RESUMO
Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (CNS) is an aggressive subtype of DLBCL with characteristic clinicopathologic features. Relapse outside the CNS involving extranodal locations has been found in a fraction of cases (16%). Here we describe a case of DLBCL arising in the CNS that relapsed 18 months after the initial diagnosis in the testis and bilateral adrenal glands. Both tumors showed equivalent morphology, phenotype, cytogenetic features, and clonal relationship. Somatic mutation analysis by next generation sequencing demonstrated MYD88L265P mutation in both tumors and de novo CD79B Y196S mutation exclusive to the relapse. The pattern of mutations suggest that the 2 tumors might have evolved from a common progenitor clone with MYD88L265P being the founder mutation. A meta-analysis of the literature shows a significantly high frequency of concurrent MYD88L265P and CD79B ITAM mutations in primary CNS lymphoma and testicular DLBCL, underscoring the role of B cell receptor and nuclear factor kB activation by somatic mutations in these lymphomas that colonize immune-privileged sites. In summary, here we illustrate that targeted next generation sequencing for the detection of hot spot somatic mutations in relapsed DLBCL is useful to confirm ABC phenotype and discovers relevant information that might influence therapeutic decision.
Assuntos
Antígenos CD79/genética , Neoplasias do Sistema Nervoso Central/genética , Evolução Clonal/genética , Linfoma Difuso de Grandes Células B/genética , Fator 88 de Diferenciação Mieloide/genética , Recidiva Local de Neoplasia/genética , Glândulas Suprarrenais/patologia , Neoplasias do Sistema Nervoso Central/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Mutação , NF-kappa B/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/metabolismo , Lobo Temporal/patologia , Neoplasias Testiculares/genética , Neoplasias Testiculares/secundárioRESUMO
Merkel cell carcinoma (MCC) is a highly malignant neuroendocrine tumor of the skin whose molecular pathogenesis is not completely understood, despite the role that Merkel cell polyomavirus can play in 55-90% of cases. To study potential mechanisms driving this disease in clinically characterized cases, we searched for somatic mutations using whole-exome sequencing, and extrapolated our findings to study functional biomarkers reporting on the activity of the mutated pathways. Confirming previous results, Merkel cell polyomavirus-negative tumors had higher mutational loads with UV signatures and more frequent mutations in TP53 and RB compared with their Merkel cell polyomavirus-positive counterparts. Despite important genetic differences, the two Merkel cell carcinoma etiologies both exhibited nuclear accumulation of oncogenic transcription factors such as NFAT or nuclear factor of activated T cells (NFAT), P-CREB, and P-STAT3, indicating commonly deregulated pathogenic mechanisms with the potential to serve as targets for therapy. A multivariable analysis identified phosphorylated CRE-binding protein as an independent survival factor with respect to clinical variables and Merkel cell polyomavirus status in our cohort of Merkel cell carcinoma patients.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Célula de Merkel/genética , Carcinoma de Célula de Merkel/virologia , Poliomavírus das Células de Merkel/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/virologia , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha , Carcinogênese/genética , Carcinoma de Célula de Merkel/mortalidade , Carcinoma de Célula de Merkel/patologia , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Poliomavírus das Células de Merkel/isolamento & purificação , Análise Multivariada , Mutação , Oncogenes/genética , Prognóstico , Medição de Risco , Transdução de Sinais/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Infecções Tumorais por Vírus/mortalidade , Infecções Tumorais por Vírus/patologia , Raios Ultravioleta/efeitos adversosRESUMO
Plasmablastic lymphoma is an uncommon aggressive non-Hodgkin B-cell lymphoma type defined as a high-grade large B-cell neoplasm with plasma cell phenotype. Genetic alterations in MYC have been found in a proportion (~60%) of plasmablastic lymphoma cases and lead to MYC-protein overexpression. Here, we performed a genetic and expression profile of 36 plasmablastic lymphoma cases and demonstrate that MYC overexpression is not restricted to MYC-translocated (46%) or MYC-amplified cases (11%). Furthermore, we demonstrate that recurrent somatic mutations in PRDM1 are found in 50% of plasmablastic lymphoma cases (8 of 16 cases evaluated). These mutations target critical functional domains (PR motif, proline rich domain, acidic region, and DNA-binding Zn-finger domain) involved in the regulation of different targets such as MYC. Furthermore, these mutations are found frequently in association with MYC translocations (5 out of 9, 56% of cases with MYC translocations were PRDM1-mutated), but not restricted to those cases, and lead to expression of an impaired PRDM1/Blimp1α protein. Our data suggest that PRDM1 mutations in plasmablastic lymphoma do not impair terminal B-cell differentiation, but contribute to the oncogenicity of MYC, usually disregulated by MYC translocation or MYC amplification. In conclusion, aberrant coexpression of MYC and PRDM1/Blimp1α owing to genetic changes is responsible for the phenotype of plasmablastic lymphoma cases.
Assuntos
Variação Genética , Linfoma Plasmablástico/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Proteínas Proto-Oncogênicas c-myc/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Infecções por HIV/complicações , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Linfoma Plasmablástico/complicações , Linfoma Plasmablástico/patologiaRESUMO
Follicular lymphoma in situ (FLIS) and mantle cell lymphoma in situ (MCLIS) are histopathologic findings of undetermined clinical significance. We studied a series of 341 consecutive lymph node resection specimens from patients diagnosed with colorectal (201 cases) and breast (140 cases) adenocarcinoma between 1998 and 2000. Incidental and isolated FLIS was identified in 11/341 patients (3.23%), whereas incidental and isolated MCLIS was found in 2/341 patients (0.59%). None of these cases developed overt lymphoma. A second series of 17 cases of FLIS (16 cases) and MCLIS (1 case) from consultation files was analyzed. Five cases with incidental and isolated FLIS were identified. None of these cases developed overt lymphoma. Overall, none of the 16 cases with incidental and isolated FLIS in both series developed overt FL after a median follow-up of 54 months (range, 7 to 187 mo). However, 12 of these cases with a clinical suspicion of lymphoproliferative disorder showed the association (in different lymph nodes) or combination (in the same sample) of FLIS or MCLIS with other lymphoid neoplasms (FL, splenic marginal zone lymphoma, nodal marginal zone lymphoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, multiple myeloma). In conclusion, the clinical relevance of FLIS and MCLIS seems to strictly depend on the clinical context. Incidental FLIS or MCLIS seem to have a very low risk for transformation, which recommends careful clinical examination after histopathologic diagnosis and conservative management with follow-up for a limited period of time.