Biomedical subjects

Manuela Mollejo

Publications and source records attributed to Manuela Mollejo.

18 recordsLinked to original sources

PubMed2006

Identification of novel candidate target genes in amplicons of Glioblastoma multiforme tumors detected by expression and CGH microarray profiling.

BACKGROUND: Conventional cytogenetic and comparative genomic hybridization (CGH) studies in brain malignancies have shown that glioblastoma multiforme (GBM) is characterized by complex structural and numerical alterations. However, the limited resolution of these techniques has precluded the precise identification of detailed specific gene copy number alterations. RESULTS: We performed a genome-wide survey of gene copy number changes in 20 primary GBMs by CGH on cDNA microarrays. A novel amplicon at 4p15, and previously uncharacterized amplicons at 13q32-34 and 1q32 were detected and are analyzed here. These amplicons contained amplified genes not previously reported. Other amplified regions containing well-known oncogenes in GBMs were also detected at 7p12 (EGFR), 7q21 (CDK6), 4q12 (PDGFRA), and 12q13-15 (MDM2 and CDK4). In order to identify the putative target genes of the amplifications, and to determine the changes in gene expression levels associated with copy number change events, we carried out parallel gene expression profiling analyses using the same cDNA microarrays. We detected overexpression of the novel amplified genes SLA/LP and STIM2 (4p15), and TNFSF13B and COL4A2 (13q32-34). Some of the candidate target genes of amplification (EGFR, CDK6, MDM2, CDK4, and TNFSF13B) were tested in an independent set of 111 primary GBMs by using FISH and immunohistological assays. The novel candidate 13q-amplification target TNFSF13B was amplified in 8% of the tumors, and showed protein expression in 20% of the GBMs. CONCLUSION: This high-resolution analysis allowed us to propose novel candidate target genes such as STIM2 at 4p15, and TNFSF13B or COL4A2 at 13q32-34 that could potentially contribute to the pathogenesis of these tumors and which would require futher investigations. We showed that overexpression of the amplified genes could be attributable to gene dosage and speculate that deregulation of those genes could be important in the development and progression of GBM. Our findings highlight the important influence in GBM of signaling pathways such as the PI3K/AKT, consistent with the invasive features of this tumor.

Adult↗

PubMed2006

BCR gene disruption in a pilomyxoid astrocytoma.

We report here a 4-month-old child with a large, solid enhancing mass involving predominantly the suprasellar and diencephalic regions, with extension of both hemispheres. The patient underwent partial resection of the mass by right temporal craniotomy. Histological diagnosis was of a low-grade glioma consistent with pilomyxoid astrocytoma. Cytogenetic analyses revealed an insertion on chromosome 17 that involved disruption of the BCR gene. This finding suggests a possible rearrangement of this gene that could act in a similar way to chronic myeloid leukemia with formation of a chimeric tyrosine kinase protein. This study may suggest the use of inhibitors of tyrosine kinase proteins as an alternative treatment approach in cases of refractory or disseminated pilocytic astrocytomas.

Astrocytoma↗

PubMed2005

Splenic marginal zone lymphoma: proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis.

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.

Biomarkers, Tumor↗

PubMed2005

Expression of the NF-kappaB targets BCL2 and BIRC5/Survivin characterizes small B-cell and aggressive B-cell lymphomas, respectively.

Nuclear factor kappa B (NF-kappaB) activation has been proposed as a cardinal feature of tumourigenesis, although the precise mechanism, frequency, relevance, and extent of NF-kappaB activation in lymphomas remain to be fully elucidated. In this study, expression profiling and tissue microarray studies of 209 and 323 non-Hodgkin's lymphomas (NHLs) respectively, including the most frequent sub-types of NHL, were employed to generate a hypothesis concerning the most common NF-kappaB targets in NHL. These analyses showed that NF-kappaB activation is a common phenomenon in NHL, resulting in the expression of distinct sets of NF-kappaB target genes, depending on the cell context. BCL2 and BIRC5/Survivin were identified as key NF-kappaB targets and their expression distinguished small and aggressive B-cell lymphomas, respectively. Interestingly, in the vast majority of B-cell lymphomas, the expression of these markers was mutually exclusive. A set of genes was identified whose expression correlates either with BIRC5/Survivin or with BCL2. BIRC5/Survivin expression, in contrast to BCL2, was associated with a signature of cell proliferation (overexpression of cell cycle control, DNA repair, and polymerase genes), which may contribute to the aggressive phenotype and poor prognosis of these lymphomas. Strikingly, mantle cell lymphoma and chronic lymphocytic leukaemia expressed highly elevated levels of BCL2 protein and mRNA, higher than that observed in reactive mantle zone cells or even in follicular lymphomas, where BCL2 expression is deregulated through the t(14;18) translocation. In parallel with this observation, BIRC5/Survivin expression was higher in Burkitt's lymphoma and diffuse large B-cell lymphoma than in non-tumoural germinal centre cells. In vitro studies confirmed that NF-kappaB activation contributes to the expression of both markers. In cell lines representing aggressive lymphomas, NF-kappaB inhibition resulted in a decrease in BIRC5/Survivin expression. Meanwhile, in chronic lymphocytic leukaemia (CLL)-derived lymphocytes, NF-kappaB inhibition resulted in a marked decrease in BCL2 expression.

Gene Expression Profiling↗

PubMed2004

Variability in the degree of expression of phosphorylated IkappaBalpha in chronic lymphocytic leukemia cases with nodal involvement.

PURPOSE: Based on previous preliminary observations, we hypothesize that the molecular and clinical variability of chronic lymphocytic leukemia (CLL) reflects differences in the degree of nuclear factor (NF)-kappaB activation, as determined by the expression of phosphorylated IkappaBalpha (p-IkappaBalpha). EXPERIMENTAL DESIGN: The expression profile (mRNA and protein expression) was analyzed with the Centro Nacional de Investigaciones Oncologicas Oncochip, a cDNA microarray containing 6386 cancer-related genes, and a tissue microarray (TMA). The results were correlated with the IgV(H) mutational status, ZAP-70 expression, cytogenetic alterations, and clinical outcome. RESULTS: We found correlations between the presence of p-IkappaBalpha, a surrogate marker of NF-kappaB activation, and changes in the expression profile (mRNA and protein expression) and clinical outcome in a series of CLL cases with lymph node involvement. Activation of NF-kappaB, as determined by the expression of p-IkappaBalpha, was associated with the expression of a set of genes comprising key genes involved in the control of B-cell receptor signaling, signal transduction, and apoptosis, including SYK, LYN, BCL2, CCR7, BTK, PIK3CD, and others. Cases with increased expression of p-IkappaBalpha showed longer overall survival than cases with lower expression. A Cox regression model was derived to estimate some parameters of prognostic interest: IgV(H) mutational status, ZAP-70, and p-IkappaBalpha expression. The multivariate analysis disclosed p-IkappaBalpha and ZAP-70 expression as independent prognostic factors of survival. CONCLUSIONS: A variable degree of activation of NF-kappaB, as determined by the expression of p-IkappaBalpha, is an identifiable event in CLL, and is correlated with changes in the expression profile and overall survival.

Adult↗

PubMed2004

Expression profiling of T-cell lymphomas differentiates peripheral and lymphoblastic lymphomas and defines survival related genes.

PURPOSE: T-Cell lymphomas constitute heterogeneous and aggressive tumors in which pathogenic alterations remain largely unknown. Expression profiling has demonstrated to be a useful tool for molecular classification of tumors. EXPERIMENTAL DESIGN: Using DNA microarrays (CNIO-OncoChip) containing 6386 cancer-related genes, we established the expression profiling of T-cell lymphomas and compared them to normal lymphocytes and lymph nodes. RESULTS: We found significant differences between the peripheral and lymphoblastic T-cell lymphomas, which include a deregulation of nuclear factor-kappaB signaling pathway. We also identify differentially expressed genes between peripheral T-cell lymphoma tumors and normal T lymphocytes or reactive lymph nodes, which could represent candidate tumor markers of these lymphomas. Additionally, a close relationship between genes associated to survival and those that differentiate among the stages of disease and responses to therapy was found. CONCLUSIONS: Our results reflect the value of gene expression profiling to gain insight about the molecular alterations involved in the pathogenesis of T-cell lymphomas.

Cell Survival↗

PubMed2004

Building an outcome predictor model for diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) patients are treated using relatively homogeneous protocols, irrespective of their biological and clinical variability. Here we have developed a protein-expression-based outcome predictor for DLBCL. Using tissue microarrays (TMAs), we have analyzed the expression of 52 selected molecules in a series of 152 DLBCLs. The study yielded relevant information concerning key biological aspects of this tumor, such as cell-cycle control and apoptosis. A biological predictor was built with a training group of 103 patients, and was validated with a blind set of 49 patients. The predictive model with 8 markers can identify the probability of failure for a given patient with 78% accuracy. After stratifying patients according to the predicted response under the logistic model, 92.3% patients below the 25 percentile were accurately predicted by this biological score as "failure-free" while 96.2% of those above the 75 percentile were correctly predicted as belonging to the "fatal or refractory disease" group. Combining this biological score and the International Prognostic Index (IPI) improves the capacity for predicting failure and survival. This predictor was then validated in the independent group. The protein-expression-based score complements the information obtained from the use of the IPI, allowing patients to be assigned to different risk categories.

Adolescent↗

PubMed2004

Aberrant Bcl6 protein expression in mantle cell lymphoma.

Mantle cell lymphoma is routinely considered as a Bcl6-negative B-cell lymphoma carrying the translocation t(11;14). Here we describe a series of five Bcl6-positive mantle cell lymphoma cases, including three classic and two blastoid variants. The proliferative index of these cases, measured with the Ki-67 antibody, was slightly higher than in Bcl6-negative mantle cell lymphoma cases (32.2 vs. 23.7%) Bcl6 expression was associated with translocations involving 3q27 in four of the five cases and an extra copy of the BCL6 gene in the fifth. A mutational study of the major mutational cluster in the BCL6 gene revealed no increased mutation rate, except in one case. One of the three cases displayed a high mutational index in the IgVH gene, suggesting exposure to a germinal center microenvironment. Chromosomal alterations involving 3q27 seem to be responsible for this increased Bcl6 expression, which needs to be considered when Bcl6 is used in lymphoma diagnosis.

Aged↗

PubMed2003

The molecular signature of mantle cell lymphoma reveals multiple signals favoring cell survival.

Mantle cell lymphoma (MCL) is a prototypical neoplastic disease in which a common cytogenetic alteration, t11;14, leading to cyclin D1 overexpression, is associated with other changes that need to be considered in an explanation of the clinical, morphological, and molecular variability of this disease. Using a cDNA microarray (Oncochip-CNIO) containing clones for 6386 cancer-related genes, we have analyzed the expression profiles of a series of 38 cases. After normalization with the expression profiling of sorted mantle zone lymphocytes, we have related the findings to conventional clinical and molecular variables, including immunoglobulin variable heavy chain somatic mutation, blastoid cytology, increased proliferation, and long-term survival. MCL signature (446 genes) includes genes involved in apoptosis, cell cycle, signal transduction, and cell structure. Especially striking was the presence of multiple concurrent alterations in the tumor necrosis factor and nuclear factor kappaB pathway, and the overexpression of IL10R and SPARC genes. We also identified a molecular signature for the presence of immunoglobulin variable heavy chain somatic mutation, which includes a number of genes potentially relevant in cancer (CDC14A, ras, and others). Signatures for proliferation and blastoid cytology were also found. An integrated analysis of these data yields a gene-expression based survival predictor (26 genes grouped into two clusters), which distinguishes half of the patients with a survival probability of 52% at 5 years. The predictive model has been confirmed by cross-validation. In conclusion, MCL seems to combine a disease-specific signature and different sets of genes of which the expression is associated with key clinical, molecular, and immunophenotypical events.

Adult↗

PubMed2003

Molecular heterogeneity in MCL defined by the use of specific VH genes and the frequency of somatic mutations.

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.

Adult↗

PubMed2003

Nodal marginal zone lymphoma: a heterogeneous tumor: a comprehensive analysis of a series of 27 cases.

We have reviewed the clinical, morphologic, immunophenotypical, and molecular features of a series of 27 cases of nodal marginal zone lymphoma with the aim of defining this entity more precisely. The series was characterized by a relatively favorable clinical course, with a low clinical stage at diagnosis (59% patients with clinical stage I-II) and a 5-year overall survival probability of 79%. However, the disease persisted in a relatively large fraction of the patients, thus yielding a 5-year failure-free survival probability of 22%. Molecular and immunohistochemical analyses of the series revealed heterogeneity in the frequency of IgV(H) somatic mutation and in the expression of IgD, CD43, MUM1, and CD38. Apart from the absence of nuclear Bcl10, no clear distinction could be made from the expression profiling of other B-cell lymphomas claimed to be derived from marginal zone B cells. Additionally, the immunophenotype of the tumoral cells in all cases but one differed from that described in monocytoid B cells. It was characterized by a Bcl2-, p21+, cyclin E+ profile. The analysis of apoptosis-regulator proteins disclosed abnormalities in the expression of survivin and active caspase 3, which could partially explain the abnormal regulation of apoptosis observed in these tumors. Molecular and immunohistochemical data obtained in this study strongly imply that there is significant heterogeneity among the cases included in the category termed nodal marginal zone lymphoma.

Adult↗

PubMed2003

Large B-cell lymphoma presenting in the spleen: identification of different clinicopathologic conditions.

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.

Adult↗

PubMed2003

Development of a real-time reverse transcription polymerase chain reaction assay for c-myc expression that allows the identification of a subset of c-myc+ diffuse large B-cell lymphoma.

Absence of a reliable method for determining the level of c-myc expression has impeded the analysis of its biological and clinical relevance in tumors. We have standardized the conditions for a real-time reverse transcription polymerase chain reaction analysis for c-myc expression, including the selection of an endogenous reference (18S rRNA), the adequate number of measurements for each sample (2 cDNA in triplicate), and suitable controls for determining inter- and intrarun variability (standard curve and calibrator). Subsequently, in a series of 56 non-Hodgkin's lymphomas, we analyzed the expression of c-myc mRNA, using real-time reverse transcription polymerase chain reaction, and of other functionally related proteins (bcl-6, p27, cyclin D3, and p53). As expected, all eight Burkitt's lymphoma cases analyzed had high levels of c-myc mRNA expression compared with that observed in reactive lymphoid tissue. There was a wider range of expression in diffuse large B-cell lymphoma, with 30% (15 of 48) of cases overexpressing c-myc. This overexpression was largely independent of c-myc translocations (4 of 5), as demonstrated by fluorescence in situ hybridization. In this large B-cell lymphoma series, a high level of c-myc expression predicted lower survival probability, irrespectively of the International Prognostic Index risk group classification. A slightly increased frequency of p53 inactivation was observed in the cases with c-myc overexpression, which suggests a growth advantage in lymphomas with concurrent deregulation of c-myc and p53. In addition, a moderate increase in bcl-6 protein expression was observed in the c-myc-positive cases, suggesting the existence of a complex interrelationship between these two genes. These findings suggest that c-myc may play a relevant role in the pathogenesis of a subset of large B-cell lymphoma and suggest the existence of additional regulatory mechanisms of c-myc expression to c-myc rearrangements.

B-Lymphocytes↗

PubMed2002

Hodgkin and Reed-Sternberg cells harbor alterations in the major tumor suppressor pathways and cell-cycle checkpoints: analyses using tissue microarrays.

Tumoral cells in Hodgkin lymphoma (HL) display an increased growth fraction and diminished apoptosis, implying a profound disturbance of the cell cycle and apoptosis regulation. However, limitations of molecular techniques have prevented the analysis of the tumor suppressor pathways and cell-cycle checkpoints. Tissue microarray (TMA) is a powerful tool for analyzing a large number of molecular variables in a large series of tumors, although the feasibility of this technique has not yet been demonstrated in heterogeneous tumors. The expression of 29 genes regulating the cell cycle and apoptosis were analyzed by immunohistochemistry and in situ hybridization in 288 HL biopsies using TMA. The sensitivity of the technique was validated by comparing the results with those obtained in standard tissue sections. The results revealed multiple alterations in different pathways and checkpoints, including G1/S and G2/M transition and apoptosis. Striking findings were the overexpression of cyclin E, CDK2, CDK6, STAT3, Hdm2, Bcl2, Bcl-X(L), survivin, and NF-kappaB proteins. A multiparametric analysis identified proteins associated with increased growth fraction (Hdm2, p53, p21, Rb, cyclins A, B1, D3, and E, CDK2, CDK6, SKP2, Bcl-X(L), survivin, STAT1, and STAT3), and proteins associated with apoptosis (NF-kappaB, STAT1, and RB). The analysis also demonstrated that Epstein-Barr virus (EBV)-positive cases displayed a characteristic profile, confirming the pathogenic role of EBV in HL. Survival probability depends on multiple biologic factors, including overexpression of Bcl2, p53, Bax, Bcl-X(L), MIB1, and apoptotic index. In conclusion, Hodgkin and Reed-Sternberg cells harbor concurrent and overlapping alterations in the major tumor suppressor pathways and cell-cycle checkpoints. This appears to determine the viability of the tumoral cells and the clinical outcome.

Apoptosis↗

PubMed2002

Splenic marginal zone lymphoma: clinical characteristics and prognostic factors in a series of 60 patients.

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.

Adult↗

PubMed2002

Analysis of the IgV(H) somatic mutations in splenic marginal zone lymphoma defines a group of unmutated cases with frequent 7q deletion and adverse clinical course.

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.

Chromosome Deletion↗

PubMed2002

A short mutational hot spot in the first intron of BCL-6 is associated with increased BCL-6 expression and with longer overall survival in large B-cell lymphomas.

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.

DNA-Binding Proteins↗

PubMedDate not supplied

Nodal and splenic marginal zone B cell lymphomas.

Splenic marginal zone lymphoma (SMZL) and nodal marginal zone lymphoma (NMZL) are newly defined, separate clinicopathological entities. Both are rare lymphoma types, with low reproducibility in the diagnosis, although a conjunction of molecular and clinical studies seems to be now facilitating a more accurate diagnosis and understanding of the neoplastic process. SMZL is a disease involving the spleen, bone marrow and peripheral blood since the initial manifestations of the disease. The diagnosis has been until very recently based on the pathological study of the spleen with the conjunction of the clinical features, although the integration of the morphology in bone marrow and peripheral blood with the immunophenotype and molecular characteristics of the tumour makes a more accurate diagnosis now possible. The most frequent molecular alteration found in SMZL is allelic loss at the 7q chromosomal region. SMZL is an indolent lymphoma, although there is small subset of patients in which it follows an aggressive course. Molecular studies of SMZL are starting to reveal new diagnostic and prognostic markers, and to identify new potentially useful therapeutic targets. Nodal marginal zone lymphoma is a B-cell neoplasm originated in the lymph node, whose histology resembles the nodal infiltration by MALT- or Splenic-type marginal zone lymphoma, in the absence of clinical evidence of extranodal or spleen disease. The lack of characteristic phenotypic or molecular diagnostic findings is still hampering the reproducibility of this diagnosis. Here we review the main morphological and immunophenotypical markers, discussing the differential with other overlapping entities, singularly follicular lymphoma. Specific therapeutic protocols and prognostic factors are required to more precisely define this tumour.

Biomarkers, Tumor↗