RESUMEN
Burkitt lymphoma (BL) is a B cell lymphoma composed of monomorphic medium-sized blastic cells with basophilic cytoplasm and a high proliferation index. BL has a characteristic immunophenotype of CD10 and BCL6 positive and BCL2 negative and harbours MYC gene rearrangements (MYCR) in >90% of the cases. Owing to its highly aggressive nature, intensified chemotherapy regimens are usually administered, requiring an exact diagnosis. Since the diagnosis usually warrants an integration of morphologic, immunophenotypic and genetic findings and because there is a morphologic overlap with the new WHO category of high-grade B cell lymphoma, not otherwise specified (HGBL, NOS) and some cases of diffuse large B cell lymphoma (DLBCL), we wanted to test the distinctiveness of the CD10+, BCL6+, BCL2- and MYCR positive immunopheno-genotype in a large cohort of >1000 DLBCL and HGBL. Only 9/982 DLBCL classified by an expert panel of haematopathologists (0.9%) displayed a single MYCR and were CD10+, BCL6+ and BCL2-. In a similar fashion, only one out of 32 HGBL, NOS (3%) displayed the "Burkitt-like" genetic/immunophenotypic constitution. The samples of non-BL showing the BL-typic immunopheno-genotype, interestingly, harboured higher copy number variations (CNV) by OncoScan analysis (mean 7.3 CNVs/sample; range: 2-13 vs. 2.4; range 0-6) and were also distinct from pleomorphic BL cases regarding their mutational spectrum by NGS analysis. This implies that the characteristic immunophenotype of BL, in concert with a single MYCR, is uncommon in these aggressive lymphomas, and that this constellation favours BL.
Asunto(s)
Biomarcadores de Tumor , Linfoma de Burkitt/genética , Linfoma de Burkitt/inmunología , Variaciones en el Número de Copia de ADN , Dosificación de Gen , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/inmunología , Mutación , Antígenos CD20/análisis , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Linfoma de Burkitt/patología , Análisis Mutacional de ADN , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Inmunofenotipificación , Hibridación Fluorescente in Situ , Linfoma de Células B Grandes Difuso/patología , Clasificación del Tumor , Neprilisina/análisis , Fenotipo , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-6/análisis , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-myc/genética , Estudios RetrospectivosRESUMEN
Diffuse large B-cell lymphoma (DLBCL) is a disease with heterogeneous outcome. Stromal signatures have been correlated to survival in DLBCL. Their use, however, is hampered by the lack of assays for formalin-fixed paraffin-embedded material (FFPE). We constructed a lymphoma-associated macrophage interaction signature (LAMIS) interrogating features of the microenvironment using a NanoString assay applicable to FFPE. The clinical impact of the signature could be validated in a cohort of 466 patients enrolled in prospective clinical trials of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Patients with high expression of the signature (LAMIShigh) had shorter EFS, PFS, and OS. Multivariate analyses revealed independence from IPI factors in EFS (HR 1.7, 95% CI 1.2-2.4, p-value = 0.001), PFS (HR 1.8, 95% CI 1.2-2.5, p-value = 0.001) and OS (HR 1.8, 95% CI 1.3-2.7, p-value = 0.001). Multivariate analyses adjusted for the IPI factors showed the signature to be independent from COO, MYC rearrangements and double expresser status (DE). LAMIShigh and simultaneous DE status characterized a patient subgroup with dismal prognosis and early relapse. Our data underline the importance of the microenvironment in prognosis. Combined analysis of stromal features, the IPI and DE may provide a new rationale for targeted therapy.
