Special Issue "Neuroendocrine Tumors"

Guest Editor
Dr. med. Volker Fendrich
Department of Surgery, Philipps University Marburg, Baldingerstrasse, 35043 Marburg, Germany
Website: http://gd1.med.uni-giessen.de/ugm_2/deu/umr_ach/umr_ach_team.php?id=1038
E-Mail: fendrich@med.uni-marburg.de
Phone: +49 06421 - 5866544
Fax: +49 06421 - 5862105
Interests: pancreatic cancer; neuroendocrine tumors; mouse models of cancer; chemoprevention

Dear Colleagues,

Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) are uncommon but clinically challenging and fascinating tumors. GEP-NETs present as either functional or as non-functional tumors. Functional tumors are commonly associated with a specific hormonal syndrome directly related to a hormone secreted by the tumor, like gastrinomas with a Zollinger-Ellison-Syndrome or carcinoid syndrome in patients with neuroendocrine tumors (NET) of the ileum. Non-functional tumors do not secrete a hormone resulting in a clinical syndrome. The natural course of GEP-NETs is highly variable. Small, benign neoplasms such as 90% of all insulinomas or gastric endocrine tumors type 1 are readily curable by surgical resection; however, most other GEP-NETs have a much less favorable prognosis. Patients with completely resected tumors generally have a good prognosis, and an aggressive surgical
approach in patients with advanced disease may also prolong survival. This special issue focuses on the current standards of management of gastric endocrine tumors, NETs of the pancreas (PNET) and NETs of the ileum. Although the evidence level is low in many instances due to the lack of randomized controlled trials, important treatment recommendations can be given.

Dr. Volker Fendrich
Guest Editor

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• neuroendocrine gastrointestinal tumor
• neuroendocrine tumors of the ileum
• neuroendocrine tumors of the pancreas
• surgical therapy

Type of Paper: Review
Title: Genetics and Molecular Biology of Gastrointestinal Carcinoid and Pancreatic Endocrine Tumors
Author: H. Christian Weber ^1,2,3
Affiliations: ¹ Section of Gastroenterology
² Department of Pathology and Laboratory Medicine, Boston University School of Medicine
³ Section of Gastroenterology, VA Boston Healthcare System Boston, MA, USA;
E-Mail: christian.weber@va.gov
Abstract: Gastrointestinal neuroendocrine tumors, comprising intestinal carcinoid and pancreatic endocrine tumors (PET), include a heterogenous group of neoplasia arising from the embryonic neural crest, neuroectoderm and endoderm. They can occur either sporadically or as part of familiar tumor syndromes and their prevalence has increased over the last 30 years for which reasons remain unclear. Tumors can be accompanied by clinical syndromes owing to secretion of biological active peptides, such as Zollinger Ellison syndrome due to hypergastrinemia, or they can be nonfunctioning. The molecular and clinical genetics of familial PETs have been further elucidated by the characterization of the tumor suppressor genes such as MEN1, VHL, NF-1, and TSC which –in part- has contributed to the development of novel treatment concepts, including tyrosine kinase inhibitor therapy. Unlike certain genetic changes typically detected in pancreatic adenocarcinoma, those have not been implicated in PET carcinogenesis whereas other chromosomal regions have been identified in a range of studies. Gene expression profiling and their correlation with clinical presentation and as prognostic markers of carcinoid tumors and PETs have been only infrequently reported. A deeper understanding of the basic molecular biology of this group of tumors will contribute to the future identification and development of novel treatment targets.
Keywords: Gastrointestinal carcinoid tumor, pancreatic neuroendocrine tumor, menin, MEN-1, NF-1, TSC, gastrointestinal tract, gene expression, microarray.

Type of Paper: Review
Title: Mixed Adenoneuroendocrine Carcinomas (MANECs) of the Gastrointestinal Tract: an Update
Author(s): Stefano La Rosa ^1,*, Alessandro Marando ², Carlo Capella ²
Affiliation(s): ¹ Department of Pathology, Ospedale di Circolo, viale Borri 57, 21100 Varese, Italy; E-Mail: stefano.larosa@ospedale.varese.it (S.LR)
² Department of Human Morphology, University of Insubria, viale Borri 57, Varese, Italy; E-Mail: ale82.mar@fastwebnet.it (A.M.); carlo.capella@ospedale.varese.it (C.C.)
Abstract: The systematic application of immunohistochemical techniques to the study of tumors has led to the recognition that neuroendocrine cells occur rather frequently in exocrine neoplasms of the gut. It is now well known that there is a wide spectrum of combination of exocrine and neuroendocrine components, ranging from adenomas or carcinomas with interspersed neuroendocrine cells at one extreme to classical neuroendocrine tumors with focal exocrine component at the other end. In addition, both exocrine and neuroendocrine components can show different morphological features ranging, for the former, from adenoma to adenocarcinoma with different degrees of differentiation and, for the latter, from well differentiated to poorly differentiated neuroendocrine tumors. However, although this spectrum of combinations of neuroendocrine and exocrine components is frequently observed in routine practice, mixed exocrine-neuroendocrine carcinomas, now renamed as mixed adenoneuroendocrine carcinomas (MANECs), are rare and are, by definition, neoplasms in which each component represents at least 30% of the lesion. Gastrointestinal MANECs can be stratified in different prognostic categories according to the grade of malignancy of each component. The present paper is an overview on the main clinicopathological, morphological, immunohistochemical and molecular features of this specific rare tumor types.
Keywords: adenoneuroendocrine carcinoma; mixed exocrine-neuroendocrine carcinoma; gut

Type of Paper: Article
Title: Neuroendocrine Tumors in MEN1
Author: Maria Luisa Brandi
Affiliation: University of Florence, Medical School, Florence, Italy; E-Mail: m.brandi@dmi.unifi.it
Abstract: Approximately 40% of individuals with MEN1 syndrome have gastrinoma, which manifests as Zollinger-Ellison syndrome (ZES). Findings can include upper abdominal pain, diarrhea, esophageal reflux, and acid-peptic ulcers; if not properly diagnosed or treated, ulcer perforation can occur from hypergastrinemia, even without prior symptoms. Heartburn and weight loss occur, but are less commonly reported. ZES-associated hypergastrinemia may result in multiple duodenal ulcers; epigastric pain generally occurs two or more hours after meals or at night and may be relieved by eating. However, the pain may also be in the right upper quadrant, chest, or back. Vomiting may be related to partial or complete gastric outlet obstruction; hematemesis or melena may result from GI bleeding. ZES usually occurs before age 40 years. 25% of individuals with MEN1 syndrome/ZES have no family history of MEN1 syndrome. The gastrinomas of MEN1 syndrome are frequently multiple and usually malignant. Half have metastasized before diagnosis. Individuals with liver metastases have a poor prognosis for survival; this contrasts with nodal metastases, which do not seem to negatively influence prognosis. The age of onset of insulinoma associated with MEN1 is generally one decade earlier than the sporadic counterpart. A prospective endoscopic ultrasonographic evaluation of the frequency of non-functioning pancreatic tumors in MEN1 suggested that their frequency of 54.9% is higher than previously thought.  Moreover, the penetrance of 34% for these tumors at age 50 years in persons with MEN 1 from the French Endocrine Tumor Study Group indicates that they are the most frequent pancreaticoduodenal tumor in MEN 1. Average life expectancy of individuals with MEN1 with non-screting tumors was shorter than life expectancy of individuals who did not have pancreaticoduodenal tumors. Thymic, bronchial, and type II gastric enterochromaffin-like (ECL) carcinoids occur in 10% of individuals with MEN1 syndrome. These are the only MEN1 syndrome-associated neoplasms currently known to exhibit an unequal male-to-female ratio: thymic carcinoids are more prevalent in males than in females; bronchial carcinoids are more prevalent in females than in males. The clinical course of carcinoid tumors is often indolent but can also be aggressive and resistant to therapy.