ABSTRACT
Background: Peripheral T-cell lymphoma (PTCL) remains a therapeutic challenge. Due to the rarity and the heterogeneity of PTCL, no consensus has been achieved regarding even the type of first-line treatment. The benefit of autologous stem-cell transplantation (ASCT) is, therefore, still intensely debated. Patients and methods: In the absence of randomized trials addressing the role of ASCT, we performed a large multicentric retrospective study and used both a multivariate proportional hazard model and a propensity score matching approach to correct for sample selection bias between patients allocated or not to ASCT in intention-to-treat (ITT). Results: Among 527 patients screened from 14 centers in France, Belgium and Portugal, a final cohort of 269 patients ≤65 years old with PTCL-not otherwise specified (NOS) (N = 78, 29%), angioimmunoblastic T-cell lymphoma (AITL) (N = 123, 46%) and anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK-ALCL) (N = 68, 25%) with partial (N = 52, 19%) or complete responses (N = 217, 81%) after induction was identified and information about treatment allocation was carefully collected before therapy initiation from medical records. One hundred and thirty-four patients were allocated to ASCT in ITT and 135 were not. Neither the Cox multivariate model (HR = 1.02; 95% CI: 0.69-1.50 for PFS and HR = 1.08; 95% CI: 0.68-1.69 for OS) nor the propensity score analysis after stringent matching for potential confounding factors (logrank P = 0.90 and 0.66 for PFS and OS, respectively) found a survival advantage in favor of ASCT as a consolidation procedure for patients in response after induction. Subgroup analyses did not reveal any further difference for patients according to response status, stage disease or risk category. Conclusions: The present data do not support the use of ASCT for up-front consolidation for all patients with PTCL-NOS, AITL, or ALK-ALCL with partial or complete response after induction.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Lymphoma, T-Cell, Peripheral/therapy , Adult , Aged , Combined Modality Therapy , Disease-Free Survival , Female , Humans , Induction Chemotherapy , Lymphoma, T-Cell, Peripheral/mortality , Male , Middle Aged , Progression-Free Survival , Proportional Hazards Models , Retrospective Studies , Transplantation, Autologous , Young AdultABSTRACT
BACKGROUND: Our aim was to evaluate whether the cell of origin (COO) as defined by the Hans algorithm and MYC/BCL2 coexpression, which are the two main biological risk factors in elderly patients treated with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone (R-CHOP), maintain their prognostic value in a large prospective clinical trial. PATIENTS AND METHODS: We evaluated 285 paraffin-embedded samples from patients (60-80 years of age) enrolled in the Lymphoma Study Association trial LNH03-6B who were treated with R-CHOP. We correlated the COO defined by the transcriptome according to the Wright algorithm with that defined by the Hans algorithm in a subset of 62 tumors with available frozen tissue samples. RESULTS: The non-germinal center B-cell-like phenotype according to the Hans algorithm and BCL2 expression (but not MYC and BCL2 coexpression) predicted worse progression-free survival [hazard ratio (HR)=1.78, P = 0.003 and HR = 1.79, P = 0.003, respectively] and overall survival (HR = 1.85, P = 0.005 and HR = 1.67, P = 0.02, respectively) independently of the International Prognostic Index. The correlation between the Hans algorithm and the Wright algorithm was 91%, with an almost perfect concordance according to a kappa test (0.81). CONCLUSIONS: Our results suggest that immunohistochemically defined COO remains a useful tool for predicting prognosis in diffuse large B-cell lymphoma when performed under optimized standardized conditions and that BCL2 expression may help to identify elderly patients at risk for relapse and who could potentially respond to anti-BCL2 targeted agents. In this prospective phase III trial, the coexpression of MYC and BCL2 does not appear to predict worse survival. CLINICAL TRIAL NUMBER: NCT00144755.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Lymphoma, Large B-Cell, Diffuse/drug therapy , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-myc/genetics , Aged , Aged, 80 and over , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antibodies, Monoclonal, Murine-Derived/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor/genetics , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Disease-Free Survival , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Middle Aged , Prednisone/administration & dosage , Prednisone/adverse effects , Prognosis , Risk Factors , Rituximab , Treatment Outcome , Vincristine/administration & dosage , Vincristine/adverse effectsABSTRACT
BACKGROUND: Most peripheral T-cell lymphoma (PTCL) patients have a poor outcome and the identification of prognostic factors at diagnosis is needed. PATIENTS AND METHODS: The prognostic impact of total metabolic tumor volume (TMTV0), measured on baseline [(18)F]2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography, was evaluated in a retrospective study including 108 PTCL patients (27 PTCL not otherwise specified, 43 angioimmunoblastic T-cell lymphomas and 38 anaplastic large-cell lymphomas). All received anthracycline-based chemotherapy. TMTV0 was computed with the 41% maximum standardized uptake value threshold method and an optimal cut-off point for binary outcomes was determined and compared with others prognostic factors. RESULTS: With a median follow-up of 23 months, 2-year progression-free survival (PFS) was 49% and 2-year overall survival (OS) was 67%. High TMTV0 was significantly associated with a worse prognosis. At 2 years, PFS was 26% in patients with a high TMTV0 (>230 cm(3), n = 53) versus 71% for those with a low TMTV0, [P < 0.0001, hazard ratio (HR) = 4], whereas OS was 50% versus 80%, respectively, (P = 0.0005, HR = 3.1). In multivariate analysis, TMTV0 was the only significant independent parameter for both PFS and OS. TMTV0, combined with PIT, discriminated even better than TMTV0 alone, patients with an adverse outcome (TMTV0 >230 cm(3) and PIT >1, n = 33,) from those with good prognosis (TMTV0 ≤230 cm(3) and PIT ≤1, n = 40): 19% versus 73% 2-year PFS (P < 0.0001) and 43% versus 81% 2-year OS, respectively (P = 0.0002). Thirty-one patients (other TMTV0-PIT combinations) had an intermediate outcome, 50% 2-year PFS and 68% 2-year OS. CONCLUSION: TMTV0 appears as an independent predictor of PTCL outcome. Combined with PIT, it could identify different risk categories at diagnosis and warrants further validation as a prognostic marker.
Subject(s)
Lymphoma, T-Cell, Peripheral/diagnostic imaging , Lymphoma, T-Cell, Peripheral/drug therapy , Prognosis , Tumor Burden , Adult , Aged , Aged, 80 and over , Anthracyclines/administration & dosage , Disease-Free Survival , Female , Fluorodeoxyglucose F18 , Humans , Lymphoma, T-Cell, Peripheral/pathology , Male , Middle Aged , Positron Emission Tomography Computed TomographyABSTRACT
BACKGROUND: ALK-negative anaplastic large cell lymphoma associated with breast implant (i-ALCL) has been recently recognized as a distinct entity. Among 43 830 lymphomas registered in the French Lymphopath network since 2010, 300 breast lymphomas comprising 25 peripheral T-cell lymphomas (PTCL) were reviewed. Among PTCL, ALK-negative ALCL was the most frequent and all of them were associated with breast implants. PATIENTS AND METHODS: Since 2010, all i-ALCL cases were collected from different institutions through Lymphopath. Immuno-morphologic features, molecular data and clinical outcome of 19 i-ALCLs have been retrospectively analyzed. RESULTS: The median age of the patients was 61 years and the median length between breast implant and i-ALCL was 9 years. Most implants were silicone-filled and textured. Implant removal was performed in 17 out of 19 patients with additional treatment based on mostly CHOP or CHOP-like chemotherapy regimens (n = 10/19) or irradiation (n = 1/19). CHOP alone or ABVD following radiation without implant removal have been given in two patients. The two clinical presentations, i.e. effusion and less frequently tumor mass correlated with distinct histopathologic features: in situ i-ALCL (anaplastic cell proliferation confined to the fibrous capsule) and infiltrative i-ALCL (pleomorphic cells massively infiltrating adjacent tissue with eosinophils and sometimes Reed-Sternberg-like cells mimicking Hodgkin lymphoma). Malignant cells were CD30-positive, showed a variable staining for EMA and were ALK negative. Most cases had a cytotoxic T-cell immunophenotype with variable T-cell antigen loss and pSTAT3 nuclear expression. T-cell receptor genes were clonally rearranged in 13 out of 13 tested cases. After 18 months of median follow-up, the 2-year overall survival for in situ and infiltrative i-ALCL was 100% and 52.5%, respectively. CONCLUSIONS: In situ i-ALCLs have an indolent clinical course and generally remain free of disease after implant removal. However, infiltrative i-ALCLs could have a more aggressive clinical course that might require additional therapy to implant removal.
Subject(s)
Breast Implants/adverse effects , Lymphoma, Large-Cell, Anaplastic/pathology , Lymphoma, T-Cell, Peripheral/pathology , Silicones/adverse effects , Adult , Aged , Aged, 80 and over , Anaplastic Lymphoma Kinase , Female , Hodgkin Disease/pathology , Humans , Immunophenotyping , Ki-1 Antigen/metabolism , Lymphoma, Large-Cell, Anaplastic/chemically induced , Lymphoma, Large-Cell, Anaplastic/mortality , Lymphoma, T-Cell, Peripheral/chemically induced , Lymphoma, T-Cell, Peripheral/mortality , Middle Aged , Receptor Protein-Tyrosine Kinases/metabolism , Receptors, Antigen, T-Cell/metabolism , Retrospective Studies , STAT3 Transcription Factor/metabolism , T-Lymphocytes, Cytotoxic/immunologyABSTRACT
BACKGROUND: Skin lesions are frequent in monoclonal cryoglobulinaemia and may be the first sign of B-cell lymphoma, especially multiple myeloma, Waldenström's macroglobulinaemia and B-cell chronic lymphocytic leukaemia. PATIENTS AND METHODS: A 74-year-old woman with no prior medical history presented with necrotic leg ulcer. Skin biopsy showed dermal angiomatosis with numerous PAS+ thromboses, associated with monoclonal intravascular deposits of IgM kappa, indicating monoclonal cryoglobulin, which was confirmed by laboratory tests. Subsequent blood immunophenotyping revealed an inconspicuous circulating monoclonal CD5(+) B-cell population and small B-cell clusters in the bone marrow, while the B-cell count was normal and no lymphadenopathy or splenomegaly were present. Overall, these findings indicated a small B-cell lymphoma, classed as non-MALT marginal zone lymphoma on the WHO classification, at a very early stage of development. The patient was first treated by cyclophosphamide and oral steroids without success. Subsequent administration of six cycles of rituximab, cyclophosphamide, vincristine and prednisone (RCVP) led to remission of her leg ulcer, cryoglobulinaemia and lymphoma. CONCLUSION: Skin biopsies of necrotic ulcers should undergo routine screening for intravascular deposits of type 1 cryoglobulin. Leg ulcers due to monoclonal cryoglobulinaemia may reveal incipient marginal zone B-cell lymphoma at the stage of circulating monoclonal lymphocytosis.
Subject(s)
Cryoglobulinemia/etiology , Leg Ulcer/etiology , Lymphoma, B-Cell, Marginal Zone/complications , Adrenal Cortex Hormones/administration & dosage , Aged , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B-Lymphocytes/chemistry , B-Lymphocytes/pathology , Bone Marrow/pathology , Cryoglobulins/analysis , Cyclophosphamide/administration & dosage , Female , Humans , Immunoglobulin M/analysis , Immunoglobulin kappa-Chains/analysis , Immunophenotyping , Leg Ulcer/pathology , Lymphocyte Count , Lymphoma, B-Cell, Marginal Zone/diagnosis , Lymphoma, B-Cell, Marginal Zone/drug therapy , Prednisone/administration & dosage , Remission Induction , Rituximab , Vincristine/administration & dosageABSTRACT
BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) arising in specific extranodal sites have peculiar clinicopathologic features. PATIENTS AND METHODS: We analyzed a cohort of 187 primary Waldeyer's ring (WR) DLBCLs retrieved from GELA protocols using anthracyclin-based polychemotherapy. RESULTS: Most patients (92%) had stage I-II disease. A germinal center B-cell-like (GCB) immunophenotype was observed in 61%, and BCL2 expression in 55%, of WR DLBCLs. BCL2, BCL6, IRF4 and MYC breakpoints were observed in, respectively, 3 of 42 (7%), 9 of 36 (25%), 2 of 26 (8%) and 4 of 40 (10%) contributive cases. A variable follicular pattern was evidenced in 30 of 68 (44%) large biopsy specimens. The 5-year progression-free survival (PFS) and the overall survival (OS) of 153 WR DLBCL patients with survival information were 69.5% and 77.8%, respectively. The GCB immunophenotype correlated with a better OS (P = 0.0015), while BCL2 expression predicted a worse OS (P = 0.037), an effect overcome by the GCB/non-GCB classification. Compared with matched nodal DLBCLs, WR DLBCLs with no age-adjusted international prognostic index factor disclosed a better 5-year PFS rate (77.5% versus 70.7%; P = 0.03). CONCLUSIONS: WR DLBCLs display distinct clinicopathologic features compared with conventional DLBCLs, with usual localized-stage disease, common follicular features and a high frequency of GCB immunophenotype contrasting with a low rate of BCL2 rearrangements. In addition, they seem to be associated with a better outcome than their nodal counterpart.
Subject(s)
Lymphoma, Large B-Cell, Diffuse/pathology , Pharyngeal Neoplasms/pathology , Anthracyclines/therapeutic use , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , DNA-Binding Proteins/metabolism , Disease-Free Survival , Female , Humans , Interferon Regulatory Factors/metabolism , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/mortality , Male , Middle Aged , Pharyngeal Neoplasms/drug therapy , Pharyngeal Neoplasms/mortality , Proto-Oncogene Proteins c-bcl-2/metabolism , Proto-Oncogene Proteins c-bcl-6 , Proto-Oncogene Proteins c-myc/metabolismABSTRACT
Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is a peculiar T cell lymphoma, as expanding B cell clones are often present besides the malignant T cell clones. In addition, large numbers of Epstein-Barr virus (EBV)-infected B cells are frequently observed. To analyze the differentiation status and clonal composition of EBV-harboring B cells in AILD, single EBV-infected cells were micromanipulated from lymph nodes of six patients with frequent EBV(+) cells and their rearranged immunoglobulin (Ig) genes analyzed. Most EBV-infected B cells carried mutated Ig genes, indicating that in AILD, EBV preferentially resides in memory and/or germinal center B cells. EBV(+) B cell clones observed in all six cases ranged from small polyclonal to large monoclonal expansions and often showed ongoing somatic hypermutation while EBV(-) B cells showed little tendency for clonal expansion. Surprisingly, many members of expanding B cell clones had acquired destructive mutations in originally functional V gene rearrangements and showed an unfavorable high load of replacement mutations in the framework regions, indicating that they accumulated mutations over repeated rounds of mutation and division while not being selected through their antigen receptor. This sustained selection-free accumulation of somatic mutations is unique to AILD. Moreover, the survival and clonal expansion of "forbidden" (i.e., Ig-deficient) B cells has not been observed before in vivo and thus represents a novel type of viral latency in the B cell compartment. It is likely the interplay between the microenvironment in AILD lymph nodes and the viral transformation that leads to the survival and clonal expansion of Ig-less B cells.
Subject(s)
B-Lymphocytes/virology , Gene Rearrangement, B-Lymphocyte , Herpesvirus 4, Human/isolation & purification , Immunoblastic Lymphadenopathy/immunology , Lymphoma, T-Cell/immunology , Mutation , Adult , Aged , Aged, 80 and over , Antigens, CD20 , Cell Differentiation , Clone Cells , Female , Genes, Immunoglobulin , Genes, T-Cell Receptor gamma , Humans , Immunoblastic Lymphadenopathy/virology , Lymph Nodes/cytology , Lymph Nodes/immunology , Lymph Nodes/virology , Lymphocyte Activation , Lymphoma, T-Cell/virology , Male , Micromanipulation , Middle Aged , RNA, Viral/isolation & purification , Virus LatencyABSTRACT
BACKGROUND: Extranodal natural killer (NK)/T-cell lymphoma, nasal type, and aggressive NK-cell leukemia are highly aggressive diseases with a poor outcome. PATIENTS AND METHODS: We report a multicentric French retrospective study of 15 patients with relapsed, refractory, or disseminated disease, treated with L-asparaginase-containing regimens in seven French centers. Thirteen patients were in relapse and/or refractory and 10 patients were at stage IV. RESULTS: All but two of the patients had an objective response to L-asparaginase-based treatment. Seven patients reached complete remission and only two relapsed. CONCLUSION: These data, although retrospective, confirm the excellent activity of L-asparaginase-containing regimens in refractory extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia. Therefore, L-asparaginase-based regimen should be considered as a salvage treatment, especially for patients with disseminated disease. First-line L-asparaginase combination therapy for extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia should be tested in prospective trials.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Asparaginase/administration & dosage , Leukemia/drug therapy , Lymphoma, Extranodal NK-T-Cell/drug therapy , Adult , Aged , Aged, 80 and over , Drug Resistance, Neoplasm/drug effects , Female , Humans , Leukemia/pathology , Lymphoma, Extranodal NK-T-Cell/pathology , Male , Middle Aged , Recurrence , Retrospective Studies , Treatment Outcome , Western WorldABSTRACT
We report a gamma-delta T-cell lymphoma, in a male patient having a hyperactive malarial splenomegaly. The immunological disorder caused by chronic antigenic stimulation could be one of the causes leading to the occurrence of such hematologic disease. The prognosis of this type of lymphoma remains poor, partly due to delayed diagnosis. Therefore, it seems appropriate to investigate any atypical hyperactive malarial splenomegaly. In our observation, the macrophagic activation syndrome led us to discover the lymphoma.
Subject(s)
Lymphoma, T-Cell/etiology , Malaria/complications , Splenomegaly/etiology , Adult , Biopsy , Bone Marrow/pathology , Hepatomegaly/diagnosis , Hepatomegaly/diagnostic imaging , Hepatomegaly/etiology , Humans , Liver/pathology , Lymphoma, T-Cell/diagnosis , Macrophage Activation , Malaria/immunology , Male , Prognosis , Radiography , Spleen/pathology , Splenomegaly/diagnosis , Splenomegaly/diagnostic imaging , Splenomegaly/immunology , Splenomegaly/pathologyABSTRACT
BACKGROUND: Overexpression of B-cell lymphoma 2 (bcl-2) protein is a simple biological adverse prognostic factor that could delimit the poor prognosis population candidate for improvement with high-dose therapy and autologous stem-cell transplantation (ASCT) in diffuse large B-cell lymphoma (DLBCL). Therefore, we conducted a risk-adapted phase II study with ASCT as consolidation therapy in low-intermediate risk (LIR) International Prognostic Index patients aged < or = 60 years with bcl-2 overexpression (bcl-2+). PATIENTS AND METHODS: Induction chemotherapy consisted of four courses of adriamycin, cyclophosphamide, vindesine, bleomycin, prednisone, once every 2 weeks. Responding bcl-2+ patients received ASCT as consolidation, and those without bcl-2 overexpression (bcl-2-) conventional chemotherapy. Three hundred and sixteen LIR patients with DLBCL, aged between 18 and 60 years, were included. Of these, 177 (56%) were bcl-2+ and 139 (44%) bcl-2-. RESULTS: Complete response rates after induction chemotherapy were similar in bcl-2+ and bcl-2- patients (74% versus 78%). Estimated 2-year event-free survival and disease-free survival for the bcl-2+ subgroup were 79% and 87%, for bcl-2- 84% and 92% and for the whole series 81% and 90%, respectively. CONCLUSIONS: These results demonstrate that taking into account biological characteristics in prospective multicenter trials allow successful adjustment of treatment and indicate that ASCT may counteract the adverse prognostic value of bcl-2 overexpression in responding LIR patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Genes, bcl-2/genetics , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/therapy , Stem Cell Transplantation , Adult , Bleomycin/administration & dosage , Cyclophosphamide/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Female , Humans , Lymphoma, Large B-Cell, Diffuse/mortality , Male , Middle Aged , Prednisone/administration & dosage , Prospective Studies , Survival Rate , Transplantation, Autologous , Vindesine/administration & dosageABSTRACT
AIMS: To report 16 cases of sclerosing angiomatoid nodular transformation (SANT) of the splenic red pulp. METHODS AND RESULTS: Patients were selected in two phases. An initial group of seven patients was diagnosed with SANT based on the presence of angiomatoid nodules. Sheets of inflammatory fibrosis were found in three patients, resembling inflammatory pseudotumour (IPT); nine further cases of IPT were reviewed. Angiomatoid nodules were detected, leading to the diagnosis of SANT in all cases. The splenic mass (10-150 mm in diameter) was polycyclic, composed of multiple small nodules of loose connective tissue comprising myofibroblasts and a dense network of capillaries as well as some remnants of sinuses. Collagenous fibrosis surrounded them. Bands or large sheets of fibrosis, infiltrated by various inflammatory cells, particularly polytypic plasmacytes, resembling IPT, were present in 10 cases. CONCLUSIONS: SANT of the red pulp is a distinct benign pseudotumorous lesion of the spleen characterized by the presence of angiomatoid nodules. We observed such angiomatoid nodules in all our cases of splenic IPT, which were not follicular dendritic cell or myofibroblastic tumours. We therefore recommend careful examination for angiomatoid nodules in all suspected cases of splenic IPT.
Subject(s)
Granuloma, Plasma Cell/pathology , Histiocytoma, Benign Fibrous/pathology , Spleen/pathology , Splenic Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Angiomatosis/metabolism , Angiomatosis/pathology , Female , Humans , Immunohistochemistry , Male , Middle Aged , Young AdultABSTRACT
Polymerase chain reaction (PCR) assessment of clonal T-cell receptor (TCR) and immunoglobulin (Ig) gene rearrangements is an important diagnostic tool in mature T-cell neoplasms. However, lack of standardized primers and PCR protocols has hampered comparability of data in previous clonality studies. To obtain reference values for Ig/TCR rearrangement patterns, 19 European laboratories investigated 188 T-cell malignancies belonging to five World Health Organization-defined entities. The TCR/Ig spectrum of each sample was analyzed in duplicate in two different laboratories using the standardized BIOMED-2 PCR multiplex tubes accompanied by international pathology panel review. TCR clonality was detected in 99% (143/145) of all definite cases of T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, peripheral T-cell lymphoma (unspecified) and angioimmunoblastic T-cell lymphoma (AILT), whereas nine of 43 anaplastic large cell lymphomas did not show clonal TCR rearrangements. Combined use of TCRB and TCRG genes revealed two or more clonal signals in 95% of all TCR clonal cases. Ig clonality was mostly restricted to AILT. Our study indicates that the BIOMED-2 multiplex PCR tubes provide a powerful strategy for clonality assessment in T-cell malignancies assisting the firm diagnosis of T-cell neoplasms. The detected TCR gene rearrangements can also be used as PCR targets for monitoring of minimal residual disease.
Subject(s)
Genes, Immunoglobulin , Leukemia, T-Cell/genetics , Lymphoma, T-Cell/genetics , Polymerase Chain Reaction/methods , Receptors, Antigen, T-Cell/genetics , Gene Amplification , Gene Rearrangement , Genotype , Humans , Immunohistochemistry , Leukemia, Prolymphocytic/genetics , Leukemia, Prolymphocytic/immunology , Leukemia, Prolymphocytic/pathology , Leukemia, T-Cell/immunology , Leukemia, T-Cell/pathology , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/immunology , Lymphoma, Large B-Cell, Diffuse/pathology , Lymphoma, T-Cell/immunology , Lymphoma, T-Cell/pathology , T-Lymphocytes/immunologyABSTRACT
The diagnosis of malignant lymphoma is a recognized difficult area in histopathology. Therefore, detection of clonality in a suspected lymphoproliferation is a valuable diagnostic criterion. We have developed primer sets for the detection of rearrangements in the B- and T-cell receptor genes as reliable tools for clonality assessment in lymphoproliferations suspected for lymphoma. In this issue of Leukemia, the participants of the BIOMED-2 Concerted Action CT98-3936 report on the validation of the newly developed clonality assays in various disease entities. Clonality was detected in 99% of all B-cell malignancies and in 94% of all T-cell malignancies, whereas the great majority of reactive lesions showed polyclonality. The combined BIOMED-2 results are summarized in a guideline, which can now be implemented in routine lymphoma diagnostics. The use of this standardized approach in patients with a suspect lymphoproliferation will result in improved diagnosis of malignant lymphoma.
Subject(s)
Lymphoma/genetics , Lymphoma/pathology , Polymerase Chain Reaction/methods , False Negative Reactions , Gene Rearrangement , Humans , Lymphoma, B-Cell/genetics , Lymphoma, B-Cell/pathology , Lymphoma, T-Cell/genetics , Lymphoma, T-Cell/pathology , Receptors, Antigen, T-Cell/genetics , Reproducibility of ResultsABSTRACT
Somatic G17V RHOA mutations were found in 50-70% of angioimmunoblastic T-cell lymphoma (AITL). The mutant RHOA lacks GTP binding capacity, suggesting defects in the classical RHOA signaling. Here, we discovered the novel function of the G17V RHOA: VAV1 was identified as a G17V RHOA-specific binding partner via high-throughput screening. We found that binding of G17V RHOA to VAV1 augmented its adaptor function through phosphorylation of 174Tyr, resulting in acceleration of T-cell receptor (TCR) signaling. Enrichment of cytokine and chemokine-related pathways was also evident by the expression of G17V RHOA. We further identified VAV1 mutations and a new translocation, VAV1-STAP2, in seven of the 85 RHOA mutation-negative samples (8.2%), whereas none of the 41 RHOA mutation-positive samples exhibited VAV1 mutations. Augmentation of 174Tyr phosphorylation was also demonstrated in VAV1-STAP2. Dasatinib, a multikinase inhibitor, efficiently blocked the accelerated VAV1 phosphorylation and the associating TCR signaling by both G17V RHOA and VAV1-STAP2 expression. Phospho-VAV1 staining was demonstrated in the clinical specimens harboring G17V RHOA and VAV1 mutations at a higher frequency than those without. Our findings indicate that the G17V RHOA-VAV1 axis may provide a new therapeutic target in AITL.
Subject(s)
Immunoblastic Lymphadenopathy/metabolism , Lymphoma, T-Cell/metabolism , Proto-Oncogene Proteins c-vav/metabolism , Signal Transduction , rhoA GTP-Binding Protein/metabolism , Biomarkers, Tumor , Cell Line, Tumor , Cytokines/metabolism , DNA Mutational Analysis , Humans , Immunoblastic Lymphadenopathy/genetics , Lymphoma, T-Cell/genetics , Mutation , NFATC Transcription Factors/metabolism , Phosphorylation , Protein Binding , Proto-Oncogene Proteins c-vav/genetics , Receptors, Antigen, T-Cell/metabolism , rhoA GTP-Binding Protein/geneticsABSTRACT
The t(3;14)(q27;q32) is the most common translocation involving BCL6 in B-cell lymphoma. Although this translocation was predominantly associated with diffuse large B-cell lymphoma (DLBCL), recent studies have shown that it can also be found in follicular lymphomas (FL), often associated with a large cell component. To further investigate the relationship that might exist between this translocation and the phenotype of the tumors, we studied 34 lymphomas with a t(3;14)(q27;q32). Twenty cases were DLBCL, 14 FL and most cases, regardless of histology, were negative for the expression of CD10 (26/32, 81%). We identified the IGH switch region involved in the translocation for 32 cases. Our data indicate that in DLBCL most breakpoints involve the switch mu (17/19; 89%), whereas in FL most involve a switch gamma (9/13; 70%) (P=0.0016, Fisher's exact test). This correlation between the histology and the structure of the translocated allele suggests that the lymphomas with Smu and Sgamma translocations may originate from different cells, or that the substituted regulatory regions that come to deregulate BCL6 may affect the presentation of the disease.
Subject(s)
Chromosomes, Human, Pair 14 , Chromosomes, Human, Pair 3 , Immunoglobulin Heavy Chains/genetics , Lymphoma, B-Cell/genetics , Lymphoma, B-Cell/pathology , Translocation, Genetic , Genetic Markers , HumansABSTRACT
Natural killer cells are well known to play an important role in immune defense against tumor development and viral infections. To further characterize new functionally relevant structures in these cells, we studied a series of monoclonal antibodies that we have raised against the NK cell line YT. One of these antibodies previously described as AY19, recognizes a 85 kD surface glycoprotein. Here we report the identification of a new secreted isoform of protocadherin 15, PCDH15C, which represents a potential associated protein for p85. Importantly, whereas protocadherins are absent from the surface of normal hematopoietic cells, we describe, for the first time, that PCDH15 is expressed in cytotoxic tumor-derived T- and NK-cell lines as well as in biopsies of nasal NK/T-cell lymphomas.