Nonfunctioning Pancreatic Tumors Research Articles

Influence of first line treatment in the 5 (5yS) and 10-year (10yS) survival outcomes of patients with gastroenteropancreatic neuroendocrine tumors (GNETs): 2001–2005 Spanish task force GNET group

14058 Background: Data on incidence, morbidity and mortality of GNETs is limited due to the low frequency of these tumors. However this survival data is critical to design studies with new agents. Methods: Data was obtained from medical records of 262 patients with GNETs and centralized in an online registry at www.retegep.net . Among the study parameters were histology, localization, stage, diagnostic workup, 1st line and subsequent treatments, 5yS and 10yS for the whole dataset and for different stages, tumor types and 1st line systemic treatment. Results: Mean age 58, 58% male. Primary tumors: 49% Carcinoids (C), 19% non-functioning pancreatic tumors (PT), 9% insulinomas, 6% gastrinomas and 8% unknown primary. Localizations: midgut (36%), head (17%) and body of pancreas (10%). Functioning symptoms led to diagnosis in 38% of cases. 4% were associated to MEN1. Stage at diagnosis was advanced (Adv) in 46%, localised (L) in 30% and locorregional (LR) in 13% (unknown in 11%). Diagnostic workup were CT Scan (84%), Octreoscan (52%) and US (52%) and serum hormone tests (65%). Treatments for Adv disease included somatostatin analogues (SA) (47%), surgery (S) (43%), chemotherapy (CT) (35%) and interferon (IFN) (34%), embolization (7%) and radiofrequency ablation (3%). 5yS and 10yS for the whole group was 61.6% (SD: 5.2%) and 49.8% (SD: 7.7%) respectively. 5yS and 10yS for the L/LR and Adv stages were 78.1% (SD: 7.3%) and 71% (SD: 10%), and 48.9% (SD: 7.7%) and 29% (SD: 12.4%), respectively. LR PT and C had similar 5 and 10yS but Adv PT did worse than Adv C (5yS of 36.2% and 61.1%, respectively). 1st line systemic treatment for LR and Adv disease (n=90) included SA (39%), CT (34.4%), IFN (5.6%), combinations of SA+IFN (13.3%), A+CT (4.4%) and other combinations (3.3%), with a 10yS rate of 69%, 79%, 50%, 89%, 66% and 50%, respectively. Adv PT perform worse than C regardless of treatment choice. As second line systemic treatment (n=43) 30% received SA, 30% CT, 26% inmunotherapy and 14% combinations. Conclusions: An extensive use of systemic therapy and a scarce use of non-surgical LR treatments is observed in the Adv stages. Choice of 1st line systemic treatment does not seem to influence survival outcomes. No significant financial relationships to disclose.

A Rare Cystic Non-Functioning Neuroendocrine Pancreatic Tumor with An Unusual Presentation

This report describes a patient with a cystic non-functioning neuroendocrine glucagon cell pancreatic tumor presenting with demyelination of the optical nerve that had initially provoked marked monolateral reduced vision and had led to a suspected diagnosis of multiple sclerosis. Cystic degeneration is uncommon in endocrine pancreatic tumors due to their abundant vascular supply. Very few cases of cystic neuroendocrine non-functioning pancreatic tumors have been reported in the international literature. The presence of atypical neurological symptoms, such as sudden visual impairment, should be taken into account in the differential diagnosis for such tumors. The prognosis is poor, because most of these tumors are malignant and diagnosed at an advanced stage. The three-year disease-free survival of our patient, however, encourages the use of aggressive surgical treatment.

Circulating Ghrelin Levels in Patients with Pancreatic and Gastrointestinal Neuroendocrine Tumors: Identification of One Pancreatic Ghrelinoma

Ghrelin is a novel gastrointestinal hormone involved in several metabolic functions. Although the expression of ghrelin has been demonstrated in most gastrointestinal carcinoids and pancreatic tumors, the circulating levels of this peptide have been marginally assessed in patients with these disorders. We measured plasma ghrelin levels in 16 patients with gastrointestinal carcinoid (10 with midgut and 6 with gastric carcinoid), 24 patients with pancreatic tumor (8 with gastrinoma, 2 with insulinoma, 2 with vipoma, 1 with glucagonoma, and 11 with nonfunctioning tumor), and 35 healthy controls. Plasma ghrelin levels recorded in patients with gastroenteropancreatic tumors were similar to controls (mean +/- SE, 182.7 +/- 66.5 pM in patients vs. 329 +/- 32 pM in controls, P = not significant), and no significant difference between gastrointestinal and pancreatic, functioning and nonfunctioning, and metastatic and nonmetastatic tumors was observed. One patient with metastatic nonfunctioning pancreatic tumor had circulating ghrelin levels of 12,000 pM that were slightly reduced during chemotherapy and interferon therapy. Immunohistochemistry performed on peritoneal lesions showed an intense, focal cytoplasmic positivity for ghrelin. Despite the 50-fold increase in ghrelin concentrations, the patient had normal serum GH and IGF-I levels. In conclusion, the study showed that carcinoids and pancreatic tumors rarely cause ghrelin hypersecretion. However, in this series, 1 pancreatic ghrelinoma not associated with clinical features of acromegaly was identified.

Transarterial Chemoembolization of Advanced Liver Metastases of Neuroendocrine Tumors – A Retrospective Single-Center Analysis

Background: In neuroendocrine tumors, metastases are a negative prognostic factor for survival and quality of life. Transcatheter arterial chemoembolization (TACE) is thought to be an effective symptomatic and antiproliferative treatment in patients with otherwise progressive disease. Methods: 62 chemoembolization procedures in 26 patients with progressive neuroendocrine tumors were reviewed. The underlying disease was carcinoid syndrome in 10, non-functional midgut tumor in 2, non-functional pancreatic tumor in 7, malignant insulinoma in 2 patients, non-functional tumor of the stomach in 1 and of unknown origin in 4 patients. Tumor burden of the liver was <25% in 3, 25–50% in 11, 50–75% in 6 and >75% in 6 patients. Results: TACE was technically successful in 57 cases. Four patients developed minor and 5 major complications. The 30-day mortality rate was 7.7%. According to WHO criteria, 14 patients had no change in tumor burden, 2 had regression and 5 progress after chemoembolization. Patients with a tumor burden >75% of the liver did not benefit from TACE due to the development of major complications, whereas patients with low (<50%) tumor burden and high (>50%) lipiodol uptake showed a trend towards longer survival. Five-year survival time after diagnosis was 48%. Patients treated with octreotide and/or α-interferon had no benefit from chemoembolization with regard to their carcinoid syndrome. Conclusions: In this retrospective study, patients with low (<50%) tumor burden and high (>50%) lipiodol uptake responded better to TACE than end-stage patients.

Radiofrequency tissue ablation using cooled tip for liver metastases of endocrine tumors.

Tumors derived from hormone-producing cells are generally highly differentiated, and vast experience indicates benefit with combinations of surgical and medical treatment for metastatic disease. Tumor debulking surgery is an accepted approach for reducing hormonal symptoms and to establish better conditions for medical treatment. Radiofrequency treatment (RF), a novel method for destroying liver tumors, was used to treat 43 liver metastases in 21 patients with endocrine tumors (12 with midgut carcinoid disease; 4 with nonfunctional endocrine pancreatic tumors; 1 with a VIPoma; 1 with a glucagonoma; 1 with a gastrinoma; 2 with adrenal carcinomas). Among these patients we treated with intention to cure in 14 by RF alone or RF plus surgery. Ablation was performed either percutaneously or intraoperatively using a cooled-tip needle, applying 50 to 90 watts over 10 to 12 minutes under ultrasound guidance. Contrast-enhanced computed tomography, liver function tests, and tumor markers were followed before and after RF. There were two complications: One patient suffered from conservatively treated bile leakage, and another had pleural effusion and fever for 7 days post-RF. Two lesions developed signs of incomplete necrosis after 6 months, yielding a local recurrence rate of (4.6%). Of the 15 patients treated with curative intent, we attained cure (i.e., no residual macroscopic tumor) in 4 patients. We conclude that RF using cooled-tip needles is safe and efficient; it may be performed percutaneously and intraoperatively; and it may expand the indications for liver resection.

10 Swiss kindreds with multiple endocrine neoplasia type 1: assessment of screening methods.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease characterised by the combined occurrence of tumours of the parathyroid glands, the enteropancreatic neuroendocrine system and the anterior pituitary gland. The genetic defect has been mapped to the long arm of chromosome 11q13, and the MEN1-gene was recently identified by positional cloning. Genetic screening for MEN1 germline mutations allows the identification of gene carriers in affected kindreds. Biochemical and radiological screening for MEN1 tumours allows an earlier diagnosis and treatment, and, thus may reduce morbidity and mortality. Since there is no consensus about the frequency and the extent of the necessary screening investigations, evaluation of proposed screening programs is of importance. The aims of our study were to identify the MEN1-gene mutations and to detect the gene-carriers in 10 Swiss MEN1 families, as well as to assess biochemical and radiological screening methods. The study included 45 members from 10 MEN1 families. Every family had a different type of MEN1-gene mutation. Thirty out of 45 family members were gene mutation carriers. Twenty-two MEN1-gene carriers had typical MEN1 tumours: parathyroid, enteropancreatic and pituitary tumours were found in 21, 14 and 1 patients, respectively. Applying a defined screening program the following manifestations in asymptomatic MEN1-gene carriers were detected: 9 primary hyperparathyroidism, 3 nonfunctioning pancreatic tumours, 1 gastrinoma, 1 nonfunctioning microadenoma of the pituitary and 1 macronodular adrenal hyperplasia. The genetic screening facilitates the identification of individuals who carry MEN1-gene mutations, and allows one to exclude non-mutant gene carriers from further investigations. The prospective biochemical and radiological screening of gene mutation carriers allows the earlier detection of MEN1-associated tumours. Therefore, it might be expected that morbidity and mortality of the MEN1 could be reduced.

10 Swiss kindreds with multiple endocrine neoplasia type 1: assessment of screening methods.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease characterised by the combined occurrence of tumours of the parathyroid glands, the enteropancreatic neuroendocrine system and the anterior pituitary gland. The genetic defect has been mapped to the long arm of chromosome 11q13, and the MEN1-gene was recently identified by positional cloning. Genetic screening for MEN1 germline mutations allows the identification of gene carriers in affected kindreds. Biochemical and radiological screening for MEN1 tumours allows an earlier diagnosis and treatment, and, thus may reduce morbidity and mortality. Since there is no consensus about the frequency and the extent of the necessary screening investigations, evaluation of proposed screening programs is of importance. The aims of our study were to identify the MEN1-gene mutations and to detect the gene-carriers in 10 Swiss MEN1 families, as well as to assess biochemical and radiological screening methods. The study included 45 members from 10 MEN1 families. Every family had a different type of MEN1-gene mutation. Thirty out of 45 family members were gene mutation carriers. Twenty-two MEN1-gene carriers had typical MEN1 tumours: parathyroid, enteropancreatic and pituitary tumours were found in 21, 14 and 1 patients, respectively. Applying a defined screening program the following manifestations in asymptomatic MEN1-gene carriers were detected: 9 primary hyperparathyroidism, 3 nonfunctioning pancreatic tumours, 1 gastrinoma, 1 nonfunctioning microadenoma of the pituitary and 1 macronodular adrenal hyperplasia. The genetic screening facilitates the identification of individuals who carry MEN1-gene mutations, and allows one to exclude non-mutant gene carriers from further investigations. The prospective biochemical and radiological screening of gene mutation carriers allows the earlier detection of MEN1-associated tumours. Therefore, it might be expected that morbidity and mortality of the MEN1 could be reduced.

Diagnostic value of plasma chromogranin A in neuroendocrine tumours.

The aim of this study was to assess the value of plasma chromogranin A (CgA), a protein produced by neuroendocrine cells, in the diagnosis of neuroendocrine tumours. Eighty subjects with neuroendocrine tumours were studied. Thirty-four had carcinoids, 21 nonfunctioning endocrine pancreatic tumours, 17 multiple endocrine neoplasia type 1 (MEN 1) (six of these also had gastrinomas), and eight had functioning pancreatic tumours (four gastrinomas, two glucagonomas, two somatostatinomas). Twenty-eight healthy subjects were studied as controls. A fasting plasma sample was obtained from each subject, and CgA plasma levels were measured by the ELISA method using a kit (Dako A/S, Denmark). In control subjects, plasma CgA values were below 5 U/l. Among the patients, 20 of the 34 with carcinoid tumours, 12 of the 21 with nonfunctioning pancreatic tumours, nine of the 17 with MEN 1 (including the six with gastrinomas), and the four gastrinomas of the eight functioning pancreatic tumours, i.e. overall, 45 of the 80 patients (56.3%) had abnormally high CgA values (22-961 U/l). Most of the patients with elevated CgA values, except nine of the 10 with gastrinomas, had multiple liver metastasis. The results show that the diagnostic value of plasma CgA in neuroendocrine tumours is relatively low; it may be of some interest only in patients with advanced disease and liver metastasis. Gastrinoma seems to be an exception, because in this tumour high CgA values are generally found even in the absence of liver metastasis.

Octreotide acetate long-acting release in patients with metastatic neuroendocrine tumors pretreated with lanreotide

In the present study we investigated the efficacy and tolerability of i.m. octreotide acetate (octreotide LAR) in patients with metastatic neuroendocrine tumors (NETs) previously treated and failed on i.m. lanreotide. Fifteen patients (8 females, 7 males, median age 67 years, range 28-81 years) with metastatic NETs (8 endocrine pancreatic tumors, 7 midgut carcinoids) were enrolled in the study. All patients were in progressive disease (objective: 11 patients, symptomatic: 10 patients, biochemical: 11 patients) after treatment with slow release lanreotide, 30 mg every 14 days for a median time of 8 months (range 3-19 months). All patients had measurable disease; 12 patients had elevated serum and/or urine markers and 11 were symptomatic. Octreotide scintigraphy was positive in 13 of 15 patients. Octreotide LAR was administered as i.m. injection at the dose of 20 mg every four weeks until disease progression. An objective partial response (PR) was documented in one patient (7%), no change (NC) in six (40%), and progressive disease (PD) in eight patients (53%). The PR was observed in one patient with non-functioning endocrine pancreatic tumor with progressive liver and lymph node metastases after 16 months of i.m. lanreotide therapy. The median duration of disease stabilization was 7.5 months (range 6-12+ months). The overall biochemical response rate was 41%, including CRs (33%) and PRs (8%); biochemical responses were observed in carcinoids as well as in endocrine pancreatic tumors; the median duration of response was 5 months for CRs and 7.5 months for PRs. The overall symptomatic response rate was 82%. The median duration of response for diarrhoea, abdominal pain, or both was 6.5 months (range 3-12+ months). Improvement in performance status (PS) was obtained in 5 of 11 patients with PS of 1 at study entry. Median duration of octreotide LAR treatment was seven months (range 3-12+ months). No serious adverse events were reported; mild side effects were reported in 26% of patients. Octreotide LAR 20 mg shows significant efficacy in terms of objective response rate (PR + SD), biochemical and symptomatic control in patients with metastatic NETs of the GEP system pretreated and progressing on slow release lanreotide.

Treatment of gastroenteropancreatic neuroendocrine tumours with octreotide LAR.

Octreotide long acting repeteable (LAR) is a new somatostatin analogue whose activity lasts 28 days. To assess its therapeutic efficacy, tolerability, and safety in patients with gastroenteropancreatic neuroendocrine tumours. A total of 16 patients were studied; 10 patients with carcinoid tumours, three with non-functioning pancreatic tumours, two with Zollinger-Ellison syndrome associated with multiple endocrine neoplasia type 1, and one with glucagonoma were studied. Octreotide LAR was administered intramuscularly at a dose of 20 mg every 28 days for a mean of 10.7 months (range 6-15 months). In carcinoid tumour patients, octreotide LAR normalized bowel movements in nine out of 10 cases, and flushing episodes disappeared in seven out of eight cases. Even in the remaining six patients the symptoms disappeared. In carcinoid tumour patients, urinary 5-hydroxyindoleacetic acid decreased significantly. In the two patients with Zollinger-Ellison syndrome/multiple endocrine neoplasma type 1 and in the patient with glucagonoma, serum gastrin and plasma glucagon, respectively, decreased considerably. Tumour size remained unchanged in 14 out of 16 patients, and increased in the remaining two. No side-effects were observed. Octreotide LAR appears to have a good therapeutic efficacy, tolerability and safety in the treatment of neuroendocrine tumours. Its effects are similar to those of octreotide and lanreotide. However, because it only needs to be administered once every 28 days, it is preferable in clinical practice.

Pancreatic endocrine tumors with loss of heterozygosity at the multiple endocrine neoplasia type I locus

Loss of heterozygosity (LOH) at chromosome 11q13 has been demonstrated in multiple endocrine neoplasia type I (MEN I) and sporadic parathyroid tumors, pituitary adenomas, and a few types of pancreatic endocrine tumors. Gastrinomas are the most common pancreatic endocrine tumor in MEN I. We hypothesized that all pancreatic endocrine tumors have LOH at 11q13, resulting in inactivation of the previously described tumor suppressor gene in this region. We analyzed a sporadic gastrinoma, a MEN I-associated gastrinoma, and a nonfunctional pancreatic endocrine tumor from a patient with Von Hippel-Lindau (VHL) disease for LOH at seven loci at 11q13: D11S149, PYGM, D11S427, D11S546, SEA, D11S97, and D11S146. We found LOH at 11q13 in all three tumors. The MEN I-associated gastrinoma we analyzed is the first tumor of this type to have LOH. This is also the first report of LOH at 11q13 in a pancreatic endocrine tumor from a patient with VHL. These findings suggest that the etiology of pancreatic endocrine tumor formation involves a common genetic pathway for sporadic, MEN I, and VHL tumors.

Magnetic resonance imaging of endocrine tumours of the pancreas

Seven patients who had functioning or non-functioning endocrine pancreatic tumours were investigated by magnetic resonance imaging. Combinations of fat suppressed T1 weighted spin echo and gradient recalled echo (n = 7), T2 weighted spin echo (n = 3) and gadolinium diethylamine triamine pentaacetic acid (Gd-DTPA) enhanced fat suppressed T1 images were acquired. Magnetic resonance imaging detected five of seven tumours prospectively (three of which were smaller than 10 mm) and a further 10 mm tumour retrospectively. Tumours were low signal on T1 weighted images and showed enhancement after Gd-DTPA. On T2 weighted images one tumour was hyperintense, and two were isointense with normal pancreas. Computed tomography, transabdominal ultrasound and angiography were performed in six patients but detected only one tumour each. Intraoperative palpation and ultrasound detected all tumours. If pre-operative imaging is required magnetic resonance imaging is the technique of choice to detect small endocrine pancreatic tumours.