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Novel Prognostic Markers Revealed by a Proteomic Approach Separating Modern Pathology (2015) 28, 69–79 & 2015 USCAP, Inc. All rights reserved 0893-3952/15 $32.00 69 Novel prognostic markers revealed by a proteomic approach separating benign from malignant insulinomas Ibrahim Alkatout1,13, Juliane Friemel2,13, Barbara Sitek3, Martin Anlauf4, Patricia A Eisenach5, Kai Stu¨ hler6, Aldo Scarpa7, Aurel Perren8, Helmut E Meyer3,9, Wolfram T Knoefel10,Gu¨ nter Klo¨ppel11 and Bence Sipos12 1Clinic of Gynecology and Obstetrics, University Hospitals Schleswig-Holstein, Kiel, Germany; 2Institute of Pathology, University of Zurich, Zurich, Switzerland; 3Medizinisches Proteom-Center, Ruhr-University Bochum, Bochum,Germany; 4Section Neuroendocrine Neoplasms, Institute of Pathology, University of Du¨sseldorf, Du¨sseldorf, Germany; 5Department of Molecular Medicine, Max-Planck Institute of Biochemistry, Martinsried, Germany; 6Molecular Proteomics Laboratory, Biologisch-Medizinisches Forschungszentrum, Heinrich-Heine-Universita¨t, Du¨sseldorf, Germany; 7ARC-NET Research Center and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy; 8Institute of Pathology, University of Bern, Bern, Switzerland; 9Institute of Pathology, University of Tu¨bingen, Tu¨bingen, Germany; 10Department of General, Visceral and Pediatric Surgery, University Hospital, Du¨sseldorf, Germany; 11Institute of Pathology, Technical University of Munich, Munich, Germany and 12Leibniz-Institut fu¨r Analytische Wissenschaften—ISAS—e.V., Dortmund, Germany 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 electro- phoresis. 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. Modern Pathology (2015) 28, 69–79; doi:10.1038/modpathol.2014.82; published online 20 June 2014 The prognostic assessment of pancreatic neuroendo- The most relevant prognostic factors proved to crine tumors has improved considerably since be tumor size, histologic differentiation, proli- the introduction of World Health Organization feration, mitotic rate, neural invasion, angio- 2010 (Bosman et al1) and the European Neuroendo- invasion, gross infiltration of adjacent organs, and, crine Tumour Society staging and grading system.2 finally, metastasis.3 However, despite this progress in prognostic stratification, the behavior of some pancreatic neuroendocrine tumors continues to Correspondence: Professor Dr B Sipos, MD, Department of be uncertain after resection. The identification of Pathology and Neuropathology, University Hospital Tu¨bingen, new prognostic biomarkers is therefore required. Liebermeisterstrasse 8, 72076 Tu¨ bingen, Germany. Proteomics enables proteins in complex protein E-mail: [email protected] 13These authors contributed equally to this work. mixtures to be quantified and identified. Here we Received 19 January 2014; accepted 3 April 2014; published took advantage of this approach to study insulino- online 20 June 2014 mas, a well-defined group of pancreatic neuroendo- www.modernpathology.org Novel markers for insulinomas 70 I Alkatout et al crine tumors. Insulinomas are solitary tumors in pean Neuroendocrine Tumour Society standard 85% of the cases; the remaining tumors are multiple procedures.2 Table 1b summarizes the clinicopatho- and are associated with either multiple endocrine logical data, including follow-up until December neoplasia 1 or insulinomatosis.4 Between 85 and 2007. One of the 51 patients, whose insulinomas 90% of solitary insulinomas are benign, and patients were considered benign, had a recurrence of are cured after resection. Between 10 and 15%, hypoglycemia after surgery. None of the benign however, develop metastases, sometimes years after cases showed metastatic disease (medium follow-up surgery. Malignant insulinomas are usually larger 95 months, range 35–295). Three of the 51 patients than 2 cm in diameter. However, in a few cases they died of diseases that were not tumor related. The may be smaller, making it difficult to detect their mean size of the insulinomas with benign behavior malignant potential, even with the help of all avail- was 1.5 cm (range 0.8–3 cm). According to the proli- able prognostic factors.5 We therefore searched feration rate, 43/51 were neuroendocrine tumors G1 for proteins whose expression in insulinomas (o2%), while 8/51 were G2 (between 2 and 6%). correlated with the clinical course of the tumors. Eleven insulinomas were malignant; of these, tissue By combining tumor microdissection, sensitive from the primary tumor was available in seven difference gel electrophoresis technique, and cases, lymph node metastasis in only one case protein mass spectrometry as well as immunohisto- (multiple endocrine neoplasia 1 associated), and chemical validation, we identified three proteins as liver metastasis in only two cases. Eight insulinomas potential prognostic markers in insulinomas. were already metastatic at the time of removal. The Materials and methods Table 1b Validation set: clinico-pathological data of 62 patients with insulinomas Supplementary Figure 1 shows an overview of the study design. Benign Malignant insulinomas insulinomas Patients and Tissues Age (median in years) 49 (16–79) 53.9 (23–82) Gender Pancreatic neuroendocrine tumors from 62 patients Male 16 (31%) 4 (36%) suffering from persistent hyperinsulinemic hypo- Female 35 (69%) 7 (64%) glycemia were studied. All patients underwent Localization of primary tumor surgery between 1975 and 2006. Their pertinent Head 15 (29%) 2 (18%) clinical data was obtained from the patients’ Body 12 (24%) 1 (9%) records. Freshly frozen (Table 1a) and formalin- Tail 24 (47%) 5 (45%) fixed paraffin-embedded tissue samples were retrie- Multicentric 0 3 (28%) ved from archives of the Departments of Pathology Operation of the university hospitals in Zu¨ rich (Switzerland), Enucleation 34 (67%) 0 Du¨ sseldorf (Germany), Kiel (Germany), and Verona Head resection 8 (16%) 1 (9%) (Italy). The study design was approved by the Tail resection 9 (17%) 3 (28%) Pancreatectomy 0 2 (18%) local ethics committee in Tu¨ bingen. The diagnosis Plus hemihepatectomy 0 4 (36%) was based on the World Health Organization Palliative operation 0 1 (9%) classification of 2010 (Bosman et al1) and the Euro- Tumor size (median 1.5 (0.8–3.5) 3.1 (1.0–8.0) in mm) Table 1a Discovery set: clinico-pathological data of 12 patients Proliferation rate with insulinomas G1 r2% 43 (84%) 6 (55%) G2 42% r20% 8 (16%) 4 (36%) Biological G3 420% 1 (9%) behavior Gender Age (years) Size (cm) Metastasis Metastases Benign Male 38 1.2 No Yes 0 11 Female 76 1.8 No No 51 0 Male 43 1.8 No Female 33 2 No Follow-up Female 44 1.5 No Recurrence 1 (9%) 7 (64%) Female 77 1.1 No No recurrence 50 (91%) 0 Not known 4 (36%) Malignant Male 65 3 Liver Female 79 3.5 Lymph node Survival (median, in months) Male 61 4 Liver Alive 47 (92%) 2 (18%) Male 56 2.5 Lymph node Death due to tumor 0 5 (45%) Male 41 6 Lymph node Tumor-unrelated death 3 (6%) 1 (9%) Male 74 3 Lymph node Not known 1 (2%) 3 (8%) Modern Pathology (2015) 28, 69–79 Novel markers for insulinomas I Alkatout et al 71 other two developed metastatic disease after surgery. 2-D Gel Electrophoresis Five of the eight patients with malignant insulino- mas died of tumor disease (medium follow-up Carrier ampholyte based isoelectric focusing (IEF) was performed in a self-made IEF chamber using period 27 months, range 1–108). The mean size of 7 the malignant insulinomas was 3 cm (range 1.0– tube gels (20 cm  1.5 mm). Briefly, after running a 8.0 cm). Six of the eight tumors were neuroendo- 21.25-h voltage gradient, the ejected tube gels were crine tumor G1, four tumors were G2 with a incubated in equilibration buffer (125 mM Tris, 40% proliferation rate between 3 and 11%, and one (w/v) glycerol, 3% (w/v) SDS, 65 mM DTT, pH 6.8) primary tumor exhibited a Ki67 rate 420% with for 10 min. The second dimension was performed in well-differentiated morphological features. a Desaphor VA 300 system using polyacrylamide gels (15.2% total acrylamide, 1.3% bisacrylamide).7 The IEF tube gels were placed onto the polyacryl- Microdissection amide gels (20 cm  30 cm  1.5 mm) and fixed using Frozen tumor tissue blocks from six benign and six 1.0% (w/v) agarose containing 0.01% (w/v) bromo-
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