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• W2034656001 abstract "Genetic alterations in enteropathy-type T-cell lymphoma (ETL) are unknown so far. In this series, 38 cases of ETL were analyzed by comparative genomic hybridization (CGH). CGH revealed chromosomal imbalances in 87% of cases analyzed, with recurrent gains of genetic material involving chromosomes 9q (in 58% of cases), 7q (24%), 5q (18%), and 1q (16%). Recurrent losses of genetic material occurred on chromosomes 8p and 13q (24% each), and 9p (18%). In this first systematic genetic study on ETL, chromosomal gains on 9q (minimal overlapping region 9q33-q34) were found to be highly characteristic of ETL. Fluorescence in situ hybridization analysis on four cases of ETL, using a probe for 9q34, indicated frequent and multiple gains of chromosomal material at 9q34 (up to nine signals per case). Among 16 patients with ETL who survived initial disease presentation, patients with more than three chromosomal gains or losses (n = 11) followed a worse clinical course than those with three or less imbalances (n = 5). The observation of similar genetic alterations in ETL and in primary gastric (n = 4) and colonic (n = 1) T-cell lymphoma, not otherwise specified, is suggestive of a genetic relationship of gastrointestinal T-cell lymphomas at either localization. Genetic alterations in enteropathy-type T-cell lymphoma (ETL) are unknown so far. In this series, 38 cases of ETL were analyzed by comparative genomic hybridization (CGH). CGH revealed chromosomal imbalances in 87% of cases analyzed, with recurrent gains of genetic material involving chromosomes 9q (in 58% of cases), 7q (24%), 5q (18%), and 1q (16%). Recurrent losses of genetic material occurred on chromosomes 8p and 13q (24% each), and 9p (18%). In this first systematic genetic study on ETL, chromosomal gains on 9q (minimal overlapping region 9q33-q34) were found to be highly characteristic of ETL. Fluorescence in situ hybridization analysis on four cases of ETL, using a probe for 9q34, indicated frequent and multiple gains of chromosomal material at 9q34 (up to nine signals per case). Among 16 patients with ETL who survived initial disease presentation, patients with more than three chromosomal gains or losses (n = 11) followed a worse clinical course than those with three or less imbalances (n = 5). The observation of similar genetic alterations in ETL and in primary gastric (n = 4) and colonic (n = 1) T-cell lymphoma, not otherwise specified, is suggestive of a genetic relationship of gastrointestinal T-cell lymphomas at either localization. Enteropathy-type T-cell lymphoma (ETL) is an extranodal T-cell non-Hodgkin's lymphoma characterized by a differentiation of tumor cells toward the phenotype of intestinal intraepithelial T cells.1Isaacson P Wright D Ralfkiaer E Jaffe ES Enteropathy-type T-cell lymphoma.in: Jaffe ES Harris NL Stein H Vardiman JW World Health Organization Classification of Tumours. Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon2001: 208-209Google Scholar ETL arises in the jejunum or ileum as multiple circumferential ulcers, frequently leading to intestinal perforation. ETLs have a dismal prognosis with most patients dying of disease within a few months after diagnosis.2Gale J Simmonds PD Mead GM Swetenham JW Wright DH Enteropathy-type T-cell lymphoma: clinical features and treatment of 31 patients in a single institution.J Clin Oncol. 2000; 18: 795-803PubMed Google Scholar Histologically, ETLs show a wide spectrum of appearances, ranging from highly pleomorphic or anaplastic tumors to cases composed of monomorphic small- to medium-sized tumor cells.3Chott A Vesely M Simonitsch I Mosberger I Hanak H Classification of intestinal T-cell neoplasms and their differential diagnosis.Am J Clin Pathol. 1999; 111: S68-S74PubMed Google Scholar Most ETLs have a CD3+CD4−CD8−CD7+CD5− immunophenotype and co-express cytotoxic markers TIA-1 and granzyme B. ETLs mainly consisting of monomorphic small- to medium-sized tumor cells frequently show a CD8+CD56+ phenotype.4Chott A Haedicke W Mosberger I Födinger M Winkler K Mannhalter C Müller-Hermelink HK Most CD56+ intestinal lymphomas are CD8+CD5− T-cell lymphomas of monomorphic small to medium size histology.Am J Pathol. 1998; 153: 1483-1490Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 5Lundquist C Baranov V Hammarström S Athlin L Hammarström ML Intra-epithelial lymphocytes: evidence for regional specialization and extrathymic T cell maturation in the human gut epithelium.Int Immunol. 1997; 7: 1473-1487Crossref Scopus (176) Google ScholarETLs show a strong association with celiac disease.6Wright DH Enteropathy associated T cell lymphoma.Cancer Surv. 1997; 30: 249-261PubMed Google Scholar Clonal intraepithelial T-cell populations with an aberrant immunophenotype are found in the intestinal mucosa of patients with therapy-refractory celiac disease and are clonally related to subsequent ETL.7Cellier C Delabesse E Helmer C Patey N Matuchansky C Jabri B Macintyre E Cerf-Besussan N Brousse N Refractory sprue, celiac disease and enteropathy-associated T-cell lymphoma.Lancet. 2000; 356: 203-208Abstract Full Text Full Text PDF PubMed Scopus (635) Google Scholar, 8Bagdi E Diss TC Munson P Isaacson PG Mucosal intraepithelial lymphocytes in enteropathy-associated T-cell lymphoma, ulcerative jejunitis, and refractory celiac disease constitute a neoplastic population.Blood. 1999; 94: 260-264PubMed Google Scholar, 9Daum S Hummel M Weiss D Pewters M Wiedenmann B Schäper F Stein H Riecken E Foss HD Refractory sprue syndromes with clonal intraepithelial lymphocytes evolving into overt enteropathy-type T-cell lymphoma.Digestion. 2000; 62: 60-65Crossref PubMed Scopus (44) Google Scholar, 10Carbonnel F Grollet-Bioul L Brouet JC Teilhac MF Cosnes J Angonin R Deschaseaux FP Gendre JP Sigaux F Are complicated forms of celiac disease cryptic T-cell lymphomas?.Blood. 1998; 92: 3879-3886PubMed Google Scholar In contrast to primary gastrointestinal B-cell lymphoma,11Barth TFE Döhner H Werner CA Stilgenbauer S Schlotter M Pawlita M Lichter P Möller P Bentz M Characteristic pattern of chromosomal gains and losses in primary large B-cell lymphomas of the gastrointestinal tract.Blood. 1998; 91: 4321-4330PubMed Google Scholar, 12Peters K Zettl A Starostik P Greiner A Rosenwald A Katzenberger T Ott G Müller-Hermelink HK Genetic imbalances in primary gastric diffuse large B-cell lymphomas: comparison of comparative genomic hybridization, microsatellite, and cytogenetic analysis.Diagn Mol Pathol. 2000; 9: 58-65Crossref PubMed Scopus (15) Google Scholar, 13Ott G Katzenberger T Greiner A Kalla J Rosenwald A Heinrich U Ott MM Müller-Hermelink HK The t(11;18)(q21;q21) chromosome translocation is a frequent and specific aberration in low-grade but not high-grade malignant non-Hodgkin's lymphoma of mucosa-associated lymphoid tissue (MALT-) type.Cancer Res. 1997; 57: 3944-3948PubMed Google Scholar only few data are available on genetic alterations occurring in ETL. Only four karyotypes of ETL have been published so far, with no recurrent genetic alterations revealed.14Wright DH Jones DB Clark H Mead GM Hodges E Howell WM Is adult-onset coeliac disease due to a low-grade lymphoma of intraepithelial T lymphocytes?.Lancet. 1991; 337: 1373-1374Abstract PubMed Scopus (79) Google Scholar, 15Carbonnel F Lavergne A Messing B Tsapis A Berger R Galian A Nemeth J Brouet JC Rambaud JC Extensive small enteropathy-type T-cell lymphoma of low-grade malignancy associated with a new chromosomal translocation.Cancer. 1994; 73: 1286-1291Crossref PubMed Scopus (47) Google Scholar, 16Ott G Katzenberger T Siebert R DeCoteau JF Fletcher JA Knoll JHM Kalla J Rosenwald A Ott MM Weber-Matthiesen K Kadin ME Müller-Hermelink HK Chromosomal abnormalities in nodal and extranodal CD30+ anaplastic large cell lymphomas: infrequent detection of the t(2;5) in extranodal lymphomas.Genes Chromosom Cancer. 1998; 22: 114-121Crossref PubMed Scopus (42) Google Scholar In contrast to ETL arising in the small intestine, the biological derivation and exact classification of primary gastric and colonic T-cell lymphomas remains controversial.1Isaacson P Wright D Ralfkiaer E Jaffe ES Enteropathy-type T-cell lymphoma.in: Jaffe ES Harris NL Stein H Vardiman JW World Health Organization Classification of Tumours. Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon2001: 208-209Google ScholarTo investigate genetic alterations in ETL, we performed a comprehensive study on genetic imbalances in 38 clinically and immunohistochemically well-characterized cases of ETL applying comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). To investigate the genetic relationship to ETL, four gastric and one colonic T-cell lymphoma, not otherwise specified (NOS), were additionally included into this series.Materials and MethodsSpecimen Selection and DNA ExtractionSeventy-five cases of ETL, all of them arising in the small intestine, were selected from the files of the Lymph Node Reference Center at the Department of Pathology, University of Würzburg, Würzburg, Germany, and from the files of the Department of Clinical Pathology, University of Vienna, Vienna, Austria. All cases were classified as ETL according to the current World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues.17Ralfkider E Müller-Hemelink HK Jaffe ES Peripheral T-cell lymphoma, unspecified. World Health Organization Classification of Tumours.in: Jaffe ES Harris NL Stein H Vardiman JW Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon, France2001: 227-229Google Scholar To assure a sufficiently high content of tumor cells for CGH, only cases with <40% nonneoplastic bystander cells were included for DNA extraction. In four cases, fresh-frozen material was available for DNA extraction. In the remaining cases, DNA was extracted from formalin-fixed, paraffin-embedded tissue blocks using the phenol-chloroform extraction method according to previously published protocols.18Zettl A Ströbel P Wagner K Katzenberger T Ott G Rosenwald A Peters K Krein A Semik M Müller-Hermelink HK Marx A Recurrent genetic aberrations in thymoma and thymic carcinoma.Am J Pathol. 2000; 147: 257-266Abstract Full Text Full Text PDF Scopus (145) Google Scholar In 32 cases, DNA extracted from paraffin-embedded material was not suitable for further genetic analysis because of DNA degradation (DNA fragment size <1000 bp). Except for three cases (cases 5, 7, and 23), all of the specimens analyzed genetically stemmed from initial diagnosis of ETL. In three cases (cases 7, 25, and 27), material from disease relapse could be additionally analyzed.In addition, for the purpose of comparison of genetic alterations, four cases of primary gastric and one case of primary colonic T-cell lymphoma were included into the study. In all of these cases, there was no clinical evidence of generalized lymphoma with manifestation in the stomach or colon. Based on clinical findings, the cases were considered as of primary gastric/colonic origin. Because the exact classification of the latter lymphomas and their relationship to enteropathy, in particular to ETL remains controversial, in the following, the term ETL will be limited to designate primary, enteropathy-associated T-cell lymphomas arising in the small intestine, whereas the five cases arising in the stomach or colon will be referred to by primary gastric and primary colonic T-cell lymphoma, not otherwise specified (NOS), respectively (extranodal peripheral T-cell lymphoma, not otherwise specified, according to the World Health Organization classification17Ralfkider E Müller-Hemelink HK Jaffe ES Peripheral T-cell lymphoma, unspecified. World Health Organization Classification of Tumours.in: Jaffe ES Harris NL Stein H Vardiman JW Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon, France2001: 227-229Google Scholar).CGHCGH was performed at the Department of Pathology, University of Würzburg, according to a standard protocol.19Lichter P Bentz M Du Manoir S Joos S Comparative genomic hybridization.in: Verma RS Babu AA Human Chromosomes: Principles and Techniques. ed 2. McGraw-Hill, New York1995: 191-210Google Scholar Tumor DNA was labeled by nick translation with biotin-16-dUTP (Roche Diagnostics, Mannheim, Germany). Reference DNA, extracted from placental tissue of a healthy newborn, was labeled with digoxigenin-11-dUTP (Roche Diagnostics). The amount of DNase I (Roche Diagnostics) and DNA polymerase I (Promega, Mannheim, Germany) were adjusted to obtain DNA fragment sizes of ∼500 to 1000 bp. After inactivation of DNase I, unincorporated nucleotides were removed by gel filtration on Sephadex G50-packed columns (Sigma, Tartkirchen, Germany). Equal amounts of tumor and reference DNA (1 μg each), together with 70 μg of Cot-1 DNA (Roche Diagnostics) for blocking repetitive sequences, were co-hybridized on commercially available metaphase slides (Vysis, Downers Grove, IL), which had been denaturated in 70% deionized formamide/2× standard saline citrate (SSC)/50 mmol/L sodium phosphate, pH 7.0, for 5 minutes at 70°C, followed by dehydration in cold ethanol. After overnight hybridization at 37°C, the slides were washed four times with 50% formamide/2× SSC, pH 7.0, at 42°C and three times at 60°C with 0.1× SSC. Biotin- and digoxigenin-labeled DNA were detected by addition of fluorescein-isothiocyanate avidin (Vector Laboratories, Burlingame, CA) or Cy3-conjugated anti-digoxigenin antibodies (Dianova, Hamburg, Germany), respectively. A 4,6-diamindino-2-phenylindole counterstain was performed for chromosomal banding.Signals were visualized with a Zeiss Axiophot fluorescence microscope and analyzed with ISIS digital image analysis system (MetaSystems, Altlussheim, Germany). Ratio values of 1.25 and 0.8 were used as upper and lower thresholds for identification of chromosomal gains or losses. A high-level amplification was defined as an overrepresentation of genetic material with the fluorescence ratio values exceeding 2.0 or based on the observation of strong focal signals in the fluorescein-isothiocyanate fluorescence.FISHFor further analysis of the most frequent genetic imbalance detected by CGH (gain of chromosomal region 9q33-q34), FISH was performed in four ETL cases, in three of them on cells isolated from the identical frozen tissue blocks that had been used for DNA extraction for CGH according to previously published protocols.20Sauter G Feichter G Torhorst J Moch H Novotna H Wagner U Durmuller U Waldman FM Fluorescence in situ hybridization for detecting erb-2 amplification in breast tumor fine needle aspiration biopsies.Acta Cytol. 1996; 40: 164-173Crossref PubMed Scopus (52) Google Scholar One case was only analyzed by FISH, but not by CGH. Briefly, 10 to 20 10-μm cryostat sections were minced and suspended in C50T (0.05 mol/L citric acid monohydrate and 0.5% Tween 20) for 10 minutes. After washing in phosphate-buffered saline, the pellet was resuspended and fixed in a −20°C Carnoy solution. For hybridization, the cell suspension was dropped onto glass slides and dried at room temperature.Dual-color FISH experiments with fluorescence-dye labeled DNA probes were performed using a probe for chromosome 9q34 (locus-specific abl probe labeled with SpectrumOrange) together with a probe for 22q11 as a control (locus-specific bcr probe labeled with SpectrumGreen) according to the manufacturer's instructions (LSI bcr/abl ES Dual Color Translocation probe, Vysis, Stuttgart, Germany). Briefly, the slides were incubated for 1 to 3 minutes at 38°C in 10 μg/ml of pepsin (4500 U/mg; Sigma, Germany)/0.01 mol/L HCl and dehydrated with ethanol, followed by denaturation in 70% formamide/2× SSC at 73°C for 5 minutes. The hybridization mixture containing 1 μl of probe mixture, 2 μl of purified H2O2, and 7 μl of hybridization buffer was denaturated at 73°C for 5 minutes. The slides were incubated for 12 to 16 hours at 37°C. After hybridization, the slides were washed in 0.4× SSC/0.3% Nonidet P-40 at 73°C and in 2× SSC/0.1% Nonidet P-40 for 2 minutes each at room temperature. Counterstaining was performed with 4′6-diamidino-2-phenylindole. Signals were visualized with a Zeiss Axiophot fluorescence microscope (Zeiss, Jena, Germany). Images were captured using the ISIS imaging system (MetaSystems, Altlussheim, Germany).For signal evaluation, nuclear signals from at least 100 cells were analyzed per case. Nuclear signals had to be observed after hybridization in >90% of cells. Only cells with clearly discernible nonoverlapping nuclei were counted. Signals should have the same intensity and split signals were counted as one signal. Cutoff levels for gains of 9q and 22q were determined for the probes at 8% (mean ± 3 SD).ImmunohistochemistryImmunohistochemical analysis was performed in all cases on formalin-fixed paraffin-embedded tissue sections in the laboratory of one of the authors (AC) according to previously published protocols.4Chott A Haedicke W Mosberger I Födinger M Winkler K Mannhalter C Müller-Hermelink HK Most CD56+ intestinal lymphomas are CD8+CD5− T-cell lymphomas of monomorphic small to medium size histology.Am J Pathol. 1998; 153: 1483-1490Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar Immunostains included markers CD2 (dilution 1:20; Novocastra, Newcastle, UK), CD3 (1:400; DAKO, Copenhagen, Denmark), CD4 (1:10, Novocastra), CD5 (1:20, Novocastra), CD7 (1:40, Novocastra), CD8 (1:30, DAKO), CD20 (1:200, DAKO); CD30 (1:80, DAKO), CD56 (1:200; Sanbio, Uden, The Netherlands), βF1 (1:10; T-Cell Sciences, Woburn, MA), EMA (1:100, DAKO), and TIA1 (1:800; Coulter, Hialeah, FL).T-Cell Clonality AnalysisFor molecular clonality studies, polymerase chain reaction for T-cell receptor rearrangement was performed using a mixture of specific and consensus primers for the T-cell receptor γ-chain.21Trainor KJ Brisco MJ Wan JH Neoh S Grist S Morley AA Gene rearrangement in B- and T-lymphoproliferative disease detected by the polymerase chain reaction.Blood. 1991; 78: 192-196PubMed Google Scholar Aliquots of polymerase chain reaction products were mixed with size standard and formamide, denatured, and subjected to electrophoresis on a 373 DNA Sequencer (Perkin-Elmer, Weiterstadt, Germany). Data were automatically collected and analyzed using Genescan software as described in the manufacturer's manual.Clinical DataMedical records were reviewed for the patient's history, type and duration of symptoms at initial presentation, and type of treatment. Follow-up information was obtained via clinical records, attending physicians or autopsy files.Statistical AnalysisStatistical correlation between immunophenotype and genetic alterations was performed using Fisher's exact test. Comparison of genetic alterations between ETL and gastrointestinal B-cell lymphoma was based on chi-square test. Survival analysis (impact of the number of genetic imbalances on survival) was performed using Kaplan-Meier statistics; for significance testing, a log rank test was used.ResultsHistological Characterization, Immunophenotyping, and TCR-γ Analysis of ETLOn histology, 41% cases of ETL were composed of monomorphic small- to medium-sized tumor cells, 26% of pleomorphic medium-sized to large cells, and 23% of anaplastic large cells (Table 1). Two cases were composed of immunoblasts and one case of pleomorphic small cells. Immunohistochemically, 87% of cases were CD3-positive (Table 1). All tumors analyzed were CD4-, CD5-, and CD20-negative, but CD7-positive (data not shown). Seventy-six percent of cases analyzed expressed cytotoxic marker TIA-1. Sixteen ETLs (41%) expressed CD56, among them 14 cases with monomorphic small- to medium-sized tumor cell morphology. T-cell receptor γ-chain rearrangement studies were performed in 21 lymphomas, all of which exhibited a monoclonal rearrangement (data not shown).Table 1Comparative Genomic Hybridization of ETLs: Clinical Data, Morphology, and Immunohistochemical PhenotypeClinical dataImmunohistochemical phenotypeNo.AgeSexSurvival (months)StageMorphologyCD3CD4CD8CD30CD56TIA1151mDOD 1EII2pleo m&l+−−−−+253fDOD 19EIpleo m&l+−−−−+350fNED 48+nspleo m&l+−−−−−465mDOD 6EIIpleo m&l+−++−−564fDOD 12EIIpleo m&l+−−+−+663mNED 7+nspleo m&l+−−+−+729mAWD 60+nspleo m&l+−+−−−857fDOD1pleo m&l−−−+−−981fLostpleo m&l+−++−+1061fDOD 2EIpleo m&l+−+−++1159fDOD 9EIIIPleo sm+−+−−+1251mLostnsALCLndnd−+−−1366fDOD 5EIVALCL−−−+−−1471mDOD 1EIVALCL+−−+−+1562mDOD 3EIVALCL+−++−+1645mDOD 3EIIALCL+−++−+1765fDOD 15NsALCL+−−+−+1865fDOD 1EIVALCL+−−+−−1953fDOD 1EIVALCL+−−+−+2066fNED 29+EI2IB+−++−+2177mDOD 1nsIB+−−+−+2255mDOD 2EIIAmono sm+−+−++2370mNED 87+EImono sm+−+−++2451mDOD 1EIVmono sm+−−−++2561mAWD 37+EIIBmono sm+−−−++2639mDOD 5EIVmono sm+−+nd++2763mDOD 16EIIBmono sm+−+−++2885mDOD 4nsmono sm+−+−++2961mDOD 5EIVmono sm+−+−++3064mAWD 6EImono sm+−+−++3143mNED 5+EI2mono sm−−−−++3277mLostnsmono sm+−+−+nd3384fDOD 1nsmono sm+−−−+−3466mLostmono sm+−−−++3556mLostmono sm+−+++−3675mDOD 1EIVmono sm−−−−−+3768fDOD 1EIIAmono sm+−−−−+3868fLostnsunclass.+−−+++39*Only FISH hybridization performed.66mLostALCL+−−+−ndAbbreviations: age, age at diagnosis of ETL; m, male; f, female; DOD, died of disease; NED, alive with no evidence of disease; AWD, alive with disease; lost, lost to follow-up; ALCL, morphology of anaplastic large cell lymphoma; pleo m&l, lymphoma composed of pleomorphic with medium and large cells; ib, immunoblastic lymphoma; mono sm, monomorphic with small- to medium-sized cells; TCR-γ: T-cell receptor γ chain rearrangement; m, monoclonal; nd, not done; ns, not staged or stage unknown. Stage according to the Ann Arbor System as modified by Musshof.45Musshof K Clinical staging of the non-Hodgkin's lymphomas.Strahlentherapie. 1977; 153: 218-221PubMed Google Scholar* Only FISH hybridization performed. Open table in a new tab CGH of ETLThirty-three of 38 ETLs (87%) showed gains and/or losses of genetic material (Table 2; Figure 1; Figure 2, a to d; Figure 3, a and b). In the entire group, gains of chromosomal material (n = 88) occurred slightly more frequently than losses (n = 69). Per case showing genetic imbalances, one to eight gains (median three gains) and one to seven losses (median two losses) were found.Table 2Comparative Genomic Hybridization of ETL: Chromosomal Gains and LossesNo.rev ish enhrev ish dim1––2+7q22-q31, +9q33-qter−9p21-pter3+7p,+7q32-qter−9p21-pter4+1p36 (high-level)−2q22-q23,−13q21-q225+1p32-p34,+1q12-q25,+1q32-q42,+7p,+7cen-q22,+8q24, +9q33-q34,+12p−4p14-pter,−4q22-q27,−8p,−16q6+1q12-q24,+12p,+12q23-qter,+15−3p12,−4q26-q287+9q22-qter–7R+5,+6p, +9q31-qter−9cen-q22,−148ampl 7q22,+9q33-q34, +12p12-pter−13q21-q229+5q35-qter,+9q33-q34, +13cen-q13,+13q31-qter−4q23-q24,−13q14-q2110+17q21-qter−8p,−9p21,−10q,−13q21-qter11––12+1p36 (high-level),+9q34,+16p, +17q−1p21-1p31,−3p12,−9p23-p24;−13q14-q2213––14–−6q15+1cen-q24,+1q32-q42,+5q13-q15,+6p, +7q11-q32,+9q−10p12-p1416––17+1q, +1p32-36,+2p21-pter,+5q35,+6p21-pter,+7q22-qter,+8q24, +9−3q26-qter,−6q22-q25,−8p,−13q14-q2218+5, +7q35-qter,+18q−13q,−16q12-q21,−8p22-pter,−X19+11q23-qter–20+9q34−18q22-qter21+1q,+5q32-qter,+9q32-qter−4p15-pter,−10,−11q14-q2222–−1823+9q,+14q31-32−6q15-q2124+9q21-qter−9p21-pter,−13q22-qter25+16p13–25R+7q,+8q,+9q22-qter, +Xp21-pter−8p26+6p23-pter,+7q32-q33,+9q,+11q13,+16p, +17,+21−3cen-p14,−8p27+5q31-qter,+8q,+9q22-qter, +21,+X−8p,−11q14-q2127R+3p21-pter,+7q21-qter,+8q, +9q22-qter,+X−5q14-q31,−7p15-pter,−8p,−11q14-q2128+9q,+21,+22−10cen-p14,−11q14-qter,−12p, −13q13-qter,−16q,−18p29+Xq−7p,−8cen-p2130+9q–31+9q22-qter,+11q15, +12q23-qter−2q14-q24,−5q21-q22,−Xq,−Xcen-p11,−7p,−8p, −9p13-pter32+7q,+9q33-q34,+Y−7p33+9q34, +11cen-q13,+12p,+22–34+9q−17p1335+8q, +9q, ampl9q33-q34,+Xq23-qter−4cen-q21,−9p21-p2236+1q21-q22,+5q31-qter,+6p,+9q,+11q13−4q26-q28, −12q21-q22,−18q22-qter37–−7p,−8p,−11q21-q23, −Xq22-qter38––Abbreviations: R, recurrent disease; rev ish enh, chromosomal gains detected by CGH; rev ish dim, chromosomal losses detected by CGH.Case 39 was only analyzed by FISH. Open table in a new tab Figure 2CGH of ETL and primary gastric T-cell lymphoma, NOS: morphological-genetic correlation. a: Histology of a case of CD56+ ETL composed of monomorphic medium-sized tumor cells (case 31). CGH showed gains at chromosomes 9q, 11q, and 12q, and losses at 2q, 5q, 7p, 8p, 9p, and X (b). c: Histology of a CD56− ETL with immunoblastic tumor cell morphology (case 21). CGH revealed gains of genetic material at chromosomes 1q, 5q, and 9q, and losses at 4p, 10, 11q (d). e: Histology of a case of primary gastric T-cell lymphoma, not otherwise specified (case 40). CGH detected gains of genetic material on chromosomes 1q, 5p, 6p, and 9q, and losses on X and 18 (f). Gains of 9q, with minimal overlapping region 9q33-34, were the most frequent alteration observed (b, d, f).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3FISH of ETL: gain of 9q as a frequent and characteristic genetic alteration. a: CGH result for chromosome 9 in case 7. Digital image analysis (b) indicates a chromosomal gain of 9q22-qter (bar on right). FISH with probes for 9q34 (c, red signals) and 22q11 (c, green signals) confirms the chromosomal gain at 9q in this case of a pleomorphic medium to large cell ETL. d: FISH of a monomorphic ETL (case 36) using the same probes, again confirming chromosomal gains at 9q (red signals) detected by CGH.View Large Image Figure ViewerDownload Hi-res image Download (PPT)The most frequent recurrent gain of genetic material was observed on chromosome 9q (22 of 38 cases, 58%), with 9q33-q34 representing the minimal overlapping region (Figure 2, b, d, and f; and Figure 3, a and b). Further recurrent gains were detected on 7q (9 cases, 24%); 5q (7 cases, 18%); 1q (6 cases, 16%); 6p, 12p, and 8q (4 cases each, 11%); 11q, 16p, and 17q (3 cases each, 8%). Minimal overlapping regions on 7q, 5q, 1q, and 6p were 7q21-q22, 1q21-q23, 1q41, 5q34-q35, and 6p22-pter, respectively.The most frequent recurrent loss of genetic material occurred on 8p (9 of 38 cases, 24%) with 8cen-p21 representing the minimal overlapping region, and on 13q (9 of 38 cases, 24%). Further recurrent losses were observed on 9p (7 cases, 18%); 4q (5 cases, 13%); 7p, 11q14-q23 (4 cases, 11%); 3p12, 6q21-22, 10p12-p13, 16q, Xq, and 18q22-q23 (3 cases each, 8%). Minimal overlapping regions on 13q and 9p were 13q21 and 9p21, respectively.In three cases, recurrent ETL could be compared genetically to primary ETL. In two cases, the recurrent ETL shared genetic alterations with the primary tumor (cases 7 and 27, period between initial disease presentation and relapse 7 and 8 months, respectively), whereas in case 25, recurrent ETL did not share genetic alterations with the primary tumor, suggesting a de novo, second ETL rather than lymphoma recurrence in this patient's relapse (period between initial disease presentation and relapse 3 years).Multivariate statistical analysis did not show correlations between genetic alterations, the immunophenotype, and the lymphoma morphology.FISH for Chromosomal Gain of 9q in ETLTo confirm the frequent gain of chromosomal material on 9q in ETL, four cases of ETL in which fresh material was available were studied by dual-color FISH, including one case in which only FISH was performed (case 33). A probe located in the minimal overlapping region 9q33-q34 (probe for abl locus at 9q34) was co-hybridized with a control probe for 22q11 (bcr locus) (Table 3, Figure 3, c and d).Table 3ETL: Comparison of Data Obtained by CGH and FISH with Probes for 9q34Case no.CGH rev ish enhCGH rev ish dimFISH 9q34 Number of signals (percentage of cells)FISH 22q11 Number of signals (percentage of cells)7+9q22-qter–7 (18%)3 (18%)9 (14%)4 (14%)13+1q,+1p32-36, +2p21-pter,+5q35,+6p21-pter,+7q22-qter,+8q24,+9−3q26-qter, −6q22-q25,−8p, −13q14-q224 (42%)2 (100%)5 (4%)6 (23%)7 (4%)36+1q21-q22,+5q31-qter,+6p,+9q, +11q13−4q26-q28,−12q21-q22, −18q22-qter3 (16%)2 (100%)4 (41%)39ndnd3 (11%)2 (100%)4 (7%) Open table in a new tab FISH results for 22q11 revealed disomic signal distribution of tumor cells in three cases and a signal constellation indicating tetraploidy in one case. In none of the four cases that had been analyzed by CGH were gains of 22q observed. In accordance with CGH profiles indicating gains at 9q34, up to seven FISH signals were observed in the diploid cases (Table 3, Figure 3, case 23330/92 not analyzed by CGH). In the tetraploid case, up to nine signals were observed at 9q34 with the number of signals at 9q34 exceeding those with the probe for 22q11. In none of the cases was co-localization of signals of both probes observed.Correlation between Genetic Imbalances in ETL and PrognosisClinical follow-up data could be obtained from 34 of the 44 patients (Table 1). The common disease presentation of the 32 clinically followed patients with ETL (19 males, 13 females) was small bowel perforation or obstruction. Only three patients had a clinical history of celiac disease. Twenty-four patients had already died: thirteen patients had succumbed to peritonitis and/or septicemia because of bowel perforation at initial disease manifestation with a median survival time of less than 1 month, whereas 11 patients had died of recurrent or disseminated disease with a median survival time of 6 months after initial diagnosis. In contrast, eight patients were still alive, among them five surviving" @default.
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• W2034656001 date "2002-11-01" @default.
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• W2034656001 title "Chromosomal Gains at 9q Characterize Enteropathy-Type T-Cell Lymphoma" @default.
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