A Distinct Entity of Ocular Adnexal MALT Lymphoma with Trisomy 18.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 983-983
Author(s):  
Kazuki Tanimoto ◽  
Naohiro Sekiguchi ◽  
Yukiko Yokota ◽  
Akihiro Kaneko ◽  
Shigenobu Suzuki ◽  
...  
Keyword(s):  
Malt Lymphoma ◽  
Plasma Cells ◽  
Germinal Centers ◽  
Trisomy 18 ◽  
Female Dominance ◽  
Fish Analysis ◽  
Trisomy 12 ◽  
Monocytoid B Cell ◽  
Distinct Features ◽  
Histopathologic Features

Abstract Background: It remains unknown whether primary ocular adnexal MALT lymphoma is a homogenous disease, because there have been few reports on cytogenetic or molecular analysis of this disease. Patients and Methods: In 34 cases of ocular adnexal MALT lymphoma, we performed interphase fluorescence in situ hybridization (FISH) analysis to detect IgH/MALT1 and API2/MALT1 fusion genes. Aneuploidy of chromosome 3, 7, 12 and 18 was also identified using corresponding centromere probes. We defined trisomy when three centromeres were recognized in FISH analysis. Histopathologic features were reviewed and categorized according to the degree of plasma cell differentiation, monocytoid B cell feature, nodularity, abundance of reactive germinal centers, multikaryocytic cells, contaminated T cells, Duthcer bodies, and lymphoepithelial lesions (LELs). Correlations among FISH analysis, histopathologic features, and clinical data were analyzed. Results: FISH analysis showed 1 (3%) IgH/MALT1 fusion, 21 (62%) trisomy 3, 16 (47%) trisomy 18, and 3(9%) trisomy 7 cases. No cases showed API2/MALT1 fusion or trisomy 12. Existence of these cytogenetic change did not influence the degree of morphological features significantly, except for trisomy 18; Cases with trisomy 18 had significantly more abundant LEL cells, monocytoid B cells and residual reactive germinal centers, but less nodules, contaminated plasma cells and large cells. Cases with trisomy 18 showed distinct features of female dominance, younger age, and included more cases originated from conjunctiva. In total, five (15%) of 34 patients relapsed between 21 and 103 months, and all of them were found to have trisomy 18. Conclusions: Aneuploidy is found in a ceratin subset of ocular adnexal MALT lymphoma by FISH analysis. Cases with trisomy18 may make a distinct clinicopathlogic entity.

scholarly journals CELLULAR SITES OF FORMATION OF GAMMA GLOBULIN

1957 ◽  
Vol 106 (5) ◽  
pp. 627-640 ◽  
Author(s):  
L. G. Ortega ◽  
R. C. Mellors
Keyword(s):  
Germinal Center ◽  
Gamma Globulin ◽  
Plasma Cells ◽  
Serum Proteins ◽  
Fluorescent Antibody ◽  
Germinal Centers ◽  
Fluorescent Antibody Technique ◽  
Antibody Technique ◽  
Reticular Cells ◽  
Parenchymal Cells

The cellular sites of formation of γglobulin in lymphatic tissues of man and in a representative human lymphoid infiltrate have been studied by fluorescent antibody technique. The findings indicate that γ-globulin is formed in the germinal centers of lymphatic nodules and in the cytoplasm of mature and immature plasma cells of two types—those with and those without Russell bodies. The germinal center cells that synthesize γ-globulin have been designated "intrinsic" cells to distinguish them from the medium and large lymphocytes, and the primitive reticular cells that occur elsewhere and do not produce γ-globulin. Unlike the plasma cells, which function as individual units, the intrinsic cells apparently form γ-globulin only when they are arranged in discrete aggregations. The function, the blood supply, and the systematic cellular arrangement of germinal centers justifies the postulate that they are miniature organs of internal secretion of γ-globulin. The release of γ-globulin from its sites of formation appears to be accomplished by holocrine and apocrine secretion. Presumably, these secretory mechanisms are adaptations required for the production of antibody since they have not been described in parenchymal cells that form the other serum proteins. The cells found to form γ-globulin appear to be identical with those previously shown to form specific antibody in response to a variety of antigens in the experimental animal. This evidence indicates that normal γ-globulin, if it exists, originates in the same cells that produce antibody. It is suggested, also, that each of the 3 morphologically distinct categories of cells that synthesize γ-globulin represents a response to a particular form of antigenic stimulation. Nuclear participation in the process of γ-globulin synthesis was not detected by the technique employed.

scholarly journals High incidence of chromosome 13 deletion in multiple myeloma detected by multiprobe interphase FISH

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1505-1511 ◽  
Author(s):  
John Shaughnessy ◽  
Erming Tian ◽  
Jeffrey Sawyer ◽  
Klaus Bumm ◽  
Reid Landes ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Poor Prognosis ◽  
Plasma Cells ◽  
Suppressor Gene ◽  
Homozygous Deletion ◽  
Cell Labeling ◽  
Fish Analysis ◽  
Chromosome 13 ◽  
High Incidence ◽  
Homozygous Deletions

Abstract Multiple myeloma (MM) is a hypoproliferative malignancy yielding informative karyotypes in no more than 30% of newly diagnosed cases. Although cytogenetic and molecular deletion of chromosome 13 is associated with poor prognosis, a MM tumor suppressor gene (TSG) has not been identified. To localize a minimal deleted region of chromosome 13, clonotypic plasma cells from 50 consecutive patients with MM were subjected to interphase fluorescence in situ hybridization (FISH) analysis using a panel of 11 probes spanning the entire long arm of chromosome 13. Whereas chromosome 13 abnormalities were absent in plasma cells from 25 normal donors, 86% of patients with MM demonstrated such aberrations. Heterogeneity, both in deletion frequency and extent, was confirmed by simultaneous FISH with 2 chromosome 13 probes. Deletion hot spots were noted at D13S272 (70%) and D13S31 (64%), 2 unlinked loci at 13q14. Homozygous deletions at these loci occurred in 12% (simultaneously in 8%) of the cases. Molecular deletions were found in all 14 patients with morphologic deletions, in 21 of 24 with uninformative karyotypes, and 8 of 12 patients with karyotype abnormalities lacking chromosome 13 deletion. Homozygous deletion of any marker was noted in 4% with low and in 36% with higher plasma cell labeling index greater than 0.4% (P = .01). The absence of increasing deletion incidence and extent with therapy duration suggests that the observed lesions are not induced by treatment. The high incidence and extent of chromosome 13 deletions require the correlation of specific deletion(s) with poor prognosis. These analyses will provide valuable guidance toward cloning of an MM-TSG.

scholarly journals IgG4-Related Disease: A Reminder for Practicing Pathologists

2017 ◽  
Vol 141 (11) ◽  
pp. 1476-1483 ◽  
Author(s):  
Steven C. Weindorf ◽  
John Karl Frederiksen
Keyword(s):  
Autoimmune Pancreatitis ◽  
Plasma Cells ◽  
Clinical Manifestations ◽  
Organ System ◽  
Related Disease ◽  
Igg4 Related Disease ◽  
Resection Specimen ◽  
Histopathologic Features

IgG4-related disease (IgG4-RD) is a systemic autoimmune fibroinflammatory disease that produces sclerotic, tumefactive masses containing dense lymphoplasmacytic infiltrates rich in immunoglobulin (Ig) G4+ plasma cells. Initially characterized as a form of autoimmune pancreatitis, the distinctive histopathology of IgG4-RD has now been described in almost every organ system. However, because the clinical manifestations of IgG4-RD are diverse and nonspecific, the disease may go unsuspected until a biopsy or resection specimen is obtained to diagnose a presumed malignancy. Pathologists thus play a key role in the diagnosis of IgG4-RD, and familiarity with its histopathologic features is essential to preventing the irreversible comorbidities associated with this treatable disease. This brief review outlines the epidemiology, clinical manifestations, and histopathology of IgG4-RD, with the aim of furthering pathologists' awareness of and ability to diagnose this disorder.

B- Prolymphocytic Leukemia Shows Heterogeneous IgVH Mutational Status and Expression of ZAP-70 and CD38.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2004-2004
Author(s):  
Ilaria Del Giudice ◽  
Zadie Davis ◽  
Nnenna Osuji ◽  
Nilima Parry-Jones ◽  
Estella Matutes ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Peripheral Blood ◽  
Fish Analysis ◽  
Laboratory Findings ◽  
Prolymphocytic Leukemia ◽  
Mutational Status ◽  
Number Of Patients ◽  
Trisomy 12 ◽  
Igvh Mutational Status

Abstract B-cell prolymphocytic leukemia (B-PLL) is a rare lymphoid leukemia with an aggressive course. Diagnosis is based on morphology (>55% peripheral blood prolymphocytes), immunophenotype and histology when available, as there is no cytogenetic hallmark for this disease. There are scanty data regarding the mutational status of the variable region of immunoglobulin heavy chain (IgVH) genes and ZAP-70 expression in B-PLL. Davi et al (Blood1996;88:970–6) showed that 9 of 11 B-PLL cases had mutated IgVH genes (<98% homology) with a preferential use of the V3-23 and V4-34 genes, accounting for more than half of the B-PLL repertoire.We analyzed the mutational status of IgVH genes and ZAP-70 expression in 16 B-PLL cases and correlated the findings with clinical and biological features such as CD38 expression, chromosome abnormalities detected by FISH and overall survival. There were 7 females and 9 males, with a median age of 71 years (range 42–91). All except one were untreated at the time of the study. The diagnosis was established by peripheral blood morphology and immunophenotype (CLL score ≤ 3) in all cases and bone marrow and spleen histology in 6. Mantle cell lymphoma was excluded by the absence of t(11;14) by FISH in 12 out of 12 cases tested, including 4 which were CD5 positive. IgVH mutational status was performed by PCR (cut off >98% homology) and ZAP-70 expression was evaluated by 4-colour flow cytometry. Seven of 13 cases (54%) in which IgVH mutational status was evaluable, showed unmutated IgVH genes (99.7–100% homology) and 6 (46%) mutated IgVH genes (90.1–97.4% homology). V3-23 and V4-34 genes were used in one third of the cases. ZAP-70 was expressed (≥ 20% CD19+ cells) in 7 of 10 evaluable cases and CD38 (≥ 30% of CD19+ cells) in 7 of 11 cases. FISH analysis showed delp53 in 6/13 (46%) and del(13)(q14) in 3/11 (27%) cases; trisomy 12 was absent in 7 cases tested. Correlation between IgVH status and other features is shown in the table. There was a prevalence of delp53 (83%) among the unmutated group, while ZAP-70 expression did not correlate with IgVH mutational status. Median overall survival was 41 months. Six patients (4 mutated, 2 unmutated) are alive at 50 months (range 8-112) from diagnosis, 9 (5 unmutated and 2 mutated) died at 17 months (range 0–55) and 1 was lost to follow-up at 4 months. The number of patients is too small to conclude whether IgVH mutational status and/or ZAP-70 expression have a significant impact on survival. In summary, B-PLL is heterogeneous with respect to IgVH mutational status as in most chronic B-cell disorders, with equal representation of unmutated and mutated cases. P53 deletion is more common in the unmutated subgroup and most of the cases express ZAP-70 and CD38. Laboratory findings according to mutational status ZAP (>/=20%) CD38 (>/=30%) Del p53 Del (13)(q14) Trisomy 12 Unmutated (7) 4/5 1/4 5/6 2/5 0/3 Mutated (6) 2/3 4/5 1/5 0/4 0/4

Analysis of B-CLL with Discordant ZAP-70 Expression and IgVH Mutational Status.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1194-1194 ◽  
Author(s):  
Remi Letestu ◽  
Magali Le Garff-Tavernier ◽  
Dominique Vaur ◽  
Michel Ticchioni ◽  
Fanny Baran-Marszak ◽  
...  
Keyword(s):  
B Cells ◽  
Somatic Mutations ◽  
Staining Procedure ◽  
Fish Analysis ◽  
Prognostic Information ◽  
Proliferation Markers ◽  
Cd38 Expression ◽  
Mutational Status ◽  
Trisomy 12 ◽  
Igvh Mutational Status

Abstract The clinical course of CLL is heterogeneous and presence or absence of IgVH somatic mutations has been correlated with stable and evolutive disease respectively. ZAP-70 protein expression was shown to be associated with unmutated IgVH genes in CLL and was proposed as a surrogate for mutational status. Recent studies of large number of cases have shown various percentage of discrepancy with respect to ZAP-70 expression and IgVH mutational status. As aggressive disease is not always associated with unmutated IgVH genes we aimed at better characterize the ZAP-70 discordant cases by determining the other prognostic factors such as cytogenetics, expression of CD38 and proliferation markers (thymidine kinase and sCD23). We investigated 292 patients with previously untreated B-CLL. Although several antiZAP-70 antibodies adapted to flow cytometry (FCM) are commercially available, staining procedure and interpretation of the results still remain controversial. Therefore, ZAP-70 expression was determined in the four participating centers by the same FCM method using the 2F3.2 mAb with indirect staining, and expression of the results was standardized. Moreover, ZAP-70 expression was investigated by RQ-PCR in 62 cases and by Western blot in 61 further cases on isolated B cells. The results obtained with these techniques were correlated with FCM data. ZAP-70 was found expressed in 141 cases, among which 38 cases (27%) exhibited ≥2% somatic mutations. Conversely, among the 151 ZAP-70 negative cases, only 6 cases (4%) were found unmutated (≥ 98% VH homology). We focused on the characteristics of the mutated ZAP-70 positive cases. Only 26/38 were in stage A at diagnosis. Incidence of CD38 expression >10% B cells was low (7/28 cases). Analysis of VH sequences pointed to the frequency of VH3-21 usage in 8/38 cases (21%) as compared to an expected 3% frequency in the French population. FISH analysis identified one case with del11q22.3, one case with del17p and two cases with trisomy 12. Del13q14 was present in half of cases. Proliferation markers were significantly higher in these cases than in ZAP-70 negative mutated cases, even among stage A patients. Follow-up of these patients is still too short for significant event free survival as compared with other groups of patients but the number of evolutive Binet stage A patients and advanced B and C stages was already higher than among the ZAP negative mutated cases. In conclusion, in our hands, ZAP-70 was almost always expressed in unmutated cases (103/109). Among mutated cases, ZAP-70 expression was present in 38/183 cases (21%), and brought prognostic information, independently of CD38 or chromosomal alterations. The correlation between ZAP-70 and proliferation markers suggests that ZAP-70 expression may result in a survival advantage of the malignant cells independently of the mutational status.

Analysis of Genetic Lesions in Atypical B-CLL by Pangenomic CGH-Arrays.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4985-4985
Author(s):  
Christophe Roumier ◽  
Olivier Nibourel ◽  
Valérie Soenen ◽  
Céline Villenet ◽  
Sébastien Lignon ◽  
...  
Keyword(s):  
Human Genome ◽  
Copy Number ◽  
Region Of Interest ◽  
Hybridization Experiment ◽  
Fish Analysis ◽  
Dna Labeling ◽  
First Results ◽  
Micro Array ◽  
Trisomy 12 ◽  
Definition Of

Abstract Among B-CLPD, characterized primarily by morphology and expression of cell surface markers, is is important to identify patients with CD5+ atypical B-CLL that is regarded as clinically more aggressive than typical B-CLL. However these cases are not well defined. To better characterize the genetic lesion observed in atypical B-CLL we have analysed a cohort of 40 patients by CGH microarrays.Study was made on 5 typical B-CLL and on 35 atypical B-CLL patients with either CD20dim or bright expression that do not express cyclin D1. All the patients with atypical B-CLL will be defined as the presence of an absolute B-CD5-positive lymphocytosis &gt; 4 x 109/l and a RMH score &lt; 4. DNA was extracted using QuiAmp kit according to manufacturer recommendations. 2μg of DNA was used in each hybridization experiment. DNA labeling was performed using Cy3dUTP and Cy5 dUTP respectively for control and tumoral sample respectively. CGH-arrays was performed using the 1 Mb Human genome micro-array from “arraygenomics” that contains 3400 BAC clones fully FISH mapped and end sequenced all printed in triplicate. Each experiment was made using two slides in dye swap method. Cy5 and Cy3 fluorescence intensities spot were quantified using Axon Scanner 4100 and Acuity Software. Data were imported into SpectralWare 2.0 software and Normalise Suite, version 2.0, Profiler from Squire lab. Results: Identification of known and previously uncharacterized copy number alterations (CNAs) in the a-B-CLL cells genome was made in all the cases. The CGH profiles revealed that a-B-CLL genome is highly rearranged harbouring large numbers of distinct copy-number aberrations (75 CNAs among 31 chromosomal regions were found). Some of these CNAs are recurrent across different samples, allowing the definition of minimal common regions (MCR) of amplification or deletion. The size of the CNAs was extremely variable from one Bac probe to complete chromosome gains or losses. Specifically, our dataset included the known gains of chromosome 12 (14 cases), and the known deletion at 11q23, 13q14.3, 17p region but also new region of interest as +3p, 3q22 to 3qter, 4pter to 4q35.2, 5p15, 6p25.3 to 6p22, 8q22 to 8q24, 15q15.3 to 15q26, 17q11 to 17qter, +18 and +19 for gains and 1p35,1, 1p33, 2q22.3, 3p26.3 to 3p21.3, 5q34, 6p25.3, 6q16, 6q25.3 to 6q27, 7q31.3 to 7q32.2, 8p23.3 to 8p12, 10q11.2 to 10q21.1, 10q21.3, 10q23.2 to 10q24, 11q22.3 to 11q24.2, 15q14 to 15q21, 16p11.2 to 16q21, 21q22.1 for the deletions.To further corroborate the above finding, we had performed conventional FISH analysis using known probes for del 13q, del 11q, trisomy 12, del 17p and correlate our results with conventional cytogenetic findings when they were available. In all the cases CGH-arrays findings were confirmed by fish analysis or karyotype. The above findings were confirmed also in few cases using the Agilent’s Human Genome CGH Microarray 44K that contains over 40,000 probes. Our first results confirmed BAC arrays results. CGH-arrays appears to be very informative to detect lesion in B-CLPD and show the high frequency of genetic lesions in a-CLL. The biological impact of this lesions by transcriptome analysis on the same sample and the prognosis impact is in progress.

Incidence of Genomic Aberrations and Associated Efficacy from a Phase III Study Comparing Alemtuzumab (CAMPATH®, MABCAMPATH®) vs Chlorambucil as First Line Therapy for B-Cell Chronic Lymphocytic Leukemia (BCLL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2092-2092 ◽  
Author(s):  
Tadeusz Robak ◽  
Anna Dmoszynska ◽  
Raouf Fetni ◽  
Ying Wang ◽  
Malika Belkacz ◽  
...  
Keyword(s):  
Chromosomal Aberrations ◽  
Small Sample Size ◽  
Variable Region ◽  
Small Sample ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Chain Gene ◽  
Fish Analysis ◽  
Myc Oncogene ◽  
Trisomy 12

Abstract CAM307 is a randomized Phase III trial comparing the efficacy and safety of alemtuzumab (CAM) with chlorambucil (CHLO). The trial enrolled 297 previously untreated patients (pts) requiring therapy according to NCI-WG criteria. Pts were randomized 1:1 to CAM (n=149) vs CHLO (n=148) using standard dosing regimens. Fluorescence in situ hybridization (FISH) on interphase nuclei of lymphocytes isolated from blood was analyzed for cytogenetic abnormalities prior to the start of therapy. FISH analysis was performed using 13 DNA probes to detect chromosomal aberrations in 17p13.1 (P53), 13q14 (RB1, D13S319 and D13S25), 11q22.3-11q23 (ATM and MLL), 6q27 (subtelomere), 6q21 (chromosome 6q21/alphasatellite 6 cocktail probe), trisomy 8q24 (c-myc), trisomy 12 (CEP12) and translocations involving the locus of immunoglobulin heavy chain gene (IGH, 14q32.33). Samples were analyzed in 282 pts (95%); chromosomal aberrations were detected in 231 pts (82%) while 51 pts (18%) exhibited a normal interphase FISH pattern. The most frequent abnormalities were deletions (del) at loci 13q (49%), sole del 13q (24%), 11q (19%), 17p (7 %), 6q (4 %), and trisomies 12 (14%) and 8q (5%). Translocations IGH, 14q32.33 were detected in 10 pts (4%). An exploratory analysis was performed to correlate time to event variables (assessed by an independent response review panel) with cytogenetics. Overall 165 pts (59%) revealed combination abnormalities. The most frequently observed chromosomal associations were: del 13q + del 14q (N=20, 12%), del 11q + del 13q (N=17, 10%), del 11q + del 13q + del 14q (N=11, 7%), del 11q + del 14q (N=7, 4%), trisomy 12 + del 13q (N=5, 3%), del 13q + del 17p (N=4, 2%), del 11q + trisomy 12 (N=3, 2%) and del 17p + del 6q (N=3, 2%). Coexistence of del 17p and del 11q was not observed. Although del 13q was observed with all chromosome abnormalities, nearly half of the cases del 13q14.3 (D13S25 and D13S319) coincided with an ATM deletion (11q22.3). FISH analysis has allowed the detection of uncommon abnormalities: tetraploidy (n=1), hyperdiploidy (n=1), trisomy 18 (n=1) and c-myc oncogene amplification (>15 copies per nuclei) (n=2). The latter is a well known abnormality in solid tumors but rarely seen in leukemia. In addition, del of the IGH variable region was detected in 70 pts. The biological and clinical significance of this abnormality is to be investigated. Conclusions: Overall, 82% of treatment naïve BCLL pts revealed cytogenetic aberrations and 59% were combination abnormalities. CAM307 demonstrates a significant improvement in PFS in pts treated with CAM vs CHLO who present with del 13q as the sole abnormality; no difference in pts with del 11q. However, a trend towards improved PFS was observed in pts with trisomy 12 and del 17p, which did not reach significance due to small sample size. Further investigation of CAM therapy in high risk cytogenetic subgroups is warranted.

Molecular Profiling of Extramedullary and Medullary Plasmacytomas.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1806-1806 ◽  
Author(s):  
Anuj Mahindra ◽  
Samir B Amin ◽  
Gabriela Motyckova ◽  
Aliyah R. Sohani ◽  
Kishan Patel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Plasma Cell ◽  
Research Funding ◽  
Plasma Cells ◽  
Expression Patterns ◽  
Tissue Microarrays ◽  
Molecular Characteristics ◽  
Fish Analysis ◽  
New Therapeutic Approaches ◽  
Risk Of Progression

Abstract Abstract 1806 Poster Board I-832 Plasmacytomas are rare clonal proliferations of plasma cells that though cytologically identical to plasma cell myeloma, present with osseous or extraosseous growth pattern. Understanding their molecular characteristics can provide crucial insights into their pathogenesis and risk of progression to multiple myeloma (MM). To investigate the differences between extramedullary (EMP) and medullary plasmacytomas (MP) and MM without plasmacytomas, we sought to molecularly profile these tumors by tissue microarrays, gene expression, microRNA, and FISH. We identified 85 patients from our data base with a pathological diagnosis of plasmacytoma. Of the 85 patients, 13 patients presented with EMP, and 72 had MP. Among the patients with EMP (n=13), 2 patients presented with multiple lesions. Three of 13 (23%) patients progressed to develop MM at a median of 12 months. 72 patients presented with MP, of which 21 had solitary lesions and 27 (37%) progressed to MM at a median of 20.5months. There was a male preponderance (67% vs 33%) and the median age at diagnosis was 60.5 years (range 27.7-87.6). The mean overall survival for patients with EMP was 121 months (95% confidence interval[CI] 97-144 months) and for patients with MP was 102 months (95% CI 93-128 months) { p=0.025} MicroRNA (miRNAs) profiling was performed on MP (n=19) and MM samples (n=66). Data was normalized using U6 endogenous control. Three hundred and one miRNAs out of a total 665 were significantly differentially expressed between MP vs MM samples. Gene expression profiling performed on MP will be correlated with the miRNA data to identify genes and transcripts of interest which will be functionally validated. Tissue microarrays were performed on 52 patients (8: EMP, 44: MP,) in whom paraffin-embedded tissue was available. Of samples analyzed, CD56 positivity was observed in 55% MP and 71% EMP samples (p=0.67). Additional staining for cyclin D1, Bcl 2 and FISH analysis will be reported. Differential expression patterns of factors involved in proliferation, survival, adhesion, and stroma-tumor cell interactions may help explain plasmacytoma biology and identify factors responsible for progression to MM. These insights may help identify new therapeutic approaches and targets in the treatment of these plasma cell disorders. Disclosures Hochberg: Enzon: Consultancy, Speakers Bureau; Biogen-Idec: Speakers Bureau; Genentech: Speakers Bureau; Amgen: Speakers Bureau. Anderson:Millennium: Research Funding. Raje:Celgene, Norvartis, Astrazeneca: Research Funding.

Detection of 13q14 Deletion by FISH Is Not Sufficient to Define a Group of Good Prognosis Patients with Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2332-2332
Author(s):  
Virginie Eclache ◽  
Vincent Levy ◽  
Fanny Baran-Marszak ◽  
Remi Letestu ◽  
Florence Cymbalista
Keyword(s):  
Prognostic Markers ◽  
Prognostic Significance ◽  
Genetic Alterations ◽  
Large Cohort ◽  
Fish Analysis ◽  
Prognostic Impact ◽  
Trisomy 12 ◽  
Conventional Cytogenetics ◽  
The Impact ◽  
13Q Deletion

Abstract Abstract 2332 Poster Board II-309 Deletion of a 13q14.3 region is by far the most common genomic alteration in CLL. In a large cohort of CLL patients, the presence of deletion 13q as sole anomaly detected by FISH was predominantly found in Binet stage A CLL and associated with a favorable outcome (Dohner et al., N Engl J Med 2000). Further studies have evidenced some heterogeneity among CLL cases with 13q deletion, such as the size of the clone carrying the deletion, the existence of mono versus biallelic deletions, and the presence of other concomitant genetic aberrations. Therefore, we aimed at analysing the impact of this heterogeneity on the prognostic value of 13q14 deletion (del13q) in CLL. Patients and methods In a cohort of 329 previously untreated newly diagnosed stage A CLL, we detected del13q by FISH in 172 patients (52%) using the D13S319 probe. Conventional cytogenetics was performed in the 105 cases with del13q followed in our institution. The other important prognostic markers ( ZAP70, IgVH, CD38, proliferation markers) and clinical progression were also available for all patients. Results We first studied the large cohort of stage A patients and found that deletion 13q had no prognostic impact on PFS. When considering more specifically the presence of deletion 13q as sole anomaly (n=143), PFS was not significantly different from that of patients with no aberration detected by FISH analysis (del 13q, del11q, del17p and trisomy 12) (n=98). Moreover, the distribution of prognostic factors (ZAP70, sTK, mutational status, CD38 expression, lymphocytosis) was not statistically different among these two groups. We aimed at deciphering further these del13q cases through analysis of the percentage of deleted cells, the presence of mono versus biallelic deletions, and the presence of additional aberrations as detected by FISH and conventional cytogenetics in the 105 del13q cases followed in our institution. The size of the del13q clone, as reflected by the percentage of del13q cells by FISH, was highly variable, ranged from 7 to 90 %, and had no prognostic significance on PFS. Monoallelic deletions were present in 77 cases, fully biallelic deletions in 9 cases, and concomitant bi and monoallelic deletions in 19 cases. The 9 cases with biallelic deletions had a significantly shorter PFS and were associated with other unfavorable prognostic markers. As biallelic deletions are most likely to represent progression from monoallelic cases, it is understandable that no clear prognostic impact was evidenced between cases with monoallelic deletions and with concomitant variable amount of bi and monoallelic deleted cells. Twenty cases (20 monoallelic and 6 biallelic) were further studied by array-CGH. Minimal deleted region (MDR) was included in all deletions but the size of the deletion was variable and in most cases much larger than MDR. Among the 6 bi allelic cases, one of the deletions was restricted to the MDR in all cases, pointing out to the importance of the level of miRNA expression. Additional aberrations were found in 44/105 del13q cases. In 17 patients, one or more alterations were detected by FISH techniques : del11q (n=8), trisomy 12 (n=8) or del17p (n=5). By conventional cytogenetic all these aberrations were also detected, as well as other rare ones in 16 additional cases, either isolated or associated in a complex karyotype in 5 cases. Presence of additional aberrations had a significant unfavourable impact on PFS, even when excluding del11q, del17p and tri12, and considering the non recurrent aberrations that were detected by conventional cytogenetics only. Conclusion Presence of 13q deletion should not be considered as a good prognostic marker by itself among stage A patients. Moreover, del13q cases are highly heterogeneous, and the presence of deletion 13q should not be interpreted without considering both alleles or the presence of concomitant genetic alterations. Disclosures: No relevant conflicts of interest to declare.

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