BackgroundPlasmablastic lymphoma (PL) is a subtype of diffuse large B-cell lymphoma (DLBCL). Studies have suggested that tumors with PL morphology represent a group of neoplasms with clinopathologic characteristics corresponding to different entities including extramedullary plasmablastic tumors associated with plasma cell myeloma (PCM). The goal of the current study was to evaluate the genetic similarities and differences among PL, DLBCL (AIDS-related and non AIDS-related) and PCM using array-based comparative genomic hybridization.ResultsExamination of genomic data in PL revealed that the most frequent segmental gain (> 40%) include: 1p36.11-1p36.33, 1p34.1-1p36.13, 1q21.1-1q23.1, 7q11.2-7q11.23, 11q12-11q13.2 and 22q12.2-22q13.3. This correlated with segmental gains occurring in high frequency in DLBCL (AIDS-related and non AIDS-related) cases. There were some segmental gains and some segmental loss that occurred in PL but not in the other types of lymphoma suggesting that these foci may contain genes responsible for the differentiation of this lymphoma. Additionally, some segmental gains and some segmental loss occurred only in PL and AIDS associated DLBCL suggesting that these foci may be associated with HIV infection. Furthermore, some segmental gains and some segmental loss occurred only in PL and PCM suggesting that these lesions may be related to plasmacytic differentiation.ConclusionTo the best of our knowledge, the current study represents the first genomic exploration of PL. The genomic aberration pattern of PL appears to be more similar to that of DLBCL (AIDS-related or non AIDS-related) than to PCM. Our findings suggest that PL may remain best classified as a subtype of DLBCL at least at the genome level.
Application of array comparative genomic hybridization (aCGH) has allowed an unprecedented high-resolution analysis of cancer genomes. We developed a custom genome-wide oligonucleotide microarray interrogating 493 genes involved in hematological disorders. We analyzed 55 patients with hematological neoplasms by using this microarray. In 33 patients with apparent normal conventional cytogenetic analysis , aneuploidy or isochromosomes were detected in 12% (4 of 33) of the patients by aCGH. The chromosomal changes included trisomy of chromosomes 10, 14 , and 15 , tetrasomy 11 , and isochromosome 17q. In 17 patients with chronic lymphocytic leukemia who were initially investigated by using a panel of standard fluorescence in situ hybridization probes , additional copy number changes that were not interrogated by the fluorescence in situ hybridization (FISH) panel were detected in 47% (8 of 17) of the patients by aCGH. Important copy number changes included gain on 2p16 involving REL and BCL11A genes , rearrangements of chromosomes 8 and 15 , and trisomy of chromosomes 19 and 22. In five patients with known abnormal karyotypes , aCGH identified the origin of two marker chromosomes and detected microdeletions at five breakpoints involved in three apparent balanced translocations. Our results suggest that a subset of potentially significant genomic alterations is missed by the currently available cytogenetic techniques. This pilot study clearly demonstrates high sensitivity of oligonucleotide aCGH for potential use in diagnosis and follow-up in patients with hematological neoplasms.
2478 Introduction: Flow cytometric immunophenotyping is critical for accurate diagnosis of CD5-positive chronic lymphocytic leukemia (CLL). CLL is classically positive for CD23 and negative for FMC-7, which are useful markers for distinguishing it from CD5-positive mantle cell lymphoma (MCL). However, a subset of CLLs express FMC-7 and rare cases additionally lack CD23, exhibiting a classic MCL phenotype. While CLL generally has an indolent clinical course, the disease is heterogeneous in clinical behavior and several molecular genetic markers are identified that predict poor prognostic subgroups. Prior studies have shown CLL with atypical phenotypic and morphologic features to be associated with trisomy 12. In this retrospective study, we analyzed a large cohort of consecutive CLL cases to determine if expression of FMC-7 identifies a subset of CLL that differs clinically and genetically from typical CLL. Methods: 1848 cases of CLL with complete cytogenetics/FISH and IgVH studies were retrieved from our database over a 2-year period. These cases were divided into three groups based on their imunophenotypes: Group I (1562 cases) with a typical CLL phenotype (CD23+/FMC7-); Group II (238 cases) with co-expression of CD23 and FMC7; and Group III (48 cases) with a mantle-like phenotype (CD23-/FMC7+). Other clinicopathologic parameters obtained for those cases included age, gender, CBC, bone marrow (BM) tumor burden, Zap-70, CD38 and surface light chain intensity. Results: There were 1144 men and 704 women in age ranging from 30 to 99 years (mean: 70 years). Cytogenetic results showed that group II had a higher percentage of cases with trisomy 12 (50%; p<0.001) and complex cytogenetic abnormalities (9.6%; p=0.005) than group I(14% and 4.8%, respectively). Group III also had a higher percentage of cases with trisomy 12 (29%; p=0.005) and complex cytogenetic abnormalities (14.6%; p<0.001) as compared to group I. However, deletion of 17p was more frequently observed in group III (31%) than in groups I (9%; p<0.001) and II (6%; p<0.001). Deletion of 13q14 occurred more frequently in group I (59%) than in groups II (43%; p=0.002) and III (35%; p<0.001). IgVH hypermutation was more frequent in both groups II (65%; p<0.001) and III (71%; p=0.007) as compared to group I (51%). CD38 expression was higher in group II than group I (45% vs. 25%; p<0.001), but showed no significant difference between groups I and III. FMC7 expression correlated with higher light chain intensity in groups II (66%; p<0.001) and III (72%; p<0.001), compared to group I (43%). Average BM tumor burden was higher in group II than group I (63% vs. 56%; p=0.012) and no significant difference was seen between groups I and III. A low Hb subgroup was identified in the group III (10 vs. 14 g/dL), significantly associated with 17p deletion (p=0.012). In addition group III also showed a lower average platelet count than group I (166k/uL vs. 192k/uL; p=0.04). Notably, 17p deletion was not associated with lower Hb in group I and II CLLs. There was no significant difference in average Hb and platelet count between groups I and II, nor were there significant differences in age, gender, WBC and ZAP-70 between all three groups. Conclusions: We have identified three groups of CLL based on CD23 and FMC-7 expression. In contrast to group I with typical CLL phenotype, group II (13%) with CD23+/FMC7+ phenotype correlated significantly with higher light chain intensity, trisomy 12, and IgVH hypermutation. Furthermore, group II is more frequently associated with high CD38, complex cytogenetic abnormalities, and a higher BM tumor burden. Thus, FMC7 alone may be sufficient to identify phenotypically atypical CLL with features suggestive of a more aggressive behavior. Group III represents a small subset (2.6%) of CLL with mantle- like phenotype (CD23-/FMC7+). Similar to group II, group III correlated with higher light chain intensity, trisomy 12, complex cytogenetic abnormalities, and IgVH hypermutation. However, group III is highly associated with 17p deletion with lower platelet count and Hb. Group III CLL with mantle-like phenotype is likely biologically to be distinct from group II. Future clinical studies may be warranted to confirm inferior outcome in phenotypically atypical CLL in general and CLL with mantle-like phenotype in particular. Disclosures: No relevant conflicts of interest to declare.
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