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Pancreatic Neoplasms: HELP
Articles by Martin Anlauf
Based on 20 articles published since 2008
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Between 2008 and 2019, M. Anlauf wrote the following 20 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Guideline ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas. 2016

Garcia-Carbonero, R / Sorbye, H / Baudin, E / Raymond, E / Wiedenmann, B / Niederle, B / Sedlackova, E / Toumpanakis, C / Anlauf, M / Cwikla, J B / Caplin, M / O'Toole, D / Perren, A / Anonymous6950853. ·Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid, Spain. ·Neuroendocrinology · Pubmed #26731334.

ABSTRACT: -- No abstract --

2 Review Hyperplasia to neoplasia sequence of duodenal and pancreatic neuroendocrine diseases and pseudohyperplasia of the PP-cells in the pancreas. 2014

Klöppel, Günter / Anlauf, Martin / Perren, Aurel / Sipos, Bence. ·Department of Pathology, Technical University, Ismaningerstr. 22, 81675, München, Germany, guenter.kloeppel@alumni.uni-kiel.de. ·Endocr Pathol · Pubmed #24718881.

ABSTRACT: Hyperplastic changes of the neuroendocrine cell system may have the potential to evolve into neoplastic diseases. This is particularly the case in the setting of genetically determined and hereditary neuroendocrine tumor syndromes such as MEN1. The review discusses the MEN1-associated hyperplasia-neoplasia sequence in the development of gastrinomas in the duodenum and glucagon-producing tumors in the pancreas. It also presents other newly described diseases (e.g., glucagon cell adenomatosis and insulinomatosis) in which the tumors are (or most likely) also preceded by islet cell hyperplasia. Finally, the pseudohyperplasia of PP-rich islets in the pancreatic head is defined as a physiologic condition clearly differing from other hyperplastic-neoplastic neuroendocrine diseases.

3 Review Neuroendocrine neoplasms of the gastroenteropancreatic system: pathology and classification. 2011

Anlauf, M. ·Institute of Pathology and Endocrine Tumor Center, University Clinic of Düsseldorf, Germany. martin.anlauf@med.uni-duesseldorf.de ·Horm Metab Res · Pubmed #22105474.

ABSTRACT: Neuroendocrine neoplasms (NEN) appear homogeneous in terms of morphology, but constitute a very heterogeneous group of tumors in terms of biological and clinical features. NEN may occur in any organ, but are most commonly observed in the lung and the gastroenteropancreatic system (GEP). The European Neuroendocrine Tumor Society (ENETS) developed guidelines in the last 5 years to standardize and improve the diagnosis and therapy of GEP-NEN. Taking these guidelines into account, the TNM classification of the Union for International Cancer Control (UICC) was introduced in 2009. The new GEP-NEN classification of the World Health Organization (WHO) was presented 1 year later. According to the guidelines of the ENETS, the UICC, and the WHO, the pathology classification of NEN of GEP consists of several basic components: (1) evidence of the neuroendocrine nature of the tumor, (2) histological distinction between well and poorly differentiated tumors, (3) proliferation-based grading. (4) TNM staging (including data about vascular invasion and resection margins), (5) with reference to the clinical question: evidence of hormones and biogenic amines, and (6) optional, especially in cases of initial diagnosis of NEN: expression of the somatostatin receptor type 2A. Based on these criteria, a standardized prognostic stratification of GEP-NEN can be performed in combination with other clinical parameters. The novel classifications constitute the basis for selecting the procedures of molecular and metabolic imaging as well as for tumor-specific treatments and permit comparisons of larger tumor populations. Close interdisciplinary cooperation is a prerequisite.

4 Review [Diagnostics and treatment in functional pancreatic neuroendocrine tumours]. 2011

Müssig, K / Dudziak, K / Horger, M / Anlauf, M / Goretzki, P E. ·Klinik für Innere Medizin mit Gastroenterologie und Onkologie, Florence-Nightingale-Krankenhaus, Kaiserswerther Diakonie, Düsseldorf. ·Dtsch Med Wochenschr · Pubmed #21656454.

ABSTRACT: Pancreatic neuroendocrine tumours (PNET) are rare entities with an annual incidence of < 100,000. About 1 - 2 % of pancreatic neoplasias are neuroendocrine tumours. About one third of these tumours secrete biologically active substances that lead to development of specific clinical syndromes. PNET may occur sporadically or in association with hereditary syndromes, such as multiple endocrine neoplasia type 1 (MEN1). Among the functional PNET, insulinomas and gastrinomas are the most common entities. In contrast, vasoactive intetinale peptide (VIP)-secreting tumours, glucagonomas, serotonin-secreting carcinoid tumors, and tumours with secretion of ectopic hormones, such as calcitonin, are extremely rare. Once diagnosis has been established on the basis of clinical and laboratory findings, localization of the source of pathologic hormone secretion is warranted. Imaging methods frequently used for localization of PNET comprise anatomical imaging modalities, computed tomography, and magnetic resonance imaging, endoscopic ultrasound, selective arterial catheterization with hepatic venous sampling, DTPA-octreotid scintigraphy and DOTA-D-Phe(1)-Tyr(3)-octreotid positron emission tomography. Therapy is based on the specific tumour entity and the extent of the disease. In the majority of patients, even in the case of malignant disease, a surgical approach is warranted, eventually combined with a medical treatment.

5 Article BRAF 2019

Dizdar, Levent / Werner, Thomas A / Drusenheimer, Jasmin C / Möhlendick, Birte / Raba, Katharina / Boeck, Inga / Anlauf, Martin / Schott, Matthias / Göring, Wolfgang / Esposito, Irene / Stoecklein, Nikolas H / Knoefel, Wolfram T / Krieg, Andreas. ·Department of Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany. · Institute of Pathology, Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany. · Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany. · Institute of Pathology and Cytology, St. Vincenz Hospital Limburg, Limburg, Germany. · Division for Specific Endocrinology, Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany. ·Int J Cancer · Pubmed #30144031.

ABSTRACT: To determine the role of BRAF

6 Article Establishment of the First Well-differentiated Human Pancreatic Neuroendocrine Tumor Model. 2018

Benten, Daniel / Behrang, Yasmin / Unrau, Ludmilla / Weissmann, Victoria / Wolters-Eisfeld, Gerrit / Burdak-Rothkamm, Susanne / Stahl, Felix R / Anlauf, Martin / Grabowski, Patricia / Möbs, Markus / Dieckhoff, Jan / Sipos, Bence / Fahl, Martina / Eggers, Corinna / Perez, Daniel / Bockhorn, Maximillian / Izbicki, Jakob R / Lohse, Ansgar W / Schrader, Jörg. ·I. Medical Department - Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of Gastroenterology, Helios Klinik Duisburg, Duisburg, Germany. · Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of General-, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of Radiotherapy and Radiation Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Institute of Pathology, Limburg, Germany. · Department of Gastroenterology, Rheumatology and Infectious Diseases, Charite Campus Benjamin Franklin, Berlin, Germany. · Institute of Pathology, Charité - Universitaetsmedizin Berlin, Berlin, Germany. · Department for Interventional and Diagnostic Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of Pathology, University Hospital Tübingen, Tübingen, Germany. · I. Medical Department - Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. j.schrader@uke.de. ·Mol Cancer Res · Pubmed #29330294.

ABSTRACT: Clinical options for systemic therapy of neuroendocrine tumors (NET) are limited. Development of new drugs requires suitable representative

7 Article Syndromic versus non-syndromic sporadic gastrin-producing neuroendocrine tumors of the duodenum: comparison of pathological features and biological behavior. 2016

Rosentraeger, M Johannes / Garbrecht, Nele / Anlauf, Martin / Raffel, Andreas / Knoefel, Wolfram T / Wiedenmann, Bertram / Klöppel, Günter. ·First Department of Medicine, University Hospital Schleswig-Holstein, Christian-Albrechts University, Arnold-Heller-Str. 3, Kiel, 24105, Germany. johannes.rosentraeger@uksh.de. · Department of Pathology, University Hospital Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany. · Institute of Pathology and Cytology, St. Vincenz Hospital, Limburg, Germany. · Department of General, Visceral and Pediatric Surgery, University Hospital of Düsseldorf, Düsseldorf, Germany. · Department of Hepatology and Gastroenterology, Charité, Campus Virchow Clinic, Berlin, Germany. · Department of Pathology, Consultation Center for Pancreatic and Endocrine Tumors, Technical University, Munich, Germany. ·Virchows Arch · Pubmed #26649731.

ABSTRACT: Sporadic gastrin-producing neuroendocrine tumors of the duodenum present either with the Zollinger-Ellison syndrome (ZES) or with unspecific symptoms. While syndromic gastrin-producing neuroendocrine tumors often show metastases at the time of diagnosis, those without a syndrome do not. The aim of the study was to search for clinicopathological features that may distinguish the two categories of gastrin-producing duodenal tumors. In a retrospective study, we analyzed the clinical and pathological data in a series of 41 patients with syndromic (i.e., gastrinomas) or non-syndromic duodenal gastrin-producing neuroendocrine tumors (ns-gas-NETs). Twenty-four (59 %) of the 41 patients had tumors that were associated with a ZES and were classified as gastrinomas. These tumors showed a higher Ki-67 index than that of the ns-gas-NETs (1.74 vs. 0.85 %, p = 0.012). In addition, they had more lymph node metastases (75 vs. 6 %, p < 0.001) and showed liver metastases and thus presented much more frequently in TNM stage ≥III (75 vs. 6 %; p < 0.001) than their non-syndromic counterparts. Gastrinomas were removed surgically, ns-gas-NETs endoscopically. We did not observe any significant differences in overall survival or recurrence of disease. Duodenal gastrinomas show no clear morphological features that distinguish them from their non-syndromic counterparts. However, the patients with gastrinomas present in a more advanced stage of disease and need surgical treatment, while non-syndromic gastrin-producing duodenal NETs may be cured by complete endoscopical removal.

8 Article Glucagon cell hyperplasia and neoplasia with and without glucagon receptor mutations. 2015

Sipos, Bence / Sperveslage, Jan / Anlauf, Martin / Hoffmeister, Maike / Henopp, Tobias / Buch, Stephan / Hampe, Jochen / Weber, Achim / Hammel, Pascal / Couvelard, Anne / Höbling, Walter / Lieb, Wolfgang / Boehm, Bernhard O / Klöppel, Günter. ·Department of Pathology (B.S., J.S., M.H.), University of Tübingen, 72076 Germany · Institute of Pathology (M.A.), Limburg, 65549 Germany · Institute of Pathology (T.H.), Traunstein, 83278 Germany · POPGEN Biobank Project (S.B.), Christian-Albrechts-University, Kiel, 24105 Germany · First Department of Internal Medicine (J.H.), University Hospital, Dresden, 01304 Germany · Department of Clinical Pathology (A.W.), University Hospital Zürich, 8091 Switzerland · Service de Gastroentérologie-Pancréatologie (P.H.), Hôpital Beaujon, Clichy La Garenne, 92110 France · Department of Pathology (A.C.), Hôpital Bichat, Paris, 75018 France · Institute of Pathology (W.H.), Hospital Wels-Grieskirchen, Wels, 4600 Austria · Institute of Epidemiology and Biobank POPGEN (W.L.), Christian-Albrechts-University, 24105 Kiel, Germany · LKC Medicine (B.O.B.), Nanyang Technological University, 639798 Singapore and Imperial College London, London WC1E 6BT, UK and Department of Internal Medicine I, University of Ulm Medical Centre, Ulm, 89081 Germany · and Department of Pathology (G.K.), Technical University München, 80333 Germany. ·J Clin Endocrinol Metab · Pubmed #25695890.

ABSTRACT: CONTEXT: Glucagon cell adenomatosis (GCA) was recently recognized as a multifocal hyperplastic and neoplastic disease of the glucagon cells unrelated to multiple endocrine neoplasia type 1 and von-Hippel-Lindau disease. OBJECTIVE: The study focused on the molecular analysis of the glucagon receptor (GCGR) gene in GCA and a description of the clinicopathological features of GCA with and without GCGR mutations. DESIGN: Pancreatic tissues from patients showing multiple glucagon cell tumors were morphologically characterized and macro- or microdissected. All exons of the GCGR gene were analyzed for mutations by Sanger and next-generation sequencing. Genotyping for all detected GCGR variants was performed in 2560 healthy individuals. PATIENTS: Six patients with GCA, and the parents of one patient were included in the study. MAIN OUTCOME MEASURES: The main outcome measures were the correlations between the patients' GCGR mutation status and the respective clinicopathological data. RESULTS: GCGR germline mutations were found in three of six patients. Patient 1 harbored a homozygous stop mutation. This patient's parents showed an identical but heterozygous GCGR mutation. Patient 2 had two different heterozygous point mutations leading each to premature stop codons. Patient 3 exhibited two homozygous missense mutations. No GCGR mutations were identified in the three other patients and in a large cohort of healthy subjects. The patients harboring GCGR mutations exhibited a greater number of tumors and larger tumors than patients with wild-type GCGR. One of the patients with wild-type GCGR showed lymph node micrometastases. CONCLUSIONS: GCA with GCGR germline mutations seems to follow an autosomal-recessive trait. By interrupting the GCGR signaling pathways GCGR mutations probably cause GCA via glucagon cell hyperplasia. GCA also occurs in patients without GCGR mutations, but seems to be associated with fewer and smaller tumors.

9 Article Novel prognostic markers revealed by a proteomic approach separating benign from malignant insulinomas. 2015

Alkatout, Ibrahim / Friemel, Juliane / Sitek, Barbara / Anlauf, Martin / Eisenach, Patricia A / Stühler, Kai / Scarpa, Aldo / Perren, Aurel / Meyer, Helmut E / Knoefel, Wolfram T / Klöppel, Günter / Sipos, Bence. ·Clinic of Gynecology and Obstetrics, University Hospitals Schleswig-Holstein, Kiel, Germany. · Institute of Pathology, University of Zurich, Zurich, Switzerland. · Medizinisches Proteom-Center, Ruhr-University Bochum, Bochum,Germany. · Section Neuroendocrine Neoplasms, Institute of Pathology, University of Düsseldorf, Düsseldorf, Germany. · Department of Molecular Medicine, Max-Planck Institute of Biochemistry, Martinsried, Germany. · Molecular Proteomics Laboratory, Biologisch-Medizinisches Forschungszentrum, Heinrich-Heine-Universität, Düsseldorf, Germany. · ARC-NET Research Center and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy. · Institute of Pathology, University of Bern, Bern, Switzerland. · 1] Medizinisches Proteom-Center, Ruhr-University Bochum, Bochum,Germany [2] Institute of Pathology, University of Tübingen, Tübingen, Germany. · Department of General, Visceral and Pediatric Surgery, University Hospital, Düsseldorf, Germany. · Institute of Pathology, Technical University of Munich, Munich, Germany. · Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany. ·Mod Pathol · Pubmed #24947143.

ABSTRACT: The prognosis of pancreatic neuroendocrine tumors is related to size, histology and proliferation rate. However, this stratification needs to be refined further. We conducted a proteome study on insulinomas, a well-defined pancreatic neuroendocrine tumor entity, in order to identify proteins that can be used as biomarkers for malignancy. Based on a long follow-up, insulinomas were divided into those with metastases (malignant) and those without (benign). Microdissected cells from six benign and six malignant insulinomas were subjected to a procedure combining fluorescence dye saturation labeling with high-resolution two-dimensional gel electrophoresis. Differentially expressed proteins were identified using nano liquid chromatography-electrospray ionization/multi-stage mass spectrometry and validated by immunohistochemistry on tissue microarrays containing 62 insulinomas. Sixteen differentially regulated proteins were identified among 3000 protein spots. Immunohistochemical validation revealed that aldehyde dehydrogenase 1A1 and voltage-dependent anion-selective channel protein 1 showed significantly stronger expression in malignant insulinomas than in benign insulinomas, whereas tumor protein D52 (TPD52) binding protein was expressed less strongly in malignant insulinomas than in benign insulinomas. Using multivariate analysis, low TPD52 expression was identified as a strong independent prognostic factor for both recurrence-free and overall disease-related survival.

10 Article "Cherry picking", a multiple non-anatomic liver resection technique, as a promising option for diffuse liver metastases in patients with neuroendocrine tumours. 2014

Krausch, Markus / Raffel, Andreas / Anlauf, Martin / Schott, Matthias / Lehwald, Nadja / Krieg, Andreas / Topp, Stefan Andreas / Cupisti, Kenko / Knoefel, Wolfram Trudo. ·Department of General, Visceral and Pediatric Surgery, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany, krausch@med.uni-duesseldorf.de. ·World J Surg · Pubmed #24101025.

ABSTRACT: INTRODUCTION: Liver metastases of GEP-NETs are a known major prognostic factor with a strong effect on patients' survival. To date, various treatment options are available, whereas surgery remains the only curative option. Because large liver resections often cannot be performed due to insufficient remnant liver volume, a special operative technique, "cherry picking" (multiple nonanatomic liver resections), can be used as a tissue-preserving procedure. METHODS: Of 91 patients with various GEP-NETs, 16 patients were identified with synchronous or metachronous multifocal, bilobular liver metastases (>10). All were treated with "cherry picking." Patient records were reviewed retrospectively and clinical data and pathology results were analyzed. RESULTS: Mean survival after primary tumour resection was 82.8 versus 41.2 months after liver surgery. All 16 patients are still alive. Mean recurrence-free survival after primary tumour operation was 49.8 versus 24.6 months after liver surgery. Complications of cherry picking included two postoperative biliary leakages and three small hepatic abscesses (conservative/interventional approach 25 % (n = 4), surgical approach 6.25 % (n = 1). There was no postoperative mortality. Initial hormonal symptoms (5/16 patients) completely disappeared postoperatively in 2 patients and were significantly decreased in 3 patients. CONCLUSIONS: The tissue-preserving surgical technique "cherry picking" has developed due to improved imaging techniques and increased knowledge in liver anatomy, which has helped to make this approach safer and easier. Highly selected patients with multiple bilobular liver metastases of GEP-NET can benefit from this special surgical approach, also applicable for recurrent metastases.

11 Article Secondary malignancy in patients with sporadic neuroendocrine neoplasia. 2013

Krausch, M / Raffel, A / Anlauf, M / Schott, M / Lehwald, N / Krieg, A / Kröpil, F / Cupisti, K / Knoefel, W T. ·Department of General, Visceral and Pediatric Surgery, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany, krausch@med.uni-duesseldorf.de. ·Endocrine · Pubmed #23494366.

ABSTRACT: The incidence of neuroendocrine neoplasias (NENs), especially of the gastro-entero-pancreatic (GEP), system relatively increased over the past decades, as a result of advanced diagnostic tools, a better clinical awareness, and distinguished pathological diagnostic recognition. Previous reports hypothesized an increased risk for secondary malignancies in patients with NEN especially in GEP-NENs. The present study was designed to investigate the coincidence of NENs and secondary malignancies in a large patient collective. A retrospective analysis was performed on 161 patients (85 female and 76 male) with NEN of various origins. Clinical data of these patients, different classification systems (TNM/WHO), proliferations-based grading, and clinical follow-up were collected and analyzed. Out of 143 patients with a sporadic NEN, 15 (10.49 %) patients were identified with secondary malignant tumors. Median age at the time of the primary operation for NEN was 65 years, whereas the median age of initial diagnosis of associated tumors was 59 years. Mean follow-up time was 61 months. The risk of developing a secondary malignancy was most elevated for patients with an NEN of the lung, the stomach, and the ileum (60, 50 and 20 %, respectively). The spectrum of secondary malignancies included various types of cancer. Kaplan-Meier survival analysis shows a difference suggesting that patients with a secondary malignancy demonstrate a worse survival compared to patients without a secondary tumor; no significance was detected (p = 0.349). Our data suggest that secondary malignancies in patients with NEN's especially in GEP-NENs are found more frequently than in general population. Therefore, patients with NEN need a continuous and detailed follow-up. The reason for the increased incidence of secondary malignancies in patients with NENs remains to be elucidated.

12 Article Notch 1 tumor expression is lacking in highly proliferative pancreatic neuroendocrine tumors. 2013

Krausch, Markus / Kroepil, Feride / Lehwald, Nadja / Lachenmayer, Anja / Schott, Matthias / Anlauf, Martin / Cupisti, Kenko / Knoefel, Wolfram Trudo / Raffel, Andreas. ·Department of General, Visceral and Pediatric Surgery, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany. ·Endocrine · Pubmed #23225326.

ABSTRACT: To date, very little is known about the development of benign organic hyperinsulinism and its metastatic potential. Typical morphologic, biochemical, or genetic differentiations for benign or malign tumor course of insulinomas do not exist. As signaling pathways may affect pancreatic cancer development and the maintenance of the neoplastic phenotype, the purpose of this study was to examine the role of Notch1 expression in organic hyperinsulinism. We examined 32 well-differentiated pancreatic endocrine tumors (wd PET); 11 wd PET of unknown behavior (wd PET ub); and 15 wd pancreatic endocrine cancer (wd PEC) for Notch1 expression by immunohistochemistry. Demographic data, clinical data, and follow-up of all patients were analyzed. Islets of the Langerhans show the strongest Notch1 staining in nearly 90 %. Positive Notch1 staining was absent in the acinar of the pancreas. In patients with a wd PET more than every second tumor (56.3 %/n = 18/32) demonstrated a negative Notch1 staining. The other 14 patients were positive for Notch1. Tumors of unknown behavior (wd PET ub) and malignant insulinomas had no signs of Notch expression in contrast to benign insulinomas. Considering the clinical and histomorphological tumor behavior, no correlation between Notch1 expression and clinical data was found. The missing Notch expression in the malignant tumor course might be used as a potential predictive marker, but further studies are needed to investigate the underlying molecular mechanism.

13 Article Advanced Pancreatic Adenocarcinoma: Complete Histological Response After Palliative Therapy with Gemcitabine and Cisplatin. 2012

Alexander, A / Rehders, A / Riediger, R / Schmitt, M / Anlauf, M / Knoefel, W T. ·Klinik für Allgemein-, Viszeral- und Kinderchirurgie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität, Moorenstr. 5, 40225, Düsseldorf, Germany. · Klinik für Allgemein-, Viszeral- und Kinderchirurgie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität, Moorenstr. 5, 40225, Düsseldorf, Germany. rehders@med.uni-duesseldorf.de. · Klinik für Gastroenterologie, Hepatologie und Infektiologie, Heinrich-Heine-Universität, Moorenstr. 5, 40225, Düsseldorf, Germany. · Institut für Pathologie, Heinrich-Heine-Universität, Moorenstr. 5, 40225, Düsseldorf, Germany. ·J Gastrointest Cancer · Pubmed #22528322.

ABSTRACT: -- No abstract --

14 Article Loss of PTEN expression in neuroendocrine pancreatic tumors. 2011

Krausch, M / Raffel, A / Anlauf, M / Schott, M / Willenberg, H / Lehwald, N / Hafner, D / Cupisti, K / Eisenberger, C F / Knoefel, W T. ·Department of General, Visceral and Pediatric Surgery, Heinrich-Heine University of Düsseldorf, Germany. krausch@med.uni-duesseldorf.de ·Horm Metab Res · Pubmed #22105477.

ABSTRACT: PTEN (phosphatase and tensin homologue deleted from chromosome 10) is a well established tumor suppressor gene, which was cloned to chromosome 10q23. PTEN plays an important role in controlling cell growth, apoptosis, cell adhesion, and cell migration. In various studies, a genetic change as well as loss of PTEN expression by different carcinomas has been described. To date, the role of PTEN as a differentiation marker for neuroendocrine tumors (NET) and for the loss of PTEN expression is still unknown. It is assumed that loss of PTEN expression is important for tumor progression of NETs. We hypothesize that PTEN might be used as a new prognostic marker. We report 38 patients with a NET of the pancreas. Tumor tissues were surgically resected, fixed in formalin, and embedded in paraffin. PTEN expression was evaluated by immunohistochemistry and was correlated with several clinical and pathological parameters of each individual tumor. After evaluation of our immunohistochemistry data using a modified Remmele Score, a widely accepted method for categorizing staining results for reports and statistical evaluation, staining results of PTEN expression were correlated with the clinical and pathological parameters of each individual tumor. Our data demonstrates a significant difference in survival with existence of lymph node or distant metastases. Negative patients show a significant better survival compared with positive patients. Furthermore, we show a significant difference between PTEN expression and WHO or TNM classification. Taken together, our data shows a positive correlation between WHO classification and the new TNM classification of NETs, and loss of PTEN expression as well as survival. These results strongly implicate that PTEN might be helpful as a new prognostic factor.

15 Article VHL inactivation is an important pathway for the development of malignant sporadic pancreatic endocrine tumors. 2009

Schmitt, A M / Schmid, S / Rudolph, T / Anlauf, M / Prinz, C / Klöppel, G / Moch, H / Heitz, P U / Komminoth, P / Perren, A. ·Department of Pathology, Institute of Surgical Pathology, Zurich, Switzerland. anja.schmitt@pathology.unibe.ch ·Endocr Relat Cancer · Pubmed #19690016.

ABSTRACT: A small subset of familial pancreatic endocrine tumors (PET) arises in patients with von Hippel-Lindau syndrome and these tumors may have an adverse outcome compared to other familial PET. Sporadic PET rarely harbors somatic VHL mutations, but the chromosomal location of the VHL gene is frequently deleted in sporadic PET. A subset of sporadic PET shows active hypoxia signals on mRNA and protein level. To identify the frequency of functionally relevant VHL inactivation in sporadic PET and to examine a possible prognostic significance we correlated epigenetic and genetic VHL alterations with hypoxia signals. VHL mutations were absent in all 37 PETs examined. In 2 out of 35 informative PET (6%) methylation of the VHL promoter region was detected and VHL deletion by fluorescence in situ hybridization was found in 14 out of 79 PET (18%). Hypoxia inducible factor 1alpha (HIF1-alpha), carbonic anhydrase 9 (CA-9), and glucose transporter 1 (GLUT-1) protein was expressed in 19, 27, and 30% of the 152 PETs examined. Protein expression of the HIF1-alpha downstream target CA-9 correlated significantly with the expression of CA-9 RNA (P<0.001), VHL RNA (P<0.05), and VHL deletion (P<0.001) as well as with HIF1-alpha (P<0.005) and GLUT-1 immunohistochemistry (P<0.001). These PET with VHL alterations and signs of hypoxia signalling were characterized by a significantly shortened disease-free survival. We conclude that VHL gene impairment by promoter methylation and VHL deletion in nearly 25% of PET leads to the activation of the HIF-pathway. Our data suggest that VHL inactivation and consecutive hypoxia signals may be a mechanism for the development of sporadic PET with an adverse outcome.

16 Article Insulinomatosis: a multicentric insulinoma disease that frequently causes early recurrent hyperinsulinemic hypoglycemia. 2009

Anlauf, Martin / Bauersfeld, Juliane / Raffel, Andreas / Koch, Christian A / Henopp, Tobias / Alkatout, Ibrahim / Schmitt, Anja / Weber, Achim / Kruse, Marie L / Braunstein, Stefan / Kaserer, Klaus / Brauckhoff, Michael / Dralle, Henning / Moch, Holger / Heitz, Philipp U / Komminoth, Paul / Knoefel, Wolfram T / Perren, Aurel / Klöppel, Günter. ·Department of Pathology, University of Kiel, Kiel, Germany. ·Am J Surg Pathol · Pubmed #19011561.

ABSTRACT: BACKGROUND: Multicentric insulinoma disease was characterized with regard to its histopathology, multiple endocrine neoplasia type 1 (MEN1) status, precursor lesions, and the risk of hyperinsulinemic hypoglycemia recurrence. METHODS: Fourteen patients with multicentric insulinoma disease were compared with 267 patients with sporadic and familial insulinomas. The tumors were classified according to the World Health Organization (WHO) criteria. The MEN1 status was defined clinically and by germline mutation analysis. Detection of the MEN1 gene locus was performed using fluorescence in situ hybridization. The surgical interventions and the duration of disease-free survival were recorded. RESULTS: Fourteen patients (5%) without evidence of MEN1 showed 53 macrotumors and 285 microtumors expressing exclusively insulin. In addition, they had small proliferative insulin-expressing monohormonal endocrine cell clusters (IMECCs). No allelic loss of the MEN1 locus was detected in 64 tumors. All but one patient had benign disease. Recurrent hypoglycemia occurred in 6/14 patients (11 recurrences; mean time to relapse 8.4 y). Thirteen patients with MEN1 (4.6%) showed 41 insulinomas and 133 tumors expressing islet hormones other than insulin. IMECCs were not detected. Allelic loss of the MEN1 locus was found in 17/19 insulinomas. Recurrent hypoglycemia occurred in 4/13 patients (4 recurrences; mean time to relapse 14.5 y). Solitary insulinomas were found in 254/281 patients (90.4%). IMECCs were absent. There was no recurrent hypoglycemia in 84 patients with benign insulinomas. CONCLUSIONS: Insulinomatosis is characterized by the synchronous and metachronous occurrence of insulinomas, multiple insulinoma precursor lesions, and rare development of metastases, but common recurrent hypoglycemia. This disease differs from solitary sporadic and MEN1-associated insulinomas.

17 Article Glucagon cell adenomatosis: a newly recognized disease of the endocrine pancreas. 2009

Henopp, Tobias / Anlauf, Martin / Schmitt, Anja / Schlenger, Regina / Zalatnai, Attila / Couvelard, Anne / Ruszniewski, Philippe / Schaps, Klaus-Peter / Jonkers, Yvonne M H / Speel, Ernst-Jan M / Pellegata, Natalia S / Heitz, Philipp U / Komminoth, Paul / Perren, Aurel / Klöppel, Günter. ·Department of Pathology, University of Tübingen, Liebermeisterstr. 8, 72076 Tübingen, Germany. Tobias.Henopp@med.uni-tuebingen.de ·J Clin Endocrinol Metab · Pubmed #18957496.

ABSTRACT: BACKGROUND: Glucagon-producing tumors are either solitary neoplasms of the pancreas, occasionally associated with a glucagonoma syndrome, or multiple neoplasms associated with multiple endocrine neoplasia type 1 (MEN1). We observed a previously undescribed multicentric glucagon-producing tumor disease that is not related to MEN1. METHODS: Pancreatic tissue from four patients showing multiple neuroendocrine microadenomas and in two cases also macrotumors were screened for hormones using immunohistochemical and morphometric methods. MEN1, von Hippel-Lindau, and p27 germ line and somatic mutation analysis was performed. Deletion of MEN1 (11q13), von Hippel-Lindau (3p25), and the centromere 11 and 3 gene locus was determined by fluorescence in situ hybridization. DNA copy number changes were studied using array comparative genomic hybridization. RESULTS: The pancreatic tissue from the four patients contained more than 870 microadenomas and 10 macrotumors, all of which expressed exclusively glucagon and none of which showed evidence of malignancy. In addition, many islets were unusually large and showed glucagon cell hyperplasia. There was no clinical or molecular evidence of any hereditary tumor disease, and changes in the MEN1 gene were only seen in individual tumors. Array comparative genomic hybridization of one macrotumor and 20 pooled microadenomas revealed a homogeneous diploid chromosome set. CONCLUSIONS: The findings are sufficiently distinctive to suggest a new neoplastic disease of the endocrine pancreas that we recommend calling glucagon cell adenomatosis. Clinically, this disease may be an incidental finding, or it may lead to a glucagonoma syndrome.

18 Article Primary lymph node gastrinoma or occult duodenal microgastrinoma with lymph node metastases in a MEN1 patient: the need for a systematic search for the primary tumor. 2008

Anlauf, Martin / Enosawa, Tetsuji / Henopp, Tobias / Schmitt, Anja / Gimm, Oliver / Brauckhoff, Michael / Dralle, Henning / Musil, Anette / Hauptmann, Steffen / Perren, Aurel / Klöppel, Günter. ·Department of Pathology, University of Kiel, Kiel, Germany. manlauf@path.uni-kiel.de ·Am J Surg Pathol · Pubmed #18520436.

ABSTRACT: Gastrinoma tissue has been found frequently in lymph nodes located near the duodenum without a known primary tumor. Therefore, it has been suggested that a primary lymph node gastrinoma exists. We report on a 38-year-old woman suffering from multiple endocrine neoplasia type 1 (MEN1) confirmed by menin gene mutation analysis. MEN1 disease started with primary hyperparathyroidism followed by Cushing disease, the detection of tumors of the pituitary, adrenal cortex, and the pancreas and also an elevated serum gastrin level. An octreotide scan revealed 4 tumors in the upper abdomen. A selective arterial calcium stimulation test located the source of the hypergastrinemia to the area of the gastroduodenal and the superior mesenteric arteries. Total pancreatoduodenectomy was performed and conventional histopathologic examination revealed a well-differentiated cystic neuroendocrine tumor of the pancreas expressing glucagon and accompanied by several microadenomas. In addition, 3 suprapancreatic lymph nodes with gastrin-positive endocrine tissue were found. None of the pancreatic microadenomas expressed gastrin and no duodenal endocrine tumor was found despite careful macroscopic examination. Only after complete embedding of the duodenal and pancreatic tissue in 65 paraffin blocks, 2 microgastrinomas (0.45 and 0.8 mm in diameter) were identified in the duodenum. It is concluded that duodenal gastrinomas that give rise to lymph node metastases may be so tiny that they are easily overlooked in a routine examination and that systematic tissue monitoring is required to identify them.

19 Article Somatostatin-producing neuroendocrine tumors of the duodenum and pancreas: incidence, types, biological behavior, association with inherited syndromes, and functional activity. 2008

Garbrecht, Nele / Anlauf, Martin / Schmitt, Anja / Henopp, Tobias / Sipos, Bence / Raffel, Andreas / Eisenberger, Claus F / Knoefel, Wolfram T / Pavel, Marianne / Fottner, Christian / Musholt, Thomas J / Rinke, Anja / Arnold, Rudolf / Berndt, Uta / Plöckinger, Ursula / Wiedenmann, Bertram / Moch, Holger / Heitz, Philipp U / Komminoth, Paul / Perren, Aurel / Klöppel, Günter. ·Department of Pathology, University of Kiel, Michaelisstr 11, Kiel, Germany. ngarbrecht@path.uni-kiel.de ·Endocr Relat Cancer · Pubmed #18310290.

ABSTRACT: Somatostatin-producing neuroendocrine tumors (SOM-NETs) of the duodenum and pancreas appear to be heterogeneous. To determine their clinicopathological profiles, respective data were analyzed on a series of 82 duodenal and 541 pancreatic NETs. In addition, the clinical records of 821 patients with duodenal or pancreatic NETs were reviewed for evidence of a somatostatinoma syndrome. Predominant or exclusive expression of somatostatin was found in 21 (26%) duodenal and 21 (4%) pancreatic NETs. They were classified as sporadic (n=31) or neurofibromatosis type 1 (NF1)-associated duodenal NETs (n=3), gangliocytic paragangliomas (GCPGs; n=6), or poorly differentiated neuroendocrine carcinomas (pdNECs; n=2). In addition, five duodenal and four pancreatic SOM-NETs were found in five patients with multiple endocrine neoplasia type 1 (MEN1). Metastases occurred in 13 (43%) patients with sporadic or NF1-associated SOM-NETs, but in none of the duodenal or pancreatic MEN1-associated SOM-NETs or GCPGs. Sporadic advanced (stage IV) SOM-NETs were more commonly detected in the pancreas than in the duodenum. None of the patients (including the 821 patients for whom only the clinical records were reviewed) fulfilled the criteria of a somatostatinoma syndrome. Our data show that somatostatin expression is not only seen in sporadic NETs but may also occur in GCPGs, pdNECs, and hereditary NETs. Surgical treatment is effective in most duodenal and many pancreatic SOM-NETs. MEN1-associated SOM-NETs and GCPGs follow a benign course, while somatostatin-producing pdNECs are aggressive neoplasms. The occurrence of the so-called somatostatinoma syndrome appears to be extremely uncommon.

20 Article Islet 1 (Isl1) expression is a reliable marker for pancreatic endocrine tumors and their metastases. 2008

Schmitt, Anja M / Riniker, Florian / Anlauf, Martin / Schmid, Sonja / Soltermann, Alex / Moch, Holger / Heitz, Philipp U / Klöppel, Günther / Komminoth, Paul / Perren, Aurel. ·Department of Pathology, Institute of Surgical Pathology, University Hospital Zürich, Zürich, Switzerland. Anja.Schmitt@triemli.stzh.ch ·Am J Surg Pathol · Pubmed #18300808.

ABSTRACT: BACKGROUND: Tracing the origin of a metastasis of a neuroendocrine carcinoma is a challenge. The transcription factors Cdx2 and TTF1 have been found to be helpful in identifying well-differentiated neuroendocrine tumors of gastrointestinal and pulmonary origin, respectively. So far, such a marker is lacking for pancreatic neuroendocrine tumors (PETs) and metastases thereof. Islet1 (Isl1) is a transcription factor expressed in pancreatic islet cells. The aim of this study was (1) to test the specificity and sensitivity of Isl1 as a marker of PETs, and (2) to test the specificity and sensitivity of a panel of markers, including Isl1, Cdx2, and TTF1, for the localization of the primary. DESIGN: One hundred eighty-eight primary gastroenteropancreatic and pulmonary endocrine tumors and 49 metastases thereof were examined. Immunohistochemistry using antibodies directed against Isl1, Cdx2, and TTF1 was performed and the staining results were scored semiquantitatively. RESULTS: Isl1 proved to be a highly specific marker for pancreatic endocrine tumors. In 84 primary PET its specificity was 78.4% (sensitivity 74.3%) and in 18 metastases of PET the specificity reached 100% (sensitivity 77.8%). Strong Cdx2 staining showed a specificity for gastrointestinal origin of 83.9% (sensitivity 82%) in primary tumors and of 100% (sensitivity 40%) in metastases. Including weakly positive tumors lead to a decreased specificity but an increased sensitivity. TTF1 expression was detected in 2 PET and 1 ileal primary tumor only and was absent in all metastases of gastroenteropancreatic endocrine tumors. CONCLUSIONS: Isl1 is a reliable marker of pancreatic endocrine tumors and metastases thereof. It shows a comparable sensitivity and specificity as Cdx2 as a marker of ileal and appendiceal neuroendocrine tumors and their metastases. TTF1 is very rarely expressed in well-differentiated gastroentero-PETs. Therefore, the panel of Isl1, Cdx2, and TTF1 seems useful for examining metastases of well-differentiated endocrine carcinomas of unknown origin.