RESUMEN
The B cell receptor immunoglobulin (Ig) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n = 488), i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL), as well as provisional entities (n = 76), according to the WHO classification. The most striking Ig gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different Ig gene distributions depending on the primary site of involvement. Cross-entity comparisons of the MZ Ig sequence dataset with a large dataset of Ig sequences (MZ-related or not; n = 65 837) revealed four major clusters of cases sharing homologous ('public') heavy variable complementarity-determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia, but also rheumatoid factors and non-malignant splenic MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen-triggered, immune-mediated mechanisms may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Genes de Inmunoglobulinas/genética , Linfoma de Células B de la Zona Marginal/genética , Regiones Determinantes de Complementariedad/genética , Reordenamiento Génico de Linfocito B/genética , Genes de las Cadenas Pesadas de las Inmunoglobulinas/genética , Humanos , Región Variable de Inmunoglobulina/genética , Mutación/genética , Receptores de Antígenos de Linfocitos B/genética , Microambiente TumoralRESUMEN
To obtain insight into the ontogeny of mantle cell lymphoma (MCL), we assessed 206 patients from a morphological, immunohistochemical, and immunogenetic perspective. Our series included nodal (n = 151), extranodal (n = 28), and primary splenic (n = 27) MCL cases. Skewing of the immunoglobulin heavy variable (IGHV) gene repertoire was noted, with only four IGHV genes accounting for 46% of cases and approximately 70% of cases (107/154) bearing an imprint of somatic hypermutation (SHM) ranging from minimal to pronounced. Interestingly, a distinctive immunophenotypic and immunogenetic profile was identified for primary splenic MCL, which was enriched for DBA.44-positive cases (P < 0.001) and used the IGHV1-8 gene more frequently (P = 0.02) compared to nodal or extranodal cases, alluding to distinct immunopathogenetic and antigen selection processes. Expression of CD27 (considered a marker of activated B cells) was generally dissociated from SHM and was more prevalent in cases with no or minimal/borderline SHM. These findings support the idea that antigen drive is relevant for most MCL cases, although the specific antigens and the precise location of affinity maturation remain to be elucidated. Moreover, they raise the intriguing hypothesis of multiple cellular origins for MCL.
Asunto(s)
Biomarcadores de Tumor/genética , Inmunogenética , Inmunoglobulinas/genética , Linfoma de Células del Manto/genética , Antígenos/genética , Antígenos/metabolismo , Biomarcadores de Tumor/metabolismo , Médula Ósea/metabolismo , Médula Ósea/patología , Estudios de Cohortes , Europa (Continente) , Humanos , Inmunoglobulinas/metabolismo , Inmunohistoquímica , Inmunofenotipificación , Linfoma de Células del Manto/inmunología , Linfoma de Células del Manto/patología , Bazo/metabolismo , Bazo/patología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismoRESUMEN
We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBε, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Because preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, we screened a large patient cohort (n = 1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary central nervous system lymphoma (3% to 4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases [22.7%]) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases [27.3%]). NFKBIE-deleted PMBL patients were more often therapy refractory (P = .022) and displayed inferior outcome compared with wild-type patients (5-year survival, 59% vs 78%; P = .034); however, they appeared to benefit from radiotherapy (P =022) and rituximab-containing regimens (P = .074). NFKBIE aberrations remained an independent factor in multivariate analysis (P = .003) and when restricting the analysis to immunochemotherapy-treated patients (P = .008). Whole-exome sequencing and gene expression profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.
Asunto(s)
Biomarcadores de Tumor/genética , Eliminación de Gen , Proteínas I-kappa B/genética , Linfoma de Células B , Neoplasias del Mediastino , Proteínas Proto-Oncogénicas/genética , Adolescente , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Linfoma de Células B/genética , Linfoma de Células B/mortalidad , Masculino , Neoplasias del Mediastino/genética , Neoplasias del Mediastino/mortalidad , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
To further our understanding about antigen involvement in mantle cell lymphoma (MCL), we analyzed the expression levels of activation-induced cytidine deaminase (AID), a key player in B-cell responses to antigen triggering, in 133 MCL cases; assessed the functionality of AID by evaluating in vivo class switch recombination in 52 MCL cases; and sought for indications of ongoing antigen interactions by exploring intraclonal diversification within 14 MCL cases. The AID full-length transcript and the most frequent splice variants (AID-ΔE4a, AID-ΔE) were detected in 128 (96.2%), 96 (72.2%), and 130 cases (97.7%), respectively. Higher AID full-length transcript levels were significantly associated (P < 0.001) with lack of somatic hypermutation within the clonotypic immunoglobulin heavy variable (IGHV) genes. Median AID transcript levels were higher in lymph node material compared to cases in which peripheral blood was analyzed, implying that clonal behavior is influenced by the microenvironment. Switched tumor-derived IGHV-IGHD-IGHJ transcripts were identified in 5 of 52 cases (9.6%), all of which displayed somatic hypermutation and AID-mRNA expression. Finally, although most cases exhibited low levels of intraclonal diversification, analysis of the mutational activity revealed a precise targeting of somatic hypermutation indicative of an active, ongoing interaction with antigen(s). Collectively, these findings strongly allude to antigen involvement in the natural history of MCL, further challenging the notion of antigen naivety.
Asunto(s)
Linfocitos B/metabolismo , Citidina Desaminasa/metabolismo , Región Variable de Inmunoglobulina , Linfoma de Células del Manto/metabolismo , Hipermutación Somática de Inmunoglobulina , Linfocitos B/inmunología , Linfocitos B/patología , Humanos , Linfoma de Células del Manto/inmunología , Linfoma de Células del Manto/patologíaRESUMEN
The biological and clinical significance of a clonal B-cell lymphocytosis with an immunophenotype consistent with marginal-zone origin (CBL-MZ) is poorly understood. We retrospectively evaluated 102 such cases with no clinical evidence to suggest a concurrent MZ lymphoma. Immunophenotyping revealed a clonal B-cell population with Matutes score ≤2 in all cases; 19/102 were weakly CD5 positive and all 35 cases tested expressed CD49d. Bone marrow biopsy exhibited mostly mixed patterns of small B-lymphocytic infiltration. A total of 48/66 (72.7%) cases had an abnormal karyotype. Immunogenetics revealed overusage of the IGHV4-34 gene and somatic hypermutation in 71/79 (89.8%) IGHV-IGHD-IGHJ gene rearrangements. With a median follow-up of 5 years, 85 cases remain stable (group A), whereas 17 cases (group B) progressed, of whom 15 developed splenomegaly. The clonal B-cell count, degree of marrow infiltration, immunophenotypic, or immunogenetic findings at diagnosis did not distinguish between the 2 groups. However, deletions of chromosome 7q were confined to group A and complex karyotypes were more frequent in group B. Although CBL-MZ may antedate SMZL/SLLU, most cases remain stable over time. These cases, not readily classifiable within the World Heath Organization classification, raise the possibility that CBL-MZ should be considered as a new provisional entity within the spectrum of clonal MZ disorders.
Asunto(s)
Linfocitos B/patología , Linaje de la Célula/inmunología , Linfocitosis/patología , Linfoma de Células B de la Zona Marginal/patología , Adulto , Anciano , Anciano de 80 o más Años , Linaje de la Célula/genética , Bandeo Cromosómico , Células Clonales/patología , Progresión de la Enfermedad , Femenino , Citometría de Flujo , Estudios de Seguimiento , Reordenamiento Génico de Cadena Pesada de Linfocito B/genética , Reordenamiento Génico de Cadena Pesada de Linfocito B/inmunología , Humanos , Inmunofenotipificación , Linfocitosis/clasificación , Linfocitosis/genética , Linfoma de Células B de la Zona Marginal/clasificación , Linfoma de Células B de la Zona Marginal/genética , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of primary cutaneous T-cell lymphoproliferative processes, mainly composed of mycosis fungoides and Sézary syndrome, the aggressive forms of which lack an effective treatment. The molecular pathogenesis of CTCL is largely unknown, although neoplastic cells show increased signaling from T-cell receptors (TCRs). DNAs from 11 patients with CTCL, both normal and tumoral, were target-enriched and sequenced by massive parallel sequencing for a selection of 524 TCR-signaling-related genes. Identified variants were validated by capillary sequencing. Multiple mutations were found that affected several signaling pathways, such as TCRs, nuclear factor κB, or Janus kinase/signal transducer and activator of transcription, but PLCG1 was found to be mutated in 3 samples, 2 of which featured a redundant mutation (c.1034T>C, S345F) in exon 11 that affects the PLCx protein catalytic domain. This mutation was further analyzed by quantitative polymerase chain reaction genotyping in a new cohort of 42 patients with CTCL, where it was found in 19% of samples. Immunohistochemical analysis for nuclear factor of activated T cells (NFAT) showed that PLCG1-mutated cases exhibited strong NFAT nuclear immunostaining. Functional studies demonstrated that PLCG1 mutants elicited increased downstream signaling toward NFAT activation, and inhibition of this pathway resulted in reduced CTCL cell proliferation and cell viability. Thus, increased proliferative and survival mechanisms in CTCL may partially depend on the acquisition of somatic mutations in PLCG1 and other genes that are essential for normal T-cell differentiation.
Asunto(s)
Linfoma de Células T/genética , Mutación , Fosfolipasa C gamma/genética , Neoplasias Cutáneas/genética , Animales , Línea Celular Tumoral , Supervivencia Celular/genética , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Linfoma de Células T/patología , Masculino , Ratones , Células 3T3 NIH , Neoplasias Cutáneas/patologíaRESUMEN
Richter syndrome (RS) occurs in up to 15% of patients with chronic lymphocytic leukemia (CLL). Although RS, usually represented by the histologic transformation to a diffuse large B-cell lymphoma (DLBCL), is associated with a very poor outcome, especially when clonally related to the preexisting CLL, the mechanisms leading to RS have not been clarified. To better understand the pathogenesis of RS, we analyzed a series of cases including 59 RS, 28 CLL phase of RS, 315 CLL, and 127 de novo DLBCL. RS demonstrated a genomic complexity intermediate between CLL and DLBCL. Cell-cycle deregulation via inactivation of TP53 and of CDKN2A was a main mechanism in the histologic transformation from CLL phase, being present in approximately one half of the cases, and affected the outcome of the RS patients. A second major subgroup was characterized by the presence of trisomy 12 and comprised one third of the cases. Although RS shared some of the lesions seen in de novo DLBCL, its genomic profile was clearly separate. The CLL phase preceding RS had not a generalized increase in genomic complexity compared with untransformed CLL, but it presented clear differences in the frequency of specific genetic lesions.
Asunto(s)
Transformación Celular Neoplásica/genética , Regulación Leucémica de la Expresión Génica/genética , Leucemia Linfocítica Crónica de Células B/genética , Linfoma de Células B Grandes Difuso/genética , Cromosomas Humanos Par 12/genética , Progresión de la Enfermedad , Femenino , Genes p16/fisiología , Estudio de Asociación del Genoma Completo , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Trisomía/genética , Proteína p53 Supresora de Tumor/genéticaAsunto(s)
Ciclina D3/genética , Ciclina D3/metabolismo , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Mutación , Neoplasias del Bazo/genética , Neoplasias del Bazo/metabolismo , Expresión Génica , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Linfoma de Células B/patología , Neoplasias del Bazo/patologíaRESUMEN
Deregulated signalling through phosphatidylinositol 3-kinase (PI3K) pathway plays a critical role in tumour initiation and progression. We have already shown that AKT is activated in skin lesions in Mycosis Fungoides (MF) and we herein further investigate the frequency and clinical significance of PTEN and PI3K at the protein and at the DNA level as well as the presence of AKT1 mutations in skin lesions from 50 patients with MF clinical stages I-IV in relation to clinicopathological features. Increased p-AKT expression correlated with poor prognosis in plaques (P = 0.0198), whereas p-AKT was an independent predictor of poor survival in the entire cohort (P = 0.017, HR = 1.012). PTEN cytoplasmic expression was found low or absent in all 77.3% of cases and inversely correlated with advanced clinical stages (P = 0.0744). Molecular analysis showed no AKT1 mutation, no PI3KCA copy number gain, only 1 case with PI3KCA mutation in exon 9 and 3 cases with PTEN mutations (7%) in exons 7, 8 and 5. The latter correlated with disease (P = 0.0253) and progression (P < 0.0001) free survival in tumour stage. Although activation of PI3K/AKT signalling pathway due to PTEN alterations is rarely attributed to abnormalities in PTEN, PI3K, and AKT1 genes, PTEN mutations exert a negative effect on patients' prognosis with tumours.
Asunto(s)
Micosis Fungoide/genética , Micosis Fungoide/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasa/genética , Fosfatidilinositol 3-Quinasa/metabolismo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Análisis Mutacional de ADN , Humanos , Inmunohistoquímica , Mutación , Proteínas Nucleares/genética , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Treatment of splenic marginal zone lymphoma (SMZL) patients is not standardized. Recent data suggest that rituximab is highly effective and could be considered as initial therapy. AIM: To assess the efficacy of rituximab monotherapy in a large series of patients with SMZL and compare these results with splenectomy results. METHODS: The studied population included 85 patients. Fifty-eight received rituximab at a dose of 375 mg/m2 per week for 6 weeks as induction followed by maintenance at the same dose every 2 months for 1-2 years, whereas 27 patients were treated using splenectomy only. RESULTS: The overall response rate to rituximab 2 months after the end of induction was 95% (complete response [CR], 45%; unconfirmed CR, 26%; partial response, 24%). The median times to hematologic and clinical response were 2 weeks and 3 weeks, respectively. Forty-three of 55 patients already completed the maintenance phase: 28 sustained their initial response, 14 improved their response, and one progressed. Eighty-five percent of splenectomized patients responded, and two were treated with rituximab as consolidation after splenectomy and achieved a CR. The 5-year overall and progression-free survival (PFS) rates for rituximab-treated and splenectomized patients were 92% and 77% (p = .09) and 73% and 58% (p = .06), respectively. Furthermore, maintenance therapy with rituximab resulted in a longer duration of response (at 5 years, PFS was 84% for patients receiving maintenance and 36% for patients without maintenance, p <.0001). CONCLUSIONS: Rituximab is a very effective and well-tolerated therapy and may be substituted for splenectomy as the first-line treatment of choice for patients with SMZL.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antineoplásicos/uso terapéutico , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Linfoma de Células B de la Zona Marginal/cirugía , Esplenectomía/métodos , Neoplasias del Bazo/tratamiento farmacológico , Neoplasias del Bazo/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Antineoplásicos/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Linfoma de Células B de la Zona Marginal/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Rituximab , Esplenectomía/efectos adversos , Neoplasias del Bazo/patología , Resultado del TratamientoRESUMEN
We examined 807 productive IGHV-IGHD-IGHJ gene rearrangements from mantle cell lymphoma (MCL) cases, by far the largest series to date. The IGHV gene repertoire was remarkably biased, with IGHV3-21, IGHV4-34, IGHV1-8, and IGHV3-23 accounting for 46.3% of the cohort. Eighty-four of 807 (10.4%) cases, mainly using the IGHV3-21 and IGHV4-34 genes, were found to bear stereotyped heavy complementarity-determining region 3 (VH CDR3) sequences and were placed in 38 clusters. Notably, the MCL stereotypes were distinct from those reported for chronic lymphocytic leukemia. Based on somatic hypermutation (SHM) status, 238/807 sequences (29.5%) carried IGHV genes with 100% germ line identity; the remainder (569/807; 70.5%) exhibited different SHM impact, ranging from minimal (in most cases) to pronounced. Shared replacement mutations across the IGHV gene were identified for certain subgroups, especially those using IGHV3-21, IGHV1-8, and IGHV3-23. Comparison with other entities, in particular CLL, revealed that several of these mutations were "MCL-biased." In conclusion, MCL is characterized by a highly restricted immunoglobulin gene repertoire with stereotyped VH CDR3s and very precise SHM targeting, strongly implying a role for antigen-driven selection of the clonogenic progenitors. Hence, an antigen-driven origin of MCL could be envisaged, at least for subsets of cases.
Asunto(s)
Epítopos/genética , Reordenamiento Génico de Cadena Pesada de Linfocito B , Inmunogenética , Linfoma de Células del Manto/etiología , Linfoma de Células del Manto/inmunología , Secuencia de Aminoácidos , Análisis por Conglomerados , Estudios de Cohortes , Epítopos/fisiología , Reordenamiento Génico de Cadena Pesada de Linfocito B/genética , Reordenamiento Génico de Cadena Pesada de Linfocito B/fisiología , Genes de Inmunoglobulinas/genética , Genes de Inmunoglobulinas/fisiología , Humanos , Inmunogenética/métodos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Linfoma de Células del Manto/genética , Datos de Secuencia MolecularRESUMEN
Richter syndrome (RS) represents the development of diffuse large B-cell lymphoma in the context of chronic lymphocytic leukemia. The scarcity of biologic information about RS has hampered the identification of molecular predictors of RS outcome. We addressed this issue by performing a comprehensive molecular characterization of 86 pathologically proven RS. TP53 disruption (47.1%) and c-MYC abnormalities (26.2%) were the most frequent alterations, whereas common genetic lesions of de novo diffuse large B-cell lymphoma were rare or absent. By multivariate analysis, lack of TP53 disruption (hazard ratio, 0.43; P = .003) translated into significant survival advantage with 57% reduction in risk of death. An algorithm based on TP53 disruption, response to RS treatment, and Eastern Cooperative Oncology Group performance status had 80.9% probability of correctly discriminating RS survival (c-index = .809). RS that were clonally unrelated to the paired chronic lymphocytic leukemia phase were clinically and biologically different from clonally related RS because of significantly longer survival (median, 62.5 months vs 14.2 months; P = .017) and lower prevalence of TP53 disruption (23.1% vs 60.0%; P = .018) and B-cell receptor stereotypy (7.6% vs 50.0%; P = .009). The molecular dissection of RS into biologically distinct categories highlights the genetic heterogeneity of this disorder and provides clinically relevant information for refining the prognostic stratification of patients.
Asunto(s)
Transformación Celular Neoplásica/genética , Heterogeneidad Genética , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Estudios de Cohortes , Femenino , Genes p53/genética , Humanos , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/diagnóstico , Masculino , Persona de Mediana Edad , Técnicas de Diagnóstico Molecular , Estudios Multicéntricos como Asunto , Mutación/fisiología , Pronóstico , Análisis de SupervivenciaRESUMEN
BACKGROUND: Although the expression pattern of phosphorylated (p)-mTOR pathway components has attracted scientific interest in several neoplasms, to our knowledge, there is no published information regarding its significance in mycosis fungoides (MF). OBJECTIVE: We sought to perform a comprehensive simultaneous assessment of key members of AKT/mTOR pathway along with p-extracellular signal-regulated kinase (ERK), NOTCH1, and p-STAT3 in patients with MF. METHODS: In all, 54 skin biopsy specimens (21 tumors, 30 plaques, and 3 folliculotropic MF) from 50 patients with MF were analyzed immunohistochemically for p-mTOR, its upstream p-AKT, its downstream effectors p-p70S6K and p-4E-BP1, and for p-ERK1/2, NOTCH1, and p-STAT3. RESULTS: p-mTOR was coexpressed with p-p70S6K in 67.3% of lesions, but coexpression with other molecules was less common. p-p70S6K and marginally NOTCH1 displayed higher H-scores in tumors than in plaques. Significant correlations were recorded between p-ERK and p-4E-BP1, as well as between NOTCH1 and p-p70S6K or p-4E-BP1. NOTCH1, p-4E-BP1, and p-p70S6K expression were associated with advanced stage. In survival analysis simultaneous overexpression of p-AKT and p-p70S6K, along with p-4E-BP1 positivity, adversely affected cancer-specific, disease-free, and progression-free survival in advanced-stage cases. LIMITATIONS: A limitation may be the small number of cases included in our investigation, precluding multivariate survival analysis. CONCLUSIONS: Activation of AKT/mTOR pathway in MF appears to be correlated with NOTCH1, p-ERK, and p-STAT3 and is implicated in the acquisition of a more aggressive phenotype. The combination of p-AKT, p-p70S6K, and p-4E-BP1 emerges as a significant potential prognostic marker in patients with advanced stage.
Asunto(s)
Micosis Fungoide/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT3/metabolismo , Neoplasias Cutáneas/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de Ciclo Celular , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Sistema de Señalización de MAP Quinasas , Masculino , Persona de Mediana Edad , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosfoproteínas/metabolismo , Fosforilación , Receptor Notch1/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Adulto JovenRESUMEN
We conducted a retrospective collaborative study to cytogenetically characterize splenic marginal zone lymphoma (SMZL) and ascertain the prognostic value of chromosomal aberrations. Of 330 cases, 72% displayed an aberrant karyotype, 53% were complex, and 29% had a single aberration. The predominant aberrations were gains of 3/3q and 12q, deletions of 7q and 6q and translocations involving 8q/1q/14q. CD5 expression was detected in 39 of 158 cases (25%). The cytogenetic makeup of the CD5(+) group differed significantly from that of the CD5(-) group. Cases with unmutated IGHV were significantly associated with deletions of 7q and TP53. A strong association was noted between usage of the IGVH1-2 and deletion 7q, 14q alterations, and abnormal karyotype. On univariate analysis, patients with more than or equal to 2 aberrations, 14q alterations, and TP53 deletions had the shortest survival; 7q deletion did not affect survival. On multivariate analysis, cytogenetic aberrations did not retain prognostic significance; the parameters negatively affecting survival were hemoglobin and age. In conclusion, the cytogenetic profile of SMZL is distinct from other B-cell lymphomas. Complexity of the karyotype, 14q aberrations, and TP53 deletions are poor prognostic indicators and may be considered together with other clinicobiologic parameters to ascertain the prognosis of SMZL.
Asunto(s)
Aberraciones Cromosómicas , Linfoma de Células B de la Zona Marginal/genética , Neoplasias del Bazo/genética , Adulto , Anciano , Anciano de 80 o más Años , ADN de Neoplasias/genética , Femenino , Genes p53 , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Hibridación Fluorescente in Situ , Cariotipificación , Linfoma de Células B de la Zona Marginal/patología , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Pronóstico , Estudios Retrospectivos , Neoplasias del Bazo/patología , Tasa de SupervivenciaRESUMEN
Herein is reported the case of a mantle cell lymphoma (MCL) with synchronous double intestinal location. A 74-year old male presented with mild abdominal pain. CT scan imaging indicated invasion of lateral intestinal cavity by large mass formation. Exploratory laparotomy was performed and two solid extra-mural masses were isolated and excised. Histology revealed non-polypoid double synchronous lymphoma of mantle cell origin, an unusual presentation of the disease.
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Neoplasias Intestinales/complicaciones , Intestino Delgado/patología , Linfoma de Células del Manto/complicaciones , Anciano , Humanos , Neoplasias Intestinales/patología , Neoplasias Intestinales/cirugía , Intestino Delgado/cirugía , Linfoma de Células del Manto/patología , Linfoma de Células del Manto/cirugía , Masculino , Pronóstico , Tomografía Computarizada por Rayos XRESUMEN
Immunoglobulin kappa gene usage and somatic mutation patterns were studied in a series of 47 IGKV-J rearrangements amplified in 42 follicular lymphoma (FL) cases. The IGKV1-39/1D-39 gene predominated and was significantly over-represented compared to normal cells, autoreactive cells or other B cell lymphomas. The impact of somatic hypermutation varied significantly; nevertheless, mutation distribution patterns indicated pressure for preservation of the B cell receptor. In conclusion, the present series demonstrates biased usage of IGKV genes in FL and alludes to the important role of immunoglobulin kappa light chains in antigen selection of the clonogenic B cells in FL.
Asunto(s)
Cadenas kappa de Inmunoglobulina/genética , Linfoma Folicular/genética , Hipermutación Somática de Inmunoglobulina , Linfocitos B/inmunología , Células Clonales , Reordenamiento Génico , Humanos , Linfoma Folicular/patología , Receptores de Antígenos de Linfocitos B/genéticaRESUMEN
Splenic marginal zone lymphoma (SMZL) is a rare indolent lymphoma subtype which accounts for less than 1% of all non-Hodgkin's lymphomas. We here report a unique case of IgD-only SMZL with mutated immunoglobulin variable region genes and discuss possible ontogenetic derivation.
Asunto(s)
Genes de Inmunoglobulinas , Inmunoglobulina D/metabolismo , Región Variable de Inmunoglobulina/genética , Neoplasias del Bazo/genética , Anciano , Femenino , Humanos , Inmunohistoquímica , Linfoma de Células B de la Zona Marginal , MutaciónRESUMEN
We analyzed 42 splenic marginal-zone lymphoma (SMZL) cases diagnosed on splenectomy specimens after established World Health Organization criteria. A predominantly nodular growth pattern was observed in 24 cases; the remainder showed predominantly (11/42) or exclusively (7/42) diffuse infiltration. Twenty-one cases showed the "classic" biphasic appearance; 13 cases exhibited marginal-zone morphology; finally, 8 cases were composed predominantly of small cells. CD21 and CD35 were expressed by 12/42 and 17/38 cases, respectively. DBA.44 was detected in 24/42 cases. Seventeen of 37 cases were surface IgD (SIgD)-positive. Twenty-one of 22 analyzed cases were SIgM-positive (12/21 coexpressed SIgD). Five of 37 cases were SIgG-positive. CD27 staining was observed in 21/35 cases; 7/18 CD27-positive cases coexpressed SIgD; 7/14 CD27-negative cases were SIgD-positive. Forty IGHV-D-J rearrangements were amplified in 34/42 cases: the IGHV4-34 gene predominated, followed by IGHV1-2. Using the 98% homology cut-off, 25/40 (62.5%) IGHV sequences were considered as "mutated": 10/11 cases with monomorphous, marginal-zone morphology were IGHV-mutated; in contrast, 4/6 cases with monomorphous, small-cell morphology were IGHV-unmutated. Five of 7 cases expressing IGHV1 subgroup genes had biphasic morphology, whereas 6/9 IGHV3-expressing cases had monomorphous, marginal-zone morphology. Most IGHV-mutated cases (14/20; 70%) were SIgD-negative; in contrast, 8/11 IGHV-unmutated cases expressed SIgD. CD27 was detected in 10/17 IGHV-mutated and 6/10 IGHV-unmutated cases. Seven of 11 CD27-negative cases were IGHV-mutated; 5/7 CD27-negative/IGHV-mutated cases expressed DBA.44. These results confirm the considerable histologic, immunohistochemical, and molecular heterogeneity of SMZL and indicate an origin from the diverse resident B-cell populations of the normal SMZ.