-pentetreotide scintigraphy (and intraoperative radionuclide probe), 123I (131I)-metaiodobenzylguanidine (MIBG) scintigraphy, bone scintigraphy and 11C-5-HT positron emission tomography (PET). Therapies for carcinoid tumors/syndrome are: surgery, somatostatin analogs, interferon-alpha, radiotherapy, liver dearterialization, liver (chemo, or radio)-embolization, alcohol sclerotherapy of liver metastases, radiofrequency ablation of liver metastases, cryosurgery of liver metastases, occasionally liver transplantation, radiotherapy-coupled somatostatin analogs, 131I-MIBG and occasionally chemotherapy.     

Value of endoscopic ultrasonography and somatostatin receptor scintigraphy in the preoperative localization of insulinomas and gastrinomas. Experience of 54 cases

AIM: The classic morphological techniques for the localization of insulinomas and gastrinomas are of limited value. Endoscopic ultrasonography and somatostatin receptor scintigraphy have shown high sensitivity for the detection of gastroenteropancreatic endocrine tumors. The aim of the study was to evaluate the sensitivity of endoscopic ultrasonography and that of somatostatin receptor scintigraphy in the localization of insulinomas and gastrinomas.PATIENTS AND METHODS: This retrospective study concerned 54 patients with insulinoma (n=29) or gastrinoma (n=26) operated on between March 1991 and March 2000 and who had at least one among the two tested examinations. Forty-two patients had scintigraphy (17 with insulinoma, 25 with gastrinoma), 47 had endoscopic ultrasonography (28 with insulinoma, 17 with gastrinoma). One of the ten patients with MEN 1 had both tumors. All diagnosis were confirmed by histologic examination.RESULTS: The sensitivity of scintigraphy for the localization of insulinomas was 47%. There was one false positive. Sensitivity of endoscopic ultrasonography for insulinomas was 85%. The sensitivity of scintigraphy in the detection of gastrinomas was 65% for the tumors in the duodenopancreatic area, 20% for the tumors in the pancreatic tail and 71% for metastasis. The sensitivity of endoscopic ultrasonography was 46% for duodenal tumors, 75% for pancreatic tumors and 57% for lymph node metastasis. The combination of both localization studies increased sensitivity to 94%.CONCLUSION: Endoscopic ultrasonography and somatostatin receptor scintigraphy are the gold standard for localization of gastrinomas. Association of both examinations increases the sensitivity. Scintigraphy for the detection of insulinomas should be performed when endoscopic ultrasonography is negative.     

Nuclear medicine in the detection and management of pancreatic islet-cell tumours

Over the last decade somatostatin receptor scintigraphy using various derivatives of long-acting somatostatin analogues has gained its place in the management of pancreatic islet-cell tumours. Scintigraphy is based on the high-affinity binding of such somatostatin analogues to receptors over-expressed by these tumour types. Following the introduction of (111)In-DTPA-D-Phe(1)-octreotide, clinical studies with radiolabelled DOTA-Tyr(3)-octreotide and DOTA-Tyr(3)-octreotate derivatives have shown considerable improvement of imaging results with increased tumour uptake. One of the newer developments, (68)Ga-labelled DOTA-Tyr(3)-octreotide, has shown promising results in patients with pancreatic islet-cell tumours, based on the high-affinity binding to the somatostatin receptor subtype 2 in combination with positron emission tomography (PET) technology. Other peptides--such as ligands for the gastrin/CCK2 receptors or vasoactive intestinal peptide (VIP)--have also been studied for imaging pancreatic cell tumours. Whereas small-sized gastrinoma, somatostatinoma, glucagonoma, carcinoid and VIPoma are frequently detected by somatostatin receptor scintigraphy, insulinoma may escape detection due to reduced receptor expression. Following peptide receptor scintigraphy, a change in patient management is reported in up to 30% of patients. When labelled with (90)Y or (177)Lu, some somatostatin analogues have been applied to patients in advanced stages of the disease. Despite positive response data in 50% of patients, long-term results and survival rates are lacking.     

Endoscopic ultrasonography of neuroendocrine tumours

Neuroendocrine tumours (NETs) of the upper gastrointestinal tract are mainly located in the pancreas, stomach or duodenum. The aims of preoperative work-up are the localization of primary tumour(s), determination of local tumour invasion, of lymph node metastases and of the hormones secreted by the tumour. Endoscopic ultrasonography (EUS) offers ideal conditions to localize and stage NETs of the foregut. We report our results in localizing and staging NETs of the foregut in 40 patients examined between 1990 and 1997 by EUS, somatostatin receptor scintigraphy (SRS), computed tomography (CT), magnetic resonance imaging (MRI) and transabdominal ultrasound (US). EUS shows the highest sensitivity in localizing insulinomas compared with SRS, US, CT and MRI. US and EUS should be the first-line diagnostics if insulinoma has been proven by a fasting test. Further diagnostic procedures are unnecessary in most cases. Further diagnostics such as CT or MRI to search for distant metastases are necessary in large tumours or local invasive tumours. EUS shows the highest accuracy to detect or exclude pancreatic gastrinomas, but fails to detect extrapancreatic gastrinomas in about 50%. The combination of EUS and SRS gives additional information. First-line diagnostics in gastrinoma patients should be SRS and CT or MRI. If no metastases are detected, EUS should be the next preoperative imaging procedure. In nonfunctional NETs, EUS provides the best information on local tumor invasion and regional lymph node involvement.     

Regression of a large malignant gastrinoma on treatment with Sandostatin LAR: a case report

Gastrinomas may occur in the pancreas, duodenum or peripancreatic lymph nodes. The gastrin overproduction leads to the Zollinger-Ellison syndrome with multiple gastric and duodenal ulcers and diarrhea. About two thirds of gastrinomas are malignant. Diagnosis is made by clinical history, gastroscopy, and measurement of serum gastrin, gastric juice pH, CT scan, endoscopic ultrasonography and somatostatin receptor scintigraphy. Surgery should always be considered if the liver is not involved. Proton pump inhibitors offer symptomatic relief. Medical therapy for tumor control includes biotherapy with alpha-interferon and somatostatin analogs yielding a response rate of about 10-15%, chemotherapy or targeted radiotherapy. We describe a patient with almost complete response on treatment with Sandostatin LAR, a long-acting somatostatin analog. In patients with metastatic gastrinomas not suitable for chemotherapy, interferon or targeted radiotherapy, single therapy with somatostatin analogs may be an alternative.     

Recent standardization of treatment strategy for pancreatic neuroendocrine tumors

Recent advances in localization techniques,such as the selective arterial secretagogue injection test(SASI test) and somatostatin receptor scintigraphy have promoted curative resection surgery for patients with pancreatic neuroendocrine tumors(PNET).For patients with sporadic functioning PNET,curative resection surgery has been established by localization with the SASI test using secretin or calcium.For curative resection of functioning PNET associated with multiple endocrine neoplasia type 1(MEN 1) which are usually multiple and sometimes numerous,resection surgery of the pancreas and/or the duodenum has to be performed based on localization by the SASI test.As resection surgery of PNET has increased,several important pathological features of PNET have been revealed.For example,in patients with Zollinger-Ellison syndrome(ZES),duodenal gastrinoma has been detected more frequently than pancreatic gastrinoma,and in patients with MEN 1 and ZES,gastrinomas have been located mostly in the duodenum,and pancreatic gastrinoma has been found to co-exist in 13% of patients.Nonfunctioning PNET in patients with MEN 1 becomes metastatic to the liver when it is more than 1 cm in diameter and should be resected after careful observation.The most important prognos-tic factor in patients with PNET is the development of hepatic metastases.The treatment strategy for hepatic metastases of PNET has not been established and aggressive resection with chemotherapy and trans-arterial chemoembolization have been performed with significant benefit.The usefulness of octreotide treatment and other molecular targeting agents are currently being assessed.     

Multimodality treatment for gastric carcinoid tumor with liver metastases

Carcinoid tumors are the most common neuroendocrine tumors in the gastrointestinal tract, and between 10% and 30% of these tumors are gastric in origin. Three types of gastric carcinoid tumors are recognized: type I, associated with chronic atrophic gastritis type A; type II, associated with multiple endocrine neoplasia; and type III, sporadic and the most malignant. We present a patient with an aggressive, sporadic-type gastric carcinoid that metastasized to the liver. Her symptomatic treatment included the somatostatin analog octreotide. Octreotide scintigraphy demonstrated that this tumor avidly bound the peptide. The patient's gastric carcinoid (assessed by endoscopy and endoscopic ultrasound) regressed and she underwent hepatic artery embolization for her liver metastases. After initial partial CT resolution the tumor grew, compressing the inferior vena cava. The patient underwent orthotopic liver transplant with excellent recovery, although she was subsequently found to have two small lung metastases. She has responded well to adjuvant Indium-111 octreotide receptor targeted therapy. This case highlights the therapeutic options for metastatic neuroendocrine tumors, including liver transplantation and adjuvant receptor targeted therapy.     

Carcinoid tumours presenting as breast cancer: the utility of radionuclide imaging with 123I-MIBG and 111In-DTPA pentetreotide

Secondary tumours of any type in the breast are rare. A review of the literature demonstrated only 23 cases of carcinoid tumours with associated breast metastasis, as distinct from primary carcinoid tumours of the breast. Distant metastases from carcinoid tumours are correlated with poor prognosis and survival. Although both primary and metastatic mammary carcinoid tumours are uncommon, the recognition of the true origin of the tumours may be of importance owing to the different clinical management and prognosis of the two conditions. Recently, radionuclide-labelled imaging techniques have been applied to the localization of such lesions, based on isotope uptake by receptors present in these neuroendocrine tumours. We report two new cases of carcinoid tumours with breast metastases, the primaries being in the ileocaecal valve and the bronchus, respectively. The diagnosis of a carcinoid tumour was based on the clinical, biochemical, histopathological and immunostaining features. Furthermore, these patients had both 123I-MIBG and 111In pentetreotide scintigraphy performed. These radionuclides play a useful role in the localization and potentially in the management of carcinoid tumours and their distant metastases.     

Octreoscan in patients with bronchial carcinoid tumours

OBJECTIVES: Scintigraphy with radiolabelled octreotide (octreoscan) is useful for imaging various neuroendocrine tumours, especially in patients with midgut carcinoids. We were interested in estimating the efficacy of octreoscan for detection of the primary tumour and metastases in patients with bronchial carcinoids. PATIENTS AND METHODS: Twenty-eight patients with histologically verified bronchial carcinoids underwent octreoscan and the imaging results were compared to CT regarding soft tissue metastases, and to bone scan and MRI regarding bone metastases. The primary tumour had been removed prior to the octreoscan in 12 patients. Metastatic disease was diagnosed in 22 patients. RESULTS: Altogether, 20 patients (71%) had octreoscan-positive tumours, including 2/5 patients with ectopic ACTH secretion resulting in Cushing's syndrome and 8/9 patients with carcinoid syndrome. The primary tumour was octreoscan-positive in 13/16 patients and could be detected on CT in 15/16 patients. CT failed to localize the primary tumour in one octreoscan-positive patient, presenting with ectopic ACTH secretion and Cushing's syndrome. Intrathoracic recurrences/metastases were visualized by octreoscan in 7/9 patients and by CT in 8/9 patients. CT showed liver metastases in 14 patients; nine of these patients (64%) had octreoscan-positive liver metastases. Ten patients had bone metastases; octreoscan was positive in seven and bone scan in nine of these 10. CONCLUSIONS: Octreoscan may be used for follow-up and detection of recurrent disease in patients with somatostatin receptor-positive bronchial carcinoids. In our limited patient material, CT however, seems to be better than octreoscan for visualization of the primary tumour as well as liver metastases.     

Localization of gastrinomas by transhepatic portal catheterization and gastrin assay.

Gastrinomas were localized by concurrent blood sampling in the hepatic vein and portal vein tributaries in 10 of 12 Zollinger-Ellison patients. In one patient, the portal vein could not be catheterized; in the other, a gastrin gradient could not be picked up in either of two examinations. Six of the patients were subsequently operated upon: 5 had pancreatoduodenal resection and 1 had laparotomy at which metastases were found. Four of the resections were probably curative as the patients have done well without treatment since with concentrations of gastrin in serum near zero. The observation period ranges from 17 to 20 mo. It is concluded that transhepatic catheterization of the hepatic vein and portal vein tributaries with blood sampling for gastrin determination permit the verification of the Zollinger-Ellison diagnosis and the localization of the gastrinomas. The latter may lead to the selection of a curative operative treatment in some of the patients.     

Expression of peptide receptors in human endocrine tumours of the pancreas.

BACKGROUND: Gut peptides are known to influence hormone release and growth of endocrine tumours of the pancreas. Although information on somatostatin receptors has been provided recently, little is known on the receptor status of other gastrointestinal hormones in such tumours. AIMS: To analyse the spectrum of gut hormone receptors on endocrine tumours of pancreas. SUBJECTS: Four types of endocrine tumours from eight patientS. METHODS: The receptors for bombesin, secretin, vasoactive intestinal peptide, cholecystokinin, and somatostatin have been visualised and quantified with storage phosphor autoradiography. RESULTS: Bombesin receptors were present in all five gastrinomas and two primary VIPomas. Secretin receptors were expressed in four primary gastrinomas and one primary VIPoma from pancreas. Vasoactive intestinal peptide receptors were identified in four primary gastrinomas and all VIPomas. Furthermore, all VIPomas expressed cholecystokinin-B (gastrin) receptors, whereas, gastrinomas did not contain cholecystokinin-B receptors. The receptors for somatostatin were detected in all gastrinomas and VIPomas. Both somatostatinoma and glucagonoma were negative for all five types of peptide receptors studied. CONCLUSIONS: Besides somatostatin receptors, most of gastrinomas and VIPomas also express receptors for bombesin, secretin, and vasoactive intestinal peptide.     

Clinical presentation and prognosis of gastrointestinal carcinoid tumours

Clinical data about 104 patients with gastrointestinal carcinoids emphasized the heterogeneous nature of these tumours in different organs. The sites of the primary tumours were the stomach in 12 (11%), the duodenum in 3 (3%), the small bowel in 48 (45%), the appendix in 28 (26%), the colon in 6 (6%), and the rectum in 6 cases (6%). Gastric carcinoids were multiple in 4 (33%) and small-bowel carcinoids in 11 cases (23%). None of the gastric, duodenal, or rectal carcinoids had generated metastases, as contrasted to 34 (72%) small-bowel carcinoids. Twelve patients had symptoms of the carcinoid syndrome caused by hepatic metastases from ileal (11) or appendiceal (1) primary tumours. At least two patients with duodenal carcinoids had Zollinger-Ellison syndrome produced by the tumours. The cumulative 5-year survival rate was 91-100% for gastric, appendiceal, and rectal carcinoids, 77% for small-bowel carcinoids, and 33% for colonic carcinoids. Resectable mesenteric lymph node metastases did not affect the 5-year survival of patients with small-bowel carcinoids as compared with the tumours confined to the bowel wall. Poor prognosis was associated with hepatic metastases at the time of diagnosis. Small-bowel carcinoids remain a challenge in clinical work because of their distinct metastatic propensity and problematic diagnosis.     

Carcinoid tumours

Carcinoid tumours offer a diagnostic and therapeutic challenge. Although new biochemical markers and improved methods for tumour detection, including PET and somatostatin receptor scintigraphy, have been developed during the last two decades many patients are still diagnosed at late stages of the disease. This is supported by the fact that the age of diagnosis is about the same today as it was 10 years ago. It is our opinion that plasma chromogranin A levels should be be determined in all patients which are investigated because of symptoms that might be connected to a neuroendocrine tumour. In cases with flushing or diarrhoea, U-5-HIAA should also be determined and these two tumour markers are enough to diagnose most patients with midgut carcinoid tumours. In patients with foregut or hindgut tumours other specific hormones should be included. For the localization procedure conventional radiological techniques including CT, MRI and ultrasound investigations should be supplemented with somatostatin receptor scintigraphy. Endoscopic ultrasound investigations might in the future be relevant for diagnosis of duodenal carcinoids, whereas gastric and rectal carcinoids are diagnosed by endoscopy. A combination of more aggressive surgery combined with medical treatment such as somatostatin analogues and α-interferon has significantly increased the survival rates in patients with classical midgut carcinoid tumours. Metastatic foregut and hindgut tumours are still a therapeutic challenge and it is important in the future to classify all carcinoid tumours based on specific tumour biology patterns. Such a tumour biology based treatment is a prerequisite for a more individually based therapy in the future.     

Allelic deletion of the MEN1 gene in duodenal gastrin and somatostatin cell neoplasms and their precursor lesions

BACKGROUND: Patients with a multiple endocrine neoplasia type 1 (MEN1)-associated Zollinger-Ellison syndrome (ZES) show multifocal duodenal gastrinomas and precursor lesions. AIMS: To test these lesions for loss of heterozygosity (LOH) of the MEN1 gene locus on chromosome 11q13, and to investigate whether the MEN1-related endocrine cell changes also involved somatostatin cells. MATERIAL AND METHODS: Tissue specimens from six patients with MEN1 and ZES were analysed by immunohistochemistry and immunofluorescence. LOH analysis was performed by fluorescence in situ hybridisation (FISH), using probes containing the MEN1 gene locus and the centromere 11 (C11) region. For simultaneous analysis of hormones and allelic deletions, a combined FISH/immunofluorescence protocol was established. RESULTS: 28 of a total of 33 duodenal neuroendocrine tumours (NETs) were gastrin-producing tumours; 13/28 (46.4%) revealed LOH on 11q13 and/or C11. Five of the NETs were somatostatin-expressing tumours, two revealing LOH. Allelic loss was detected in tumours as small as 300 microm (gastrin) and 400 microm (somatostatin) in diameter. The gastrin-producing tumours showed different deletion/retention patterns. Hyperplastic somatostatin cell lesions, similar to those of the gastrin cells, were present in all patients. The hyperplastic lesions of both cell lines consistently retained both 11q13 alleles. CONCLUSIONS: Allelic deletion of the MEN1 gene may reflect a pivotal event in the development of multifocal gastrin and somatostatin cell neoplasms in the duodenum of patients with MEN1. The observation of distinct deletion patterns in small synchronous tumours supports the concept that each gastrin-producing tumour in an individual MEN1 patient arises from an independent cell clone.     

Chemoembolization and other ablative therapies for liver metastases of gastrointestinal endocrine tumours

Hepatic metastases are frequent in patients with gastroentero-pancreatic (GEP) endocrine tumours; their presence significantly influences overall prognosis. Surgery, although the treatment of choice for hepatic metastases, is frequently impossible due to disease extent. Systemic chemotherapy in patients with diffuse and/or progressive liver metastases yields disappointing results especially in patients with metastases from midgut origin. In addition, in patients with carcinoid syndrome, the efficacy of somatostatin analogues wanes due to disease progression and development of tachyphylaxis. Locoregional strategies with vascular occlusion inducing ischemia in these highly vascular GEP tumours are indeed other options and may be performed using either surgical or radiological techniques (e.g. surgical ligation of the hepatic artery, transient hepatic ischemia, or sequential hepatic arterialization). Trans-catheter arterial chemoembolization is efficacious in both the control of hormonal symptoms and yields reliable objective tumour responses. Treatments aimed at regional destruction either alone or in combination with surgery include radiofrequency ablation and cryotherapy and may also be considered in certain circumstances.