RESUMO
Only a few series of splenic large B-cell lymphoma have been previously reported, including limited immunophenotypic studies and clinical data. Here we review the clinical data, morphology, and immunophenotype of series of 33 cases of large B-cell lymphoma presenting in the spleen. Three main groups of tumors are identified. Group A was characterized by macronodular tumors (20 cases), with predominantly stage I disease and a favorable clinical outcome. All cases were bcl6 positive. Group B was characterized by a micronodular pattern (nine cases), including a subset with T-cell-rich B-cell lymphoma features. Most of the patients in this group were diagnosed at advanced clinical stages and died of the disease. All cases were bcl6 positive. Group C was characterized by diffuse red pulp infiltration (four cases) and advanced clinical stages and showed an aggressive behavior. All but one case were bcl6 positive. The results of this series define a characteristic type of large B-cell lymphoma presenting in the spleen as a tumoral mass, associated with a relatively favorable clinical course. Additionally, they provide evidence that clinical presentation as a tumor confined to the spleen and the hilar lymph nodes is associated with lower aggressivity.
Assuntos
Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/patologia , Neoplasias Esplênicas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Feminino , Herpesvirus Humano 4/isolamento & purificação , Humanos , Imuno-Histoquímica , Imunofenotipagem , Hibridização In Situ , Linfoma de Células B/classificação , Linfoma de Células B/imunologia , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias Esplênicas/classificação , Neoplasias Esplênicas/imunologia , Análise de SobrevidaRESUMO
Splenic marginal zone lymphoma (SMZL) is a newly recognized lymphoma type whose precise molecular pathogenesis is still essentially unknown. This hampers differential diagnosis with other small B-cell malignancies. With the aim of characterizing this tumor more comprehensively, and of identifying new diagnostic and prognostic markers, we performed cDNA microarray expression profiling and tissue microarray (TMA) immunohistochemical studies in a relatively large series of 44 SMZLs. The results were related to immunoglobulin heavy chain variable region (IgV(H)) mutational status and clinical outcome. SMZLs display a largely homogenous signature, implying the existence of a single molecular entity. Of the genes deregulated in SMZLs, special mention may be made of the genes involved in B-cell receptor (BCR) signaling, tumor necrosis factor (TNF) signaling and nuclear factor-kappaB (NF-kappaB) activation, such as SYK, BTK, BIRC3, TRAF3, and LTB. Other genes observed were SELL and LPXN, which were highly expressed in spleen, and lymphoma oncogenes, such as ARHH and TCL1. In contrast, the genes CAV1, CAV2, and GNG11 located in 7q31, a commonly deleted area, were down-regulated in the entire series. A comparison with the genes comprising the signature of other small B-cell lymphomas identified 3 genes whose expression distinguishes SMZL, namely ILF1, SENATAXIN, and CD40. Shorter survival was associated with CD38 expression, naive IgV(H) genes, and the expression of a set of NF-kappaB pathway genes, including TRAF5, REL, and PKCA.
Assuntos
Biomarcadores Tumorais/análise , Linfoma/diagnóstico , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Neoplasias Esplênicas/diagnóstico , Análise Serial de Tecidos/métodos , Mutação em Linhagem Germinativa , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma/genética , Linfoma/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Filogenia , Prognóstico , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/fisiologia , Neoplasias Esplênicas/genética , Neoplasias Esplênicas/metabolismo , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BCL-6 somatic mutations have been described in normal and tumoral B lymphocytes, associated with germinal center transit. We analyzed mutations in the major mutation cluster of BCL-6 in a series of 45 large B-cell lymphomas (LBCLs) and 15 Burkitt's lymphomas, and their relation to the level of BCL-6 expression and clinical outcome. Mutations in LBCL cases revealed the existence of two distinct, short mutational hot spots, spanning positions 106 to 127 and 423 to 443, in which the mutation frequency was higher than expected (P < 0.001). Mutations in the 423 to 443 subcluster were associated with an increased level of expression, although this was not the case with the 106 to 127 cluster. Additionally, LBCL cases characterized by the presence of mutations in the 423 to 443 cluster showed an increased overall survival (P < 0.05) when compared with the nonmutated LBCL cases in these positions. Burkitt's lymphoma cases showed a slightly lower frequency of mutations with a nonclustered distribution and lacked any relationship with the level of expression or any clinical characteristic. Findings from LBCLs suggest that the 423 to 443 cluster includes a regulatory region that is of importance for BCL-6 expression. Deregulation of BCL-6 expression caused by these mutations could play an important role in lymphoma genesis or progression.
Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Íntrons/genética , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Mutação , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Humanos , Família Multigênica , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas c-bcl-6 , Análise de SobrevidaRESUMO
This study aimed to correlate the frequency of somatic mutations in the IgV(H) gene and the use of specific segments in the V(H) repertoire with the clinical and characteristic features of a series of 35 cases of splenic marginal zone lymphoma (SMZL). The cases were studied by seminested polymerase chain reaction by using primers from the FR1 and J(H) region. The results showed unexpected molecular heterogeneity in this entity, with 49% unmutated cases (less than 2% somatic mutations). The 7q31 deletions and a shorter overall survival were more frequent in this group. Additionally a high percentage (18 of 40 sequences) of SMZL cases showed usage of the V(H)1-2 segment, thereby emphasizing the singularity of this neoplasia, suggesting that this tumor derives from a highly selected B-cell population and encouraging the search for specific antigens that are pathogenically relevant in the genesis or progression of this tumor.
Assuntos
Cromossomos Humanos Par 7/genética , Genes de Imunoglobulinas/genética , Linfoma de Células B/genética , Mutação , Neoplasias Esplênicas/genética , Deleção Cromossômica , Análise Mutacional de DNA , Progressão da Doença , Seguimentos , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Cariotipagem , Linfoma de Células B/etiologia , Linfoma de Células B/imunologia , Neoplasias Esplênicas/etiologia , Neoplasias Esplênicas/imunologia , Taxa de SobrevidaRESUMO
Knowledge about the molecular mechanisms involved in the pathogenesis of tumoral progression in mycosis fungoides (MF) is still scarce. Because the 9p21 locus seems to be a good target for a detailed study in MF, this prompted us to compare the mechanisms of inactivation of the p16(INK4a), p15(INK4b), and p14(ARF) genes in aggressive and stable forms of MF, performing microsatellite analysis, methylation-specific polymerase chain reaction, direct sequencing, and p16(INK4a) protein expression by immunohistochemistry. Additionally, the p53 gene was also sequenced in tumoral lesions. Thirty-nine patients with stable MF were studied. Alterations in p16(INK4a) and p15(INK4b) genes were detected in 18% and 5% of the cases, respectively. None of the cases analyzed showed alterations of the p14(ARF) gene. In contrast with these findings, in the 11 patients with aggressive MF, alterations of the p16(INK4a), p15(INK4b), or p14(ARF) genes were found in 8 (73%), 3 (27%), and 2 (18%) cases, respectively. A significant proportion (4/11) of these alterations were already present in the p16(INK4a) gene in the initial plaque lesions in these aggressive forms of MF. Alterations in the p16(INK4a) gene, either methylation or loss of heterozygosity, were clearly more frequent than those in the p15(INK4b) and p14(ARF) genes. These p16(INK4A) alterations were confirmed using immunohistochemistry. None of the nine tumoral lesions analyzed showed mutations in exons 1-2 of the p16(INK4a) gene or in exons 5-8 of the p53 gene. These results seem to suggest that 9p21 alterations, and selectively p16(INK4a) silencing, could be a characteristic phenomenon in MF progression.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Inativação Gênica , Micose Fungoide/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Cromossomos Humanos Par 9 , Metilação de DNA , Feminino , Humanos , Imuno-Histoquímica , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Mutação , Micose Fungoide/patologiaRESUMO
A precise description of clinical features at presentation and analysis of clinical and biologic prognostic factors in splenic marginal zone lymphoma (SMZL) are still lacking. Here we describe the clinical and biologic features of a series of 60 SMZL patients diagnosed after splenectomy. Analysis for overall survival (OS), failure-free survival (FFS), and the probability of obtaining a response was performed using univariate and multivariate tests. The median age of the patient was 63 years (range, 35-84 years). Performance status according to the Eastern Cooperative Oncology Group (ECOG scale) was 0 = 16%, 1 = 58%, and 2 = 25%. Of the 60 patients, 53 (86.6%) were at Ann Arbor stage IV. All 60 patients received splenectomies, 29 of 60 also received chemotherapy, and 2 received spleen radiotherapy. A complete response (CR) was achieved by 38.3% of patients, and a partial response (PR) was achieved by 55%. Mean OS of the series was 103 months (range, 2-164 months); mean FFS was 40 months (range, 3-164 months). At 5 years from diagnosis, 39 patients (65%) were alive. Patients dying from the disease had a relatively aggressive clinical course, with a short survival (17.5 months [range, 2-72 months]). Significant prognostic factors in multivariate analysis were (1) (for OS and FFS) lack of response to therapy (CR versus noncomplete response [nCR]) and involvement of nonhematopoietic sites, and (2) (for the probability of obtaining CR) bone marrow involvement. Chemotherapy did not influence OS or FFS. p53 overexpression predicted a shorter OS in the univariate analysis. These data confirm the relative indolence of this disease, indicating the existence of a subset of more aggressive cases, which should stimulate the search for predictive biologic factors and alternative therapies.
Assuntos
Linfoma de Células B , Neoplasias Esplênicas , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Intervalo Livre de Doença , Feminino , Humanos , Linfoma de Células B/mortalidade , Linfoma de Células B/patologia , Linfoma de Células B/fisiopatologia , Linfoma de Células B/terapia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Neoplasias Esplênicas/mortalidade , Neoplasias Esplênicas/patologia , Neoplasias Esplênicas/fisiopatologia , Neoplasias Esplênicas/terapia , Análise de SobrevidaRESUMO
This study explores whether the presence of somatic mutations or a biased use of IgV(H) genes were associated with the clinical features in a series of 96 patients with mantle cell lymphoma (MCL). The cases were studied by seminested polymerase chain reaction using primers from the FR1 and J(H) regions. There was an unexpectedly high frequency of somatic mutations, with 29 of 103 sequences showing more than 2% of mutations. Biased usage of specific V(H) segments was also found; the most widely used genes in this series were V(H)3-21 (10 cases), V(H)3-23 (9 cases), V(H)4-34 (11 cases), and V(H)4-59 (9 cases). V(H) mutation frequency, taking into account different thresholds, did not distinguish different overall survival probabilities. Nevertheless, a more frequent use of V(H)3-21 or V(H)4-59 (8 of 18) was observed in the group of long-term survivors (18 cases > 5 years; P <.01). None of these long-term survivors presented the V(H)3-23 gene rearrangement. As in other lymphoproliferative disorders, the expression of CD38 or p53 or both was associated with a poorer survival probability. This nonrandom usage of IgV(H) segments suggests that specific antigens may play a pathogenically relevant role in the genesis or progression of subsets of MCL cases and may help in distinguishing a significant group of MCL long-term survivors.