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

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phomas). Most prominent gains or amplifications (6/21 large cell lymphomas) concern region 2p16.1a-15d containing PAPOLG, REL, PUS10 and PEX13. Amplification of REL was confirmed by FISH in these cases. In all these lymphomas, immunohistochemical staining for c-Rel was positive in at least 30% of the tumor cells. Regions with putative acquired uniparental disomies (aUPD) are more present in the large cell lymphomas: on the average 40 regions vs. 9 regions in the small cell lymphomas. Comparing the SNP profiles of two areas of the same tumor both with a t(11;18) Api2/Malt1 but with slightly different morphology, the analysis revealed additional gains in the more blastic part. Investigating two lymphoma samples from the same patient with an interval of two years, FISH analysis showed a signal pattern pointing to a large deletion in the IGH locus exclusively in the later sample. SNP analysis confirmed the FISH result and revealed about ten additional aberrations illustrating increasing genomic complexity during lymphoma progression. Conclusions. Small and large cell variants of gastrointestinal marginal zone B-cell lymphomas have distinct patterns of genomic aberrations but share some overlapping features. REL is frequently amplified in the large cell variants. In general, during lymphoma progression, the SNP data correlate with a more complex pattern of aberrations. DO-057 Comparative analysis of gene expression profiles defines large cell variants of gastric marginal zone B-cell lymphoma as a distinct subgroup L . Floßbach1 , J . Kraus2 , K . Holzmann3 , P . Möller1 , H .A . Kestler2 , T .F .E . Barth1 1 2 Ulm University, Pathology, Ulm, Ulm University, Neural Information Processing, Ulm, 3Ulm University, IZKF, Ulm Aims. Gastrointestinal marginal zone B-cell lymphomas (MALT Lymphomas) often collocalize with a more aggressive, large cell component. The WHO classifies these lymphomas as “extranodal DLBCL with or without residing MALT component”. We have shown that the small and the large cell components of these composite lymphomas (ComL) are mostly clonal and, in addition to that, that the gene expression profiles of small cell MALT lymphomas and lymphoma components are similar to those of the large cell components or lymphomas. This suggests that most of the gastrointestinal DLBCL are indeed blastic variants of marginal zone B-cell lymphomas (MZBL) [Barth et al., J Pathol 2007; 211(3):305; Flossbach et al. Int J Cancer 2011 129(1):70]. To further distinguish these large cell variants of MZBL from nodal and extranodal DLBCL we performed a comparative analysis of gene expression profiles from B-cell lymphomas. Methods. We extracted RNA from frozen tissue samples of 28 gastrointestinal marginal zone B-cell lymphomas (n=7), large cell components of ComL (n=8) and large cell variants (n=13). Gene expression profiling was performed using the Affymetrix U 133 plus 2.0 array. Additional datasets created with the same chip from DLBCL (n=119), PMBL (n=20), BL (n=33), FL (n=38), MCL (n=7), pulmonary MALT lymphomas (n=35) and normal B-cells (n=20) were obtained from the Gene Expression Omnibus (GEO) database. After normalization and based on a subset of NF-κB target genes [Compagno et al., Nature, 459, 717, 2009], we performed hierarchical clustering analysis. Additionally, we performed cluster robustness analysis using the k-means algorithm. Results. Cluster number estimation was robust for k=8. These eight clusters consisted mostly of: 1. naïve B-cells and memory B-cells, 2. centroblasts and centrocytes, 3. Burkitt’s lymphoma, 4. pulmonary MALT lymphoma, 5. follicular lymphoma, mantle cell lymphoma, and gastrointestinal MALT lymphoma, 6. PMBL and DLBCL, 7. DLBCL, 8. blastic MZBL and DLBCL. The dendrogramm, generated by the hierarchical average linkage clustering process, was consistent with this classification. In comparison to all DLBCLs and PMBLs, the blastic MZBLs had relatively underexpressed PTPN3 and relatively overexpressed BANK, CD44, CD63, and FAS. Conclusions. These data confirm our view of blastic marginal zone B-cell lymphomas as a distinct group of extranodal diffuse large B-cell lymphomas. DO-058 Prognostic phenotypic and genotypic in situ biomarkers in diffuse large B-cell lymphomas: preliminary translational report of the prospective SAKK 38/07 trial A . Tzankov1 , N . Leu1 , S . Muenst1 , D . Klingbiel2 , C . Mamot3 , S . Dirnhofer1 1 2 University Hospital Basel, Pathology, Basel, Switzerland, SAKK Coordinating Center, Swiss Group for Clinical Cancer Research, Bern, Switzerland, 3Cantonal Hospital Aarau, Aarau, Switzerland Aims. Diffuse large-B cell lymphoma (DLBCL) exhibits variable outcomes and risk assessment is based on the international prognostic index (IPI), which takes into account primarily patient-related parameters. The prognostic role of tumor-related parameters is a matter of controversy. Methods. We prospectively analyzed the prognostic value of phenotypic and genotypic profiles suggested to play a role in DLBCL on a clinical trial collective of 124 DLBCL patients homogenously treated with six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, followed by 2 cycles rituximab (R-CHOP). Evaluation of the role of positron emission tomography was a main objective, and was performed before, after 2 cycles of therapy and at the end of treatment. Immunohistochemical (BCL2, BCL6, CD5, CD10, CD20, CD95, CD168, Cyclin E, FOXP1, GCET, Ki-67, MUM1p, pSTAT3) and in situ hybridization analyses [BCL2 break apart probe (BAP), C-MYC BAP and C-MYC/ IgH double-fusion probe (DFP) and Epstein-Barr virus probe (EBER)] were performed and correlated with clinicopathological parameters and outcome. Results. The median patients’ age was 59 years; 68 were males, 56 females. BCL2 gene breaks were observed in 11% of cases, and those cases also expressed BCL2 in a mean of 95% of tumor cells, compared to 42% in nonrearranged instances; 85% of the rearranged cases were of the germinal center (GC) phenotype according to the Tally algorithm. 3% of cases (all of the non-GC phenotype) showed BCL2 amplifications. C-MYC breaks were observed in 10% of cases; 66% were of the GC phenotype. Of the C- MYC rearranged cases only a third displayed C-MYC/IgH fusions corresponding to t(8;14), the others being assumed to have alternative C-MYC rearrangement partners. Cases with rearranged C-MYC showed as high Ki-67 labeling as non-rearranged. Cases with both BCL2 and C-MYC rearrangements were not observed. A complete response (CR) defined by Cheson’s criteria was achieved in 90 out of 117 patients, for 7 there were no data. Factors that were linked to failure to achieve CR were CD5 positivity (11% compared to 2%, p=0.051), EBER positivity (4% of cases compared to 0% of those with CR, p=0.072) and presence of either BCL2 or C-MYC gene rearrangements (46% compared to 18%, p=0.132), but not IPI or Tally phenotype. Conclusions. Phenotypic and genotypic studies with carefully selected biomarkers like CD5, EBER and BCL2- as well C-MYC BAP might be of prognostic value in DLBCL patients treated by R-CHOP. DO-059 Phenotype of primary testicular diffuse large B-cell lymphomas T . Menter1 , M . Ernst1 , S . Dirnhofer1 , A . Braghorn2 , P . Went1 , A . Tzankov1 1University of Basel, Institute of Pathology, Basel, Switzerland, 2Medica Zürich, Switzerland Aims. Primary testicular diffuse large B-cell lymphomas (tDLBCL) are rare neoplasms with few comprehensive studies conducted so far. We therefore aimed to systematically analyze the morphology and phenotype of tDLBCL. Der Pathologe · Supplement 1 · 2012 | 29
Abstracts Methods. Forty-three patients from 3 different Swiss hospitals were included in the study. The tumors were diagnosed between 1972 and 2009. The protein expression profile was assessed by immunohistochemistry. Results. 39 of the tumors showed centroblastic and 1 immunoblastic morphology, three were not classifiable. All cases were positive for CD79a, followed by CD20 and PAX5 (95% of cases) and CD19 (93%). Most cases (68%) expressed the post-germinal center (GC) marker FOXP1 and 21% expressed MUM1, while the GC markers CD10, LMO2, BCL6 and GCET1 were expressed in 27, 16, 8 and 6%, respectively (cut-off levels for the respective markers were determined by ROC). BCL2 was expressed on >50% of the tumor cells in 69% of cases. 83% of cases were phenotypically classifiable as non-GC DLBCL according to the Tally algorithm. There was no evidence for EBV- or HHV8-association. 70% of the tumors showed active STAT signaling by expression of either pSTAT1 or pSTAT3, but not pSTAT5. p53 was expressed in 12% of cases, but p21 staining (p21/ p53) did not suggest presence of TP53 mutations.. Mean mitotic index was 18/mm2, median MIB1 labeling index was 40% (±25%). Tumors with lymphoepithelial lesions in seminiferious tubules showed a lower mitotic activity, although the association was weak. Interestingly, one tumor was positive for OCT4. All 43 cases were negative for NUT1 and PLAP. Only limited clinical data were available: mean age at diagnosis was 69 years (range: 43–87 years, n=41). There was no side predilection of the tumors. One tumor was bilateral at diagnosis, one tumor presented simultaneously in the testis and the CNS. Of ten tumors, five did not relapse (mean follow up time 48 months). Five tDLBCL relapsed, thereof two in the contralateral testis, two in the CNS and one in the skin. Conclusions. We conclude that tDLBCL are predominantly centroblastic and of non-GC phenotype. Since occasionally tDLBCL can express germ cell markers or be CD20-negative, multimarker phenotyping is important for lineage determination. There was no shift of morphology or protein expression profile over time. tDLBCL have active STAT signalling mediated through pSTAT1 and pSTAT3. tDLBCL are of non-/post-GC origin and not hyper-proliferative. TP53 mutations are unlikely. DO-060 C-MYC aberrations characterize a subset of patients with diffuse large B-cell lymphoma with poor outcome when treated with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone A . Tzankov1 , M . Gerhard1 , S . Dirnhofer1 , C . Visco2 , K . Young3 1 2 University Hospital Basel, Pathology, Basel, Switzerland, San Bortolo Hospital, Internal Medicine, Vicenza, Italy, 3The University of Texas MD Anderson Cancer Center, Pathology, Houston, United States Aims. Diffuse large-B cell lymphoma (DLBCL) exhibits variable outcomes and risk assessment is based on the international prognostic index (IPI), which takes into account primarily patient-related parameters. Gene expression profiling (GEP) can stratify patients with different prognoses into germinal center B-cell (GCB) and activated B-cell subtype (ABC). These groups remain of prognostic importance with the addition of rituximab (R) to chemotherapy. The prognostic role of C-MYC gene status in the era of modern treatment is still debatable. Methods. To address this question, we analyzed C-MYC gene abnormalities by interphase fluorescence in situ hybridization (FISH) utilizing break-apart- (BAP) and a IgH/C-MYC double-fusion (DFP) probes in 601 patients with de novo DLBCL treated with R, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) and 332 patients treated with CHOP; all patients had clinical follow-up and GEP data. Results. C-MYC gene abnormalities were detected in 67 of 672 evaluable cases (10%), including 7 amplifications (2 ABC, 5 GCB), 4 rearrangements, detectable only with the DFP (2 ABC, 2 GCB), 23 rearrangements, detectable only with the BAP (5 ABC, 18 GCB) and 33 rearrangements, detectable with both the BAP and DFP (12 ABC, 21 GCB; p=0.032 for the differences between ABC and GCB). In multivariable models the last two C-MYC aberration types represented IPI- and GEP-independent 30 | Der Pathologe · Supplement 1 · 2012 prognostic factors for event-free survival in R-CHOP treated patients (p=0.003; relative risk 1.46) and in patients with GCB (p=0.014; relative risk 1.29), but (though being of prognostic significance in univariable models) not in CHOP treated ones and in ABC, where IPI was the sole prognosticator. Conclusions. C-MYC aberrations are observed in 10% of DLBCL, more commonly in GCB cases. Alternative C-MYC rearrangements with non- IgH partners, which are detectable only with BAP, account for a third of all C-MYC structural genetic abnormalities. C-MYC aberrations detected by BAP add IPI independent prognostic information for individual DLBCL risk estimation in R-CHOP treated cases. DO-061 MYC-binding sites in Burkitt lymphoma identified by deep sequencing V . Seitz1 , P . Butzhammer2 , B . Hirsch1 , J . Hecht3 , I . Gütgemann4 , A . Ehlers1 , D . Lenze1 , E . Oker1 , A . Sommerfeld1 , E . von der Wall1 , C . König5 , C . Zinser6 , R . Spang2 , M . Hummel1 1 2 Institute of Pathology, Charité – University Medicine, Berlin, University of Regensburg, Institute for Functional Genomics, Regensburg, 3Charité – University Medicine, Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, 4University Hospital of Bonn, Department of Pathology, Bonn, 5 6 imaGenes GmbH, Source BioScience, Berlin, Genomatix Software GmbH, Genomatix Personalized Medicine, München Aims. MYC is a key transcription factor involved in central cellular processes such as regulation of the cell cycle, histone acetylation and ribosomal biogenesis. It is overexpressed in the majority of human tumors including aggressive B-cell lymphoma. Especially Burkitt lymphoma (BL) is a highlight example for MYC overexpression due to a chromosomal translocation involving the c-MYC gene. However, so far genomewide analysis of MYC-binding sites by chromatin immunoprecipitation (ChIP) followed by next generation sequencing (ChIP-Seq) has not been conducted in BL. Therefore, our objective was the precise and representative consideration of the MYC landscape in BL due to a much higher coverage of MYC-binding sites employing ChIP-Seq. Methods. We carried out ChIP in 5 human BL cell lines, employing a MYC-specific antibody followed by next generation sequencing of the precipitated DNA fragments. To assess the functional consequences of MYC binding, the ChIP-Seq data were supplemented with siRNA-mediated knock-downs of MYC in BL cell lines followed by gene expression profiling. Results. Our ChIP-Seq analysis gave rise to 7,054 MYC-binding sites after bioinformatics analysis of a total of approx. 19 million sequence reads. In line with previous findings, binding sites accumulate in genes known to be involved in the cell cycle, ribosomal biogenesis, histone acetylation and DNA-methylation demonstrating a regulatory role of MYC in these processes. Unexpectedly, MYC-binding sites also accumulate in many B-cell relevant genes and expression analysis after knock-down of MYC by siRNA identified genes involved in the B-cell function which are upregulated in response to MYC silencing. Conclusions. The 7,054 MYC-binding sites identified by our ChIP-Seq approach greatly extend the knowledge regarding MYC binding in BL and shed further light on the enormous complexity of the MYC regulatory network. Especially our observations that (i) many B-cell relevant genes are targeted by MYC and (ii) that MYC down-regulation leads to an upregulation of B-cell genes highlight an interesting aspect of BL biology.
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 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 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
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
Page 112 and 113:
Methods. Biopsy specimens from 430
Page 114 and 115:
the OS rate was 53% for patients wi
Page 116 and 117:
FR-P-098 Immunohistological stainin
Page 118 and 119:
FR-P-104 Histopathological evaluati
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within the earliest morphologic det
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Conclusions. In primary imaging a g
Page 124 and 125:
fibrotic neointma development as we
Page 126 and 127:
FR-P-129 Alpha-1-antitrypsin-PiZ-an
Page 128 and 129:
FR-P-136 The expression of central
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cosa and in the periarterial tissue
Page 132 and 133:
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
Page 138 and 139:
FR-P-168 Autopsy findings in a 2-ye
Page 140 and 141:
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
Page 148 and 149:
internet server. A network of inter
Page 150 and 151:
Methods. HE-gefärbte Schnittpräpa
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Conclusions. The newly released 450
Page 154 and 155:
and desmoplastic reaction are diffe
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one patient revealed more than 9 mi
Page 158 and 159:
situation, the V600E mutation in th
Page 160 and 161:
SA-P-064 Evolution of molecular pat
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nic markers such as myf4 and MyoD1
Page 164 and 165:
Conclusions. To our knowledge, this
Page 166 and 167:
SA-P-085 Expression of the eukaryot
Page 168 and 169:
Results. The papillary RCC type II
Page 170 and 171:
SA-P-098 Male infertility: assessme
Page 172 and 173:
SA-P-104 Process oriented scientifi
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Conclusions. The IBDW offers a uniq
Page 176 and 177:
L Lasitschka F. DO-046 Lehmann A. F
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