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1.
J Pathol ; 247(4): 416-421, 2019 04.
Article in English | MEDLINE | ID: mdl-30484876

ABSTRACT

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.


Subject(s)
Genes, Immunoglobulin/genetics , Lymphoma, B-Cell, Marginal Zone/genetics , Complementarity Determining Regions/genetics , Gene Rearrangement, B-Lymphocyte/genetics , Genes, Immunoglobulin Heavy Chain/genetics , Humans , Immunoglobulin Variable Region/genetics , Mutation/genetics , Receptors, Antigen, B-Cell/genetics , Tumor Microenvironment
2.
Am J Pathol ; 187(7): 1454-1458, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28457696

ABSTRACT

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.


Subject(s)
Biomarkers, Tumor/genetics , Immunogenetics , Immunoglobulins/genetics , Lymphoma, Mantle-Cell/genetics , Antigens/genetics , Antigens/metabolism , Biomarkers, Tumor/metabolism , Bone Marrow/metabolism , Bone Marrow/pathology , Cohort Studies , Europe , Humans , Immunoglobulins/metabolism , Immunohistochemistry , Immunophenotyping , Lymphoma, Mantle-Cell/immunology , Lymphoma, Mantle-Cell/pathology , Spleen/metabolism , Spleen/pathology , Tumor Necrosis Factor Receptor Superfamily, Member 7/genetics , Tumor Necrosis Factor Receptor Superfamily, Member 7/metabolism
3.
Blood ; 128(23): 2666-2670, 2016 12 08.
Article in English | MEDLINE | ID: mdl-27670424

ABSTRACT

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.


Subject(s)
Biomarkers, Tumor/genetics , Gene Deletion , I-kappa B Proteins/genetics , Lymphoma, B-Cell , Mediastinal Neoplasms , Proto-Oncogene Proteins/genetics , Adolescent , Adult , Aged , Disease-Free Survival , Female , Humans , Lymphoma, B-Cell/genetics , Lymphoma, B-Cell/mortality , Male , Mediastinal Neoplasms/genetics , Mediastinal Neoplasms/mortality , Middle Aged , Survival Rate
4.
Am J Pathol ; 185(6): 1740-8, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25843681

ABSTRACT

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.


Subject(s)
B-Lymphocytes/metabolism , Cytidine Deaminase/metabolism , Immunoglobulin Variable Region , Lymphoma, Mantle-Cell/metabolism , Somatic Hypermutation, Immunoglobulin , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Humans , Lymphoma, Mantle-Cell/immunology , Lymphoma, Mantle-Cell/pathology
5.
Blood ; 123(8): 1199-206, 2014 Feb 20.
Article in English | MEDLINE | ID: mdl-24300853

ABSTRACT

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.


Subject(s)
B-Lymphocytes/pathology , Cell Lineage/immunology , Lymphocytosis/pathology , Lymphoma, B-Cell, Marginal Zone/pathology , Adult , Aged , Aged, 80 and over , Cell Lineage/genetics , Chromosome Banding , Clone Cells/pathology , Disease Progression , Female , Flow Cytometry , Follow-Up Studies , Gene Rearrangement, B-Lymphocyte, Heavy Chain/genetics , Gene Rearrangement, B-Lymphocyte, Heavy Chain/immunology , Humans , Immunophenotyping , Lymphocytosis/classification , Lymphocytosis/genetics , Lymphoma, B-Cell, Marginal Zone/classification , Lymphoma, B-Cell, Marginal Zone/genetics , Male , Middle Aged , Retrospective Studies
6.
Blood ; 123(13): 2034-43, 2014 Mar 27.
Article in English | MEDLINE | ID: mdl-24497536

ABSTRACT

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.


Subject(s)
Lymphoma, T-Cell/genetics , Mutation , Phospholipase C gamma/genetics , Skin Neoplasms/genetics , Animals , Cell Line, Tumor , Cell Survival/genetics , Cohort Studies , DNA Mutational Analysis , Female , High-Throughput Nucleotide Sequencing , Humans , Lymphoma, T-Cell/pathology , Male , Mice , NIH 3T3 Cells , Skin Neoplasms/pathology
7.
Blood ; 122(15): 2673-82, 2013 Oct 10.
Article in English | MEDLINE | ID: mdl-24004666

ABSTRACT

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.


Subject(s)
Cell Transformation, Neoplastic/genetics , Gene Expression Regulation, Leukemic/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Lymphoma, Large B-Cell, Diffuse/genetics , Chromosomes, Human, Pair 12/genetics , Disease Progression , Female , Genes, p16/physiology , Genome-Wide Association Study , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Middle Aged , Trisomy/genetics , Tumor Suppressor Protein p53/genetics
9.
Exp Dermatol ; 23(12): 931-3, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25267489

ABSTRACT

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.


Subject(s)
Mycosis Fungoides/genetics , Mycosis Fungoides/metabolism , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Phosphatidylinositol 3-Kinase/genetics , Phosphatidylinositol 3-Kinase/metabolism , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , DNA Mutational Analysis , Humans , Immunohistochemistry , Mutation , Nuclear Proteins/genetics , Proto-Oncogene Proteins c-akt/genetics , Signal Transduction , Transcription Factors/genetics
10.
Oncologist ; 18(2): 190-7, 2013.
Article in English | MEDLINE | ID: mdl-23345547

ABSTRACT

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.


Subject(s)
Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antineoplastic Agents/therapeutic use , Lymphoma, B-Cell, Marginal Zone/drug therapy , Lymphoma, B-Cell, Marginal Zone/surgery , Splenectomy/methods , Splenic Neoplasms/drug therapy , Splenic Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Murine-Derived/adverse effects , Antineoplastic Agents/adverse effects , Disease-Free Survival , Female , Humans , Lymphoma, B-Cell, Marginal Zone/pathology , Male , Middle Aged , Retrospective Studies , Rituximab , Splenectomy/adverse effects , Splenic Neoplasms/pathology , Treatment Outcome
11.
Blood ; 117(12): 3391-401, 2011 Mar 24.
Article in English | MEDLINE | ID: mdl-21266718

ABSTRACT

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.


Subject(s)
Cell Transformation, Neoplastic/genetics , Genetic Heterogeneity , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/mortality , Adult , Aged , Aged, 80 and over , Algorithms , Cohort Studies , Female , Genes, p53/genetics , Humans , Immunologic Deficiency Syndromes/complications , Immunologic Deficiency Syndromes/diagnosis , Male , Middle Aged , Molecular Diagnostic Techniques , Multicenter Studies as Topic , Mutation/physiology , Prognosis , Survival Analysis
12.
Blood ; 118(11): 3088-95, 2011 Sep 15.
Article in English | MEDLINE | ID: mdl-21791422

ABSTRACT

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.


Subject(s)
Epitopes/genetics , Gene Rearrangement, B-Lymphocyte, Heavy Chain , Immunogenetics , Lymphoma, Mantle-Cell/etiology , Lymphoma, Mantle-Cell/immunology , Amino Acid Sequence , Cluster Analysis , Cohort Studies , Epitopes/physiology , Gene Rearrangement, B-Lymphocyte, Heavy Chain/genetics , Gene Rearrangement, B-Lymphocyte, Heavy Chain/physiology , Genes, Immunoglobulin/genetics , Genes, Immunoglobulin/physiology , Humans , Immunogenetics/methods , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Lymphoma, Mantle-Cell/genetics , Molecular Sequence Data
13.
J Am Acad Dermatol ; 69(3): 375-84, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23685026

ABSTRACT

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.


Subject(s)
Mycosis Fungoides/metabolism , Proto-Oncogene Proteins c-akt/metabolism , STAT3 Transcription Factor/metabolism , Skin Neoplasms/metabolism , TOR Serine-Threonine Kinases/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Adult , Aged , Aged, 80 and over , Cell Cycle Proteins , Disease-Free Survival , Female , Humans , Immunohistochemistry , MAP Kinase Signaling System , Male , Middle Aged , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Phosphoproteins/metabolism , Phosphorylation , Receptor, Notch1/metabolism , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Young Adult
14.
Blood ; 116(9): 1479-88, 2010 Sep 02.
Article in English | MEDLINE | ID: mdl-20479288

ABSTRACT

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.


Subject(s)
Chromosome Aberrations , Lymphoma, B-Cell, Marginal Zone/genetics , Splenic Neoplasms/genetics , Adult , Aged , Aged, 80 and over , DNA, Neoplasm/genetics , Female , Genes, p53 , Humans , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , In Situ Hybridization, Fluorescence , Karyotyping , Lymphoma, B-Cell, Marginal Zone/pathology , Male , Middle Aged , Polymerase Chain Reaction , Prognosis , Retrospective Studies , Splenic Neoplasms/pathology , Survival Rate
15.
World J Surg Oncol ; 8: 69, 2010 Aug 13.
Article in English | MEDLINE | ID: mdl-20707926

ABSTRACT

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.


Subject(s)
Intestinal Neoplasms/complications , Intestine, Small/pathology , Lymphoma, Mantle-Cell/complications , Aged , Humans , Intestinal Neoplasms/pathology , Intestinal Neoplasms/surgery , Intestine, Small/surgery , Lymphoma, Mantle-Cell/pathology , Lymphoma, Mantle-Cell/surgery , Male , Prognosis , Tomography, X-Ray Computed
17.
Blood Cells Mol Dis ; 41(2): 215-8, 2008.
Article in English | MEDLINE | ID: mdl-18640859

ABSTRACT

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.


Subject(s)
Immunoglobulin kappa-Chains/genetics , Lymphoma, Follicular/genetics , Somatic Hypermutation, Immunoglobulin , B-Lymphocytes/immunology , Clone Cells , Gene Rearrangement , Humans , Lymphoma, Follicular/pathology , Receptors, Antigen, B-Cell/genetics
18.
Leuk Res ; 32(1): 155-7, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17420049

ABSTRACT

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.


Subject(s)
Genes, Immunoglobulin , Immunoglobulin D/metabolism , Immunoglobulin Variable Region/genetics , Splenic Neoplasms/genetics , Aged , Female , Humans , Immunohistochemistry , Lymphoma, B-Cell, Marginal Zone , Mutation
19.
Am J Surg Pathol ; 31(3): 438-46, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17325486

ABSTRACT

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.


Subject(s)
Lymphoma/pathology , Spleen/pathology , Splenic Neoplasms/pathology , Biomarkers, Tumor/metabolism , DNA Mutational Analysis , DNA, Neoplasm/analysis , Gene Rearrangement, B-Lymphocyte, Heavy Chain/genetics , Gene Rearrangement, B-Lymphocyte, Light Chain/genetics , Humans , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Light Chains/genetics , Immunophenotyping , Lymphoma/genetics , Lymphoma/metabolism , RNA, Neoplasm/analysis , Splenectomy , Splenic Neoplasms/genetics , Splenic Neoplasms/metabolism
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