Lekidelu Taddesse-Heath

IG/MYC rearrangements are the main cytogenetic alteration in plasmablastic lymphomas.

Plasmablastic lymphoma (PBL) is an aggressive lymphoma characterized by a terminally differentiated B-cell phenotype that usually occurs in the immunocompromised or elderly patients. Although the clinical and pathologic characteristics of these tumors have been defined, the genetic alterations involved in their pathogenesis are not well known. In this study, we have investigated the chromosomal alterations of MYC, BCL2, BCL6, MALT1, PAX5, and IGH loci using fluorescence in situ hybridization in 42 PBL and 3 extracavitary primary effusion lymphomas. MYC rearrangements were identified in 20 of 41 (49%) PBL and the immunoglobulin (IG) genes were the partners in most tumors. MYC rearrangements were more common in Epstein-Barr virus (EBV)-positive (14 of 19, 74%) than EBV-negative (9 of 21, 43%) tumors (P<0.05). No rearrangements of BCL2, BCL6, MALT1, or PAX5 were detected in any PBL but gains of these loci were observed in 31% to 41% of the cases examined. Twelve of the 40 PBL in which 3 or more loci could be investigated had multiple simultaneous gains in 3 or more loci. No differences in the survival of the patients according to MYC were observed but the 4 patients with the longest survival (>50 mo) had no or low number of gains (<3). No rearrangements of any of these loci were seen in the primary effusion lymphomas. In conclusion, PBL are genetically characterized by frequent IG/MYC translocations and gains in multiple chromosomal loci. The oncogenic activation of MYC in these lymphomas may be an important pathogenetic element associated with EBV infection.

Plasmablastic lymphoma with MYC translocation: evidence for a common pathway in the generation of plasmablastic features

Plasmablastic lymphoma, which is considered a subtype of diffuse large B-cell lymphoma, shares many similar morphological and immunophenotypic features with plasmablastic transformation of plasma cell myeloma. In the setting of human immunodeficiency virus (HIV) infection, both types of neoplasms can be associated with Epstein–Barr virus (EBV), thus making their distinction challenging. Moreover, the biological relationship between these entities remains unclear. We report four unique cases of plasmablastic lymphoma occurring in the setting of HIV infection that had overlapping clinical and genetic features with plasma cell myeloma. We reviewed the clinical, morphological, and cytogenetic findings and performed immunohistochemistry, in situ hybridization for EBV, chromosome analysis, and fluorescent in situ hybridization (FISH) using the MYC break-apart rearrangement probe. All patients were males with a median age of 45 years. In addition to extra-nodal disease, plasmablastic morphology, and phenotype typical of plasmablastic lymphoma, three of the four cases also showed clinical findings overlapping with plasma cell myeloma, that is, monoclonal serum immunoglobulin and lytic bone lesions. Furthermore, these cases showed complex cytogenetic changes that are more commonly observed in plasma cell myeloma. A unique feature was the presence of MYC (8q24.1) rearrangement confirmed by FISH in all four cases. MYC translocation has been associated with tumor progression in multiple myeloma but has only rarely been previously reported in plasmablastic lymphoma. These cases show a clinical and biological relationship between plasmablastic lymphoma and the plasmablastic variant of plasma cell myeloma. Dysregulation of MYC may be a common genetic mechanism that imparts plasmablastic morphology and aggressive clinical course to B-cell neoplasms at a later stage of differentiation.

Accelerated Appearance of Multiple B Cell Lymphoma Types in NFS/N Mice Congenic for Ecotropic Murine Leukemia Viruses

Spontaneous lymphomas occur at high frequency in NFS.V+ mice, strains congenic for ecotropic murine leukemia virus (MuLV) proviral genes and expressing virus at high titer. In the present study, a total of 703 NFS.V+ lymphomas were studied by histopathology, immunophenotypic analysis, immunoglobulin heavy chain or T cell receptor β chain rearrangements, and somatic ecotropic MuLV integrations; 90% of the lymphomas tested were of B cell lineage. Low-grade tumors included small lymphocytic, follicular, and splenic marginal zone lymphomas, while high-grade tumors comprised diffuse large-cell (centroblastic and immunoblastic types), splenic marginal zone, and lymphoblastic lymphomas. Comparison of mice of similar genetic background except for presence (NFS.V+) or absence (NFS.V−) of functional ecotropic MuLV genomes showed that NFS.V− clonal lymphomas developed at about one-half the rate of those occurring in NFS.V+ mice, and most were low-grade B cell lymphomas with extended latent periods. In NFS.V+ mice, clonal outgrowth, defined by Ig gene rearrangements, was associated with acquisition of somatic ecotropic proviral integrations, suggesting that, although generation of B cell clones can be virus independent, ecotropic virus may act to increase the rate of generation of clones and speed their evolution to lymphoma. The mechanism remains undefined, because only rare rearrangements were detected in several cellular loci previously associated with MuLV insertional mutagenesis.

Lymphomas and High-Level Expression of Murine Leukemia Viruses in CFW Mice

ABSTRACT Historically, Swiss Webster mice of the CFW subline, both inbred and random-bred stocks, have been considered to have a low spontaneous occurrence of hematopoietic system tumors, and previous reports of infectious expression of murine leukemia viruses (MuLVs) have been rare and unremarkable. In marked contrast, in the present study of CFW mice from one source observed by two laboratories over a 2-year period, nearly 60% developed tumors, 85% of which were lymphomas, the majority of B-cell origin. All tumors tested expressed ecotropic MuLVs, and most expressed mink cell focus-inducing (MCF) MuLVs. Among normal mice of weanling to advanced age, over one-half were positive for ecotropic virus in tail or lymphoid tissues, and MCF virus was frequently present in lymphoid tissue, less often in tail. Patterns of ecotropic proviral integration indicated that natural infection occurred by both genetic and exogenous routes. Lymphomas were induced in NIH Swiss mice infected as neonates with tissue culture-propagated MuLVs isolated from normal and tumor tissue of CFW mice.

ALK-positive large B-cell lymphomas express a terminal B-cell differentiation program and activated STAT3 but lack MYC rearrangements

ALK-positive large B-cell lymphoma is an aggressive lymphoid neoplasm characterized by a monomorphic proliferation of immunoblast-like cells expressing a plasmablastic phenotype and carrying ALK rearrangements. MYC rearrangements are frequent in plasmablastic lymphomas, advanced plasma cell myelomas and a subgroup of diffuse large B-cell lymphomas, but their presence in ALK-positive large B-cell lymphomas is unknown. MYC expression is downregulated by BLIMP1, a master modulator of plasma cell differentiation. BLIMP1 and MYC are upregulated by STAT3, a signal transducer activated by ALK. To determine the role of BLIMP1, MYC and STAT3 in the pathogenesis of ALK-positive large B-cell lymphomas, we investigated MYC rearrangement and the expression of MYC, phosphorylated STAT3, BLIMP1, PAX5 and XBP1 in 12 ALK-positive large B-cell lymphomas. All cases expressed ALK with a granular cytoplasmic pattern. Nine cases had a split signal consistent with an ALK rearrangement. Three additional cases showed a deletion of the 5′ or 3′ end of the ALK probe consistent with cryptic translocation. PAX5 was virtually negative in all cases tested, whereas BLIMP1 was expressed in all tumors and XBP1 in 11 of 12. Phosphorylated STAT3 was observed in all cases with a strong and diffuse nuclear pattern. MYC rearrangements were not identified in any tumor, but MYC gains and amplification were detected in six cases and one case, respectively. MYC protein was expressed in all tumors independently of MYC gene alterations. These results indicate that ALK-positive large B-cell lymphomas express a complete plasmablastic differentiation program but, contrary to plasmablastic lymphomas, do not have MYC rearrangements. STAT3 is constantly activated and may be an alternative mechanism to promote MYC expression in these tumors. The relevance of the ALK/STAT3 pathway in the pathogenesis of ALK-positive large B-cell lymphomas may offer an attractive target for new therapies.

Florid CD4+, CD56+ T-cell infiltrate associated with Herpes simplex infection simulating nasal NK-/T-cell lymphoma

We report a case of Herpes simplex virus (HSV) infection of the nasopharynx associated with a dense CD4+, CD56+ T-cell infiltrate that simulated lymphoma on clinical, histologic, and immunophenotypic grounds. Histologic examination showed a tumorlike lymphoid infiltrate with extensive necrosis. Multinucleated giant cells with “ground-glass” nuclei characteristic of HSV were observed in necrotic areas but were not prominent. Immunohistochemical studies of the lymphoid infiltrate revealed a predominance of T cells, positive for CD3, CD4, CD5, and CD56. Immunohistochemical staining with HSV antibody was focally positive in the multinucleated giant cells. Molecular studies using PCR and Southern blot were positive for HSV Type II. PCR studies for T-cell receptor gamma and immunoglobulin heavy chain gene rearrangements showed no evidence of a clonal population. In situ hybridization studies for Epstein–Barr virus (EBV) were negative. The clinical presentation of a large fungating mass, the extent of the lymphoid infiltrate, and the expression of CD56 all raised the possibility of a nasal NK/T cell lymphoma. However, the presence of HSV, lack of angioinvasion and angiodestruction, absence of EBV, and polyclonal T-cell nature of the infiltrate argued against this diagnosis. Although prior studies have not fully characterized the immunophenotypic features of the lymphocyte response to HSV in infected tissues, we postulate that the CD56+, CD4+ T-cell reaction represents a florid antiviral immune response.

A case report of T cell prolymphocytic leukemia and Kaposi sarcoma and a review of T cell prolymphocytic leukemia.

T cell prolymphocytic leukemia (T-PLL) is a rare mature T cell lymphoproliferative disease. It has been associated with an aggressive course, a poor response to conventional chemotherapy and a short median survival. Here we present a rare case of concurrent T-PLL and Kaposi sarcoma who achieved a complete hematologic and cytogenetic remission after a very short course of treatment with alemtuzumab. A review of T-PLL was done. In this review, clinical features, laboratory features and current therapeutic strategies of T-PLL are presented.

Methotrexate-associated Classic Hodgkin Lymphoma in a Patient With Dermatomyositis

P atients with dermatomyositis (DM) are at higher risk of various malignancies, and age-appropriate screening is recommended. Malignancies presenting late in the course of DM, especially in elderly patients receiving immunosuppressive therapy, can further complicate the differential diagnoses. Methotrexate (MTX) is an effective immunosuppressive agent commonly used in the treatment of rheumatic disorders and has recently been implicated in the occurrence of iatrogenic lymphoproliferative disorders (LPDs), most often with rheumatoid arthritis (RA). Lymphoproliferative disorders have also been described in treated systemic lupus erythematosus and Crohn disease, but rarely with DM. We describe a case of classic Hodgkin lymphoma (CHL) in a patient with DM following treatment with MTX.