Rolando Garcia

Plasmablastic lymphomas with MYC/IgH rearrangement: Report of three cases and review of the literature

We report detailed clinicopathologic features of 3 cases of plasmablastic lymphoma (PBL) with MYC/IgH rearrangement, representing one third of PBL cases diagnosed at our institution. This study brings the total number of reported cases in the literature to 6. All patients were HIV+ with very low CD4 counts at diagnosis. The involved locations were mediastinum, anus, and bone marrow. Tumors exhibited predominantly immunoblastic/plasmablastic morphologic features and had a plasma cell-like immunophenotype. Bright CD38 expression by flow cytometry had a tendency to be more common in these cases compared with PBL without MYC rearrangement. All cases were positive for Epstein-Barr virus-encoded RNA but lacked human herpesvirus-8 latent nuclear antigen. The 2 patients with follow-up died within 3 months. These findings show that PBL is often associated with MYC/IgH rearrangements and that this finding may portend an aggressive clinical course, suggesting that cytogenetic studies should be routinely applied in cases of PBL.

Simple karyotype and bcl-6 expression predict a diagnosis of Burkitt lymphoma and better survival in IG-MYC rearranged high-grade B-cell lymphomas

Rearrangement of MYC with immunoglobulin genes is a hallmark of Burkitt lymphoma. However, this rearrangement is not entirely specific and is often accompanied by varying numbers of additional cytogenetic abnormalities. This study aimed to assess the impact of karyotypic complexity, in correlation with comprehensive immunophenotypic analyses on the diagnosis and clinical outcomes of 34 cases of MYC-IG rearranged lymphomas that included Burkitt lymphoma (twenty-two cases), diffuse large B-cell lymphoma (three cases), unclassifiable B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (six cases), and plasmablastic lymphoma (three cases). Additional cytogenetic abnormalities were observed in 26 of 34 cases (76%), including four cases (12%) that harbored dual translocations involving BCL-2 or BCl-6. Burkitt lymphoma cases had a significantly lower number of additional abnormalities (mean of 1.7), compared with unclassified B-cell lymphoma (3.3), diffuse large B-cell lymphoma (21.7), and plasmablastic lymphoma (6.7). Cases with simple karyotype (⩽2 additional abnormalities) were more likely to have a diagnosis of Burkitt lymphoma (89 versus 33% in patients with >2 additional abnormalities, P<0.01) and express bcl-6 (95 versus 47%, P<0.01). In addition, Burkitt lymphoma, bcl-6 expression, and simple karyotype were individual predictors of better overall survival. However, in multivariate analyses, only bcl-6 expression remained an independent predictor, although survival could be further stratified by karyotypic complexity in bcl-6(+) patients. We conclude that simple karyotype and bcl-6 expression suggest a diagnosis of Burkitt lymphoma and may portend better overall survival. These results may be very useful in the diagnosis and stratification of MYC-IG rearranged high-grade B-cell lymphomas.

Genomic profiling using array comparative genomic hybridization define distinct subtypes of diffuse large b-cell lymphoma: a review of the literature

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin Lymphoma comprising of greater than 30% of adult non-Hodgkin Lymphomas. DLBCL represents a diverse set of lymphomas, defined as diffuse proliferation of large B lymphoid cells. Numerous cytogenetic studies including karyotypes and fluorescent in situ hybridization (FISH), as well as morphological, biological, clinical, microarray and sequencing technologies have attempted to categorize DLBCL into morphological variants, molecular and immunophenotypic subgroups, as well as distinct disease entities. Despite such efforts, most lymphoma remains undistinguishable and falls into DLBCL, not otherwise specified (DLBCL-NOS). The advent of microarray-based studies (chromosome, RNA, gene expression, etc) has provided a plethora of high-resolution data that could potentially facilitate the finer classification of DLBCL. This review covers the microarray data currently published for DLBCL. We will focus on these types of data; 1) array based CGH; 2) classical CGH; and 3) gene expression profiling studies. The aims of this review were three-fold: (1) to catalog chromosome loci that are present in at least 20% or more of distinct DLBCL subtypes; a detailed list of gains and losses for different subtypes was generated in a table form to illustrate specific chromosome loci affected in selected subtypes; (2) to determine common and distinct copy number alterations among the different subtypes and based on this information, characteristic and similar chromosome loci for the different subtypes were depicted in two separate chromosome ideograms; and, (3) to list re-classified subtypes and those that remained indistinguishable after review of the microarray data. To the best of our knowledge, this is the first effort to compile and review available literatures on microarray analysis data and their practical utility in classifying DLBCL subtypes.Although conventional cytogenetic methods such as Karyotypes and FISH have played a major role in classification schemes of lymphomas, better classification models are clearly needed to further understanding the biology, disease outcome and therapeutic management of DLBCL. In summary, microarray data reviewed here can provide better subtype specific classifications models for DLBCL.

Erythroblastic sarcoma presenting as bilateral ovarian masses in an infant with pure erythroid leukemia

Pure erythroid leukemia is a rare subtype of acute erythroid leukemia that is characterized by a predominant erythroid population, and erythroblastic sarcoma has not yet been described in the English literature. Here, we report a first case of erythroblastic sarcoma that presented as bilateral ovarian masses in a 3 ½-month-old infant girl with pure erythroid leukemia. Bone marrow aspirate and biopsy showed that the marrow was completely replaced by large-sized blasts consistent with erythroblasts. Immunophenotypically, both the tumor cells from the ovarian mass and bone marrow blasts were positive for CD117, glycophorin A, and hemoglobin A, demonstrating erythroid differentiation. Reverse transcriptase polymerase chain reaction showed that the tumor cells from ovarian mass expressed hemoglobin F and α1 spectrin, confirming their erythroid lineage. Conventional karyotype of the bone marrow aspirates revealed del(6)(q23q25) and trisomy 7 in all 21 cells examined. Fluorescence in situ hybridization of the ovarian mass demonstrated loss of c-myeloblastosis viral oncogene (C-MYB) at 6q23 locus in 41% of the cells, and deletion of chromosome 7 and 7q in 37% and 66% of cells, respectively. Taken together, we showed, for the first time, that pure erythroid leukemia presented as a myeloid sarcoma in the form of ovarian masses.

Unusual presentation of myeloid sarcoma in a case of acute promyelocytic leukemia with a cryptic PML–RARA rearrangement involving multiple sites including the atrium

Myeloid sarcoma is an extramedullary tumor mass composed of immature myeloid cells. Myeloid sarcoma may develop de novo, concurrently with acute myeloid leukemia (AML), or at relapse. Although myeloid sarcoma can occur at any site, myeloid sarcoma involving the heart is extremely rare. Reported here is the case of a 30-year-old man, initially diagnosed with acute promyelocytic leukemia (APL) in bone marrow, who presented later with myeloid sarcoma at multiple anatomical sites (left scapula, thoracic vertebra, right atrium, and supraclavicular mass) in multiple relapses. Conventional cytogenetic studies performed on the atrial sample revealed a karyotype with additional material on the short arm of chromosome 7, at 7p22. Fluorescence in situ hybridization studies confirmed a cryptic PML-RARA fusion on the short arm of chromosome 7, as well as a second fusion on one copy of chromosome 15. With the fourth and latest relapse, molecular cytogenetic studies performed on interphase nuclei of the myeloid sarcoma specimen (a supraclavicular mass) showed evidence of six related abnormal clones with a PML-RARA fusion, suggesting clonal evolution. This represents a rare case of APL with a cryptic PML-RARA rearrangement presenting as myeloid sarcoma at multiple relapses and involving multiple anatomical sites, including cardiac atrium.

Cytogenetic and Molecular Characterization of a Partial Trisomy 2p Arising From Inverted Duplication of 2p With Terminal Deletion of 2pter

Partial trisomy 2p is typically associated with partial monosomy of another chromosomal segment and results from a balanced translocation in one of the parents. Inverted duplications with terminal deletions have been reported in an increasing number of chromosomes. Several cases initially interpreted as terminal duplications have instead been documented to represent inverted duplications with terminal deletions. Inv dup del(2p) has been reported in patients who manifest the clinical findings of trisomy 2p syndrome. Here we report on a 2‐month‐old girl with inv dup del(2p) and clinical manifestations that overlap those found commonly in partial 2p trisomy, as previously reported in the literature. Her clinical picture helps delineate the phenotype of 2p duplication disorders.

Myeloid neoplasm with t(3;8)(q26;q24): report of six cases and review of the literature

Abstract Balanced translocation between chromosomes 3q26 and 8q24 is a very rare event. Here we report six patients with t(3;8)(q26;q24) either as a sole or as a part of genetic abnormalities. Five of the six patients were men with ages ranging from 41 to 84 years old. One patient had a long history of granulocyte colony stimulating factor (G-CSF) treatment. Three of the patients were initially diagnosed with acute myeloid leukemia, two with myelodysplastic syndrome and one with chronic myelogenous leukemia with blast crisis. The peripheral blood in all patients showed severe to moderate anemia; one had absolute neutropenia, one with neutrophilia; four had thrombocytopenia, two with thrombocytosis. The bone marrows from all patients showed dysmegakaryopoiesis with additional erythroid (three patients) and granulocytic (two patients) dysplasia. Cytogenetics revealed t(3;8)(q26;q24) as the sole abnormality in three patients. The majority of patients (4/6) had a poor clinical course, with an average survival of 10 months.

Atypical rearrangement involving 3'-IGH@ and a breakpoint at least 400 Kb upstream of an intact MYC in a CLL patient with an apparently balanced t(8;14)(q24.1;q32) and negative MYC expression

The t(8;14)(q24.1;q32), the cytogenetic hallmark of Burkitt’s lymphoma, is also found, but rarely, in cases of chronic lymphocytic leukemia (CLL). Such translocation typically results in a MYC-IGH@ fusion subsequently deregulating and overexpressing MYC on der 14q32. In CLL, atypical rearrangements resulting in its gain or loss, within or outside of IGH@ or MYC locus, have been reported, but their clinical significance remains uncertain. Herein, we report a 67 year-old male with complex cytogenetic findings of apparently balanced t(8;14) and unreported complex rearrangements of IGH@ and MYC loci. His clinical, morphological and immunophenotypic features were consistent with the diagnosis of CLL.Interphase FISH studies revealed deletions of 11q22.3 and 13q14.3, and an extra copy of IGH@, indicative of rearrangement. Karyotype analysis showed an apparently balanced t(8;14)(q24.1;q32). Sequential GPG-metaphase FISH studies revealed abnormal signal patterns: rearrangement of IGH break apart probe with the 5’-IGH@ on derivative 8q24.1 and the 3’-IGH@ retained on der 14q; absence of MYC break apart-specific signal on der 8q; and, the presence of unsplit 5’-MYC-3’ break apart probe signals on der 14q. The breakpoint on 8q24.1 was found to be at least 400 Kb upstream of 5’ of MYC. In addition, FISH studies revealed two abnormal clones; one with 13q14.3 deletion, and the other, with concurrent 11q deletion and atypical rearrangements. Chromosome microarray analysis (CMA) detected a 7.1 Mb deletion on 11q22.3-q23.3 including ATM, a finding consistent with FISH results. While no significant copy number gain or loss observed on chromosomes 8, 12 and 13, a 455 Kb microdeletion of uncertain clinical significance was detected on 14q32.33. Immunohistochemistry showed co-expression of CD19, CD5, and CD23, positive ZAP-70 expression and absence of MYC expression. Overall findings reveal an apparently balanced t(8;14) and atypical complex rearrangements involving 3’-IGH@ and a breakpoint at least 400 Kb upstream of MYC, resulting in the relocation of the intact 5’-MYC-3’ from der 8q, and apposition to 3’-IGH@ at der 14q. This case report provides unique and additional cytogenetic data that may be of clinical significance in such a rare finding in CLL. It also highlights the utility of conventional and sequential metaphase FISH in understanding complex chromosome anomalies and their association with other clinical findings in patients with CLL. To the best of our knowledge, this is the first CLL reported case with such an atypical rearrangement in a patient with a negative MYC expression.

Cytogenetic and Cytogenomic Microarray Characterization of Chromothripsis in Chromosome 8 Affecting MOZ/NCOA2 (TIF2), FGFR1, RUNX1T1, and RUNX1 in a Pediatric Acute Myeloid Leukemia

Concurrent perturbations in different driver genes have been reported primarily in lymphoma. In acute myeloid leukemia (AML), cases with concurrent alterations in 2 driver genes are infrequently reported. In contrast to pathogenetic pathways in lymphoma with concurrently perturbed genes, the initial gene alteration in AML arrests maturation and the alteration in the second gene promote self-renewal of the blasts. Here, we report a unique case of infantile leukemia in which chromothripsis in chromosome 8 completely altered the G-band structure and resulted in concurrent changes in MOZ/NCOA2, FGFR1, RUNX1T1, and RUNX1. These multiple-hit abnormalities in AML have not been reported previously.

Recombinant chromosome 7 in a mosaic 45,X/47,XXX patient

Individuals with pericentric inversions are at risk for producing offspring with chromosomal gains and losses, while those carrying paracentric inversions usually produce unviable gametes [Madan, 1995 ]. In this current study, we present a newborn with dysmorphic features and malformations, whose karyotype showed an abnormal copy of chromomosome 7 described at first as add(7)(q32) as well as mos 45,X/47,XXX. Array comparative genomic hybridization (CGH) revealed an interstitial deletion in the long arm of chromosome 7 involving bands q35 to q36.3 but retaining the 7q subtelomere. The patients deletion is believed to be due to meiotic recombination in the inversion loop in the phenotypically normal father who seems to carry two paracentric inversions in the long arm of chromosome 7, which was described as rec(7)(7pter‐ > q35::q36.3‐ > 7qter)pat. The abnormal copy of chromosome 7 in the father has been described as: der(7)(7pter‐ > q22.1::q36.3‐ > q35::q22.1‐ > q35::q36.3‐ > 7qter). This is a unique karyotype that to our knowledge has not been previously reported in the literature and predisposes to meiotic recombination that can result in deletions or duplications of 7q35–36.