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

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SO-005 Prevalence of mutations in signaling pathway components downstream of the epidermal growth-factor receptor (EGFR) in colorectal cancer J . Neumann 1 , L . Wehweck 1 , S . Maatz 1 , F . Mourched 1 , A . Hendrowarsito 1 , J . Engel 2 , T . Kirchner 1 , A . Jung 1 1 Ludwig-Maximilians-Universität München, Department of Pathology, München, 2 Ludwig-Maximilians-Universität München, Institut für medizinische Informationsverarbeitung, Biometrie und Epidemiologie, München Aims. In metastatic colorectal cancer (mCRC) KRAS-mutations are associated with clinical resistance to treatment with monoclonal antibodies targeting the epidermal growth factor receptor (EGFR). However, up to 50% of these patients do not respond to this therapy. To identify novel biomarkers, downstream effectors of the EGFR-pathway are currently validated according their predictive potential. Aim of this study was to determine the frequency and overlap of key-mutations in the EGFR-pathway. Furthermore, the concordance between primary tumor and distant metastasis was analyzed. Methods. Key mutations of KRAS, BRAF, AKT and PIK3CA were analyzed by pyrosequencing in a collection of 63 mCRC patients in primary tumor samples and corresponding metastases, respectively. Furthermore PTEN- and EGFR-Immunohistochemistry were applied. Results. Nine of the investigated 63 tumors (14.3%) had mutations in more than one gene of the EGFR-pathway. KRAS- and BRAF-mutations were detected in 50.8% and 7.9%, respectively, and were mutually exclusive. Mutations in the PIK3CA-gene (15.9%) showed huge overlap with KRASmutations (8 of 10 cases). Only one case with a mutation in the AKT-gene (1.6%) could be detected showing a simultaneous BRAF-mutation. Mutation analysis for KRAS, BRAF and AKT revealed a 100% concordance, whereas PIK3CA exhibited one discordant case showing a mutation in the primary tumor which could not be detected in the matched distant metastasis (Κ=0.9). Immunohistochemistry revealed in 49.2% high levels of EGFR-expression and in 42.9% loss of PTEN-expression, both showing huge overlap with KRAS-, BRAF-, AKT and exon 9 PIK3CA-mutations but not with exon 20 PIK3CA-mutations. Furthermore, high rates of discordant cases were found. Conclusions. We could demonstrate that KRAS- and PIK3CA-mutations as well as BRAF- and AKT-mutations can co-occur within a single tumor. However, the predictive value of these individual tumor profiles for anti-EGFR targeted therapies has to be validated in further clinical studies. Additionally, our data indicate that for molecular analysis of KRAS, BRAF and AKT either the primary tumor or the distant metastasis is suitable. Due to the lower concordance rates of PIK3CA-mutations the primary tumor site should be selected. Analysis of PTEN and EGFR protein expression are afflicted with a huge amount of discordant cases. Therefore, before these markers can be used in pathological routine diagnostics, standardized protocols are needed. SO-006 Synergistic cytotoxicity of recombinant HMGB1 and pro-apoptotic drugs in colon carcinomas G . Gdynia1 , C . Zhang1 , M . Keith1 , J . Kopitz2 , P . Schirmacher2 , W . Roth1 1Institute of Pathology, University Hospital Heidelberg, and German Cancer Research Center, Heidelberg, 2Institute of Pathology, University Hospital Heidelberg, Heidelberg Aims. Colon carcinoma cells are highly resistant to chemotherapeutic drugs. We recently described a new form of necrosis-like cell death in cancer cells induced by the HMGB1 protein. The aim of this study was to investigate whether the co-activation of cell death pathways by apoptosis inducers and HMGB1 can overcome the intrinsic resistance of colon carcinoma cells to pro-apoptotic therapeutics. Methods. ATP luciferase assay, LDH-linked lactate accumulation measurement, OXPHOS flux, FACS, western blot, immunoprecipitation, electron microscopy, subcellular fractionation, liposome transfection, generation of stably Flag-/Myc-tagged-HMGB1 and stably Bcl-2 overexpressing cells, crystal violet cytotoxicity assay, oxygen consumption measurements. Results. Colon carcinoma cell lines were differentially sensitive to recombinant HMGB1. HMGB1 treatment resulted in the formation of giant mitochondria and a steady decline of ATP. Overexpressed HMGB1 specifically bound to cytochrome c oxidase (COX IV) thus impairing mitochondrial respiration measured by a marked decrease of mitochondrial oxygen consumption. Colon carcinoma cells with depleted mitochondrial DNA (rho zero cells) were less susceptible to the cytotoxic effects of HMGB1. Combined treatment of colon cancer cells with subtoxic concentrations of HMGB1 and the death ligand TRAIL or the Bcl-2 inhibitor ABT-737 resulted in a strongly synergistic induction of cytotoxicity. The cell death was accompanied by an early activation of caspase-3 and a continuous decline of ATP. However, no cytochrome c release was measured in the co-treated cells, and the overexpression of the mitochondrial outer membrane associated anti-apoptotic Bcl-2 protein only moderately inhibited the HMGB1-mediated cytotoxicity. Conclusions. HMGB1 inhibits oxidative respiration of colon carcinoma cells thus depleting intracellular ATP levels. The administration of HMGB1 and pro-apoptotic compounds greatly increases their cytotoxic effects on colon carcinoma cells by activating both the necrotic and apoptotic cell death machinery. SO-007 Opposite effects of tissue inhibitor of metalloproteinases- 1 (TIMP-1) overexpression and knockdown on colorectal liver metastases O .R . Bandapalli1 , E . Paul1 , P . Schirmacher1 , K . Brand1 1Institute of Pathology, Heidelberg Aims. Tissue inhibitors of metalloproteinases (TIMPs) and the corresponding metalloproteinases are integral parts of the protease network and have been shown to be involved in cancer development and metastasis. Paradoxically, for TIMP-1, tumor promoting as well as tumor inhibitory effects have been observed. Methods. To address this paradox, we utilized the BALB/c/CT26 mouse model that reliably leads to liver metastasis after splenic tumor cell injection and variegated the type of target cells for therapeutic intervention and the modalities of gene transfer. Since we have observed before that overexpression of TIMP-1 in liver host cells leads to efficient tumor growth inhibition in this model, we now examined whether targeting the tumor cells themselves will have a similar effect. Results. In concordance with the earlier results, TIMP-1 overexpression in tumor cells led to a dramatic reduction of tumor growth as well. To evaluate any influence of treatment modality, we further examined whether TIMP-1 knockdown in the same animal model would have the opposite effect on tumor growth than TIMP-1 overexpression. Indeed, TIMP-1 knockdown led to a marked increase in tumor burden. Conclusions. These data indicate that in the BALB/c/CT26 model, the modification of TIMP-1 has concordant effects irrespective of the type of target cell or the technique of modulation of TIMP-1 activity, and that TIMP-1 is unequivocally tumor inhibitory in this model. Der Pathologe · Supplement 1 · 2012 | 61
Abstracts SO-008 KRAS mutational status is a prognostic biomarker in pancreatic ductal adenocarcinoma that is not influenced by p53 protein expression B .V . Sinn 1 , J .K . Striefler 2 , A . Lehmann 1 , M .A . Rudl 1 , M . Sinn 2 , A . Stenzinger 3 , M . Bahra 4 , W . Weichert 3 , H . Riess 2 , M . Dietel 1 , C . Denkert 1 1 Charité Universitätsmedizin Berlin, Institut für Pathologie, Berlin, 2 Charité Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie, Berlin, 3 Ruprecht-Karls-Universität Heidelberg, Institut für Pathologie, Heidelberg, 4 Charité Universitätsmedizin Berlin, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Berlin Aims. Mutations in the KRAS and p53 genes belong to the most frequently observed genetic alterations in pancreatic ductal adenocarcinoma (PDAC). Whereas p53 protein expression is of no prognostic value in most studies, the prognostic role of KRAS mutational status remains controversial. The aim of this study was to examine the frequency and prognostic impact of KRAS mutations in patients with PDAC (study group; n=153). In addition, we attempted to define molecular subgroups with distinct biological behaviour by combined analysis of KRAS sequencing data with p53 protein expression data. Methods. DNA was extracted from formalin-fixed and paraffin-embedded tissue cores using a fully automated extraction method. Codons 12 and 13 of the KRAS gene were sequenced using sanger sequencing technology (n=153). P53 immunostaining was performed on tissue microarrays from the same paraffin blocks. The impact of KRAS mutational status and nuclear p53 expression on patient outcome was evaluated. Results. KRAS mutations in codon 12 or 13 were found in 68% of cases. Nuclear positivity for p53 in at least 60% of tumor cells was observed in 47% of cases. We found no statistically significant association between KRAS mutational status and nuclear p53 positivity. KRAS mutational status, but not p53 expression, was an independent prognostic marker in the study group (p=0.011). Subgrouping of patients in four groups according to KRAS status and p53 expression failed to define subgroups with distinct biological behaviour and could not stratify patients beyond the impact of KRAS mutational status. Conclusions. In line with in vitro and in vivo data, we could demonstrate that the KRAS mutational status plays a crucial role in pancreatic cancer biology. KRAS may serve as a prognostic marker and potentially as a predictive marker for targeted therapies. P53 could not contribute to stratification of patients according to survival. SO-009 Collagen type V affects the tumour-stroma interaction in pancreatic cancer S . Berchtold1 , I . Esposito1 1Technische Universität München, Institute of Pathology, München Aims. Pancreatic cancer (PDAC) is characterized by a dense stroma sustaining the cancer cells. The aim of this study is to understand the role that collagen V (Col V) plays in the interaction between stromal and epithelial cells during the progression of PDAC. Methods. The expression of Col V was analysed in human PDAC, precursor lesions and PDAC cells by immunohistochemistry and immunoblotting, respectively. To study the influence of Col V on PDAC cells, in vitro assays (adhesion, migration, invasion, chemoresistance) were performed. Col V-dependent signalling pathways were investigated by immunoblotting and immunofluorescence. The impact of Col V on angiogenesis was verified by tube formation assay in Col V knocked-down HUVEC cells. Results. A progressively increasing stromal expression of Col V could be shown during cancer progression. Moreover, Col V significantly affected adhesion, migration, invasion and promoted chemoresistance of PDAC cells. Tube formation was impaired in Col V-deficient cells; however, no 62 | Der Pathologe · Supplement 1 · 2012 significant correlation between Col V expression and neoangiogenesis was found. Conclusions. The malignant phenotype of pancreatic cancer cells is enhanced by stromal Col V, potentially through activation of the integrin signalling pathway. Aktuelle Entwicklungen in der Forschung III – Translationale Forschung SO-010 The expression CDK4 and MDM2 in lipomas may point to a progression to GI liposarcomas M . Haab1 , M . Buck1 , L . Flossbach1 , S . Brüderlein1 , A . von Baer2 , M . Schult heiss2 , R . Mayer-Steinacker3 , M . Wittau4 , P . Möller1 , T .F . Barth1 1 2 Ulm University, Institute of Pathology, Ulm, Ulm University, University Hospital, Department for Orthopaedic Trauma, Hand- and Reconstructive Surgery, Ulm, 3Ulm University, University Hospital, Internal Medicine III, Ulm, 4Ulm University, University Hospital, Department of General, Visceral and Transplantation Surgery, Ulm Aims. Lipomatous tumors have the potential to progress from benign lesions to liposarcomas. Our goal was to specify changes during progression to distinguish progressing neoplasms from entirely benign lesions. Methods. We analyzed 31 lipomas of different regions including subcutaneous and deeply localized lesions, 42 liposarcomas GI and 8 hibernomas by morphology, immunohistochemistry with antibodies for MDM2, CDK4 and FISH with probes for the MDM2- and CDK4-region. Included were one lipoma with a recurrence, two ipomas that progressed to a GI liposarcoma after 8 years and 6 years respectively as well as one retroperitoneal lipomatous tumor with a lipoma and GI and GIII liposarcoma components. Furthermore, we included two own liposarcoma cell lines (LISA1 and LISA2) derived from dedifferentiated liposarcomas. Results. Of 31 lipomas 13 were CDK4+ and 8 were MDM2+ in various combinations. 19/19 showed no CDK4 aberration while two were amplified for MDM2. In GI liposarcomas 32/42 were CDK4+ and 31/42 were MDM2+. 9/13 GI sarcomas were amplified for CDK4 and 16/20 showed an amplification of MDM2. One/8 hibernoma each expressed MDM2 and CDK4 while no genetic aberrations of CDK4 or MDM2 genomic regions were detected. One lipoma with progression to GI liposarcoma showed a neoexpression of CDK4 and acquired an amplification of CDK4 and MDM2 in the GI sarcoma; in the other one an additional amplification of MDM2 was found. In one retroperitoneal lipomatous tumor we detected a neoexpression of CDK4/MDM2 in the sarcoma with an increase in copy numbers for CDK4 and MDM2. The cell lines LISA1 and LISA2 showed a heterogeneous expression of CDK4 and MDM2. Conclusions. The different patterns of CDK4 and MDM2 expression and gene amplifications in lipomas point to a progression to GI liposarcoma in morphologically unsuspicious tumors. Since hibernomas are generally negative for these markers they have different biology with no progression. LISA1 and LISA2 are in vitro models to functionally test the impact of CDK4 and MDM2 for the malignant phenotype. Immunohistochemistry and FISH-analysis for CDK4 and MDM2 may be crucial in lipomas for risk estimation.
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Inhalt Der Pathologe · Supplement
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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 24 and 25: AG Pneumopathologie III DO-032 Remo
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 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
Page 74 and 75: liver did not correlate with the mu
Page 76 and 77: AG Paidopathologie II SO-046 Overex
Page 78 and 79: Results. Histomorphology of the ova
Page 80 and 81: p42 and p27 have not yet been inves
Page 82 and 83: SO-068 Recent advances in understan
Page 84 and 85: SO-075 A novel, dual role of CCN3 i
Page 86 and 87: Pancreatic Adenocarcinoma SG-137 Se
Page 88 and 89: sease and 30 colon cancer serum sam
Page 90 and 91: Conclusions. Although CRC is charac
Page 92 and 93: differentiated and TNM stage III or
Page 94 and 95: pressed moderate levels of the prot
Page 96 and 97: FR-P-037 MALDI imaging reveals COX7
Page 98 and 99: in the context of therapy response
Page 100 and 101: on primary cells of wild-type and c
Page 102 and 103: chemotherapy was recommended and co
Page 104 and 105: aims are twofold: 1) to verify the
Page 106 and 107: Results. Her2/neu status in TMAs an
Page 108 and 109: prognostic impact was found in rect
Page 110 and 111: 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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96. Jahrestagung der Deutschen Gesellschaft für Pathologie e. V ...

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