We have continued our work exploring the nature of EBV-driven T-cell and B-cell lymphoproliferative disorders. In the past year, we described a series of EBV associated mucosal and cutaneous lymphoproliferative lesions characterized by distinctive pathological and clinical features. (Dojcinov et al., Am J Surg Pathol, 2010) This newly described entity has distinctive clinical features that impact on clinical management and treatment, and can be managed conservatively in this elderly and often immunocompromised patient population. The study group comprised 9 male and 15 female patients, median age 77 years (range 42-101). Immunosuppression in 8 cases included azathioprine (AZA), methotrexate (MTX) or cyclosporin-A (CyA). 16 patients had only age related immunosenescence. The patients presented with isolated sharply circumscribed ulcers involving mucosal or cutaneous sites. Histologically the lesions contained a polymorphous infiltrate and atypical large B-cell blasts with Hodgkin/ Reed-Sternberg (RS) cell-like morphology. The pathological features were identical regardless of the anatomical site or cause of IS. PCR revealed 31% (5/16) clonal IgH rearrangements with 43% (6/14) and 29% (4/14) clonal and restricted T-cell patterns respectively. 26% of patients (5/19) received standard chemotherapy and/or radiotherapy. 47% of lesions (9/19) regressed spontaneously with no treatment and 16% (3/19) were characterized by a relapsing and remitting course. All of the iatrogenic lesions (5/5) with available follow up responded to reduction of IS. All patients achieved complete remission with no disease associated deaths over a median follow up period of 20.5 months (range 3-72). We proposed the term EBV positive Mucocutaneous Ulcer (EBVMCU) as a newly recognized clinico-pathological entity with Hodgkin-like features and a self limited, indolent course, generally responding well to conservative management. Association with various forms of IS implies a common pathogenetic mechanism, frequently involving restricted and clonal T-cell responses. The localized nature of the disease may be due to a minimal and localized lapse in immunosurveillance over EBV. Plasmablastic lymphoma (PBL), 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 reported four unique cases of plasmablastic lymphoma occurring in the setting of HIV infection that had overlapping clinical and genetic features with plasma cell myeloma (Taddesse-Heath, et al. Mod Pathol, 2009). 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. 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. We suggested that 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. In a follow up (Valera et al. in press), MYC rearrangements were identified in 20 of 41 (49%) PBL and the immunoglobulin (IG) genes were the partners in most tumours. MYC rearrangements were more common in EBV-positive (14 of 19, 74%) than EBV-negative (9 of 21, 43%) tumours (p less than 0.05). No rearrangements of BCL2, BCL6, MALT1 or PAX5 were detected in any PBL but gains of these loci were observed in 31-41% 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 four patients with the longest survival ( greater than 50 months) had no or low number of gains ( less than 3). In another study of neoplasms with plasmacytic differentiation, we characterized extraosseous plasmacytomas expressing immunoglobulin A (IgA) These tumors are rare and not well understood. In a recent study in press (Shao et al., Am J Surg Pathol), nine cases of IgA-positive plasmacytomas presenting in lymph node and three in extranodal sites were analyzed by morphology, immunohistochemistry, and PCR examination of immunoglobulin heavy and kappa light chain genes. Laboratory features were correlated with clinical findings. The median age was 32 , with 6 patients younger than 30. 67% (6/9) of the patients with nodal disease had evidence of immune system dysfunction. An IgA M-spike was detected in 6/11 cases, and the M-protein was nearly always less than 30 g/L. All patients had an indolent clinical course without progression to plasma cell myeloma. Our results suggest that IgA plasmacytomas may represent a distinct form of extramedullary plasmacytoma characterized by young age, association with autoimmune disease, frequent lymph node involvement and low risk of progression to plasma cell myeloma. Our group previously described marginal zone lymphomas in the pediatric and young adult age group. To date, chromosomal aberrations had not been analyzed in the pediatric and young adult population. We undertook a study to analyze genetic alterations in nodal and extranodal marginal zone lymphomas in children and young adults using fluorescence in situ hybridization (FISH) and RT-PCR (Rizzo et al. Mod Pathol 2010). The findings were correlated with clinical features at presentation and immunophenotype. Forty-one cases were identified meeting these criteria. The age range was 1.5-29 years old with 49% of the cases less than 18 years of age. 85% of the marginal zone lymphoma cases tested showed evidence of immunoglobulin heavy chain gene rearrangement. Fifty-nine percent of the cases were nodal marginal zone lymphomas with a median age at presentation of 16 years and an M/F ratio of 7:1. Twenty-one percent of the nodal marginal zone lymphoma cases contained genetic aberrations. Seventeen percent contained trisomy 18 with one case containing an additional trisomy 3. A translocation of the immunoglobulin heavy chain gene to an unknown partner gene was present in one case. Forty-one percent of the cases were extranodal marginal zone lymphomas with a median age of 24 years and a M/F ratio of 1.4:1. Eighteen percent of the extranodal marginal zone lymphoma cases contained genetic aberrations. The t(14;18) involving the IGH and MALT1 genes was present in one case, tetraploidy was present in one case, and another case contained trisomy 3. Overall the incidence of genetic aberrations in marginal zone lymphomas in the pediatric and young adult population is low, but the aberrations seen are similar to those seen in the adult population. The low incidence of genetic aberrations may correlate with the generally excellent clinical outcome with conservative therapy.

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Roswarski, Joseph; Roschewski, Mark; Lucas, Andrea et al. (2018) Phase I dose escalation study of the anti-CD2 monoclonal antibody, siplizumab, with DA-EPOCH-R in aggressive peripheral T-cell lymphomas. Leuk Lymphoma 59:1466-1469
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