96. Jahrestagung der Deutschen Gesellschaft für Pathologie e. V ...

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AG Pneumopathologie III DO-032 Remodelling-related molecular profiles in interstitial pulmonary fibrosis D . Jonigk 1 , J . Rische 1 , L . Maegel 1 , H . Golpon 2 , N . Izykowski 1 , C . Bockmeyer 1 , T . Welte 2 , S . Janciauskiene 3 , J . Gottlieb 2 , G . Warnecke 4 , A . Haverich 5 , H . Kreipe 1 , F . Laenger 1 1 Hannover Medical School (MHH), Institute of Pathology, Hannover, 2 Hannover Medical School (MHH), Department of Pneumology, Hannover, 3 Hannover Medical School (MHH), Department of Respiratory Medicine, Hannover, 4 Hannover Medical School (MHH), Department of Throracic Surgery, Hannover, 5 Hannover Medical School (MHH), Department of Thoracic Surgery, Hannover Aims. Idiopathic pulmonary fibrosis (IPF) is the most important representative of the idiopathic interstitial pneumonia group (IIP) and is a disease characterized by an overall poor prognosis and unresponsiveness to currently available therapies. Thus elucidation of molecular pathways to gain better insight into the pathogenesis and identify potential therapeutic targets is warranted. Methods. We performed compartment-specific analyses using laser microdissection, RT-PCR based microarray techniques and immunohistochemistry in lung samples from well defined patients with UIP, nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP) patterns and controls (n=5 of each group). Results. Notably, we identified cardinal regulatory genes that were differentially up-regulated in UIP (BMP 4 and MMP13), NSIP (BMP6 and CXCR4) and OP (BMP1, IL-13 and TGFB3), respectively. In UIP, remodelled areas showed a prominent up-regulation of fibrosis-associated genes like BMP7, MMP2 and TIMP2, while non-remodelled zones were characterized by a significantly higher expression of BMP6 and pro-inflammatory mediators IL-8 and IL-17A. Conclusions. Our findings show that distinct, morphologically defined IPF subgroups show specific cytokine expression patterns. Moreover, BMPR2 and MMP13 up-regulation correlates significantly with the absence of interstitial scarring in UIP pattern lungs. These results are promising regarding their potential as diagnostic adjunct and therapeutic targets. DO-033 MALAT1 is essential for lung cancer metastasis in a novel human knockout model T . Gutschner1 , M . Eißmann2 , M . Hämmerle1 , M . Baas1 , C . Hildenbrand1 , M . Groß1 , M . Zörnig2 , S . Diederichs1 1Heidelberg University Hospital & German Cancer Research Center (DKFZ), Institute of Pathology, Heidelberg, 2Georg-Speyer-Haus, Frankfurt Aims. The highly conserved long non-coding RNA MALAT-1 (Metastasis-Associated in Lung Adenocarcinoma Transcript 1) had been discovered as a prognostic marker associated with poor survival and development of distant metastasis in lung adenocarcinoma. Since then, it has been found to be deregulated in numerous tumor entities and has been linked to splicing. However, its functional relevance in tumor cells remains to be elucidated. Knockdown models for MALAT1 have been described but suffer from insufficient silencing efficiency of the highly abundant, nuclear non-coding RNA (ncRNA). Methods. In this project, we have developed a novel strategy to create ncRNA knockouts in human cancer cell lines. Results. We have successfully used a synthetic Zinc Finger Nuclease engineered to target the 5’-region of MALAT1 to stably and biallelically integrate RNA-destabilizing elements into the genome of human lung cancer cells (A549). This approach resulted in a specific and more than 1000-fold silencing of MALAT1 in individual clones compared to a less than 5-fold silencing using siRNAs. Thus, this approach can be used to create functional knockouts of coding as well as non-coding genes also in human tumor cell lines allowing loss-of-function studies also of nonconserved ncRNAs in the future. Phenotypically, the MALAT1-Knockout cells (KO) greatly differ from their parental cell line and wild type clones (WT): Next to morphological changes, the migration of the KO cells is largely impaired as shown in scratch assays. In xenograft assays after i.v. injection, the KO cells form significantly fewer and smaller lung metastases than their WT counterparts. Since no large difference was observed after subcutaneous injection of the WT and the KO cells, this indicates a specific, active and essential function of MALAT1 in metastasis. Conclusions. Taken together, we have developed a novel, highly effective approach for the knockout of genes that can be used for non-coding as well as coding RNAs in human tumor cells. Knockout of MALAT1 in human lung cancer cells revealed its essential function in migration and metastasis. DO-034 Rationale for treatment of metastatic squamous cell carcinoma of the lung using FGFR inhibitors A . Franzen 1 , F . Göke1 , R . Menon1 , D . Goltz1 , R . Kirsten1 , D . Böhm1 , W . Vogel 1 , A . Göke1 , V . Scheble2 , J . Ellinger3 , U . Gerigk4 , F . Fend5 , P . Wagner6 , A . Schröck7 , S . Perner1 1 2 University Hospital of Bonn, Institute of Pathology, Bonn, University of Tübingen, Department of Hematology and Oncology, Tübingen, 3University Hospital of Bonn, Department of Urology, Bonn, 4Malteser Hospital Bonn, Department of Thorax Surgery, Bonn, 5University Hospital of Tübingen, Institute of Pathology, Tübingen, 6University of Pittsburgh Medical Center, Division of Surgical Oncology, Pittsburgh, United States, 7University Hospital of Bonn, Department of Head and Neck Surgery, Bonn Aims. We previously identified amplification of the fibroblast growth factor receptor 1 (FGFR1) gene as a potential therapeutic target for a small molecule inhibitor therapy in squamous cell lung cancer (L-SCC). Currently, clinical phase 1 trials are underway to examine whether patients with FGFR1-amplified L-SCC benefit from a targeted therapy approach using small molecule inhibitors of FGFR. As most lung cancer patients present with metastatic disease, we investigated whether lymph node metastases in L-SCC share the FGFR1 amplification status of their corresponding primary tumor. Methods. Our study cohort consisted of 72 patients with L-SCC, 39 of whom presented with regional lymph node metastases. Tissue microarrays were constructed from formalin-fixed, paraffin-embedded tissue of the primary tumors and, where present, of the corresponding lymph node metastasis. A biotin-labeled target probe spanning the FGFR1 locus (8p11.22-23) was used to determine the FGFR1 amplification status by fluorescence in-situ hybridization (FISH). Results. FGFR1 amplification was detected in 16% (12/72) of all primary lung SCC. Among patients with metastatic L-SCC, 18% (7/39) of the lymph node metastases displayed a FGFR1 amplification, and an exact correlation between the FGFR1 amplification status was observed between the primary tumor and metastatic tissue. Conclusions. FGFR1 amplification is a common genetic event in squamous cell carcinomas of the lung. Moreover, lymph node metastases derived from FGFR1-amplified L-SCCs also exhibit FGFR1 amplification. Therefore, we suggest that the FGFR1 amplification is a clonal event in tumor progression. Beyond this biologically relevant observation, our findings carry therapeutic implications, in that small-molecule inhibitors may be applicable to the treatment of squamous cell carcinomas of metastatic squamous cell carcinoma of the lung. Der Pathologe · Supplement 1 · 2012 | 23
Abstracts DO-035 FISH assays for the detection of FGFR1 amplifications and EML4- ALK translocations in NSCLC H .-U . Schildhaus 1 , K . Schmitz 1 , L . Heukamp 1 , S . Merkelbach-Bruse 1 , R . Büttner 1 1 University of Cologne, Institute of Pathology, Köln Aims. Easy, reliable and standardized tests for predictive diagnoses and targeted therapies are needed. A small subset of pulmonary adenocarcinomas (AC) harbor therapeutically relevant EML4-ALK translocations. The incidence of squamous cell carcinomas (SC) of the lung increases dramatically, but targeted therapeutic options are not well established for this subgroup of NSCLC. Recently, Fibroblast Growth Factor Receptor 1 (FGFR1) amplification in SC was described to be associated with tumor growth and survival, suggesting that FGFR inhibitors may be a viable therapeutic option in this cohort of patients. Methods. A total of 400 NSCLC samples were included in this study. For detection of EML4-ALK translocations a triple color FISH assay was used: two probes labeled orange and green flank the breakpoint region of ALK in telomeric and centromeric direction, and a third probe, labeled in blue, spans the entire EML4 gene. A dual color FGFR1/CEN8 probe was used to evaluate the prevalence of FGFR1 amplification in SC and to develop an evaluation strategy for FGFR1 FISH assays. Results. Using the triple color EML4-ALK probe specific signal patterns were found for different types of ALK rearrangements. An inversion of chromosome 2p results in (1) split (separated) orange and green signals, (2) a split (doubled) blue signal and (3) a colocalisation (fusion) of the separated orange and green signals with blue signals. Additional specific signals patterns were seen in cases with inversions/deletions and interstitial deletions alone. Investigating a subset of 254 SC with a two colour FISH assay we found FGFR1 amplifications in 20% of SCC but not in AC. Low amplification levels (as defined by ≥5 FGFR1 signals in ≥50% of tumor cells) were rare with a frequency of 6.3% while high level amplifications (as defined by a FGFR1/CEN8 ≥2.0, or average number of FGFR1 signals per tumor cell nucleus ≥6, or the percentage of tumor cells containing ≥15 FGFR1signals or large clusters ≥10%) occurred in 15% of all SC. Conclusions. The novel triple color split/fusion approach decreases the number of questionable or borderline cases at high sensitivity and specificity and allows the diagnosis of specific types of ALK translocations. FGFR1 amplification is one of the most frequent therapeutically tractable genetic lesion in NSCLC. Standardized reporting of FGFR1 amplification in SCC will become increasingly important to correlate therapeutic responses to FGFR1 inhibitors in clinical studies. DO-036 Mutation analysis from the REASON study, a Registry for the Epidemiologic and Scientific evaluation of EGFR mutation status in newly diagnosed NSCLC patients stage IIIB/IV P . Schirmacher1 , W . Schütte2 , M . Thomas3 , W . Eberhardt4 , J .-M . Graf von der Schulenburg5 , S . Zaun6 , M . Dietel7 1 2 University of Heidelberg, Institute of Pathology, Heidelberg, Städtisches Krankenhaus Martha Maria, Halle-Dölau, 3Heidelberg University Hospital, Thoraxklinik, Heidelberg, 4Universitätsklinikum der GSH Essen, Essen, 5 6 Leipniz University of Hannover, Hannover, AstraZeneca GmbH, Wedel, 7Humbold University Berlin, Institute of Pathology, Berlin Aims. Somatic mutations in the EGFR gene predict for sensitivity to EGFR tyrosine kinase inhibitors (TKI) in patients with advanced NSCLC, however, little is known about the prevalence of such mutations in the German population. The REASON study aims to generate key data on the EGFR mutation status and its association with major clinicopathological parameters derived from a sufficiently large sample of stage IIIB/IV NSCLC patients with a predominantly Caucasian ethnic background in Germany. 24 | Der Pathologe · Supplement 1 · 2012 Methods. REASON is an AstraZeneca sponsored German registry. 4255 subjects with stage IIIB/IV NSCLC for whom EGFR mutation testing was planned were enrolled at 151 participating sites throughout Germany (129 hospital-based, 22 office-based). EGFR mutation testing was done at 56 QuIP certified and 11 additional pathology institutions. While analysis of exons 19 and 21 was obligatory, analysis of exons 18 and 20 was not routinely done at all labs. The primary aim was to collect epidemiological data on EGFR mutation status (M+, M−) in the German population and to correlate EGFR mutation status with clinicopathological characteristics (e.g. smoking status, gender, histology, etc.). As secondary objectives, real-life clinical outcome data of all EGFR M+ patients (PFS, OS,DCR), clinical management and pharmaco-economic data (resource use) associated with diagnosis and treatment of EGFR M+ patients will be collected. Results. Interim analysis data was available for 3612 patients (Caucasian patients only, 99.4% of all patients). 62% of patients are male and 38% female; with 81% being ever-smokers vs. 19% non-smokers. Adenocarcinoma histology is most frequent (68%), followed by squamous epithelial carcinoma subtype (20%). 358 EGFR mutations were found, the rate of EGFR mutations predicting TKI sensitivity was 9.5%, with 0.4% resistant mutations. Most common mutations were exon 19 deletions (49.6%; predominantly Del E746-A750) followed by exon 21 mutations [38%, mostly L858R (93 or 26.8% of all mutations)]. Exon 18 and 20 mutations (incl. 3 T790M) were found in 6.3% and 9.2% of patients, respectively. The differentiated panel of identified mutations will be shown. Conclusions. REASON provides the largest data base to date on EGFR mutations status of patients with newly diagnosed stage IIIB/IV NSCLC in Germany. In addition, data on baseline epidemiological and further clinicopathological characteristics will enable us to better understand the association of these factors with different mutations and clinical outcomes. AG Hämatopathologie I DO-043 ID2 and ID3 protein expression differs between hematopoietic cell lineages and acute leukemias of distinct clinicopathological entities A .M . May1 , A .-V . Pfister1 , L . Bogatyreva2 , M . Benkisser3 , D . Hauschke2 , M . Lübbert4 , M . Werner1 , J . Hasskarl4 , S . Lassmann1 1 2 University Freiburg Medical Center, Institute of Pathology, Freiburg, University Freiburg Medical Center, Institute of Medical Biometry und Medical Informatics, Freiburg, 3University Freiburg, Freiburg, 4University Freiburg Medical Center, Department of Hematology and Oncology, Freiburg Aims. Inhibitors of DNA binding (ID) proteins regulate cellular differentiation and proliferation through formation of heterodimers with basic helix-loop-helix transcription factors. To elucidate the role of ID proteins in hematopoiesis and in acute leukemia, we analysed ID2 and ID3 protein expression in hematopoietic cells and leukemic blasts. Methods. Primary bone marrow biopsies (BMB) of patients with AML with myelodysplasia related changes (AML-MD) (n=19), de novo AML (n=20), cALL (n=23) and T-ALL (n=19) as well as BMB of healthy bone marrow stem cell donors (n=19) were stained for ID2 and ID3 protein expression by immunohistochemistry (IHC). In healthy BMB, each 200 cells/hematopoietic lineage were evaluated, differentiating between mature and immature granulopoiesis. In acute leukemias, the staining pattern and intensity of 200 blast cells/BMB were assessed. Statistical analyses were done by the nonparametric Kruskal-Wallis test (two-sided, significance level 0.05), and in case of a significant result by an additional pairwise Wilcoxon test. Results. In normal BMB hematopoietic cells and maturation stages displayed significant differences in ID2/3 protein expression. While the
Page 2 and 3: Inhalt Der Pathologe · Supplement
Page 4 and 5: Inhalt Der Pathologe · Supplement
Page 6 and 7: Editorial Liebe Kolleginnen und Kol
Page 8 and 9: Kolorektales Karzinom 2 VO-005 Tran
Page 10 and 11: Keynote Lecture VO-014 Genetic dete
Page 12 and 13: (AMACR, FASN, GOLM1, GSP-pi, ERG) t
Page 14 and 15: to assess the correct rate of R1 re
Page 16 and 17: DNA damage, and cytotoxic drugs. Au
Page 18 and 19: HCV-positive formalin-fixed and par
Page 20 and 21: well as MET activation were examine
Page 22 and 23: or BRAF mutation, c-MYC and SIRT1 e
Page 26 and 27: immature granulopoiesis showed a st
Page 28 and 29: ned, if well-defined mantle zones,
Page 30 and 31: phomas). Most prominent gains or am
Page 32 and 33: DO-062 Tumor-associated macrophages
Page 34 and 35: DO-080 DOG1: an immunohistochemical
Page 36 and 37: AG Oralpathologie DO-087 Detection
Page 38 and 39: DO-094 Do activated fibroblasts inf
Page 40 and 41: DO-101 Histopathological analysis o
Page 42 and 43: DO-108 Identification of potential
Page 44 and 45: Conclusions. In conclusion, 454 par
Page 46 and 47: subgroup of patients with B-Raf mut
Page 48 and 49: DO-002b Impact of terminologies in
Page 50 and 51: Methods. We performed MCPyV-FISH of
Page 52 and 53: FR-013 HPV-genotype distribution in
Page 54 and 55: Methods. Three different techniques
Page 56 and 57: (i.e. investment in equipment and e
Page 58 and 59: FR-032 COLD-PCR: a powerful tool in
Page 60 and 61: dissection (MBLND) technique to imp
Page 62 and 63: SO-005 Prevalence of mutations in s
Page 64 and 65: SO-011 Methylation profiling and in
Page 66 and 67: more effective than SAHA alone and
Page 68 and 69: SO-022 Specialized pathology review
Page 70 and 71: SO-027 Ki-67 in mitotic score group
Page 72 and 73: nificantly associated with advanced
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liver did not correlate with the mu
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AG Paidopathologie II SO-046 Overex
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Results. Histomorphology of the ova
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p42 and p27 have not yet been inves
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SO-068 Recent advances in understan
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SO-075 A novel, dual role of CCN3 i
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Pancreatic Adenocarcinoma SG-137 Se
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sease and 30 colon cancer serum sam
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Conclusions. Although CRC is charac
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differentiated and TNM stage III or
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pressed moderate levels of the prot
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FR-P-037 MALDI imaging reveals COX7
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in the context of therapy response
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on primary cells of wild-type and c
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chemotherapy was recommended and co
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aims are twofold: 1) to verify the
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Results. Her2/neu status in TMAs an
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prognostic impact was found in rect
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provided information on survival ti
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Methods. Biopsy specimens from 430
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the OS rate was 53% for patients wi
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FR-P-098 Immunohistological stainin
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FR-P-104 Histopathological evaluati
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within the earliest morphologic det
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Conclusions. In primary imaging a g
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fibrotic neointma development as we
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FR-P-129 Alpha-1-antitrypsin-PiZ-an
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FR-P-136 The expression of central
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cosa and in the periarterial tissue
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FR-P-149 Combination of Castleman d
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or without different concentrations
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Results. In 18 cases (79%) the caus
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FR-P-168 Autopsy findings in a 2-ye
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FR-P-174 MPGN-like glomerulonephrit
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Poster: Gynäkopathologie und Mamma
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SA-P-011 Genetic aberrations of pre
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Mechanismen, die eine Progression d
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internet server. A network of inter
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Methods. HE-gefärbte Schnittpräpa
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Conclusions. The newly released 450
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and desmoplastic reaction are diffe
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one patient revealed more than 9 mi
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situation, the V600E mutation in th
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SA-P-064 Evolution of molecular pat
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nic markers such as myf4 and MyoD1
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Conclusions. To our knowledge, this
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SA-P-085 Expression of the eukaryot
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Results. The papillary RCC type II
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SA-P-098 Male infertility: assessme
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SA-P-104 Process oriented scientifi
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Conclusions. The IBDW offers a uniq
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L Lasitschka F. DO-046 Lehmann A. F
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