RESUMO
CD37 (tetraspanin TSPAN26) is a B-cell surface antigen widely expressed on mature B cells. CD37 is involved in immune regulation and tumor suppression but its function has not been fully elucidated. We assessed CD37 expression in de novo diffuse large B-cell lymphoma (DLBCL), and investigated its clinical and biologic significance in 773 patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and 231 patients treated with CHOP. We found that CD37 loss (CD37-) in â¼60% of DLBCL patients showed significantly decreased survival after R-CHOP treatment, independent of the International Prognostic Index (IPI), germinal center B-cell-like (GCB)/activated B-cell-like (ABC) cell of origin, nodal/extranodal primary origin, and the prognostic factors associated with CD37-, including TP53 mutation, NF-κBhigh, Mychigh, phosphorylated STAT3high, survivinhigh, p63-, and BCL6 translocation. CD37 positivity predicted superior survival, abolishing the prognostic impact of high IPI and above biomarkers in GCB-DLBCL but not in ABC-DLBCL. Combining risk scores for CD37- status and ABC cell of origin with the IPI, defined as molecularly adjusted IPI for R-CHOP (M-IPI-R), or IPI plus immunohistochemistry (IHC; IPI+IHC) for CD37, Myc, and Bcl-2, significantly improved risk prediction over IPI alone. Gene expression profiling suggested that decreased CD20 and increased PD-1 levels in CD37- DLBCL, ICOSLG upregulation in CD37+ GCB-DLBCL, and CD37 functions during R-CHOP treatment underlie the pivotal role of CD37 status in clinical outcomes. In conclusion, CD37 is a critical determinant of R-CHOP outcome in DLBCL especially in GCB-DLBCL, representing its importance for optimal rituximab action and sustained immune responses. The combined molecular and clinical prognostic indices, M-IPI-R and IPI+IHC, have remarkable predictive values in R-CHOP-treated DLBCL.
Assuntos
Linfócitos B/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Antígenos CD20/genética , Antígenos CD20/metabolismo , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Centro Germinativo/patologia , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Análise Multivariada , Mutação/genética , NF-kappa B/metabolismo , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Transporte Proteico , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Risco , Análise de Sobrevida , Tetraspaninas/genética , Tetraspaninas/metabolismo , Resultado do Tratamento , Proteína Supressora de Tumor p53/genéticaRESUMO
γδ T-cell large granular lymphocytic (T-LGL) leukemia of the CD4-/CD8- subtype is rare, and data are limited in the literature. This study evaluated the clinical, morphologic, immunophenotypic, and molecular cytogenetic features of 7 cases of CD4-/CD8- γδ T-LGL leukemia. Although this variant shares several clinical and morphologic features with the more common T-LGL leukemias, the incidences of autoimmune hemolytic anemia and pure red cell aplasia are higher. Another striking feature observed in our study was the lack of increased large granular lymphocytes in the peripheral blood in the majority of cases despite prominent bone marrow or splenic involvement. CD4-/CD8- γδ T-LGL leukemia also displays an immunophenotype and pattern of splenic involvement overlapping with hepatosplenic T-cell lymphoma. Clinically, this variant of T-LGL leukemia shows an overall indolent course, but treatment is often required in the initial stages of the disease. Awareness of these features is important for early recognition and accurate diagnosis of patients with CD4-/CD8- γδ T-LGL leukemia.